USOO9474831 B2

(12) United States Patent (10) Patent No.: US 9.474,831 B2 Boyden et al. (45) Date of Patent: Oct. 25, 2016

(54) SYSTEMS, DEVICES, AND METHODS (2013.01); A61L 27/28 (2013.01); A61L INCLUDING MPLANTABLE DEVICES 27/306 (2013.01); A61L 27/54 (2013.01); WITH ANT-MICROBAL PROPERTIES A61L 29/00 (2013.01); A61L 29/16 (2013.01); A61L 31/08 (2013.01); B82Y5/00 (2013.01); (75) Inventors: Edward S. Boyden, Chestnut Hill, MA B82Y 30/00 (2013.01); A61 L 2300/606 (US); Roy P. Diaz, Seattle, WA (US); (2013.01); B82Y 40/00 (2013.01) Roderick A. Hyde, Redmond, WA (58) Field of Classification Search (US); Jordin T. Kare, Seattle, WA CPC ...... A61L 2/0011 (US); Elizabeth A. Sweeney, Seattle, USPC ...... 424/423: 600/365; 607/88-94 WA (US); Lowell L. Wood, Jr., See application file for complete search history. Bellevue, WA (US) (56) References Cited (73) Assignee: GEARBOX, LLC, Bellevue, WA (US) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 3,274.406 A 9/1966 Sommers, Jr. patent is extended or adjusted under 35 3,825,016 A 7, 1974 Lale et al. U.S.C. 154(b) by 247 days. (Continued) (21) Appl. No.: 12/931,926 FOREIGN PATENT DOCUMENTS

(22) Filed: Feb. 14, 2011 EP 1 614 442 A2 1, 2006 JP H11117.194 4f1999 (65) Prior Publication Data (Continued) US 2011/02759 12 A1 Nov. 10, 2011 OTHER PUBLICATIONS Related U.S. Application Data European Patent Office; Extended Supplementary European Search (63) Continuation-in-part of application No. 12/315,880, Report; Application No. EP 09 83 0731; Dec. 18, 2012; (Received filed on Dec. 4, 2008, now Pat. No. 8,162,924, and a continuation-in-part of application No. 12/315,881, by our associate Dec. 19, 2012); pp. 1-3. filed on Dec. 4, 2008, now abandoned, and a (Continued) (Continued) Primary Examiner — William Thomson Assistant Examiner — John R Downey (51) Int. C. (74) Attorney, Agent, or Firm — Daniel J. Honz: Advent, A6IL 2/00 (2006.01) LLP A6IL 29/08 (2006.01) A6IL 2/232 (2006.01) (57) ABSTRACT (Continued) Systems, devices, methods, and compositions are described (52) U.S. C. for providing an actively controllable implant configured to, CPC ...... A61L 29/08 (2013.01); A61L 2/00II for example, monitor, treat, or prevent microbial growth or (2013.01); A61L 2/08 (2013.01); A61L 2/14 adherence to the implant. (2013.01); A61L 2/232 (2013.01); A61L 2/24 (2013.01); A61L 2/26 (2013.01); A61L 17/145 45 Claims, 30 Drawing Sheets

100 y 02 Insertable Device

608 Circuitry configured to

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US 9,474,831 B2 Page 2

Related U.S. Application Data tinuation-in-part of application No. 12/927,287, filed continuation-in-part of application No. 12/315,882, on Nov. 10, 2010, now Pat. No. 8,706,211, and a filed on Dec. 4, 2008, now abandoned, and a contin continuation-in-part of application No. 12/927,294, uation-in-part of application No. 12/315,883, filed on filed on Nov. 10, 2010, now Pat. No. 8,585,627, and Dec. 4, 2008, now abandoned, and a continuation-in a continuation-in-part of application No. 12/927.285, part of application No. 12/315,884, filed on Dec. 4, filed on Nov. 10, 2010, now Pat. No. 8,753,304, and 2008, now abandoned, and a continuation-in-part of a continuation-in-part of application No. 12/927,290, application No. 12/315,885, filed on Dec. 4, 2008, filed on Nov. 10, 2010, now Pat. No. 8,702,640, and now abandoned, and a continuation-in-part of appli a continuation-in-part of application No. 12/927,291, cation No. 12/380,553, filed on Feb. 27, 2009, now filed on Nov. 10, 2010, now abandoned, and a con abandoned, and a continuation-in-part of application tinuation-in-part of application No. 12/927,295, filed No. 12/592,976, filed on Dec. 3, 2009, now Pat. No. on Nov. 10, 2010. 9,005.263, and a continuation-in-part of application Int. C. No. 12/660,156, filed on Feb. 19, 2010, now Pat. No. (51) 8.366.652, and a continuation-in-part of application A61L 2/24 (2006.01) No. 12/800,766, filed on May 21, 2010, now Pat. No. A6IL 2/26 (2006.01) 8.216,173, and a continuation-in-part of application A6IL 27/54 (2006.01) No. 12/800,774, filed on May 21, 2010, now aban A6IL 3L/08 (2006.01) doned, and a continuation-in-part of application No. A6IL 7/4 (2006.01) 12/800,778, filed on May 21, 2010, now abandoned, A6IL 27/28 (2006.01) and a continuation-in-part of application No. 12/800, A6IL 27/30 (2006.01) 779, filed on May 21, 2010, now abandoned, and a A6IL 29/00 (2006.01) continuation-in-part of application No. 12/800,780, A6IL 29/16 (2006.01) filed on May 21, 2010, now abandoned, and a con B825/00 (2011.01) tinuation-in-part of application No. 12/800.781, filed B823/00 (2011.01) on May 21, 2010, now abandoned, and a continu A6IL 2/08 (2006.01) ation-in-part of application No. 12/800.786, filed on A61L 2/14 (2006.01) May 21, 2010, now abandoned, and a continuation B82Y 4O/OO (2011.01) in-part of application No. 12/800,790, filed on May (56) References Cited 21, 2010, now Pat. No. 8,343,086, and a continuation in-part of application No. 12/800,791, filed on May U.S. PATENT DOCUMENTS 21, 2010, now Pat. No. 8,282.593, and a continuation in-part of application No. 12/800,792, filed on May 4,081,764 A 3, 1978 Christmann et al. 4,598,579 A 7, 1986 Cummings et al. 21, 2010, now Pat. No. 8,888,731, and a continuation 4,698,058 A 10, 1987 Greenfeld et al. in-part of application No. 12/800,793, filed on May 4,718,417 A 1/1988 Kittrell et al. 21, 2010, now Pat. No. 8,414,517, and a continuation 4,788.975 A 12/1988 Shturman et al. in-part of application No. 12/800,798, filed on May 4,863,849 A 9, 1989 Melamede 21, 2010, and a continuation-in-part of application 4,900,553 A 2f1990 Silver et al. 5,000,731 A 3/1991 Wong et al. No. 12/931,921, filed on Feb. 14, 2011, now aban 5,127,735 A T/1992 Pitt doned, and a continuation-in-part of application No. 5,155,707 A 10, 1992 Fisher 12/931,924, filed on Feb. 14, 2011, now abandoned, 5,156,839 A 10, 1992 Pennell et al. and a continuation-in-part of application No. 12/931, 5,226,902 A 7/1993 Bae et al. 5,240,675 A 8, 1993 Wilk et al. 928, filed on Feb. 14, 2011, and a continuation-in-part 5,260,020 A 11, 1993 Wilk et al. of application No. 12/931,929, filed on Feb. 14, 2011, 5,281,199 A 1/1994 Ensminger et al. and a continuation-in-part of application No. 12/931, 5,302,345 A 4, 1994 OkSman et al. 923, filed on Feb. 14, 2011, now abandoned, and a 5,324.275 A 6/1994 Raad et al. continuation-in-part of application No. 12/931,925, 5,326,567 A 7/1994 Capelli 5.431,694 A 7/1995 Snaper et al. filed on Feb. 14, 2011, now abandoned, and a con 5,445,608 A 8, 1995 Chen et al. tinuation-in-part of application No. 12/931.931, filed 5,594,544 A 1/1997 Horiuchi et al. on Feb. 14, 2011, now abandoned, and a continu 5,607,683 A 3/1997 Capelli ation-in-part of application No. 12/931,930, filed on 5,622,848 A 4, 1997 Morrow Feb. 14, 2011, now abandoned, and a continuation 5,651,767 A 7/1997 Schulman et al. 5,681.260 A 10, 1997 Ueda et al. in-part of application No. 12/931,920, filed on Feb. 5,704,352 A 1/1998 Tremblay et al. 14, 2011, now abandoned, and a continuation-in-part 5,733,270 A 3/1998 Ling et al. of application No. 12/931,927, filed on Feb. 14, 2011, 5,735,276 A 4/1998 Lemelson now abandoned, and a continuation-in-part of appli 5,750,093 A 5/1998 Menon et al. 5,766.934 A 6/1998 Guiseppi-Elie cation No. 12/931,922, filed on Feb. 14, 2011, and a 5,797,898 A 8/1998 Santini, Jr. et al. continuation-in-part of application No. 12/927,297, 5,804,563 A 9, 1998 Still et al. filed on Nov. 10, 2010, now Pat. No. 8,460,229, and 5,810,015 A 9/1998 Flaherty a continuation-in-part of application No. 12/927,284, 5,830,207 A 11/1998 Leeb et al. filed on Nov. 10, 2010, now Pat. No. 8,647,292, and 5,831,012 A 11/1998 Nilsson et al. 5,855,203 A 1, 1999 Matter a continuation-in-part of application No. 12/927,288, 5,865,744 A 2f1999 Lemelson filed on Nov. 10, 2010, now Pat. No. 8,734,718, and 5,961,923 A 10, 1999 Nova et al. a continuation-in-part of application No. 12/927,296, 5,978,713 A 11/1999 Prutchi et al. filed on Nov. 10, 2010, now abandoned, and a con 5,993,378 A 11/1999 Lemelson US 9,474,831 B2 Page 3

(56) References Cited 7,033,571 B2 4/2006 Gutowska et al. 7,041,130 B2 5/2006 Santini, Jr. et al. U.S. PATENT DOCUMENTS 7,052.488 B2 5, 2006 Uhland 7,070,590 B1 7/2006 Santini, Jr. et al. 5,993,382 A 11, 1999 Pruitt, Sr. 7,070,592 B2 7/2006 Santini, Jr. et al. 6,008,896 A 12, 1999 Sabsabi et al. 7,078,903 B2 7/2006 Paliwal et al. 6,057,561 A 5/2000 Kawasaki et al. 7,097,662 B2 8/2006 Evans, III et al. 6,086,851 A 7/2000 Boni et al. 7,116,857 B2 10/2006 Faris 6,135,990 A 10, 2000 Heller et al. 7,117,807 B2 10/2006 Bohn, Jr. et al. 6,143,035 A 1 1/2000 McDowell 7,118,548 B2 10/2006 Borgesen 6,146,409 A 1 1/2000 Overholt et al. 7,124,773 B2 10/2006 Midtgård et al. 6,162,242 A 12/2000 Peyman 7,130,459 B2 10/2006 Anderson et al. 6,222,953 B1 4/2001 Hoekstra et al. 7,134,999 B2 11/2006 Brauker et al. 6.255.461 B1 7/2001 Mosbach et al. 7,143,709 B2 12/2006 Brennan et al. 6,266,551 B1 7/2001 Osadchy et al. 7,151,139 B2 12/2006 Tiller et al. 6,280,604 B1 8/2001 Allen et al. 7,159,590 B2 1/2007 Rife 6,282,444 B1 8/2001 Kroll et al. 7,160,931 B2 1/2007 Cheng et al. 6,304.786 B1 10/2001 Heil, Jr. et al. 7,167,734 B2 1/2007 Khalil et al. 6,312,770 B1 11/2001 Sage et al. 7,167,755 B2 1/2007 Seeberger et al. 6,348,042 B1 2/2002 Warren, Jr. 7,183,048 B2 2/2007 Felkner et al. 6.350.263 B1 2/2002 Wetzig et al. 7, 195,608 B2 3/2007 Burnett 6,403,337 B1 6/2002 Bailey et al. 7,217,425 B2 5 2007 Serhan et al. 6,416.495 B1 7/2002 Kriesel et al. 7,221,456 B2 5/2007 Kanai et al. 6,418,342 B 1 7/2002 Owen et al. 7,226,441 B2 6/2007 Kulessa 6.426,066 B1 7/2002 Najafi et al. 7,232,429 B2 6/2007 Moreci 6,428,491 B1 8, 2002 Weiss 7,236,821 B2 6/2007 Cates et al. 6,440,097 B1 8/2002 Kupiecki 7,238,363 B2 7/2007 Mansouri et al. 6,443,147 B1 9, 2002 Matter 7,244,232 B2 7/2007 Connelly et al. 6,451,003 B1 9/2002 Prosl et al. 7.250,615 B1 7/2007 Soong et al. 6,451,429 B2 9, 2002 Mumick et al. 7,253,152 B2 8, 2007 Panero et al. 6,461,569 B1 10/2002 Boudreaux 7,276.255 B2 10/2007 Selkon 6,470,212 B1 10/2002 Weijand et al. 7,288,232 B2 10/2007 Morrow et al. 6,470,888 B1 10/2002 Matter 7,303,875 B1 12/2007 Bock et al. 6,478,778 B1 1 1/2002 Jacobsen et al. 7,306,620 B2 12/2007 Cumbie 6,488,704 B1 12/2002 Connelly et al. 7.309,330 B2 12/2007 Bertrand et al. 6,491.666 B1 12/2002 Santini, Jr. et al. 7,310,459 B1 12/2007 Rahman 6,506,416 B1 1/2003 Okauchi et al. 7319,038 B2 1/2008 Southard 6,533,733 B1 3/2003 Ericson et al. 7,322,965 B2 1/2008 Gibson et al. 6,542,767 B1 4/2003 McNichols et al. 7,334,594 B2 2/2008 Ludin 6,551.346 B2 4/2003 Crossley 7,345,372 B2 3, 2008 Roberts et al. 6,562.295 B1 5/2003 Neuberger 7,348,021 B2 3/2008 Klein 6,571,125 B2 5/2003 Thompson 7,354,575 B2 4/2008 Shachar et al. 6,585,677 B2 7/2003 Cowan, Jr. et al. 7,365,859 B2 4/2008 Yun et al. 6,599.274 B1 7/2003 Kucharczyk et al. 7,367,342 B2 5/2008 Butler 6,612,535 B1 9, 2003 Tai et al. 7,390,310 B2 6/2008 McCusker et al. 6,626.902 B1 9/2003 Kucharczyk et al. 7,396,676 B2 7/2008 Robotti et al. 6,667,807 B2 12/2003 Lieberman 7,425,581 B2 9, 2008 Hennink et al. 6,669,683 B2 12/2003 Santini, Jr. et al. 7,442,372 B2 10/2008 Kakkis 6,670,427 B1 12/2003 Ulbricht et al. 7,455,667 B2 11/2008 Uhland et al. 6,720,402 B2 4/2004 Langer et al. 7,504,702 B2 3/2009 Mazur et al. 6,730, 113 B2 5/2004 Eckhardt et al. 7,524.298 B2 4/2009 Gharib et al. 6,743,190 B2 6/2004 Connelly et al. 7,531,120 B2 5 2009 Van Rijn et al. 6,750,055 B1 6/2004 Connelly et al. 7,535,692 B2 5/2009 Krupenkin et al. 6,755,621 B2 6/2004 Lopez et al. 7,572,669 B2 8/2009 Tuominen et al. 6,764,501 B2 7/2004 Ganz 7,575,593 B2 8, 2009 Rea et al. 6,789, 183 B1 9, 2004 Smith et al. 7,621.905 B2 11/2009 Penner et al. 6.793,642 B2 9/2004 Connelly et al. 7,650,848 B2 1/2010 Brennan et al. 6,793,880 B2 9/2004 Kippenhan, Jr. 7,691,.684 B2 4/2010 Breitwisch et al. 6,797.522 B1 9/2004 Still et al. 7,691,894 B2 4/2010 Ono et al. 6,802,811 B1 10/2004 Slepian 7,706, 178 B2 4, 2010 Parkinson 6,808,522 B2 10/2004 Richards et al. 7,714,326 B2 5/2010 Kim et al. 6,831,748 B2 12/2004 Tittel et al. 7,837,719 B2 11/2010 Brogan et al. 6,838,292 B1 1/2005 Rajan et al. 8,197.452 B2 6/2012 Harding et al. 6.844,028 B2 1/2005 Mao et al. 8,496,610 B2 7/2013 Levenson et al. 6.849463 B2 2/2005 Santini, Jr. et al. 2002/0030.196 A1 3/2002 Iwata et al. 6.853,765 B1 2/2005 Cochran 2002/0068093 A1 6/2002 Trogolo et al. 6.866,859 B2 3/2005 Trogolo et al. 2002/0090388 A1 7/2002 Humes et al. 6.887.202 B2 5, 2005 Currie et al. 2002/O123787 A1 9, 2002 Weiss 6,908.460 B2 6/2005 DiStefano 2002/0182262 A1 12/2002 Sekon 6,913,589 B2 7/2005 Dextradeur et al. 2002/0188323 A1 12/2002 Penner et al. 6,914,279 B2 7/2005 Lu et al. 2002/0192366 A1 12/2002 Cramer et al. 6,918,869 B2 7/2005 Shaw et al. 2002/0192680 A1 12/2002 Chan et al. 6,932,787 B2 8/2005 Cowan et al. 2003/0012688 A1 1/2003 Kippenhan, Jr. 6,939,290 B2 9/2005 Iddan 2003/0014091 A1 1/2003 Rastegar et al. 6,960,201 B2 11/2005 Cumbie 2003, OO 17073 A1 1/2003 Eckhardt et al. 6,969,382 B2 11/2005 Richter 2003/0092996 A1 5.2003 Lowe et al. 6,980,716 B1 12/2005 Diaz et al. 2003/0097 121 A1 5/2003 Jolly et al. 7,020,355 B2 3/2006 Lahann et al. 2003.0109907 A1 6, 2003 Shadduck 7,030,989 B2 4/2006 Yager et al. 2003. O163079 A1 8, 2003 Burnett US 9,474,831 B2 Page 4

(56) References Cited 2006/0271112 A1 11/2006 Martinson et al. 2006/0276713 A1 12/2006 Maier U.S. PATENT DOCUMENTS 2006/0287660 A1 12/2006 Syed et al. 2006/0289761 A1 12/2006 Nabet et al. 2003/O1657 O2 A1 9, 2003 Disse et al. 2007/OOO5O24 A1 1/2007 Weber et al. 2003. O180319 A1 9/2003 Rapson et al. 2007, OO16163 A1 1/2007 Santini, Jr. et al. 2003. O1954.15 A1 10, 2003 Iddan 2007/002O240 A1 1/2007 Jayasheela et al. 2003. O1998.06 A1 10, 2003 Kieval 2007/0031777 A1 2/2007 Wang et al. 2003/0204163 A1 10, 2003 Marchitto et al. 2007, OO73135 A1 3, 2007 Lee et al. 2003/0214579 A1 11, 2003 Iddan 2007/0O87445 A1 4/2007 Tearney et al. 2003/0225331 A1 12/2003 Diederich et al. 2007/0106333 A1 5, 2007 Fernandez 2004/0018508 A1 1/2004 Friedman 2007/0111201 A1 5. 2007 Doranz 2004/0022669 A1 2, 2004 Ruan et al. 2007/0134287 A1 6/2007 Troxel et al. 2004/0073278 A1 4/2004 Pachys 2007. O142874 A1 6, 2007 John 2004/008 1646 A1 4/2004 Engler et al. 2007/01500 19 A1 6/2007 Youker et al. 2004/00980.05 A1 5, 2004 Mirza et al. 2007/0156039 A1 7/2007 Casciani et al. 2004/OO98055 A1 5, 2004 Kroll et al. 2007/O156211 A1 7/2007 Ferren et al. 2004/O149582 A1 8, 2004 Kovacs 2007/0173755 A1 7/2007 Alimi et al. 2004/0186546 A1 9, 2004 Mandrusov et al. 2007/01761 17 A1 8/2007 Redmond et al. 2004/020894.0 A1 10, 2004 Sekon 2007/O187626 A1 8, 2007 Gaska et al. 2004/0253138 A1 12, 2004 Malak 2007/01963.57 A1 8, 2007 Alimi et al. 2004/0260249 A1 12/2004 Kulessa 2007/O197890 A1 8, 2007 Boock et al. 2005/OOO8285 A1 1/2005 Kim et al. 2007/0205382 A1 9, 2007 Gaska et al. 2005/0042743 A1 2/2005 Kawai et al. 2007/0208.245 A1 9, 2007 Brauker et al...... 600,365 2005, 0043894 A1 2/2005 Fernandez 2007/0209143 A1 9, 2007 Choi et al. 2005, OO45183 A1 3, 2005 Callister et al. 2007/0225634 Al 9, 2007 Ferren et al. 2005.0049181 A1 3/2005 Madhyastha 2007/0225800 A1 9/2007 Sahatian et al. 2005/0063647 A1 3f2005 Thornton et al. 2007/0227428 A1 10/2007 Brennan et al. 2005.0089890 A1* 4/2005 Cubicciotti ...... 435/6 2007/0244423 Al 10/2007 Zumeris et al. 2005/0095.351 A1 5, 2005 Zumeris et al. 2007/0249969 AI 10/2007 Shields, Jr. 2005/01OO937 A1 5, 2005 Holmes 2007,0259.017 A1 11/2007 Francis 2005/0105077 A1 5/2005 Padmanabhan et al. 2007/0274909 A1 11/2007 Justel et al. 2005/O107289 A1 5, 2005 Ghadiri et al. 2007/0275068 A1 11/2007 Martens et al. 2005/O142157 A1 6, 2005 Alimi 2007/0276208 A1 11/2007 Connelly et al. 2005/0149000 Al 7/2005 Santini, Jr. et al. 2007/028O852 A1 12/2007 Skubal et al. 2005, 0164169 A1 7, 2005 Malak 2007,0299384 A1 12/2007 Faul et al. 2005/0171434 A1 8/2005 Madden et al. 2008/0007885 A1 1/2008 Mehrlet al. 2005/0171437 A1 8/2005 Carberry 2008, OO14632 A1 1/2008 Cunningham et al. 2005, 0175658 A1* 8, 2005 DiMauro et al...... 424/423 2008/0033519 A1 2/2008 Burwell et al. 2005, 0180678 A1 8/2005 Panepucci et al. 2008, OO39678 A1 2, 2008 Montpetit et al. 2005, 0192478 A1 9, 2005 Williams et al. 2008, OO39768 A1 2/2008 Francis 2005, 0196375 A1 9, 2005 Phaneuf et al. 2008/0051691 A1 2/2008 Dragoon et al. 2005/0196421 A1 9, 2005 Hunter et al. 2008/0051736 A1 2/2008 Rioux et al. 2005/02O3495 A1 9, 2005 Malak 2008.OO58798 A1 3/2008 Wallace et al. 2005/0203582 A1 9/2005 Healy et al. 2008/0064980 A1 3/2008 Lee et al. 2005/0209665 A1 9, 2005 Hunter et al. 2008.OO95977 A1 4/2008 Aizenberg et al. 2005/0245557 A1 11/2005 Schoenhard et al. 20080118546 Al 52008 Thatcher et al. 2005/0255604 A1 11/2005 Gjerde et al. 2008/01 19421 A1 5/2008 Tuszynski et al. 2005/0256554 A1 11, 2005 Malak 2008.0125838 A1 5/2008 Francis 2005/0263386 A9 12/2005 Pitts, Jr. et al. 2008/0195170 A1 8/2008 Asgari 2005/0266081 Al 12/2005 Rogozinski 2008, 0214909 A1 9, 2008 Fuerst et al. 2005/0266582 A1 12, 2005 Modlin et al. 2008/0223717 Al 9, 2008 Isaksson et al. 2005/0268.921 A1 12/2005 Zumeris et al. 2008/0234.786 A1 9, 2008 Cumbie 2005/0272974 A1 12, 2005 Iddan 2008/0243231 A1* 10/2008 Flanagan et al...... 623, 1.16 2005/0288654 A1 12/2005 Nieman et al. 2008/0248993 A1 10/2008 Hannappel et al. 2006, OOO4317 A1 1/2006 Mauge et al. 2008/0253712 A1 10, 2008 Allen et al. 2006/0004431 A1 1/2006 Fuller et al. 2008/0257355 A1 10, 2008 Rao et al. 2006,00098.05 A1 1/2006 Jensen et al. 2008/0265.179 A1 10, 2008 Havens et al. 2006/002O186 A1 1/2006 Brister et al. 2009/00 1261.0 A1 1/2009 Olson et al. 2006.0020239 A1 1/2006 Geiger et al. 2009 OO12626 A1 1/2009 Thompson et al. 2006/0047283 A1 3/2006 Evans, III et al. 2009/0015841 A1 1/2009 Downey 2006,0047329 A1 3/2006 Krespi et al. 2009 OO18424 A1 1/2009 Kamath et al. 2006, OO52782 A1 3/2006 Morgan et al. 2009/0048542 A1 2/2009 Varadan et al. 2006/0074479 A1 4/2006 Bailey et al. 2009/0048648 Al 2, 2009 Dacey, Jr. et al. 2006, OO7974.0 A1 4/2006 Silver et al. 2009.0054824 A1 2/2009 Melsheimer et al. 2006, 0079762 A1 4, 2006 Norris et al. 2009.0054827 A1 2/2009 Eide 2006/0105275 A1 5/2006 Maloney et al. 2009/0066195 A1 3/2009 Wang et al. 2006/O121087 A1 6/2006 Williams et al. 2009/0093713 A1 4/2009 Hyde et al. 2006/0122543 A1 6/2006 Mayer et al. 2009/0093728 A1 4/2009 Hyde et al. 2006/013.9667 A1 6/2006 Morimoto et al. 2009/0093807 A1 4/2009 Hyde et al. 2006/0140911 A1 6/2006 Sharp et al. 2009/0110711 A1 4/2009 Trollsas et al. 2006/0147492 A1 7/2006 Hunter et al. 2009/01 17001 A1 5/2009 Hyde et al. 2006, O159671 A1 7, 2006 Fischetti 2009.0118661 A1 5/2009 Moehle et al. 2006/0159916 A1* 7/2006 Dubrow et al...... 428,357 2009.0118813 A1 5/2009 Scheuermann et al. 2006/0210602 A1 9, 2006 Sehl et al. 2009, O1552.15 A1 6, 2009 Collins et al. 2006/0219143 A1 10, 2006 Brennan et al. 2009/0156460 A1* 6/2009 Jiang et al...... 514/2 2006, O247525 A1 11, 2006 Huo et al. 2009/0177254 A1 7/2009 Boyden et al. 2006/0253259 A1 11/2006 Fernandez 2009,0185988 A1 7, 2009 Maleski et al. 2006/0263.033 A1 11/2006 Lahann et al. 2009/O195120 A1 8/2009 Knospe US 9,474,831 B2 Page 5

(56) References Cited tidisciplinary intensive care unit': Critical Care; Feb. 2004; pp. R42-R47; vol. 8, No. 1: BioMed Central Ltd. U.S. PATENT DOCUMENTS Albert, Richard K. and Condie, Frances; “Medical Intelligence: Hand-Washing Patterns in Medical Intensive-Care Units’; New 2009/0209897 A1 8/2009 Limaye et al. England Journal of Medicine; Jun. 1981; pp. 1465-1466; vol. 304. 2009/0209904 A1* 8/2009 Peeters ...... 604f66 No. 24. 2009, 0214617 A1 8, 2009 Scott et al. Alexander et al., “Molecular imprinting science and technology: a 2009,0259089 A1 10/2009 Gelbart et al. Survey of the literature for the years up to and including 2003”; 2009,0281412 A1 11/2009 Boyden et al. 2009,028.1635 A1 11/2009 Li et al. Journal of Molecular Recognition; 2006; pp. 106-180; vol. 19; John 2009,0294.732 A1 12/2009 Atanasoska et al. Wiley & Sons Ltd. 2009,0297574 A1 12/2009 Ahn et al. Ammor, Mohammed Salim; "Recent Advances in the Use of 2009,0299.153 A1 12/2009 Gerber et al. Intrinsic Fluorescence for Bacterial Identification and Characteriza 20090316195 A1 12/2009 Tseng et al. tion'. J. Fluoresc.; 2007: pp. 1-5: Springer Science+Business Media 2010, OOO8822 A1 1/2010 Hyde et al. LLC. 2010, OO 10327 A1 1/2010 Merz et al. Apple et al., “Review: Future Biomarkers for Detection of Ischemia 2010, 0046902 A1 2/2010 Kaplan et al. and Risk Stratification in Acute Coronary Syndrome'; Clinical 2010.0049422 A1 2/2010 Moriya Chemistry; bearing a date of 2005; pp. 810-824; vol. 51, No. 5; 2010 OO63404 A1 3/2010 Kaplan et al. American Association for Clinical Chemistry. 2010 OO65784 A1 3/2010 Kaplan et al. “Arglaes(R Controlled-Release Silver Technology': Medline; 2003; 2010.006874.0 A1 3/2010 Kaplan et al. 2010, 007.0068 A1 3/2010 Kaplan et al. 6 pages; Medline Industries, Inc.; located at: www.medline.com. 2010, 0096.763 A1 4/2010 Kaplan et al. Ashush, Hagit et al.; “Apoptosis Induction of Human Myeloid 2010, 0100160 A1 4/2010 Edman et al. Leukemic Cells by Ultrasound Exposure': Cancer Research; bear 2010, 0104652 A1 4/2010 Biris et al. ing a date of Feb. 15, 2000; pp. 1014-1020; vol. 60. 2010, 0145286 A1 6/2010 Zhang et al. Baddour et al., “High Frequency Ultrasound Imaging of Changes in 2010/0174346 A1 7/2010 Boyden et al. Cell Structure Including Apoptosis”; Ultrasonics Symposium; 2002; 2010/O1983.57 A1 8, 2010 Fuller et al. pp. 1639-1644; IEEE. 2010/0204802 A1 8, 2010 Wilson et al. Barlen et al., “Detection of Salmonella by Surface Plasmon Reso 2010, O234792 A1 9/2010 Dacey, Jr. et al. nance'; Sensors; 2007: pp. 1427-1446; vol. 7: MDPI. 2010/0249692 A1 9/2010 Dacey, Jr. et al. Barnes et al.: “Novel Biomarkers Associated with Deep Venous 2010, O2566O7 A1 10/2010 Burnett Thrombosis: A Comprehensive Review”; Biomarker Insights; bear 2011/O116967 A1 5/2011 Roy et al. ing a date of 2008; pp. 93-100; vol. 3; Creative Commons Attribu 2011/0117582 A1 5, 2011 Malima et al. tion. 2011 0160643 A1 6/2011 Dacey, Jr. et al. 2013/0273564 A1 Beebe et al.; “Nanosecond, High-Intensity Pulsed Electric Fields 10/2013 Quinn Induce Apoptosis in Huthan Cells'. The FASEB Journal; bearing a date of Jun. 17, 2003; pp. 1-23. FOREIGN PATENT DOCUMENTS Bouchard et al.; "Optical characterization of Pseudomonas WO WO 91,6855 A2 5, 1991 fluorescens on meat Surfaces using time-resolved fluorescence': WO WO/92/O1222 1, 1992 Journal of Biomedical Optics; Jan./Feb. 2006; pp. 014011-1 to WO WO 97.00586 1, 1997 014011-7; vol. 11, No. 1; Society of Photo-Optical Instrumentation WO WOOOO9733 2, 2000 Engineers. WO WOOOf 296.13 5, 2000 Bozhevolnyi, Sergey I. et al.; “Photonic bandgap structures for WO WOOO, 56.185 9, 2000 long-range Surface plasmon polaritons'; Optics Communications; WO WO O1? 13926 A2 3, 2001 bearing a date of 2005; pp. 328-333; vol. 250; Elsevier B.V. WO WO O1, 54704 8, 2001 Brogden, Kim A.; “Antimicrobial Peptides: Pore Formers or Meta WO WO 02/068049 A1 9, 2002 bolic Inhibitors in Bacteria?”; Nature Reviews, Microbiology; Mar. WO WO O2/102421 A1 12/2002 WO WO 2004/027116 A2 4/2004 2005; pp. 238-250; vol. 3. WO WO 2004/O31077 A2 4/2004 Burton et al., “Molecular Grandients of Bioinertness Reveal a WO WO 2005,100 100 10/2005 Mechanistic Difference between Mammalian Cell Adhesion and WO WO 2005,117914 A2 12/2005 Bacterial Biofilm Formation': Langmuir; 2009: pp. 1547-1553; vol. WO WO 2006,000764 A1 1, 2006 25, No. 3; American Chemical Society. WO WO 2006/044324 4/2006 Byrne et al.; “Molecular imprinting within hydrogels'; Advanced WO WO 2007/070801 A3 6, 2007 Drug Delivery Reviews; 2002: pp. 149-161; vol. 54; Elsevier WO WO 2007/085021 7/2007 Science B.V. WO WO 2007 140544 A1 12/2007 Cao et al.; "Combining use of a panel of ssDNA aptamers in the WO WO 2008/O2O77O A1 2, 2008 detection of Staphylococcus aureus'; Nucleic Acids Research; WO WO 2008/073774 A1 6, 2008 2009: pp. 1-8. WO WO 2008.083390 A2 T 2008 WO WO 2008, 118211 A2 10, 2008 Cao et al.; “Molecular Beacon Aptamers for Protein Monitoring in WO WO 2009/067682 A2 5, 2009 Real-Time and in Homogeneous Solutions'; Current Proteomics; WO WO 2009,148728 A2 12/2009 2005; pp. 31-40; vol. 2, No. 1; Bentham Science Publishers Ltd. Carcillo, Joseph A. et al.; “Early Markers of Infection and Sepsis in Newborns and Children': Leading Article, Advances in Sepsis: OTHER PUBLICATIONS 2006; pp. 118-125; vol. 5, No. 4. Aarabi, Shahram et al., “Research in Translation: Hypertrophic Scar Caricchio, Roberto et al.: “Ultraviolet B Radiation-Induced Cell Formation Following Burns and Trauma: New Approaches to Death: Critical Role of Ultraviolet Dose in Inflammation and Lupus Treatment”. PLoS Medicine; Sep. 2007: pp. 1464-1470; vol. 4, Autoantigen Redistribution': The Journal of Immunology; 2003; Issue 9, No. e234; located at: www.plosmedicine.org. pp. 5778-5786; vol. 171; The American Association of Immunolo Abdollahi et al.; “Apoptosis Signals in Lymphoblasts Induced by gists, Inc. Focused Ultrasound”; The FASEB Journal-FJ Express; Sep. 2004; Chen et al.; "Aptamer from whole-bacterium SELEX as new pp. 1413-1414; vol. 18; FASEB. therapeutic reagent against virulent Mycobacterium tubercolosis”; Agvald-Ohman et al.; “Multiresistant coagulase-negative staphylo Biochemical and Biophysical Communications; 2007: pp. 743-748; cocci disseminate frequently between intubated patients in a mul vol. 357; Elsevier Inc. US 9,474,831 B2 Page 6

(56) References Cited Fenelon et al.; “Production of Specific Monoclonal Antibodies to Aspergillus Species and Their Use in Immunohistochemical Iden OTHER PUBLICATIONS tification of Aspergillosis'; Journal of Clinical Microbiology; Apr. 1999: pp. 1221-1223; vol. 37, No. 4; American Society for Micro Chen, Ting-Hsuan et al.; "A Wettability Switchable Surface Driven biology. by Electrostatic Induced Surface Morphology Change Without Feng, Xinjian et al.; "Reversible Super-Hydrophobicity to Super Energy Interference on Reagents in Droplets': MEMS; Jan. 2006; Hydrophilicity Transition of Aligned ZnO Nanorod Films'; JACS pp. 178-181; IEEE. Communications; 2004; pp. 62-63; vol. 126; American Chemical Chen, Ting-Hsuan et al.; "A Wettability Switchable Surface by Society. microscale Surface morphology change'; Journal of Micromechan Feng, Yi et al.; “Gastric Cancer: Low Intensity Ultrasound-Induced ics and Microengineering: 2007: pp. 489-495; vol. 17, No. 3; IOP Apoptosis in Human Gastric Carcinoma Cells’; World Journal of Publishing Ltd. Gastroenterology; bearing a date of Aug. 21, 2008; pp. 4873-4879; Cheng et al.; "Electrically Switchable and Optically Rewritable vol. 14, No. 31; The WJG Press; located at: www.wgnet.com. Reflective Fresnel Zone Plate in Dye-Doped Cholesteric Liquid Feng et al.; “Plasmonic Effects in Dynamic Tunable Metal-Dielec Crystals'; Optics Express; bearing a date of Oct. 17, 2007: pp. tric Composites”; PIERS Online; bearing a date of 2008; pp. 14078-14085; vol. 15, No. 21; OSA. 625-630; vol. 4, No. 6. Cheng, Gang et al.; "Switchable Polymer Surfaces: A Switchable Fogh-Andersen, Niels et al.; “Composition of Interstitial Fluid': Biocompatible Polymer Surface with Self-Sterilizing and Nonfoul General Clinical Chemistry; 1995; pp. 1522-1525; vol. 41, No. 10. ing Capabilities”: Angewandte Chemie Int. Ed., 2008; pp. 8831 Forbes, Peter; "Scientific American: Self-Cleaning Materials: Lotus 8834; vol. 47; Wiley-VCH Verlag GmbH & Co. Leaf-Inspired Nanotechnology': Scientific American Magazine; Chung et al., “Size Comparisons among Integral Membrane Trans bearing a date of Jul. 30, 2008; pp. 1-5; printed on Nov. 21, 2008. port Protein Homologues in Bacteria, Archaea, and Eucarya'; Frasca et al., “Review: Prevention of Central Venous Catheter Journal of Bacteriology; Feb. 2001; pp. 1012-1021; vol. 183, No. 3; Related Infection in the Intensive Care Unit': Critical Care; bearing American Society for Microbiology. a date of 2010; pp. 1-8; vol. 14, No. 212; Springer-Verlag Berlin Chung et al., “Impact of Engineered Surface microtopography on Heidelberg. biofilm formation of Staphylococcus aureus'; Biointerphases; Jun. Gao et al.; "A Micro Sensing Probe for Detecting Individual 2007: pp. 89-94; vol. 2, No. 2: American Vacuum Society. Biological Cells”; Proceedings of the 25" Annual International Cohen et al.: “Whole Cell Imprinting in Sol-Gel Thin Films for Conference of the IEEE EMBS; Cancun, Mexico, Sep. 17-21, 2003; Bacterial Recognition in Liquids: Macromolecular Fingerprinting'; pp. 3348-3351; IEEE. In. J. Mol. Sci., 2010; pp. 1236-1252; vol. 11. Gavrieli et al.: “Identification of Programmed Cell Death in situ via Coppola et al.; “Visualization of Optical Deflection and Switching Specific Labeling of Nuclear DNA Fragmentation': The Journal of Operations by a Domain-Engineered-Based LiNbO. Electro-Optic Cell Biology; bearing a date of Nov. 1992: pp. 493-501; vol. 119, Device'; Optics Express; bearing a date of May 19, 2003; vol. 11, No. 3; The Rockefeller University Press; located at: http://cb. No. 10; OSA. rupress.org/. Crawford et al.; “Peptide aptamers: Tools for biology and drug Giannitsis et al., “Risk Stratification in Pulmonary Embolism Based discovery; Briefings in Functional Genomics and Proteomics; Apr. on Biomarkers and Echocardiography'. Circulation: Journal of the 2003; pp. 72-79; vol. 2, No. 1; Henry Stewart Publications. American Heart Association; bearing a date of 2005; pp. 1520-1521; Davis et al.; "A New Electro-Optic Waveguide Architecture and the American Heart Association, Inc.; located at: http://circ.ahajournals. Unprecedented Devices it Enables': Proc. of SPIE; bearing a date org/cgi/content/full/112/11/1520. of 2008; pp. 697503-1-697503-12; vol. 6975. Givrad et al.; “Implantable Minipump with MEMS Electrothermal De Fabo, Edward C.; "Advances in Brief. Ultraviolet B but not Valve for Bolus Injection in Mice"; Proceedings of BIOMed: 3 Ultraviolet A Radiation-Initiates Melanoma'; Cancer Research; Frontiers in Biomedical Devices Conference; Jun. 18-20, 2008; pp. bearing a date of Sep. 15, 2004; pp. 6372-6376; vol. 64; American 1-2; ASME. Association for Cancer Research. Gjerde et al.: “Carbon nanotube forests: a non-stick workbench for Donlan, R. M. et al.; “Model System for Growing and Quantifying nanomanipulation': Institute of Physics Publishing: 2006; pp. 4917 Streptococcus pneumoniae Biofilms in Situ and in Real Time'; 4922; vol. 17: IOP Publishing Ltd. Applied and Environmental Microbiology; Aug. 2004; pp. 4980 Goclawski, Jaroslaw et al.; "The Measurement of Wetting Angle by 4988; vol. 70, No. 8: American Society for Microbiology. Applying an ADSA Model of Sessile Drop on Selected Textile Donlan; Rodney M.: "Biofilms and Device-Associated Infections'; Surfaces': Fibres and Textiles in Eastern Europe; Apr./Jun. 2008; Emerging Infectious Diseases; Mar.-Apr. 2001; pp. 277-281; vol. 7. pp. 84-88; vol. 16, No. 2(67). No. 2. Gras et al.: “Intelligent control of surface hydrophobicity': Doornbos et al.: “White Blood Cell Differentiation Using a Solid Chemphyschem.; Oct. 8, 2007: pp. 2036-2050; Abstract; one page; State Flow Cytometer'; Cytometry; 1993; pp. 589-594; vol. 14; vol. 8, No. 14. Wiley-Liss, Inc. Greene, Mark E.: “Light Switches surface hydrophobicity: Optical Dubinsky et al., “High-Intensity Focused Ultrasound: Current materials': Materialstoday; Nov. 2006; p. 15; vol. 9, No. 11. Potential and Oncologic Applications'; Ultrasound Imaging-Re Grunfeld, Carl; "Lipids, Lipoproteins, Triglyceride Clearance, and view, AJR; bearing a date of Jan. 2008; pp. 191-199; vol. 190; Cytokines in Human Immunodeficiency Virus Infection and the American Roentgen Ray Society. Acquired Immunodeficiency Syndrome'; Journal of Clinical Endo Elman et al., “An Implantable MEMS Drug Delivery Device for crinology and Metabolism; 1992: pp. 1045-1052; vol. 74, No. 5; Rapid Delivery in Ambulatory Emergency Care”; Biomedical The Endocrine Society. Microdevices; Jun. 2009: pp. 625-631; vol. 11; Springer Nether Gu et al., “Precise engineering of targeted nanoparticles by using lands. self-assembled biointegrated block copolymers'; PNAS; Feb. 19, European Search Report; European App. No. EP 08 25 1153; Jul. 2008; pp. 2586-2591; vol. 105, No. 7: The National Academy of 10, 2009: pp. 1-2. Sciences of the USA. European Search Report; European App. No. EP 0883 4851; Dec. Hall et al.; “Nanosecond Pulsed Electric Fields Induce Apoptosis in 2, 2010 (received by our Agent on Dec. 14, 2010); pp. 1-6. p53-wildtype and p53-null HCT 116 Colon Carcinoma Cells'; "Fact Sheet: Cerebrospinal Fluid Shunt Systems for the Manage Apoptosis; bearing a date of May 23, 2007: pp. 1721-1731; vol. 12; ment of Hydrocephalus'; Hydrocephalus Association; 2000; 7 Springer Science+Business Media, LLC. pages; Hydrocephalus Association; located at: www.hydroassoc. Harmon et al.; "Cell Death Induced in a Murine Mastocytoma by Org. 42-47°C Heating in vitro: Evidence that the Form of Death Changes Fan et al.; “Sensitive optical biosensors for unlabeled targets: A From Apoptosis to Necrosis Above a Critical Heat Load”; Int. J. review”: Analyticca Chimica Acta; 2008; pp. 8-26; vol. 620; Radiat. Biol. Rights Links; 1990; pp. 845-858; vol. 58, No. 5; Elsevier B.V. Taylor & Francis Ltd. US 9,474,831 B2 Page 7

(56) References Cited Kupper et al., “Generation of human antibody fragments against Streptococcus mutans using a phage display chain shuffling OTHER PUBLICATIONS approach”: BMC Biotechnology; 2005; pp. 1-12; vol. 5, No. 4; BioMed Central Ltd. Harlow & Lane; "Antibodies: A Laboratory Manual”: Jan. 1988: 1 Lahann et al., “A Reversibly Switching Surface'; Reports, Science; edition; one page; Cold Spring Harbor Laboratory Press. bearing a date of Jan. 17, 2003; pp. 371-374 (plus Erratum); vol. Heo et al., “An Overview of Recent Strategies in Pathogen Sens 299; located at: www.sciencemag.org. ing'; Sensors; 2009: pp. 4483-4502; vol. 9. Lau et al.; "Superhydrophobic Carbon Nanotube Forests'; Nano Herchline, Thomas; “Staphylococcal Infections'; eMedicine; pp. Letters; pp. 1-21; printed on Jan. 20, 2011. 1-22; located at http://emedicine.medscape.com/article/228816 Lepock, James R.; "Cellular Effects of Hyperthermia: Relevance to print; accessed May 24, 2010. the Minimum Dose for Thermal Damage”; International Journal of Horng et al.; "Tunable Optical Switch Using Magnetic Fluids'; Hyperthermia, Taylor & Francis healthSciences; May-Jun. 2003; pp. Applied Physics Letters; bearing a date of Dec. 6, 2004; pp. 252-266; vol. 19, No. 3; Taylor & Francis Ltd. 5592-5594; vol. 85, No. 23; American Institute of Physics. Liet al.; “Muscle-Driven in Vivo Nanogenerator'; Advanced Mate Hsu et al.; “Artificial Hairy Surfaces with a Nearly Perfect Hydro rials; 2010; pp. 1-4; vol. 22; Wiley-VCH Verlag GmbH & Co. phobic Response'; Langmuir, 2010; pp. 1504-1506; Abstract; one KGaA, Weinheim. page; vol. 26, No. 3; American Chemical Society. Li et al., “Feasibility of Interstitial Doppler Optical Coherence Imam, S.K. et al., “Radiotracers for Imaging of Infection and Tomography for In Vivo Detection of Microvascular Changes Inflammation—A Review’’; World Journal Nuclear Medicine.; Jan. During Photodynamic Therapy'. Lasers in Surgery and Medicine; 2006; pp. 40-55; vol. 5, No. 1. bearing a date of Jul. 2, 2006; pp. 754-761; vol. 38; Wiley-Liss Inc. Ivanova et al.; “Impact of Nanoscale Roughness of Titanium Thin Liou et al., “An ASIC Control Circuit for Thermal Actuated Large Film Surfaces on Bacterial Retention': Langmuir, 2010; pp. 1973 Optical Packet Switch Array'; Proceedings of the World Congress 1982; vol. 26, No. 3; American Chemical Society. of Engineering; bearing a date of Jul. 2-4, 2008; pp. 1-6; vol. I; Jaffer et al.: “In Vivo Imaging of Thrombin Activity in Experimental WCE. Thrombi with Thrombin-Sensitive Near-Infrared Molecular Probe': Lin, Yi-Hsin; “Electrically Tunable Wettability of Liquid Crystal/ Arteriosclerosis, Thrombosis, and Vascular Biology: Journal of the Polymer Composite Films'; Optics Express; bearing a date of Oct. American Heart Association; bearing a date of Nov. 2002: pp. 27, 2008; pp. 17591-17598; vol. 16, No. 22: OSA. 1929-1935; American Heart Association, Inc.; located at: http:// Liu et al., “Fabricating Super-Hydrophobic Lotus-Leaf-Like Sur atvb.ahajournals.org/cgi/content/full/22/11/1929. faces through Soft-Lithographic Imprinting'; Macromolecular Jaiswal et al.: “Long-Term Multiple Color Imaging of Live Cells Rapid Communications; Nov. 2, 2006; pp. 1859-1864: Abstract; one Using Quantum Dot Bioconjugates'; Nature Biotechnology; bear page; vol. 27, No. 21; Wiley-VCH Verlag GmbH & Co. KGaA. ing a date of Jan. 2003; pp. 47-51; vol. 21; Nature Publishing Group. Weinheim. Liu et al.; "Thermally sensitive micelles self-assembled from Jayasena et al.; "Aptamers: An Emerging Class of Molecules That poly(N- isopropylacrylarnide-co-N, N-dimethylacrylamide)b- Rival Antibodies in Diagnostics': Clinical Chemistry; 1999: pp. poly(D.L-lactide-co-glycolide) for controlled delivery of 1628-1650; vol. 45, No. 9; American Association for Clinical paclitaxel'; Molecular BioSystems; 2005; pp. 158-165; vol. 1; The Chemistry. Royal Society of Chemistry. Kalchenko et al.: “Use of lipophilic near-infrared dye in whole-body Lockhart et al., “Antimicrobial Resistance among Gram-Negative optical imaging of hematopoietic cell homing'; Journal of Biomedi Bacilli Causing Infections in Intensive Care Unit Patients in the cal Optics; Sep./Oct. 2006; pp. 050507-1-050507-3; vol. 11, No. 5; United States between 1993 and 2004: Journal of Clinical Micro SPIE. biology; Oct. 2007: pp. 3352-3359; vol. 45, No. 10; American Kamphuisen et al.; "Can Anticoagulant Treatment be Tailored with Society for Microbiology. Biomarkers in Patients with Venous Thromboembolism?': Journal Long et al.; "A model that predicts the attachment behavior of Ulva of Thrombosis and Haemostasis; bearing a date of 2006; pp. linza Zoospores on Surface topography: Biofouling; May 2010, pp. 1206-1207; vol. 4; International Society on Thrombosis and 411-419; vol. 26, No. 4; Taylor & Francis. Haemostasis. Long et al., “Potential for tunable static and dynamic contact angle Kashyap et al.; "Surface Plasmon Resonance Based Fiber and anisotropy on gradient microscale patterned topographies”; Planar Waveguide Sensors'; pp. 1-15; printed on Jan. 25, 2011. Langmuir, Nov. 17, 2009: pp. 12982-12989; Abstract; one page; Khan et al.; "The Effect of Hyperthermia on the Induction of Cell vol. 25, No. 22. Death in Brain, Testis, and Thymus of the Adult and Developing Low et al., “DNA Aptamers Bind Specifically and Selectively to Rat': Cell Stress & Chaperones; 2002: pp. 73-90; vol. 7, No. 1: Cell (1->3)-B-D-glucans'; Biochem. Biophys. Res. Commun.; Jan. 23. Stress Society International. 2009: pp. 701-705; vol. 378, No. 4. Luckevich, Mark; “MEMS microvalves: the new valve world': Killer, H. E. et al.; “The Optic Nerve: A New Window into Valve World; May 2007: pp. 79-83. Cerebrospinal Fluid Composition?”; Brain; 2006; pp. 1027-1030; Masteikova, Ruta et al.; "Stimuli-Sensitive Hydrogels in Controlled vol. 129. and Sustained Drug Delivery': Medicina; 2003; pp. 19-24; vol.39, Kim et al.; "Shape-Tunable Polymer Nanofibrillar Structures by No. 2. Oblique Electron Beam Irradiation': Langmuir; 2009: pp. 8879 Masuoka, James; "Surface Glycans of Candida albicans and,Other 8882; Abstract; one page; vol. 25, No. 16; American Chemical Pathogenic Fungi: Physiological Roles, Clinical Uses, and Experi Society. mental Challenges': Clinical Microbiology Reviews; Apr. 2004; pp. Knappik et al., “Fully Synthetic Human Combinatorial Antibody 281-310; vol. 17, No. 2: American Society for Microbiology. Libraries (HuCAL) (Based on Modular Consensus Frameworks and Mateus et al., “Adherence of Candida albicans to Silicone Induces CDRs Randomized with Trinucleotides'; J. Mol. Biol. 2000; pp. Immediate Enhanced Tolerance to Fluconazole'; Antimicrobial 57-86; vol. 296; Academic Press. Agents and Chemotherapy; Sep. 2004; pp. 3358-3366; vol. 48, No. Koenig et al., “Laser-Induced Autofluorescence for Medical Diag 9; American Society for Microbiology. nosis”; Journal of Fluorescence; 1994; pp. 17-40; vol. 4. No. 1; McDannold et al.; “Microbubble Contrast Agent with Focused Plenum Publishing Corporation. Ultrasound to Create Brain Lesions at Low Power Levels: MR Kolodkin-Gal et al., “-Amino Acids Trigger Biofilm Disassem Imaging and Histologic Study in Rabbits''. Original Research, bly': Science; Apr. 30, 2010; pp. 627-629; vol. 328. Experimental Studies, Radiology; bearing a date of Oct. 2006; pp. Krupenkin et al.; “Electrically Tunable Superhydrophobic 95-106; vol. 241, No. 1; RSNA. Nanostructured Surfaces': Bell Labs Technical Journal; bearing a Mckenna, Susan M. et al.; "The Inhibition of Bacterial Growth by date of 2005; pp. 161-170; vol. 10, No. 3; Lucent Technologies Inc. Hypochlorous Acid”; Biochemistry; 1988; pp. 685-692; vol. 254. US 9,474,831 B2 Page 8

(56) References Cited Reynolds et al.; "Early Biomarkers of Stroke'; Clinical Chemistry: Oak Ridge Conference; bearing a date of Apr. 7, 2003; pp. 1733 OTHER PUBLICATIONS 1739; vol. 49, No. 10; American Association for Clinical Chemistry. Richards Grayson, Amy C. et al.: “A BioMEMS Review: MEMS Miyata et al.; "Tumor marker-responsive behavior of gels prepared Technology for Physiolocially Integrated Devices': Proceedings of by biomolecular imprinting”; PNAS; Jan. 31, 2006; pp. 1190-1193; the IEEE; Jan. 2004; pp. 6-21; vol. 92, No. 1; IEEE. vol. 103, No. 5: The National Academy of Sciences of the USA. Rosalki et al.; "Cardiac Biomarkers for Detection of Myocardial Nejat. Farideh et al.; "Original Article: A Randomized Trial of Infarction: Perspectives from Past to Present’: Clinical Chemistry; Ceftriaxone Versus Trimethoprimsulfamethoxazole to Prevent bearing a date of Aug. 17, 2004; pp. 2205-2213; vol. 50, No. 11; Ventriculoperitoneal Shunt Infection': Journal of Microbiology, American Association for Clinical Chemistry. Immunology and Infection; 2008; pp. 112-117; vol. 41; Journal of Roti Roti, Joseph L.; “Review: Cellular Responses to Hyperthermia Microbiology, Immunology and Infection. (40-46°C): Cell Killing and Molecular Events”; Int. J. Hyperther Ng, PC; “Review: Diagnostic Markers of Infection in Neonates'; mia; Feb. 2008; pp. 3-15; vol. 24, No. 1; Informa UK Ltd. Sage et al.; "A Rapid and Nondestructive Method for Microbio Arch Dis Child Fetal Neonatal Ed: 2004; pp. F229-F235; vol. 89: logical Testing in Pharmaceutical Manufacturing; American Bio located at: www.archdischild.com. technology Laboratory; Nov./Dec. 2006; pp. 1-5. Oberreuter et al.: “Identification of coryneform bacteria and related Sahly et al., “Recognition of Bacterial Surface Polysaccharides by taxa by Fourier-transform infrared (FT-IR) spectroscopy”; Interna Lectins of the Innate Immune System and Its Contribution to tional Journal of Systematic and Evolutionary Microbiology; 2002; Defense against Infection: the Case of Pulmonary Pathogens'; pp. 91-100; vol. 52; IUMS. Infection and Immunity; Apr. 2008; pp. 1322-1332; vol. 76, No. 4; O'Grady et al.; "Guidelines for the Prevention of Intravascular American Society for Microbiology. Catheter-Related Infections”: MMWR Morbidity and Mortality Seehusen, Dean A. et al.; "Cerebrospinal Fluid Analysis”; American Weekly Report; Aug. 9, 2002; 32 pgs.; vol. 51, No. RR-10. Family Physician; bearing a date of Sep. 15, 2003; pp. 1103-1108; Okada, Ayako et al.; "Inhibition of Biofilm Formation Using Newly vol. 68, No. 6; located at: www.aafp.org/afp. Developed Coating Materials with Self-Cleaning Properties': Den Sendid et al., “Antibodies against Glucan, Chitin, and Sac tal Materials Journal: 2008; pp. 565-572; vol. 27, No. 4. charomyces cerevisiae Mannan as New Biomarkers of Candida Olcum et al.; "Tunable Surface Plasmon Resonance on an albicans Infection That Complement Tests Based on C. albicans Elastomeric Substrate'; Optics Express; bearing a date of May 11, Mannan'; Clinical and Vaccine Immunology; Dec. 2008; pp. 1868 2009: pp. 8542-8547; vol. 17, No. 10; OSA. 1877; vol. 15, No. 12; American Society for Microbiology. PCT International Search Report; International App. No. PCT/ Serra et al.: “Lectin-modified piezoelectric biosensors for bacteria US 10/00579; May 3, 2010; pp. 1-2. recognition and quantification'. Anal. Bioanal. Chem.; 2008; pp. PCT International Search Report; International App. No. PCT/ 1853-1860; vol. 391; Springer-Verlag. US09/06393; May 13, 2010; pp. 1-4. Setroikromo, R.; “Heat Shock Proteins and Bcl-2 Expression and Peleg et al.: “Hospital-Acquired Infections Due to Gram-Negative Function in Relation to the Differential Hyperthermic Sensitivity between Leukemic and Normal Hematopoietic Cells”; Cell Stress & Bacteria”: N. Engl. J. Med.; May 13, 2010; pp. 1804-1813; vol. 362, Chaperones; 2007: pp. 320-330; vol. 12, No. 4; Cell Stress Society No. 19; Massachusetts Medical Society. International. Peppas et al.; “Polymers and Gels as Molecular Recognition Shackleford et al.: “Integrated Plasmonic Lens Photodetector': Agents”; Pharmaceutical Research; May 2002: pp. 578-587; vol. Applied Physics Letters; bearing a date of Nov. 24, 2008; pp. 1-3: 19, No. 5: Plenum Publishing Corporation. vol. 94, No. 08.3501; American Institute of Physics. Piccolo et al., “Antifuse Injectors for SOI LEDs”: printed in 2009; Shangguan et al.; "Aptamers evolved from live cells as effective pp. 573-575. molecular probes for cancer study”: PNAS; Aug. 8, 2006; pp. Piper, Kerryl E. et al.; “MIST Ultrasound Therapy Device Removal 11838-11843; vol. 103, No. 32: The National Academy of Sciences of In Vitro Bacterial Biofilms'; one page; Mayo Clinic; printed on of the USA. Jan. 25, 2011. Sharklet Technologies Awarded NIH SBIR (Small Business Inno Prescott et al., “Chronic, programmed polypeptide delivery from an vation Research) Grant for Development of Urinary Catheter with implanted, multireservoir microchip device'; Nature Biotechnol SharkletTM Pattern; Sharklet Technologies; Nov. 16, 2009: pp. 1-3: ogy; Apr. 2006; pp. 437-438; vol. 24, No. 4; Nature Publishing located at www.sharklet.com/2009/11/sharklet-technologies Group. awarded-nih. Pronovost et al.; “Sustaining reductions in catheter related blood Shellman et al.; “Hyperthermia Induces Endoplasmic Reticulum stream infections in Michigan intensive care units: observational Mediated Apoptosis in Melanoma and Non-Melanoma Skin Cancer study: BMJ: 2010; pp. 1-6. Cells': Original Article, Journal of Investigative Dermatology; Proske et al.; "Aptamers-basic research, drug development, and 2008; pp. 949-956; vol. 128; The Society for Investigative Derma clinical applications'; Appl. Microbiol. Biotechnol. 2005; pp. 367 tology; located at: www.jidonline.org. 374; vol. 69; Springer-Verlag. “SilvaSorb(R) Targeted Antimicrobial Protection”; Medline; 2005; Rafiee et al.; "Superhydrophobic to Superhydrophillic Wetting 16 pages; Medline Industries Inc.; located at www.medline.com. Control in Graphene Films'; Advanced Materials; 2010; pp. 1-4; Smith et al.; “Evanescent Wave Imaging in Optical Lithography”; vol. 22: Wiley-VCH Verlag GmbH & Co. KGaA. Weinheim. printed on Dec. 10, 2010; pp. 1-9. Rathmell, James P. et al.; "Infectious Risks of Chronic Pain Treat Sodja et al.; "Splenic T Lymphocytes Die Preferentially During ments: Injection Therapy, Surgical Implants, and Intradiscal Tech Heat-Induced Apoptosis: NuMA Reorganization as a Marker'; niques'; Regional Anesthesia and Pain Medicine; 2006; pp. 346 Journal of Cell Science; 1998; pp. 2305-2313; vol. 111: The 352; vol. 31, No. 4. Company of Biologists Limited. Rediske, Andrea M. et al.; “Pulsed Ultrasound Enhances the Killing Somwaru et al.: “Heat Induced Apoptosis of Mouse Meiotic Cells of Escherichia coli Biofilms by Aminoglycoside Antibiotics In is Suppressed by Ectopic Expression of Testis-Specific Vivo”: Antimicrobial Agents and Chemotherapy; Mar. 2000; pp. Calpastatin': Journal of Andrology; bearing a date of Jul/Aug. 771-772; vol. 44, No. 3; American Society for Microbiology; 2004; pp. 506-513; vol. 25, No. 4; American Society of Anthology. downloaded on Aug. 24, 2009. Spori et al.; "Cassie-State Wetting Investigated by Means of a Reid, Marvin et al.; "The Acute-Phase Protein Response to Infection Hole-to-Pillar Density Gradient'; Langmuir Article; bearing a date in Edematous and Nonedematous Protein-Energy Malnutrition”; Dec. 15, 2009: pp. 9465-9473; vol. 26, No. 12; American Chemical The American Journal of Clinical Nutrition; 2002: pp. 1409-1415; Society. vol. 76; American Society for Clinical Nutrition. Stankiewicz et al.; “Hsp70 Inhibits Heat-Induced Apoptosis Remington: The Science and Practice of Pharmacy; 20' Edition; Upstream of Mitochondria by Preventing Bax Translocation': The 2000; 2 pgs.; Lippincott Williams & Wilkins, Baltimore, Maryland. Journal of Biological Chemistry; Bearing a date of Nov. 18, 2005; US 9,474,831 B2 Page 9

(56) References Cited Wissing et al.; "Illumination of the Malaria Parasite Plasmodium falciparum Alters Intracellular pH'; The Journal of Biological OTHER PUBLICATIONS Chemistry; Oct. 4, 2002: pp. 37747-37755; vol. 277, No. 40: The American Society for Biochemistry and Molecular Biology, Inc. pp. 38729-38739; vol. 280, No. 46; The American Society for Xanthos, Marino; “Polymers and Fillers, Part One'; Functional Biochemistry and Molecular Biology, Inc. Fillers for Plastics; Second, updated and enlarged edition; 2010; Stubbe et al.; “Programmed Polymeric Devices for Pulsed Drug cover page; pp. 3-18; Wiley-Veh Verlag GmbH & Co. KGaA. Delivery': Pharmaceutical Research; Oct. 2004; pp. 1732-1740; Weinheim. vol. 21, No. 10; Springer Science+Business Media, Inc. Yang et al., “Engineering Target-Responsive Hydrogels Based on “Study E: Comparison of the Moisture Uptake and Retention Aptamer-Target Interactions'; J. Am. Chem. Soc.; 2008; pp. 6320 Properties of Biopatch(R) and SilvaSorb SiteR', 2 pages. 6321; vol. 130; American Chemical Society. Suslow, Trevor V.; "Introduction to ORP as the Standard of Post Yang et al.; "On-Chip Electrochemical Impedance Spectroscopy for harvest Water Disinfection Monitoring”; UC Davis, Vegetable Biosensor Arrays'; IEEE Sensors; Oct. 22-25, 2006; pp. 93-96; Research and Information Center; pp. 1-4. IEEE “Switchable Lotus Effect: Material Becomes Super Water-Repellent Yang et al.; “Polyimide-Waveguide-Based Thermal Optical Switch With the Flick of a Light': Science Daily; Sep. 17, 2006; one page; Using Total-Internal-Reflection Effect”; Applied Physics Letters; printed on May 11, 2010; located at www.sciencedaily.com/re bearing a date of Oct. 14, 2002: pp. 2947-2949; vol. 81, No. 16; leases/2006/09/060915204838.htm. American Institute of Physics. Tamura et al.; "One-chip sensing device (biomedial photonic LSI) Ye et al.; “Molecularly imprinted polymers as antibody and receptor enabled to assess hippocampal steep and gradual up-regulated mimics for assays, sensors and drug discovery': Anal. Bioanal. proteolytic activities'; Journal of Neuroscience Methods; 2008; pp. Chem.; 2004; pp. 1887-1897; vol. 378; Springer-Verlag. 114-120; vol. 173; Elsevier B.V. Zelada-Guillén et al.; “Immediate Detection of Living Bacteria at Taylor et al.; "Surface Plasmon Resonance (SPR) Sensors for the Ultralow Concentrations. Using a Carbon Nanotube Based Detection of Bacterial Pathogens'; Principles of Bacterial Detec Potentiometric Aptasensor'; Angew. Chem. Int. Ed., 2009: pp. 1-4; tion: Biosensors, Recognition Receptors and Microsystems; 2008; vol. 48; Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. pp. 83-108; Springer Science+Business Media, LLC. Zharov et al., “In vivo high-speed imaging of individual cells in fast Thai et al., “Development of a Fully-Integrated Ultrasensitive blood flow”: Journal of Biomedical Optics; Sep./Oct. 2006; pp. Wireless Sensor Utilizing Carbon Nanotubes and Surface Plasmon 054034-1 to 054034-4; vol. 11, No. 5; SPIE. Theory”; Electronic Components and Technology Conference; Zharov et al.: “In vivo Photothermal Flow Cytometry: Imaging and bearing a date of 2008; pp. 436-439; IEEE. Detection of Individual Cells in Blood and Lymph Flow”: Journal Timko et al., “Remotely Triggerable Drug Delivery Systems'; of Cellular Biochemistry; 2006; pp. 916-932; vol. 97; Wiley-Liss, Advanced Materials; bearing a date of Jun. 4, 2010; pp. 4925-4943; Inc. vol. 22: Wiley-VCH Verlag GmbH& Co. Zheng et al., “Design and Fabrication of a Micro Coulter Counter Tsutsui et al., “Research: The use of Microbubbles to Target Drug with Thin Film Electrodes': Proceedings of 2006 International Delivery': BioMed Central-Open Access; bearing a date of Aug. 17. Conference on Microtechnologies in Medicine and Biology; May 2004; pp. 1-7: vol. 2, No. 23: BioMed Central Ltd. 9-12, 2006; pp. 16-19; IEEE. Tuteja et al.; "Robust Omniphobic Surfaces': PNAS; bearing a date Zhong et al., “Review: Biomaterials for the Central Nervous Sys of Nov. 25, 2008; pp. 18200-18205; vol. 105, No. 47: The National tem”: Journal of the Royal Society Interface; 2008; pp. 957-975; Academy of Sciences of the USA. vol. 5: The Royal Society. Ulrich et al.: “In Vitro Selection of RNAAptamers That Bind to Cell European Patent Office; Extended European Search Report; App. Adhesion Receptors of Trypanosoma cruzi and Inhibit Cell Inva No. EP 1074 6554; Apr. 5, 2013 (received by our agent on Apr. 8, sion': The Journal of Biological Chemistry; Jun. 7, 2002: pp. 2013); 8 pages (1 cover page, 1 Supplementary European search 20756-20762; vol. 277, No. 23: The American Society for Bio report, 6 European search opinion pages). chemistry and Molecular Biology, Inc. PCT International Search Report; International App. No. PCT/ Vashist, Sandeep Kumar; “A Review of Microcantilevers for Sens US2010/003088; Apr. 1, 2011; pp. 1-4. ing Applications'; Open Access Rewards System; Jun. 2007, pp. PCT International Search Report; International App. No. PCT/ 1-15; vol. 3. US 11/01883; May 3, 2012: pp. 1-5. Vazquez et al.; "Optical Router for Optical Fiber Sensor Networks McCarthy et al.; "Steroid Modulation of Astrocytes in the Neonatal Based on a Liquid Crystal Cell'; IEEE Sensors Journal; bearing a Brain: Implications for Adult Reproductive Function”: Biology of date of Aug. 2003; pp. 513-518; vol. 3, No. 4; IEEE. Reproduction; bearing a date of Apr. 5, 2002: pp. 691-698; vol. 67; Vogel et al.; "Capillarity-based switchable adhesion': PNAS; Feb. Society for the Study of Reproduction, Inc. 23, 2010; pp. 3377-3381; vol. 107, No. 8. Dienel et al.; Astrocyte activation in vivo during graded photic Vykhodtseva et al.: “Induction of Apoptosis in vivo in the Rabbit stimulation; Journal of Neurochemistry; bearing a date of 2007: pp. Brain Focused Ultrasound and Optison R’; Original Contribution, 1506-1522; vol. 103: International Society for Neurochemistry. Ultrasound in Med. & Biol.; 2006; pp. 1923-1929; vol. 32, No. 12; Elmore, Susan; "Apoptosis: A Review of Programmed Cell Death'; World Federation for Ultrasound in Medicine & Biology. Toxicol Pathology; Dec. 6, 2007: pp. 495-516 (pp. 1-40 as pro Wang et al., “Review: Photoresponsive Surfaces with Controllable vided); vol. 35. No. 4; National Institute of Health. Wettability”; Journal of Photochemistry and Photobiology C. Pho Hashimoto et al.; "TiO, Photocatalysis: A Historical Overview and tochemistry Review, Science Direct; 2007: pp. 18-29; vol. 8: Future Prospects’; Japanese Journal of Applied Physics; bearing a Elsevier B.V. date of 2005, published Dec. 8, 2005; pp. 8269-8285; vol. 44, No. Wang et al.; “Effective in Plane Launching and Focusing Surface 12; The Japan Society of Applied Physics. Plasmons by a Plasmonic Lens'; OSA; bearing a date of 2009: pp. Gal'China et al.; “Electroluminescence Spectra of Ultraviolet Light 1-2; IEEE. Emitting Diodes Based p-n-Heterostructures Coated with Phos Wang et al.; “APD: The Antimicrobial Peptide Database': Nucleic phors'; Semiconductors; bearing a date of 2007: pp. 1126-1131; vol. Acids Research; 2004; pp. D590-D592; vol. 32: Oxford University 41, No. 9; Pleiades Publishing Ltd.: ISSN 1063–7826. Press. Kim et al., “Realization of p-type ZnO thin films via phosphorus Watson et al., “Review: Clinical Utility of Biochemical Analysis of doping and thermal activation of the dopant'. Applied Physics Cerebrospinal Fluid”; Clinical Chemistry; 1995; pp. 343-360; vol. Letters; bearing a date of Jul. 7, 2003; pp. 63-65; vol. 83, No. 1; 41, No. 3. American Institute of Physics. Wentworth et al., “Reports: Evidence for Antibody-Catalyzed Könenkamp et al.: “Ultraviolet Electroluminescence from ZnO/ Ozone Formation in Bacterial Killing and Inflammation': Science; Polymer Heterojunction Light-Emitting Diodes'; Nano Letters; 2002: pp. 2195-2199; vol. 298; downloaded on Jul. 14, 2009; bearing a date of 2005; pp. 2005-2008; vol. 5, No. 10; American located at: www.sciencemag.org. Chemical Society. US 9,474,831 B2 Page 10

(56) References Cited Zhang et al.; "Milliwatt power deep ultraviolet light-emitting diodes over sapphire with emission at 278 nm”: Applied Physics Letters; OTHER PUBLICATIONS bearing a date of Dec. 23, 2002: pp. 4910-4912; vol. 81, No. 26: American Institute of Physics. Li et al., “Ultraviolet nanophosphors'; Journal of Luminescence; Gjerde, Kjetil, “Carbon nanotube forests: a non-stick workbench for bearing a date of 2007: pp. 345-347; vol. 122-123; Elsevier B.V. nanomanipulation.” Institute of Physics Publishing, 2006, pp. 4917 Lim et al.: “UV Electroluminescence Emission from ZnO Light Emitting Diodes Grown by High-Temperature Radiofrequency 4922, Nanotechnology 17, IOP Publishing Ltd, UK. Sputtering'; Advanced Materials; bearing a date of 2006; pp. Dost?leket al.; “Multichannel Surface plasmon resonance biosensor 2720-2724; vol. 18; Wiley-VCH Verlag GmbH & Co. with wavelength division multiplexing'; Sensors and Actuators B Sun et al., “Realization of ultraviolet electroluminescence from 108 Chemical; Feb. 5, 2005; pp. 758-764; Elsevier B.V. ZnO homojunction with n-ZnO/p-ZnO:AS/GaAs structure': Nugaeva et al.; Micromechanical cantilever array sensors for selec Applied Physics Letters; bearing a date of 2007: pp. 121128-1- tive fungal immobilization and fast growth detection; Biosensors & 121128-3; vol. 90; American Institute of Physics. Bioelectronics 21; Mar. 2, 2005; pp. 849-856; Elsevier B.V. Tang et al.; "Cerium Phosphate Nanotubes: Synthesis, Valence State, and Optical Properties”: Angew. Chem. Int. Ed.; bearing a date of 2005; pp. 576-579; vol. 44; Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim. * cited by examiner U.S. Patent Oct. 25, 2016 Sheet 1 of 30 US 9,474,831 B2

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US 9,474,831 B2 1. 2 SYSTEMS, DEVICES, AND METHODS For purposes of the United States Patent and Trademark INCLUDING IMPLANTABLE DEVICES Office (USPTO) extra-statutory requirements, the present WITH ANT-MICROBAL PROPERTIES application constitutes a continuation-in-part of U.S. patent application Ser. No. 12/931,925, titled SYSTEMS, CROSS-REFERENCE TO RELATED DEVICES, AND METHODS INCLUDING IMPLANT APPLICATIONS ABLE DEVICES WITH ANTI-MICROBIAL PROPER TIES, naming ELEANORV. GOODALL, RODERICK A. The present application is related to and claims the benefit HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, of the earliest available effective filing dates from the JR. as inventors, filed 14 Feb. 2011 now abandoned. following listed applications (the “Related Applications') 10 For purposes of the United States Patent and Trademark (e.g., claims earliest available priority dates for other than Office (USPTO) extra-statutory requirements, the present provisional patent applications or claims benefits under 35 application constitutes a continuation-in-part of U.S. patent U.S.C. S 116(e) for provisional patent applications, for any application Ser. No. 12/931,931, titled SYSTEMS, and all parent, grandparent, great-grandparent, etc. applica DEVICES, AND METHODS INCLUDING IMPLANT tions of the Related Applications). All subject matter of the 15 ABLE DEVICES WITH ANTI-MICROBIAL PROPER Related Applications and of any and all parent, grandparent, TIES, naming ELEANORV. GOODALL, RODERICK A. great-grandparent, etc. applications of the Related Applica HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, tions is incorporated herein by reference to the extent such JR. as inventors, filed 14 February 2011 now abandoned. Subject matter is not inconsistent herewith. For purposes of the United States Patent and Trademark Office (USPTO) extra-statutory requirements, the present RELATED APPLICATIONS application constitutes a continuation-in-part of U.S. patent application Ser. No. 12/931,930, titled SYSTEMS, For purposes of the United States Patent and Trademark DEVICES, AND METHODS INCLUDING IMPLANT Office (USPTO) extra-statutory requirements, the present ABLE DEVICES WITH ANTI-MICROBIAL PROPER application constitutes a continuation-in-part of U.S. patent 25 TIES, naming ELEANORV. GOODALL, RODERICK A. application Ser. No. 12/931,921, titled SYSTEMS, HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, DEVICES, AND METHODS INCLUDING IMPLANT JR. as inventors, filed 14 February 2011 now abandoned. ABLE DEVICES WITH ANTI-MICROBIAL PROPER For purposes of the United States Patent and Trademark TIES, naming ELEANORV. GOODALL, RODERICK A. Office (USPTO) extra-statutory requirements, the present HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, 30 application constitutes a continuation-in-part of U.S. patent JR. as inventors, filed 14 Feb. 2011 now abandoned. application Ser. No. 12/931,920, titled SYSTEMS, For purposes of the United States Patent and Trademark DEVICES, AND METHODS INCLUDING IMPLANT Office (USPTO) extra-statutory requirements, the present ABLE DEVICES WITH ANTI-MICROBIAL PROPER application constitutes a continuation-in-part of U.S. patent TIES, naming EDWARD S. BOYDEN, ROY P. DIAZ, application Ser. No. 12/931,924, titled SYSTEMS, 35 RODERICK A. HYDE, JORDIN T. KARE, ELIZABETH DEVICES, AND METHODS INCLUDING IMPLANT A. SWEENEY. LOWELL L. WOOD, JR. as inventors, filed ABLE DEVICES WITH ANTI-MICROBIAL PROPER 14 Feb. 2011 now abandoned. TIES, naming ELEANORV. GOODALL, RODERICK A. For purposes of the United States Patent and Trademark HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, Office (USPTO) extra-statutory requirements, the present JR. as inventors, filed 14 Feb. 2011 now abandoned. 40 application constitutes a continuation-in-part of U.S. patent For purposes of the United States Patent and Trademark application Ser. No. 12/931,927, titled SYSTEMS, Office (USPTO) extra-statutory requirements, the present DEVICES, AND METHODS INCLUDING IMPLANT application constitutes a continuation-in-part of U.S. patent ABLE DEVICES WITH ANTI-MICROBIAL PROPER application Ser. No. 12/931,928, titled SYSTEMS, TIES, naming EDWARD S. BOYDEN, ROY P. DIAZ, DEVICES, AND METHODS INCLUDING IMPLANT 45 RODERICK A. HYDE, JORDIN T. KARE, ELIZABETH ABLE DEVICES WITH ANTI-MICROBIAL PROPER A. SWEENEY. LOWELL L. WOOD, JR. as inventors, filed TIES, naming ELEANORV. GOODALL, RODERICK A. 14 Feb. 2011 now abandoned. HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, For purposes of the United States Patent and Trademark JR. as inventors, filed 14 Feb. 2011. Office (USPTO) extra-statutory requirements, the present For purposes of the United States Patent and Trademark 50 application constitutes a continuation-in-part of U.S. patent Office (USPTO) extra-statutory requirements, the present application Ser. No. 12/931,922, titled SYSTEMS, application constitutes a continuation-in-part of U.S. patent DEVICES, AND METHODS INCLUDING IMPLANT application Ser. No. 12/931,929, titled SYSTEMS, ABLE DEVICES WITH ANTI-MICROBIAL PROPER DEVICES, AND METHODS INCLUDING IMPLANT TIES, naming EDWARD S. BOYDEN, ROY P. DIAZ, ABLE DEVICES WITH ANTI-MICROBIAL PROPER 55 RODERICK A. HYDE, JORDIN T. KARE, ELIZABETH TIES, naming ELEANORV. GOODALL, RODERICK A. A. SWEENEY. LOWELL L. WOOD, JR. as inventors, filed HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, 14 Feb. 2011. JR. as inventors, filed 14 Feb. 2011. For purposes of the United States Patent and Trademark For purposes of the United States Patent and Trademark Office (USPTO) extra-statutory requirements, the present Office (USPTO) extra-statutory requirements, the present 60 application constitutes a continuation-in-part of U.S. patent application constitutes a continuation-in-part of U.S. patent application Ser. No. 12/315,880, titled SYSTEM, application Ser. No. 12/931,923, titled SYSTEMS, DEVICES, AND METHODS INCLUDING ACTIVELY DEVICES, AND METHODS INCLUDING IMPLANT CONTROLLABLE SUPEROXIDE WATER GENERAT ABLE DEVICES WITH ANTI-MICROBIAL PROPER ING SYSTEMS, naming EDWARDS. BOYDEN, RALPH TIES, naming ELEANORV. GOODALL, RODERICK A. 65 G. DACEY, JR., GREGORY J. DELLA ROCCA, JOSHUA HYDE, ELIZABETHA. SWEENEY. LOWELL L. WOOD, L. DOWLING, RODERICK A. HYDE, MURIEL Y. JR. as inventors, filed 14 Feb. 2011 now abandoned. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT, US 9,474,831 B2 3 4 NATHAN P. MYHRVOLD, DENNIS J. RIVET, PAUL For purposes of the United States Patent and Trademark SANTIAGO, MICHAEL A. SMITH, TODDJ. STEWART, Office (USPTO) extra-statutory requirements, the present ELIZABETHA. SWEENEY, CLARENCET. TEGREENE, application constitutes a continuation-in-part of U.S. patent LOWELL L. WOOD, JR., VICTORIA Y. H. WOOD as application Ser. No. 12/315,885, titled CONTROLLABLE inventors, filed 4 Dec. 2008 now U.S. Pat. No. 8,162,924. 5 ELECTROSTATIC AND ELECTROMAGNETIC STER For purposes of the United States Patent and Trademark ILIZING EXCITATION DELIVERY SYSTEMS, DEVICE, Office (USPTO) extra-statutory requirements, the present AND METHODS, naming EDWARD S. BOYDEN, application constitutes a continuation-in-part of U.S. patent RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, application Ser. No. 12/315,881, titled SYSTEM, JOSHUAL. DOWLING, RODERICKA. HYDE, MURIEL DEVICES, AND METHODS INCLUDING STERILIZING 10 Y. ISHIKAWA, JORDIN T. KARE, ERIC C. EXCITATION DELIVERY IMPLANTS WITH CRYPTO LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. GRAPHIC LOGIC COMPONENTS, naming EDWARDS. RIVET, PAUL SANTIAGO, MICHAEL A. SMITH, TODD BOYDEN, RALPH G. DACEY, JR., GREGORY J. DELLA J. STEWART, ELIZABETHA. SWEENEY, CLARENCET. ROCCA, JOSHUAL DOWLING, RODERICKA. HYDE, TEGREENE, LOWELL L. WOOD, JR., VICTORIA Y. H. MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. 15 WOOD as inventors, filed 4 Dec. 2008 now abandoned. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. For purposes of the United States Patent and Trademark RIVET, PAUL SANTIAGO, MICHAEL A. SMITH, TODD Office (USPTO) extra-statutory requirements, the present J. STEWART, ELIZABETHA. SWEENEY, CLARENCET. application constitutes a continuation-in-part of U.S. patent TEGREENE, LOWELL L. WOOD, JR, VICTORIA Y. H. application Ser. No. 12/380,553, titled SYSTEM, WOOD as inventors, filed 4 Dec. 2008 now abandoned. DEVICES, AND METHODS INCLUDING ACTIVELY For purposes of the United States Patent and Trademark CONTROLLABLE STERILIZING EXCITATION DELIV Office (USPTO) extra-statutory requirements, the present ERY IMPLANTS, naming EDWARD S. BOYDEN, application constitutes a continuation-in-part of U.S. patent RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, application Ser. No. 12/315,882, titled SYSTEM, JOSHUAL. DOWLING, RODERICKA. HYDE, MURIEL DEVICES, AND METHODS INCLUDING STERILIZING 25 Y. ISHIKAWA, JORDIN T. KARE, ERIC C. EXCITATION DELIVERY IMPLANTS WITH GENERAL LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. CONTROLLERS AND ONBOARD POWER, naming RIVET, PAUL SANTIAGO, MICHAEL A. SMITH, TODD EDWARD S. BOYDEN, RALPH G. DACEY, JR., J. STEWART, ELIZABETHA. SWEENEY, CLARENCET. GREGORY J. DELLA ROCCA, JOSHUAL DOWLING, TEGREENE, LOWELL L. WOOD, JR., VICTORIA Y. H. RODERICK A. HYDE, MURIELY. ISHIKAWA, JORDIN 30 WOOD as inventors, filed 27 Feb. 2009 now abandoned. T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHR For purposes of the United States Patent and Trademark VOLD, DENNIS J. RIVET, PAUL SANTIAGO, Office (USPTO) extra-statutory requirements, the present MICHAEL A. SMITH, TODDJ. STEWART, ELIZABETH application constitutes a continuation-in-part of U.S. patent A. SWEENEY, CLARENCET. TEGREENE, LOWELL L. application Ser. No. 12/592,976, titled SYSTEM, WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 4 35 DEVICES, AND METHODS INCLUDING ACTIVELY Dec. 2008 now abandoned. CONTROLLABLE STERILIZING EXCITATION DELIV For purposes of the United States Patent and Trademark ERY IMPLANTS, naming EDWARD S. BOYDEN, Office (USPTO) extra-statutory requirements, the present RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, application constitutes a continuation-in-part of U.S. patent JOSHUAL. DOWLING, RODERICKA. HYDE, MURIEL application Ser. No. 12/315,883, titled SYSTEM, 40 Y. ISHIKAWA, JORDIN T. KARE, ERIC C. DEVICES, AND METHODS INCLUDING STERILIZING LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. EXCITATION DELIVERY IMPLANTS WITH GENERAL RIVET, PAUL SANTIAGO, MICHAEL A. SMITH, TODD CONTROLLERS AND ONBOARD POWER, naming J. STEWART, ELIZABETHA. SWEENEY, CLARENCET. EDWARD S. BOYDEN, RALPH G. DACEY, JR., TEGREENE, LOWELL L. WOOD, JR., VICTORIA Y. H. GREGORY J. DELLA ROCCA, JOSHUAL DOWLING, 45 WOOD as inventors, filed 3 Dec. 2009 now U.S. Pat. No. RODERICK A. HYDE, MURIELY. ISHIKAWA, JORDIN 9,005,263. T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHR For purposes of the United States Patent and Trademark VOLD, DENNIS J. RIVET, PAUL SANTIAGO, Office (USPTO) extra-statutory requirements, the present MICHAEL A. SMITH, TODDJ. STEWART, ELIZABETH application constitutes a continuation-in-part of U.S. patent A. SWEENEY, CLARENCET. TEGREENE, LOWELL L. 50 application Ser. No. 12/660,156, titled SYSTEMS, WOOD, JR, VICTORIAY. H. WOOD as inventors, filed 4 DEVICES, AND METHODS INCLUDING INFECTION Dec. 2008 now abandoned. FIGHTING AND MONITORING SHUNTS, naming For purposes of the United States Patent and Trademark RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL Office (USPTO) extra-statutory requirements, the present Y. ISHIKAWA, JORDIN T. KARE, ERIC C. application constitutes a continuation-in-part of U.S. patent 55 LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. application Ser. No. 12/315,884, titled SYSTEM, RIVET, MICHAEL A. SMITH, ELIZABETH A. DEVICES, AND METHODS INCLUDING ACTIVELY SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. CONTROLLABLE STERILIZING EXCITATION DELIV WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 19 ERY IMPLANTS, naming EDWARD S. BOYDEN, Feb. 2010 now U.S. Pat. No. 8,366,652. RALPH G. DACEY, JR., GREGORY J. DELLA ROCCA, 60 For purposes of the United States Patent and Trademark JOSHUAL. DOWLING, RODERICKA. HYDE, MURIEL Office (USPTO) extra-statutory requirements, the present Y. ISHIKAWA, JORDIN T. KARE, ERIC C. application constitutes a continuation-in-part of U.S. patent LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. application Ser. No. 12/800,766, titled SYSTEMS, RIVET, PAUL SANTIAGO, MICHAEL A. SMITH, TODD DEVICES, AND METHODS INCLUDING INFECTION J. STEWART, ELIZABETHA. SWEENEY, CLARENCET. 65 FIGHTING AND MONITORING SHUNTS, naming TEGREENE, LOWELL L. WOOD, JR., VICTORIA Y. H. RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL WOOD as inventors, filed 4 Dec. 2008 now abandoned. Y. ISHIKAWA, JORDIN T. KARE, ERIC C. US 9,474,831 B2 5 6 LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. RIVET, MICHAEL A. SMITH, ELIZABETH A. WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. May 2010 now abandoned. WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 For purposes of the United States Patent and Trademark May 2010 now U.S. Pat. No. 8,216,173. 5 Office (USPTO) extra-statutory requirements, the present For purposes of the United States Patent and Trademark application constitutes a continuation-in-part of U.S. patent Office (USPTO) extra-statutory requirements, the present application Ser. No. 12/800,786, titled SYSTEMS, application constitutes a continuation-in-part of U.S. patent DEVICES, AND METHODS INCLUDING INFECTION application Ser. No. 12/800,774, titled SYSTEMS, FIGHTING AND MONITORING SHUNTS, naming DEVICES, AND METHODS INCLUDING INFECTION 10 FIGHTING AND MONITORING SHUNTS, naming RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. RIVET, MICHAEL A. SMITH, ELIZABETH A. RIVET, MICHAEL A. SMITH, ELIZABETH A. 15 SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 May 2010 now abandoned. May 2010 now abandoned. For purposes of the United States Patent and Trademark For purposes of the United States Patent and Trademark Office (USPTO) extra-statutory requirements, the present Office (USPTO) extra-statutory requirements, the present application constitutes a continuation-in-part of U.S. patent application constitutes a continuation-in-part of U.S. patent application Ser. No. 12/800,790, titled SYSTEMS, application Ser. No. 12/800,778, titled SYSTEMS, DEVICES, AND METHODS INCLUDING INFECTION DEVICES, AND METHODS INCLUDING INFECTION FIGHTING AND MONITORING SHUNTS, naming FIGHTING AND MONITORING SHUNTS, naming RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL 25 Y. ISHIKAWA, JORDIN T. KARE, ERIC C. Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. RIVET, MICHAEL A. SMITH, ELIZABETH A. RIVET, MICHAEL A. SMITH, ELIZABETH A. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 30 May 2010 now U.S. Pat No. 8,343,086. May 2010 now abandoned. For purposes of the United States Patent and Trademark For purposes of the United States Patent and Trademark Office (USPTO) extra-statutory requirements, the present Office (USPTO) extra-statutory requirements, the present application constitutes a continuation-in-part of U.S. patent application constitutes a continuation-in-part of U.S. patent application Ser. No. 12/800,791, titled SYSTEMS, application Ser. No. 12/800,779, titled SYSTEMS, 35 DEVICES, AND METHODS INCLUDING INFECTION DEVICES, AND METHODS INCLUDING INFECTION FIGHTING AND MONITORING SHUNTS, naming FIGHTING AND MONITORING SHUNTS, naming RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. 40 RIVET, MICHAEL A. SMITH, ELIZABETH A. RIVET, MICHAEL A. SMITH, ELIZABETH A. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 May 2010 now U.S. Pat No. 8,282,593. May 2010 now abandoned. For purposes of the United States Patent and Trademark For purposes of the United States Patent and Trademark 45 Office (USPTO) extra-statutory requirements, the present Office (USPTO) extra-statutory requirements, the present application constitutes a continuation-in-part of U.S. patent application constitutes a continuation-in-part of U.S. patent application Ser. No. 12/800,792, titled SYSTEMS, application Ser. No. 12/800,780, titled SYSTEMS, DEVICES, AND METHODS INCLUDING INFECTION DEVICES, AND METHODS INCLUDING INFECTION FIGHTING AND MONITORING SHUNTS, naming FIGHTING AND MONITORING SHUNTS, naming 50 RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. Y. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. RIVET, MICHAEL A. SMITH, ELIZABETH A. RIVET, MICHAEL A. SMITH, ELIZABETH A. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. 55 WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 May 2010 now U.S. Pat No. 8,888,731. May 2010 now abandoned. For purposes of the United States Patent and Trademark For purposes of the United States Patent and Trademark Office (USPTO) extra-statutory requirements, the present Office (USPTO) extra-statutory requirements, the present application constitutes a continuation-in-part of U.S. patent application constitutes a continuation-in-part of U.S. patent 60 application Ser. No. 12/800,793, titled SYSTEMS, application Ser. No. 12/800,781, titled SYSTEMS, DEVICES, AND METHODS INCLUDING INFECTION DEVICES, AND METHODS INCLUDING INFECTION FIGHTING AND MONITORING SHUNTS, naming FIGHTING AND MONITORING SHUNTS, naming RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. Y. ISHIKAWA, JORDIN T. KARE, ERIC C. 65 LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. RIVET, MICHAEL A. SMITH, ELIZABETH A. RIVET, MICHAEL A. SMITH, ELIZABETH A. SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. US 9,474,831 B2 7 8 WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 For purposes of the USPTO extra-statutory requirements, May 2010 now U.S. Pat No. 8,414,517. the present application is related to U.S. patent application For purposes of the United States Patent and Trademark Ser. No. 12/927,287, titled SYSTEMS, DEVICES, AND Office (USPTO) extra-statutory requirements, the present METHODS INCLUDING CATHETERS HAVING SELF application constitutes a continuation-in-part of U.S. patent CLEANING SURFACES, naming RALPH G. DACEY, JR., application Ser. No. 12/800,798, titled SYSTEMS, RODERICK A. HYDE, MURIELY. ISHIKAWA, JORDIN DEVICES, AND METHODS INCLUDING INFECTION T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHR FIGHTING AND MONITORING SHUNTS, naming VOLD, DENNIS.J. RIVET, MICHAEL A. SMITH, ELIZA RALPH G. DACEY, JR., RODERICKA. HYDE, MURIEL BETHA. SWEENEY, CLARENCET. TEGREENE, LOW 10 ELL L. WOOD, JR., VICTORIAY. H. WOOD as inventors, Y. ISHIKAWA, JORDIN T. KARE, ERIC C. filed 10 Nov. 2010 now U.S. Pat No. 8,706,211. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. For purposes of the USPTO extra-statutory requirements, RIVET, MICHAEL A. SMITH, ELIZABETH A. the present application is related to U.S. patent application SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. Ser. No. 12/927,294, titled SYSTEMS, DEVICES, AND WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 21 15 METHODS INCLUDING CATHETERS CONFIGURED May 2010, which is currently co-pending or is an application TO MONITOR BIOFILM FORMATION HAVING BIO of which a currently co-pending application is entitled to the FILMSPECTRAL INFORMATION CONFIGURED ASA benefit of the filing date. DATA STRUCTURE, naming RALPH G. DACEY, JR., For purposes of the USPTO extra-statutory requirements, RODERICK A. HYDE, MURIELY. ISHIKAWA, JORDIN the present application is related to U.S. patent application T. KARE, ERIC C. LEUTHARDT, NATHAN P. MYHR Ser. No. 12/927,297, titled SYSTEMS, DEVICES, AND VOLD, DENNIS.J. RIVET, MICHAEL A. SMITH, ELIZA METHODS INCLUDING CATHETERS HAVING COM BETHA. SWEENEY, CLARENCET. TEGREENE, LOW PONENTS THAT ARE ACTIVELY CONTROLLABLE ELL L. WOOD, JR., VICTORIAY. H. WOOD as inventors, BETWEEN TRANSMISSIVE AND REFLECTIVE filed 10 Nov. 2010 now U.S. Pat No. 8,585,627. STATES, naming RALPH G. DACEY, JR., RODERICKA. 25 For purposes of the USPTO extra-statutory requirements, HYDE, MURIELY. ISHIKAWA, JORDIN T. KARE, ERIC the present application is related to U.S. patent application C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. Ser. No. 12/927,285, titled SYSTEMS, DEVICES, AND RIVET, MICHAEL A. SMITH, ELIZABETH A. METHODS INCLUDING CATHETERS HAVING SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. ACOUSTICALLY ACTUATABLE WAVEGUIDE COM WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 10 30 PONENTS FOR DELIVERING ASTERILIZING STIMU Nov. 2010 now U.S. Pat No. 8,460,229. LUS TO A REGION PROXIMATE A SURFACE OF THE For purposes of the USPTO extra-statutory requirements, CATHETER, naming RALPH G. DACEY, JR., RODER the present application is related to U.S. patent application ICK A. HYDE, MURIEL Y. ISHIKAWA, JORDIN T. Ser. No. 12/927,284, titled SYSTEMS, DEVICES, AND KARE, ERIC C. LEUTHARDT, NATHAN P. MYHR METHODS INCLUDING CATHETERS HAVING COM 35 VOLD, DENNIS.J. RIVET, MICHAEL A. SMITH, ELIZA PONENTS THAT ARE ACTIVELY CONTROLLABLE BETHA. SWEENEY, CLARENCET. TEGREENE, LOW BETWEEN TWO OR MORE WETTABILITY STATES, ELL L. WOOD, JR., VICTORIAY. H. WOOD as inventors, naming RALPH G. DACEY, JR., RODERICK A. HYDE, filed 10 Nov. 2010 now U.S. Pat No. 8,753,304. MURIEL Y. ISHIKAWA, JORDIN T. KARE, ERIC C. For purposes of the USPTO extra-statutory requirements, LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. 40 the present application is related to U.S. patent application RIVET, MICHAEL A. SMITH, ELIZABETH A. Ser. No. 12/927,290, titled SYSTEMS, DEVICES, AND SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. METHODS INCLUDING CATHETERS HAVING LIGHT WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 10 REMOVABLE COATINGS BASED ON A SENSED CON Nov. 2010 now U.S. Pat No. 8,647,292. DITION, naming RALPH G. DACEY, JR., RODERICKA. For purposes of the USPTO extra-statutory requirements, 45 HYDE, MURIELY. ISHIKAWA, JORDIN T. KARE, ERIC the present application is related to U.S. patent application C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. Ser. No. 12/927,288, titled SYSTEMS, DEVICES, AND RIVET, MICHAEL A. SMITH, ELIZABETH A. METHODS INCLUDING CATHETERS HAVING AN SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. ACTIVELY CONTROLLABLE THERAPEUTICAGENT WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 10 DELIVERY COMPONENT, naming RALPH G. DACEY, 50 Nov. 2010 now U.S. Pat No. 8,702,640. JR., RODERICKA. HYDE, MURIELY. ISHIKAWA, JOR For purposes of the USPTO extra-statutory requirements, DIN T. KARE, ERIC C. LEUTHARDT, NATHAN P. the present application is related to U.S. patent application MYHRVOLD, DENNIS J. RIVET, MICHAEL A. SMITH, Ser. No. 12/927,291, titled SYSTEMS, DEVICES, AND ELIZABETHA. SWEENEY, CLARENCET. TEGREENE, METHODS INCLUDING CATHETERS HAVING LIGHT LOWELL L. WOOD, JR., VICTORIA Y. H. WOOD as 55 REMOVABLE COATINGS BASED ON A SENSED CON inventors, filed 10 Nov. 2010 now U.S. Pat No. 8,734,718. DITION, naming RALPH G. DACEY, JR., RODERICKA. For purposes of the USPTO extra-statutory requirements, HYDE, MURIELY. ISHIKAWA, JORDIN T. KARE, ERIC the present application is related to U.S. patent application C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. Ser. No. 12/927,296, titled SYSTEMS, DEVICES, AND RIVET, MICHAEL A. SMITH, ELIZABETH A. METHODS INCLUDING CATHETERS HAVING 60 SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. UV-ENERGY EMITTING COATINGS, naming RALPH G. WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 10 DACEY, JR., RODERICK A. HYDE, MURIEL Y. Nov. 2010 now abandoned. ISHIKAWA, JORDIN T. KARE, ERIC C. LEUTHARDT, For purposes of the USPTO extra-statutory requirements, NATHAN P. MYHRVOLD, DENNIS.J. RIVET, MICHAEL the present application is related to U.S. patent application A. SMITH, ELIZABETH A. SWEENEY, CLARENCE T. 65 Ser. No. 12/927,295, titled SYSTEMS, DEVICES, AND TEGREENE, LOWELL L. WOOD, JR., VICTORIA Y. H. METHODS INCLUDING CATHETERS CONFIGURED WOOD as inventors, filed 10 Nov. 2010 now abandoned. TO RELEASE ULTRAVIOLET ENERGY ABSORBING US 9,474,831 B2 9 10 AGENTS, naming RALPH G. DACEY, JR., RODERICKA. addressable and actively controllable anti-microbial nano HYDE, MURIELY. ISHIKAWA, JORDIN T. KARE, ERIC structure; and one or more instructions for determining the C. LEUTHARDT, NATHAN P. MYHRVOLD, DENNIS J. presence of at least one microorganism on at least one of the RIVET, MICHAEL A. SMITH, ELIZABETH A. at least one independently addressable and actively control SWEENEY, CLARENCE. T. TEGREENE, LOWELL L. 5 lable anti-microbial nanostructure of the body structure. WOOD, JR., VICTORIAY. H. WOOD as inventors, filed 10 In an embodiment, the insertable device system includes Nov. 2010, which is currently co-pending or is an applica a body structure having an outer Surface and an inner Surface tion of which a currently co-pending application is entitled defining one or more fluid-flow passageways; a plurality of to the benefit of the filing date. independently addressable anti-microbial regions including The United States Patent Office (USPTO) has published a 10 at least one actuatable anti-microbial property, the plurality notice to the effect that the USPTO's computer programs of independently addressable anti-microbial regions being require that patent applicants reference both a serial number included in at least one of the outer surface, or the inner and indicate whether an application is a continuation, con surface of the body structure; and circuitry configured for tinuation-in-part, or divisional of a parent application. Ste determining the presence of at least one microorganism phen G. Kunin, Benefit of Prior-Filed Application, USPTO 15 Official Gazette Mar. 18, 2003. The present Applicant Entity proximate at least one of the independently addressable (hereinafter “Applicant”) has provided above a specific anti-microbial regions of the body structure. reference to the application(s) from which priority is being In an embodiment, the insertable device includes a body claimed as recited by statute. Applicant understands that the structure having an outer Surface and an inner Surface statute is unambiguous in its specific reference language and defining one or more fluid-flow passageways, the body does not require either a serial number or any characteriza structure having a plurality of actuatable regions that are tion, such as “continuation' or “continuation-in-part.” for selectively actuatable between at least a first actuatable state claiming priority to U.S. patent applications. Notwithstand and a second actuatable state; and one or more sensors ing the foregoing, Applicant understands that the USPTO's configured to detect at least one anti-microbial component computer programs have certain data entry requirements, 25 associated with a biological sample proximate the body and hence Applicant has provided designation(s) of a rela Structure. tionship between the present application and its parent In an embodiment, the insertable device includes an outer application(s) as set forth above, but expressly points out Surface and an inner Surface of the body structure, at least that such designation(s) are not to be construed in any way one Surface including at least one anti-microbial nanostruc as any type of commentary and/or admission as to whether 30 ture. or not the present application contains any new matter in The foregoing Summary is illustrative only and is not addition to the matter of its parent application(s). intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described SUMMARY above, further aspects, embodiments, and features will 35 become apparent by reference to the drawings and the The present disclosure is directed to, among other things, following detailed description. an insertable device. In an embodiment, the insertable device includes a body structure having an outer Surface and BRIEF DESCRIPTION OF THE FIGURES an inner Surface defining one or more fluid-flow passage ways. In an embodiment, a system or method is disclosed for 40 FIG. 1A illustrates a particular embodiment of a device operating the insertable device. disclosed herein. In an embodiment, the insertable device system includes FIG. 1B illustrates a close up view of a component of the a body structure having an outer Surface and an inner Surface device illustrated in FIG. 1A., defining one or more fluid-flow passageways; at least one FIG. 2A illustrates a particular embodiment of a device independently addressable and actively controllable anti 45 disclosed herein. microbial nanostructure projecting from at least one of the FIG. 2B illustrates a close up of the device illustrated in outer surface, or the inner surface of the body structure; and FIG. 2A circuitry configured for determining the presence of at least FIG. 3 illustrates a particular embodiment of a device in one microorganism on at least one of the independently an embodiment of a system disclosed herein. addressable and actively controllable anti-microbial nano 50 FIG. 4A illustrates a close up of a particular embodiment structure of the body structure. of a component of a device disclosed herein. In an embodiment, the insertable device system includes FIG. 4B illustrates a close up of a particular embodiment a body structure having an outer Surface and an inner Surface of a component of a device disclosed herein. defining one or more fluid-flow passageways; at least one FIG. 5A illustrates a close up of a particular embodiment independently addressable and actively controllable anti 55 of a component of a device disclosed herein. microbial nanostructure projecting from at least one of the FIG. 5B illustrates a close up of a particular embodiment outer surface, or the inner surface of the body structure; at of a component of a device disclosed herein. least one sensor configured to detect one or more microor FIG. 6 illustrates a particular embodiment of a component ganisms present on the body structure; and means for of a device disclosed herein. determining the presence of at least one microorganism on 60 FIG. 7 illustrates a particular embodiment of a device in at least one of the independently addressable and actively an embodiment of a system disclosed herein. controllable anti-microbial nanostructure of the body struc FIG. 8 illustrates a particular embodiment of a device in ture. an embodiment of a system disclosed herein. In an embodiment, the insertable device system includes FIG. 9 illustrates a partial view of an embodiment of a a computer-recordable medium bearing: a body structure 65 method disclosed herein. having an outer Surface and an inner Surface defining one or FIG. 10 illustrates a partial view of an embodiment of a more fluid-flow passageways; at least one independently method disclosed herein. US 9,474,831 B2 11 12 FIG. 11 illustrates a partial view of an embodiment of a fluids; as well as for administering therapeutics, medica method disclosed herein. tions, pharmaceuticals, intravenous fluids, blood products, FIG. 12 illustrates a partial view of an embodiment of a or delivering parenteral nutrition. method disclosed herein. Infections, malfunctions (e.g., blocked or clogged fluid FIG. 13 illustrates a partial view of an embodiment of a flow passageways), and failures account for many of the method disclosed herein. complications associated with catheter devices and pose FIG. 14 illustrates a partial view of an embodiment of a tremendous consequences for patients. For example, during method disclosed herein. an infection, an infectious agent (e.g., fungi, micro-organ FIG. 15 illustrates a partial view of an embodiment of a isms, parasites, pathogens (e.g., viral pathogens, bacterial method disclosed herein. 10 pathogens, or the like), prions, Viroids, viruses, or the like) FIG. 16 illustrates a partial view of an embodiment of a generally interferes with the normal functioning of a bio method disclosed herein. logical Subject, and causes, in Some cases, chronic wounds, FIG. 17 illustrates a partial view of an embodiment of a gangrene, loss of an infected tissue, loss of an infected limb, method disclosed herein. and occasionally death of the biological Subject. Infections FIG. 18 illustrates a partial view of an embodiment of a 15 associated with catheter devices account for a significant method disclosed herein. number of nosocomial infections. Despite Sterilization and FIG. 19 illustrates a partial view of an embodiment of a aseptic procedures, infection remains a major impediment to method disclosed herein. medical implants and catheter devices, including artificial FIG. 20 illustrates a partial view of an embodiment of a hearts or heart valves, Subcutaneous sensors, contact lens, method disclosed herein. artificial joints, artificial prosthetics, breast implants, FIG. 21 illustrates a partial view of an embodiment of a cochlear implants, dental implants, neural implants, ortho method disclosed herein. pedic implants, ocular implants, prostheses, implantable FIG. 22 illustrates a partial view of an embodiment of a electronic devices, implantable medical devices, catheters, method disclosed herein. contact lens, implantable biological fluid drainage system, FIG. 23 illustrates a partial view of an embodiment of a 25 mechanical heart valves, stents, Subcutaneous sensors, method disclosed herein. shunts, vertebral spacers, and the like. Implant associated FIG. 24 illustrates a partial view of an embodiment of a (including catheter device-associated) infections are often method disclosed herein. difficult to detect, problematic to cure, and expensive to FIG. 25 illustrates a partial view of an embodiment of a manage. For example, in cases where the infection does not method disclosed herein. 30 quickly Subside, it sometimes becomes necessary to remove FIG. 26 illustrates a partial view of an embodiment of a the catheter device. Implant device-associated infections can method disclosed herein. result from microorganism (e.g., bacteria) adhesion and FIG. 27 illustrates a partial view of an embodiment of a possibly Subsequent biofilm formation proximate an implan method disclosed herein. tation site. For example, biofilm-forming microorganisms FIG. 28 illustrates a partial view of an embodiment of a 35 Sometimes colonize catheter devices at least partially method disclosed herein. implanted into a biological Subject. Once a biofilm-induced FIG. 29 illustrates a partial view of an embodiment of a infection takes hold, it can prove difficult to treat, and can method disclosed herein. even be fatal for the biological subject. FIG. 30 illustrates a partial view of an embodiment of a The present disclosure includes, but is not limited to, method disclosed herein. 40 systems, devices, and methods, of a catheter device config ured to, for example, detect (e.g., assess, calculate, evaluate, DETAILED DESCRIPTION determine, gauge, identify, measure, monitor, quantify, resolve, sense, or the like) an infectious agent (e.g., micro In the following detailed description, reference is made to organism) present in, for example, a biological fluid. A the accompanying drawings, which form a part hereof. In 45 non-limiting example includes systems, devices, and meth the drawings, similar symbols typically identify similar ods including a catheter device configured to, for example, components, unless context dictates otherwise. The illustra detect an infectious agent present in, for example, a biologi tive embodiments described in the detailed description, cal sample proximate a catheter device that is at least drawings, and claims are not meant to be limiting. Other partially implanted into a biological Subject. embodiments can be utilized, and other changes can be 50 An aspect includes systems, devices, methods, and Com made, without departing from the spirit or scope of the positions for actively or passively detecting, treating, or Subject matter presented here. preventing an infection, a fluid vessel abnormality (e.g., an Insertable devices, such as implantable shunts (e.g., car obstruction), a biological fluid abnormality (e.g., cerebro diac shunts, cerebral shunts, portacaval shunts, portosys spinal fluid abnormality, hematological abnormality, com temic shunts, pulmonary shunts, or the like), catheters (e.g., 55 ponents concentration or level abnormality, flow abnormal central venous catheters, multi-lumen catheters, peripherally ity, or the like), or the like. A non-limiting example includes inserted central catheters, Quinton catheters, Swan-Ganz systems, devices, and methods for actively detecting, treat catheters, tunneled catheters, or the like), or medical ports ing, or preventing an infection or presence of at least one (e.g., arterial ports, low profile ports, multi-lumen ports, microorganism associated with a shunt or other catheter vascular ports, or the like) are useful for, among other things, 60 device. An aspect includes systems, devices, and methods managing movement of fluids; directly detecting (e.g., for managing movement of fluids; directly detecting and assessing, calculating, evaluating, determining, gauging, monitoring functions or conditions (e.g., mechanical, physi identifying, measuring, monitoring, quantifying, resolving, cal, physiological, or biochemical functions or conditions) sensing, or the like) mechanical, physical, or biochemical associated with a biological Subject, draining or collecting information (e.g., the presence of a biomarker, intracranial 65 body fluids; providing access to an interior of a biological pressure, blood pressure, a disease state, or the like) asso Subject; distending at least one passageway; as well as for ciated with a biological Subject; draining or collecting body administering therapeutics, medications, pharmaceuticals, US 9,474,831 B2 13 14 intravenous fluids, or parenteral nutrition. A non-limiting Switchable Surface, including, for example a metal/polymer example includes systems, devices, and methods for actively membrane with hydrophobic microposts. See Chen, et al. J. detecting, treating, or preventing fluid-flow obstructions in Micromech. Microeng. Vol. 17, pp. 489-495 (2007), which shunts or other catheter devices. is incorporated herein by reference. For example, the water In certain aspects, at least one of the inner Surface or the contact angles can be manipulated from 131 degrees to 152 outer surface of the body structure of a catheter device degrees, depending on the fraction of a liquid/solid interface. disclosed herein includes at least one surface with reversibly Id. The process of Surface wetting induced by morphology switchable or actuatable properties. For example, a revers change (SWIM) allows a change in total surface area that ibly switchable surface generally includes a chemical switch contacts a water droplet, based on the number of microposts (e.g., Surface chemistry or Surface charge that can be 10 that are articulated at any given time, this allows for the manipulated by the presence of a pathogen or other stimu change in wettability state. Id. lus). For example, in an embodiment, the Surface includes a In an embodiment, the anti-microbial region includes at nanolayer or microlayer of a material that Switches from a least one patterned Surface configured to resist or enhance first conformation (i.e. a first anti-microbial state) to a bioadhesion of microbes compared to the base surface. In an second conformation (i.e. a second anti-microbial state). In 15 embodiment, the at least one anti-microbial region includes another example, when an external stimulus is applied (e.g., a surface with reversibly switchable properties (e.g., the electrical, electrochemical, magnetic, optical, electro-opti Surface Switches from a first conformation state to a second cal, etc.), the Surface is actuatable (e.g., by an electrical conformation state when an external stimulus is applied). potential). See, for example, U.S. Patent App. Pub. No. See, for example, U.S. Patent App. Pub. No. 2006/0263033, 2006/0263033, which is incorporated herein by reference. In which is incorporated herein by reference. an embodiment, the presence of at least one microorganism In an embodiment, at least one sensor is operably coupled acts as the external stimulus. In an embodiment, the external to the Surface and is configured to detect at least one stimulus includes at least one of a chemical, electrical, or microbial component. For example, in particular instances electro-chemical property. In an embodiment, the external the surface properties are switchable or actuatable between stimulus includes at least one temporal gradient, spatial 25 or among at least one of hydrophilicity, hydrophobicity, gradient, or concentration gradient. electrical charge, chemical composition, polarizability, For example, wettability of a surface can be switched or transparence, conductivity, light absorption, osmotic poten actuated. The wettability of a substrate can be determined tial, Zeta potential, Surface energy, coefficient of friction, or using various technologies and methodologies including tackiness. contact angle methods, the Goniometer method, the 30 Infections account for one of the many complications Whilemy method, or the Sessile drop technique. Wetting is associated with Surgery and pose tremendous consequences a process by which a liquid interacts with a solid. Wettability for patients. During an infection, an infecting agent (e.g., (the degree of wetting) is determined by a force balance fungi, micro-organisms, parasites, pathogens (e.g., viral between adhesive and cohesive force and is often charac pathogens, bacterial pathogens, and the like), prions, Viroids, terized by a contact angle. The contact angle is the angle 35 viruses, and the like) generally interferes with the normal made by the intersection of the liquid/solid interface and the functioning of a biological Subject, and causes, in some liquid/air interface. Alternatively, it is the angle between a cases, chronic wounds, gangrene, loss of an infected tissue, Solid sample's Surface and the tangent of a droplet’s ovate loss of an infected limb, and occasionally death of the shape at the edge of the droplet. Contact angle measure biological Subject. ments provide a measure of interfacial energies and conveys 40 Implant-associated infections account for a significant direct information regarding the degree of hydrophilicity or amount of nosocomial infections and despite sterilization hydrophobicity for a surface. For example, superhydrophilic and aseptic procedures, remain as a major impediment to Surfaces have contact angles less than about 5 degrees, medical implants including artificial hearts, artificial joints, hydrophilic surfaces have contact angles less than about 90 artificial prosthetics, breast implants, catheters, contact lens, degrees, hydrophobic surfaces have contact angles greater 45 mechanical heart valves, Subcutaneous sensors, vertebral than about 90 degrees, and superhydrophobic surfaces have spacers, and the like. Implant-associated infections are often contact angles greater than about 150 degrees. difficult to detect, problematic to cure, and at times expen In an embodiment, the anti-microbial region includes at sive to manage. For example, in cases where the infection least one nanotube forest of Vertically aligned carbon nano does not quickly Subside, it sometimes becomes necessary to tubes. See, for example, Gjerde, et al., Nanotech. Vol. 17, pp. 50 remove the implant. 4917-4922 (2006), which is incorporated herein by refer Implant-associated infections can result from bacterial ence. For example, the nanotube forest, due to its roughness, adhesion and Subsequent biofilm formation proximate an not only exhibits very low static friction and dynamic implantation site. For example, biofilm-forming microor friction, but it also acts as a springy and mechanically ganisms sometimes colonize implants. Once a biofilm compliant Surface, making it possible to lift up and manipu 55 induced infection takes hold, it can prove difficult to treat. late delicate nanostructures such as organic nanofibers. Id. As a non-limiting example, certain systems, devices, In an embodiment, the surface of at least one of the inner methods, and compositions described herein provide an surface or outer surface of the body structure includes a actively controllable disinfecting implantable device config capillary-based switchable surface, which includes a surface ured to, for example, treat or prevent an infection (e.g., an tension force from several Small liquid bridges, whose 60 implant-associated infection, hematogenous implant-associ contacts are quickly made or broken with electronic con ated infection, and the like), a hematological abnormality, trols, thus Switching the Surface. See, for example, Vogel and and the like. One non-limiting approach for treating or Steen, PNAS Early Edition on the web at pnas.org/cgi/doi/ preventing an infection, a hematological abnormality, and 10.1073/pnas.0914720107), the content of which is incor the like includes systems, devices, and methods for admin porated herein by reference. 65 istrating a perioperative antibiotic prophylaxis to a patient. In an embodiment, at least one of the inner Surface or Another non-limiting approach includes systems, devices, outer surface of the body structure includes a wettablity methods, and compositions for actively forming an antimi US 9,474,831 B2 15 16 crobial agent, in vivo. Another non-limiting approach (PICC)); its pathway from skin to vessel (e.g., tunneled includes systems, devices, methods, and compositions for versus nontunneled); its physical length (e.g., long versus impeding bacterial adherence to the implant Surface. short); or some specific characteristic of the catheter (e.g., Another non-limiting approach includes systems, devices, presence or absence of a cuff, impregnation with heparin, methods, and compositions for actively impeding biofilm antibiotics, or antiseptics, and the number of lumens). See, formation on an implant. Another non-limiting approach e.g., O'Grady, et al., MMWR Recomm. Rep., 51(RR-10):1- includes systems, devices, and methods including coating an 32, 2002, which is incorporated herein by reference. implant with active agent compositions having, for example, In some instances, a bloodstream infection can occur anti-biofilm activity. Another non-limiting approach when bacteria or other microorganisms travel down a cath includes systems, devices, methods, and compositions for 10 eter and enter the blood and/or tissue. Catheter related providing an implant with a scaffold-forming material. bloodstream infections cause considerable morbidity, mor Another non-limiting approach includes systems, devices, tality, and healthcare costs. An estimated 82,000 catheter and methods including coating an implant with one or more related bloodstream infections and up to 28,000 attributable coatings having self-cleaning properties. Another non-lim deaths occur in intensive care units annually at an estimated iting approach includes systems, devices, and methods 15 cost of $45,000 per infection. Over 250,000 cases of central including an implant with a self-cleaning coating having venous catheter-associated bloodstream infections have self-cleaning, and anti-bacterial activity. Another non-limit been estimated to occur annually in the hospital setting with ing approach includes systems, devices, and methods includ an attributable mortality estimated at 12%-25%. See, e.g., ing an implant having one or more self-cleaning Surfaces. Provonost, et al., BMJ, 340:c309, 2010; O'Grady, et al., For example, in an embodiment the implantable device MMWR Recomm. Rep., 51(RR-10): 1-32, 2002, each of includes at least one actively controllable anti-microbial which is incorporated herein by reference. region. In an embodiment, the actively controllable anti The most common microorganism associated with intra microbial region includes at least one actively-controllable vascular catheters is reportedly coagulase-negative staphy excitation component, which may include at least one lococci accounting for 37% of isolated causes of hospital energy-emitting element (e.g., electric circuits, electrical 25 acquired bloodstream infection. Other microorganisms asso conductors, electrodes, electrocautery electrodes, cavity ciated with intravascular catheter biofilms and hospital resonators, conducting traces, ceramic patterned electrodes, acquired bloodstream infections include bacteria, e.g., electro-mechanical components, lasers, quantum dots, laser Staphylococcus epidermidis, Staphylococcus aureus, diodes, light-emitting diodes, arc flashlamps, continuous Pseudomonoas aeruginosa, Klebsiella pneumoniae, Entero wave bulbs, ultrasonic emitting elements, ultrasonic trans 30 bacteriaceae and Enterococcus faecalis and fingi, e.g., ducers, thermal energy emitting elements, etc.). Candida albicans and other Candida species. Microor In an embodiment, the medical device includes a power gamisms commonly contaminating urinary catheters films Source. In an embodiment, the power Source includes at least include S. epidermidis, Enterococcus faecalis, E. coli, Pro one piezoelectric material. In an embodiment, the power teus mirabilis, P. aeruginosa, K. pneumoniae, and other Source includes at least one alternating-current nanogenera 35 gram-negative organisms. Donlan, Emerging Infectious Dis tor. For example, a two-ends-bonded piezoelectric nanowire eases, 7:277-281, 2001; O'Grady, et al., MMWR Recomm. (e.g., Zinc) is subjected to a periodic mechanical stretching Rep., 51(RR-10): 1-32, 2002, each of which is incorporated and releasing, the mechanical-electric coupling effect of the herein by reference nanowire, combined with the gate effect of the Schottky Of particular concern are emerging multi-drug resistant contact at the interface, results in an alternating flow of the 40 gram-negative bacteria for which there are increasingly charge in the external circuit. See, Li, et al., Adv. Mater. Vol. fewer effective antibiotics. Gram negative bacteria 22, pp. 1-4 (2010), which is incorporated herein by refer accounted for 14% of catheter-associated bloodstream infec CCC. tions during the period spanning 1992-1999. An increasing In an embodiment, at least one of the inner Surface or the percentage of ICU-related bacterial isolates contain Entero outer surface of the body structure includes at least one 45 bacteriaceae that produce extended spectrum beta-lactama tunable static or dynamic contact angle anisotropy on gra ses, particularly Klebsiella pneumonia, which tend to be dient microscale patterned topography. See, Long, et al., resistant to extended spectrum cephalosporins and broad Langmuir Abstract, vol. 25, no. 22, pp. 12982-12989 (2009), spectrum antimicrobial agents. Examples of gram-negative which is incorporated herein by reference. For example, bacteria associated with hospital acquired bacterial infec translationally symmetric topographies are designed to 50 tions include but are not limited to Pseudomonas aerugi induce anisotropy of static or dynamic contact angles fab nosa, Escherichia coli, Klebsiella pneumoniae, Entero ricated out of a polymer (e.g., poly (dimethyl siloxane) bacter cloacae, Acinetobacter spp., Serratia marcescens, elastomer). Id Enterobacter aerogenes, Stenotrophomonas maltophilia, Microorganisms Associated with Catheter Use Proteus mirabilis, Klebsiella Oxytoca, and Citrobacter fre A catheter device is described herein for detecting and 55 undii. See, e.g., Lockhart et al., J. Clin. Microbiol. 45:3352 treating microorganisms in at least one of a plurality of 3359, 2007, which is incorporated herein by reference. anti-microbial regions of the body structure of the catheter. Antibiotics for use in treating gram-negative bacteria Examples of catheters include but are not limited to intra include but are not limited to carbapenems, exemplified by vascular catheters, hemodialysis catheters, urinary catheters, imipenem and meropenem. Multidrug resistance of gram peritoneal dialysis catheters, enteral feeding tubes, gastro 60 negative bacteria is defined as resistance to at least one stomy tubes, endotracheal tubes, tracheostomy tubes, and extended-spectrum cephalosporin, one aminoglycoside, and umbilical catheters. An intravascular catheter can be further ciprofloxacin and is increasing among isolates of Acineto designated by the type of vessel it occupies (e.g., peripheral bacter spp., P. aeruginosa, K. pneumoniae, and E. cloacae. venous, central venous, or arterial); its intended life span Colistin and polymyxin B can be used to treat gram-negative (e.g., temporary or short-term versus permanent of long 65 bacterial infection. These drugs were largely abandoned term); its site of insertion (e.g., Subclavian, femoral, internal Sometime ago due to kidney and nerve damage, but because jugular, peripheral, and peripherally inserted central catheter of their infrequent use, bacteria have not had an opportunity US 9,474,831 B2 17 18 to develop resistance to them at present. See, e.g., Peleg & lymphocytes) or by making them less Susceptible to anti Hooper, N. Engl. J. Med., 362:1804-1813, 2010, which is microbial agents (e.g., forming a matrix that binds antimi incorporated herein by reference. crobials before their contact with the organism cell wall). As The types of organisms that most commonly cause hos another example, S. aureus can adhere to host proteins (e.g., pital-acquired blood stream infections change over time. fibronectin) commonly present on catheters. Certain Can During 1986-1989, for example, coagulase-negative staphy dida spp., in the presence of glucose-containing fluids, can lococci and Staphylococcus aureus were the most frequently produce slime similar to that of their bacterial counterparts, reported causes of bloodstream infections, accounting for potentially explaining the increased proportion of blood 27% and 16% of bloodstream infections, respectively. From stream infections caused by fungal pathogens among 1992 to 1999, coagulase-negative staphylococci and entero 10 patients receiving parenteral nutrition fluids. See, e.g., cocci were the most frequently isolated causes of hospital O'Grady, et al., MMWR Recomm. Rep., 51(RR-10):1-32, acquired bloodstream infections. Coagulase-negative 2002, which is incorporated herein by reference. staphylococci accounted for 37% and S. aureus accounted Sensors for Sensing Microorganisms on Catheter from 12.6% BSIs. By 1999, >50% of all S. aureus isolated The catheter device includes at least one sensor config from ICUs were resistant to oxacillin. In 1999, enterococci 15 ured to detect the presence of at least one microorganism in accounted for 13.5% of BSIs with Vancomycin resistance at least one of a plurality of anti-microbial regions on the escalating from 0.5% in 1989 to 25.9% in 1999. Candida body structure of the device. The at least one sensor includes spp. caused 8% of hospital-acquired BSIs reported during at least one of a plasmon sensor, pH sensor, temperature 1986-1989 and during 1992-1999. Resistance of Candida sensor, piezoelectric sensor, electrostrictive sensor, magne spp. to commonly used antifungal agents is increasing. For tostrictive sensor, biochemical sensor, optical sensor, or example, 10% of C. albicans bloodstream isolates from electronic sensor. Sensors can be incorporated directly onto hospital patients were resistant to fluconazole. Additionally the inner or outer surface of the catheter body structure. In 48% of Candida BSIs were caused by nonalbicans species an embodiment, the sensor is located in microchannels including C. glabrata and C. krusei which are more likely to incorporated into the inner and/or outer surface of the exhibit fluconazole resistance. See, e.g., O'Grady, et al., 25 catheter body structure, providing a localized measurement MMWR Recomm. Rep., 51(RR-10): 1-32, 2002, which is chamber. See, e.g., U.S. Patent Applications 2008/0214909; incorporated herein by reference. 2009/0297574; each of which is incorporated herein by Pathogenesis reference. The most common route of infection for peripherally In an aspect, the at least one sensor can be a plasmon inserted, short-term catheters is migration of microorgan 30 sensor configured to detect at least one microorganism based isms associated with the patient's skin at the insertion site on changes in the refractive index on the sensor Surface in into the cutaneous catheter tract with subsequent coloniza response to interaction of the microorganism with the sensor. tion of the catheter tip. Contamination of the catheter hub In an aspect, the Surface of the sensor is a glass Support or contributes substantially to intraluminal colonization of other solid support coated with a thin film of metal, for long-term catheters by microorganisms. Occasionally, cath 35 example, gold. The sensor Surface can include a matrix to eters might become hematogenously seeded from another which is immobilized one or more binding agents configured focus of infection. Rarely, contamination of an infusate leads to recognize at least one microorganism. The binding agents to catheter related bloodstream infections. can be antibodies or fragments thereof, oligonucleotide or There are a number of important determinants of catheter peptide based aptamers, receptors or ligands, artificial bind related infection including the material from which the 40 ing Substrates formed by molecular imprinting, or any other device is made and the intrinsic virulence factors of the examples of molecules and or Substrates that bind microor infecting microorganism. Catheters made of polyvinyl chlo ganisms. As a microorganism moves along the inner or outer ride or polyethylene appear to be less resistant to the Surface of the catheter device, the microorganism interacts adherence of microorganisms than are catheters made of with binding agents on the Surface of the sensor. The sensor Teflon, silicone elastomer, or polyurethane. Surface irregu 45 is illuminated with a light source, e.g., a light emitting diode larities of Some catheter materials can also enhance the or optical fiber. Resonance occurs at a specific angle of microbial adherence of certain species (e.g., coagulase incident light and is dependent on the concentration of negative staphylococci, Acinetobacter calcoaceticus, and microorganisms on the Surface. See, e.g., Barlen, et al., Pseudomonas aeruginosa) and catheters made from these Sensors, 7:1427-1446, 2007; Taylor, et al., “Surface plas materials are especially Vulnerable to microbial colonization 50 mon resonance (SPR) sensors for the detection of bacterial and Subsequent infection. In addition, some catheter mate pathogens.’ in Principles of Bacterial Detection: Biosen rials are more thrombogenic than others, a characteristic that sors, Recognition Receptors and Microsystems, ed. M. may predispose to catheter colonization and catheter-related Zourob, S. Elwary, & A. Turner, pp. 83-108, 2008, Springer infection. This association has led to emphasis on preventing New York; and Kashyap & Nemova, J. Sensors, 2009: catheter-related thrombus as an additional mechanism for 55 Article ID 645162, each of which is incorporated herein by reducing catheter-related bloodstream infections and inclu reference. sion of anticoagulant flush solutions in the treatment regi The one or more sensors can be one or more label-free men. The adherence properties of a given microorganism optical biosensors that incorporate other optical methodolo also are important in the pathogenesis of catheter-related gies, e.g., interferometers, waveguides, fiber gratings, ring infection. In general, coagulase-negative staphylococci 60 resonators, and photonic crystals. See, e.g., Fan, et al., Anal. adhere to polymer surfaces more readily than do other Chim. Acta 620:8-26, 2008, which is incorporated herein by pathogens and certain strains of coagulase-negative staphy reference. lococci produce an extracellular polysaccharide often In an aspect, the catheter device can include at least one referred to as “slime'. This slime potentiates the pathoge impedance based sensor configured to detect a microorgan nicity of coagulase-negative staphylococci by allowing the 65 ism based on changes in electrical impedance. The sensor bacteria to withstand host defense mechanisms (e.g., acting can include a measurement chamber, e.g., a microfluidics as a barrier to engulfment and killing by polymorphonuclear channel, incorporated into the inner or outer Surface of the US 9,474,831 B2 19 20 catheter device, with at least one surface functionalized with methods can be used to measure microorganism binding a binding agent, e.g., antibodies, specific for one or more including, among other things, piezoresistive deflection components of a microorganism. Microorganisms entering detection, optical deflection detection, capacitive deflection the measurement chamber by diffusion and/or surface detection, interferometry deflection detection, optical dif migration bind to the functionalized chamber surface. The 5 fraction grating deflection detection, and charge coupled cell membrane of the entrapped microorganism acts as an device detection. In some aspects, the one or more micro insulator at low alternating current frequency and produces cantilever can be a nanocantilever with nanoscale compo a measurable change in the impedance within the chamber. nents. The one or more microcantilevers and/or nanocanti Microorganisms may be detected based on Volume using levers can be arranged into arrays for detection of one or electrical impedance as commonly practiced using a Coulter 10 more target cells. Both microcantilevers and nanocantilevers counter. A MEMS resembling a miniaturized Coulter coun can find utility in microelectromechnical systems (MEMS) ter can be incorporated into the device described herein and and/or nanoelectromechnical systems (NEMS). can be constructed using thin platinum electrodes with a In an aspect, catheter device can include a field effect sensing Zone of for example, 20-100 microns (see, e.g., transistor (FET) based biosensor, in which a change in Zheng et al. (2006) Proceedings of 2006 International Con 15 electrical signal is used to detect interaction of one or more ference on Microtechnologies in Medicine and Biology, microorganisms with one or more components of the sensor. IEEE, Okinawa, Japan, 9-12 May, 2006; Gao et al. (2003) See, e.g., U.S. Pat. No. 7,303,875, which is incorporated Proceedings of the 25" Annual International Conference of herein by reference. An example includes the use of carbon the IEEE EMBS, Cancun, Mexico, Sep. 17-21, 2003), which nanotubes functionalized with a microorganism-specific is incorporated herein by reference. binding agent. See, e.g., Zelada-Guillén, et al., Angew. In an aspect, the at least one sensor can incorporate Chem. Int. Ed., 48:7334-7337, 2009, which is incorporated electrochemical impedance spectroscopy. Electrochemical herein by reference. Single walled carbon nanotubes can act impedance spectroscopy can be used to measure impedance as efficient ion-to-electron transducers in potentiometric across a natural and/or artificial lipid bilayer. The sensor can analysis. The carbon nanotubes can be functionalized with a incorporate an artificial bilayer that is tethered to the surface 25 binding agent, e.g., an oligonucleotide aptamer, configured of a Solid electrode. One or more receptors, e.g., ion chan to selectively bind one or more microorganisms. The bind nels, can be embedded into, the lipid bilayer and configured ing agent is modified with an amine group and covalently to open and close in response to binding of a specific immobilized onto a layer of previously carboxylated single microorganism. The open and closed States can be quanti walled carbon nanotubes. The aptamers are self-assembled tatively measured as changes in impedance across the lipid 30 on the carbon nanotubes through stacking interactions bilayer. See, e.g., Yang, et al., IEEE SENSORS 2006, between the purine and pyrimidine bases of the oligonucle EXCO, Daegu, Korea/Oct. 22-25, 2006, which is incorpo otide aptamers and the walls of the carbon nanotubes. Upon rated herein by reference. Other examples of impedance microorganism binding to the aptamer, the aptamers change based sensors for detecting bacteria and fungi are reviewed conformation, separating the phosphate groups of the in Heo & Hua, Sensors, 9:4483-4502, 2009, which is 35 aptamer from the side-walls of the carbon nanotubes and incorporated herein by reference. inducing a charge change to the carbon nanotube and In an aspect, the at least one sensor can include a parallel recorded potential. Carbon nanotubes can be used to form set of electrode configuration like interdigitated array (IDA) composites with silicone, polyurethane, and poly(vinyl) microelectrodes. An IDA sensor consists of a pair of micro chloride, materials commonly used in production of medical comb array electrodes functionalized with a binding agent, 40 catheters. See, e.g., Xanthos, “Polymers and Polymer Com e.g., microorganism selective antibody. A large number of posites, in Functional Fillers for Plastics, ed. M. Xanthos, parallel electrodes can be used to improve detection. An IDA 2010, pp. 3-18, WILEY-VCH Verlag GMBH & Co. KGaA, sensor can be placed in a microfluidic channel using pho Weinheim; U.S. Patent Applications 2009/0012610 and tolithographic techniques. Binding of a microorganism, e.g., 2010/0104652, which is incorporated herein by reference. bacteria, on the surface of the array of electrodes alters both 45 In a further aspect, the catheter device can include at least current flow and capacitance between the neighboring elec one sensor that relies on optical imaging to sense one or trodes, causing a measurable impedance change in a fre more microorganisms. The microorganisms may be sensed quency-dependent manner. See, e.g., Heo & Hau, Sensors, using any of a number of imaging or optical methods 9:4483-4502, 2009, which is incorporated herein by refer including among other things light scattering, electrical CCC. 50 impedance, infrared spectroscopy, acoustic imaging, ther In an aspect, the at least one sensor can include a mal imaging, photothermal imaging, visible light absorption microcantilever configured to detect changes in cantilever and refraction, and autofluorescence. See, e.g., U.S. Patent bending or vibrational frequency in response to binding of Application 2009/0093728; Doornbos et al. Cytometry one or more microorganisms to the Surface of the sensor. In 14:589-594, 1993; Gao et al. Proceedings of the 25' Annual an aspect the sensor can be bound to a microcantilever or a 55 International Conference of the IEEE EMBS, Cancun, microbead as in an immunoaffinity binding array. In another Mexico, Sep. 17-21, 2003: Oberreuter et al. Int. J. Syst. Evol. aspect, a biochip can be formed that uses microcantilever Microbiol. 52:91-100, 2002; Baddour et al. Ultrasonics bi-material formed from gold and silicon, as sensing ele Symposium IEEE 2:1639-1644, 2002: Zharov et al. J. ments. See, e.g. Vashist J. Nanotech Online 3: DO: 10.2240/ Biochem. 97:916-932, 2006: Zharov et al. J. Biomed. Opt. azojono0115, 2007, which is incorporated herein by refer 60 11:054034-1-4, 2006; Koenig et al. J. Fluoresc. 4:17-40, ence. The gold component of the microcantilever can be 1994; which are each incorporated herein by reference functionalized with one or more binding elements config In another aspect, the device can include at least one ured to bind one or more microorganisms. Aptamers or sensor configured to detect microorganisms based on auto antibodies specific for one or more microorganisms can be fluorescence. A microorganism can be detected by autofluo used to functionalize the microcantilevers. See, e.g., U.S. 65 rescence induced by electromagnetic energy. Naturally Pat. No. 7,097,662, which is incorporated herein by refer occurring autofluorescence in bacteria is derived from ence. A number of microcantilever deflection detection biomolecules containing fluorophores, such as porphyrins, US 9,474,831 B2 21 22 amino acids tryptophan, tyrosine, and phenylalanine, and the BHQ1, BHQ2, and BHQ3 (Biosearch Technologies, Inc., coenzymes NADP, NADPH, and flavins. See, e.g., Koenig Novato, Calif., USA) and Eclipse (Applera Corp., Norwalk, et al. J. Fluoresc. 4:17-40, 1994 which is incorporated herein Conn., USA). A variety of donor fluorophore and quencher by reference. Bacteria can be detected using fluorescence pairs can be considered for FRET associated with the lifetimes measured at 280-540 nm after excitation at 250 binding molecule including, among other things, fluorescein 450 nm (Bouchard et al. J. Biomed. Opt. 11:014011, 2006, with DABCYL, EDANS with DABCYL; or fluorescein which is incorporated herein by reference). For example, with QSY 7 and QSY 9. In general, QSY 7 and QSY 9 dyes Streptococcus pneumoniae, can be detected using fluores efficiently quench the fluorescence emission of donor dyes cence spectroscopy at excitation wavelengths of 250 and including blue-fluorescent coumarins, green- or orange 550 nm and emission wavelengths of 265 and 700 nm 10 fluorescent dyes, and conjugates of the Texas Red and Alexa (Ammor J. Fluoresc. 17:455-459, 2007, which is incorpo Fluor 594 dyes. QSY 21 dye efficiently quenches all red rated herein by reference). Autofluorescence may also be fluorescent dyes. A number of the Alexa Fluor (AF) fluoro used to detect members of the fungi family. Candida albi phores (Molecular Probes-Invitrogen, Carlsbad, Calif., cans and Aspergillus niger autofluoresce at wavelengths USA) can be paired with quenching molecules as follows: ranging from 515 nm to 560 nm when irradiated with 15 AF 350 with QSY 35 or DABCYL: AF 488 with QSY 35, electromagnetic energy at wavelengths of 465-495 nm. See, DABCYL, QSY7 or QSY9: AF 546 with QSY 35, DAB e.g., Mateus et al. Antimicrob. Agents and Chemother: CYL, QSY7 or QSY9;AF 555 with QSY7 or QSY9; AF568 48:3358-3336, 2004; Sage et al. American Biotechnology with QSY7, QSY9 or QSY21: AF 594 with QSY21; and AF Laboratory 24:20-23, 2006, each of which is incorporated 647 with QSY 21. herein by reference. Autofluorescence associated with the Possible Microorganism Specific Biomolecules Recognized food vacuole of the malaria parasite Plasmodium spp. can by Catheter Associated Sensors used to detect infected red blood cells within the blood In an aspect, the catheter device includes at least one stream. See, e.g., Wissing et al. J. Biol. Chem. 277:37747 sensor configured to detect a microorganism. The at least 37755, 2002, which is incorporated herein by reference. one sensor can be configured to detect at least one compo In an aspect, the catheter device includes at least one 25 nent of at least one microorganism. The at least one com sensor configured to detect a microorganism based on ponent of a microorganism can include at least one of a lipid, changes in fluorescent signaling. The sensor can include a peptide, polypeptide, glycolipid, proteoglycan, lipoprotein, charged coupled device (CCD) or complementary metal glycoprotein, glycopeptide, metalloprotein, enzyme, carbo oxide-semiconductor (CMOS) sensor in combination with a hydrate, cytokine, microorganism cell membrane, microor binding agent that exhibits altered optical, e.g., fluorescence, 30 ganism cell receptor, or other microorganism component. properties in response to binding a microorganism. In an For example, the sensor can be configured to detect at least aspect, the sensor can include a one-chip CMOS detector one component of the outer membrane, cell wall, and/or and light emitting diode for exciting and measuring fluo cytoplasmic membrane of bacteria. Components of bacterial rescence associated with the sensor. See, e.g., Tamura, et al., cell walls include peptidoglycan, a mesh-like polymer of J. Neurosci. Methods, 173:114-120, 2008, which is incor 35 N-acetyl glucosamine, N-acetyl muramic acid and amino porated herein by reference. acids, most commonly L-alanine, D-alanine, D-glutamic In an aspect, the at least one sensor includes a binding acid, and diaminopimelic acid. The cell wall of Gram molecule, e.g., an antibody or oligonucleotide aptamer, positive bacteria contains a thick layer of peptidoglycan that configured to exhibit Förster or fluorescence resonance encircles the cell and further includes teichoic acid, a energy transfer (FRET) in response to binding one or more 40 phosphodiester polymer of glycerol or ribitol joined by microorganisms. FRET is a distance-dependent interaction phosphate groups. In contrast, the cell wall of Gram-nega between the electronic excited states of two fluorophore tive bacteria contains a thin layer of peptidoglycan separat molecules in which excitation is transferred from a donor ing the cytoplasmic membrane and the outer membrane. The molecule to an acceptor molecule without emission of a cell wall of gram-negative bacteria further includes Braun's photon. For use in a sensor, one or more binding molecules, 45 lipoprotein, which is covalently linked to the peptidoglycan e.g., antibodies or oligonucleotide aptamers, associated with and extends a hydrophobic anchor into the lipid bilayer of the one or more sensors are configured with at least one the outer membrane. Components of the outer membrane of donor molecule and at least one acceptor molecule. The Gram-negative bacteria include, but are not limited to, interaction of a metabolic analyte with the binding molecule lipids, proteins, and lipopolysaccharides. Lipopolysaccha of the sensor results in a conformation change in the binding 50 rides are composed of Lipid A, a conserved core polysac molecule, leading to changes in the distance between the charide, and a highly variable O-polysaccharide. Proteins donor and acceptor molecules and changes in measurable associated with the outer membrane include the OMP (outer fluorescence. membrane protein) porins, exemplified by OmpC, Ompl A variety of donor and acceptor fluorophore pairs can be and PhoP of E. coli. The at least one sensor can be config considered for FRET including, among other things, fluo 55 ured to detect components of the inner bacterial cytoplasmic rescein and tetramethylrhodamine; IAEDANS and fluores membrane including, but are not limited to, the MPA1-C cein; fluorescein and fluorescein; and BODIPY FL and (also called polysaccharide copolymerase, PCP2a) family of BODIPY FL, and various Alexa Fluor pairings as described proteins, the MPA2 family of proteins, and the ABC bacte herein. The cyanine dyes Cy3, Cy5, Cy5.5 and Cy7, which riocin exporter accessory protein (BEA) family of proteins. emit in the red and far red wavelength range (>550 nm) as 60 Other examples of components of bacteria include, but are well as semiconductor quantum dots can also be used for not limited to, transporters, e.g., Sugar porter (major facili FRET-based detection systems. Quenching dyes can also be tator Superfamily), amino-acid/polyamine/organocation used to quench the fluorescence of visible light-excited (APC) superfamily, cation diffusion facilitator, resistance fluorophores, examples of which include DABCYL, the nodulation-division type transporter, SecDF, calcium:cation non-fluorescing diarylrhodamine derivative dyes QSY 7. 65 antiporter, inorganic phosphate transporter, monovalent cat QSY 9 and QSY 21 (Molecular Probes, Carlsbad, Calif., ion-proton antiporter-1, monovalent cation: proton anti USA), the non-fluorescing Black Hole Quenchers BHQ0, porter-2, potassium transporter, nucleobase:cation sym US 9,474,831 B2 23 24 porter-2, formate-nitrite transporter, divalent anion:Sodium ogy, Inc., Santa Cruz, Calif.; Novus Biologicals, LLC, Symporter, ammonium transporter, and multi-antimicrobial Littleton, Colo. GenWay Biotech, Inc., San Diego, Calif.). extrusion; channels, e.g., major intrinsic protein, chloride Fungi can be distinguished from bacteria based on the channel, and metal ion transporter, and primary active detection of glucan, chitin, mannan, or combinations transporters, e.g., P-type ATPase, arsenite-antimonite efflux, thereof. For example, Sendid, et al., describe development Type II secretory pathway (SecY), and Sodium-transporting of antibodies against glucan, chitin and mannan for detec carboxylic acid decarboxylase. A number of other compo tion of Candida albicans (in, Clin. Vaccine Immunol., nents of bacteria have been described in Chung, et al., J. 15:1868-1877, 2008, which is incorporated herein by refer Bacteriology 183: 1012-1021, 2001, which is incorporated ence). herein by reference. 10 Binding Agents Specific for Recognition Targets In an aspect, the catheter device includes at least one The at least one sensor can include at least one binding sensor configured to sense one or more components on the agent configured to bind a component of a microorganism. outer Surface of a pathogenic fungus, examples of which The at least one binding agent for selectively binding a include Candida albicans, Candida glabrata, and Asperigil component of a microorganism can include, but is not lus species. The cell wall of most fungi is composed of 15 limited to, antibodies, antibody fragments, peptides, oligo glycoproteins embedded within a polysaccharide matrix or nucleotides, DNA, RNA, aptamers, protein nucleic acids, scaffolding. Additionally, Some fungal species produce a proteins, receptors, receptor ligands, lectins, an artificial polysaccharide capsule that Surrounds the cell wall (e.g., the binding Substrate formed by molecular imprinting, or other glucuronoxylomannan capsule produced by Cryptococcus examples of binding agents configured to bind microorgan neoformans). In certain instances, carbohydrates are the first 1SS. fungal components to contact the host tissue. Carbohydrate The at least one binding agent associated with the chains or glycans within the cell wall of fungi are composed sensor(s) include, but is not limited to, antibodies configured of various combinations and derivatives of three monosac to bind one or more components of a microorganism. charides: D-glucose, N-acetyl-D-glucosamine, and D-man Antibodies or fragments thereof for use as one or more nose. The cell envelope of Candida albicans, for example, 25 binding agents can include, but are not limited to, mono contains highly branched polymers of glucose (glucan), clonal antibodies, polyclonal antibodies, Fab fragments of linear polymers of N-acetyl-D-glucosamine (chitin), and monoclonal antibodies, Fab fragments of polyclonal anti mannose (mannan) incorporated into various glycoproteins. bodies, Fab fragments of monoclonal antibodies, and Fab Sialic acid may also be a component of the fungal cell wall. fragments of polyclonal antibodies, chimeric antibodies, See, e.g., Masuoka, Clin. Microbiol. Rev 17:281-310, 2004, 30 non-human antibodies, fully human antibodies, among oth which is incorporated herein by reference. ers. Single chain or multiple chain antigen-recognition sites In an aspect, the at least one sensor can be configured to can be used. Multiple chain antigen-recognition sites can be sense one or more components secreted by a microorganism. fused or unfused. Antibodies or fragments thereof can be Examples include various membrane-active peptides and generated using standard methods. See, e.g., Harlow & Lane exotoxins, in particular those produced by bacteria, for 35 (Antibodies: A Laboratory Manual, Cold Spring Harbor example, pneumolysins secreted by Streptococci and alpha Laboratory Press; 1 edition 1988), which is incorporated toxin a major cytolysin secreted by Staphylococcus aureus. herein by reference. Other examples of toxins secreted by S. aureus include toxic Alternatively, an antibody or fragment thereof directed shock syndrome toxin-1, enterotoxins, leukicidins, and phe against one or more inflammatory mediators can be gener nyl-soluble modulins. Secretion of pore-forming exotoxins 40 ated, for example, using phage display technology. See, e.g., by bacteria is abundant and endotoxins, such as lipopoly Kupper, et al. BMC Biotechnology 5:4, 2005, which is saccharides (LPS). Examples of pore-forming toxins include incorporated herein by reference. An antibody, a fragment but are not limited to perfringiolysin, hemolysin, listerioly thereof, or an artificial antibody, e.g., Affibody(R) artificial sin, alpha toxin, pneumolysin, streptolysin O, and leukoci antibodies (Affibody AB, Bromma, Sweden) can be pre din. Examples of pyrogenic exotoxins include but are not 45 pared using in silico design (Knappik et al., J. Mol. Biol. limited to staphylococcal enterotoxins serotypes A-E, G, and 296: 57-86, 2000), which is incorporated herein by refer H; group A Streptococcal pyrogenic exotoxins A-c; staphy ence. In some aspects, antibodies directed against one or lococcal exfoliatin toxin; and Staphylococcal toxic shock more components of a microorganism may be available syndrome toxin-1. Other toxins include exotoxin A from a commercial Source (from, e.g., Novus Biological, (Pseudomonas aeruginosa). Examples of toxins secreted by 50 Littleton, Colo.: Sigma-Aldrich, St. Louis, Mo.; United other microorganisms include fungal toxins such as, for States Biological, Swampscott, Mass.). Fenelon, et al., example, aflatoxin and gliotoxin secreted by Aspergillus describe development of antibodies specific for three Asper species. gillus species commonly associated with human disease; A. In an aspect, the catheter device can include at least one filmigatus, A. flavus, and A. niger (m, J. Clin. Microbiol., sensor configured to differentiate between microorganisms 55 37: 1221-1223, 1999, which is incorporated herein by refer based on detecting distinguishing components specific for a ence). Sendid, et al., describe development of antibodies given microorganism. For example, Gram-positive bacteria against glucan, chitin and mannan for detection of Candida can be differentiated from Gram-negative bacteria based on albicans (in, Clin. Vaccine Immunol., 15:1868-1877, 2008, detection of lipoteichoic acid, the latter of which is which is incorporated herein by reference) expressed on the Gram-positive bacteria Listeria monocy 60 The at least one binding agent associated with the togenes, Streptococcus pneumoniae, Staphylococcus aureus, sensor(s) includes but is not limited to, aptamers configured and Staphylococcus epidermidis. Gram-negative bacteria to bind one or more components of a microorganism. The can be detected based on detection of lipopolysaccharides. aptamer can be an oligonucleotide RNA- or DNA-based In general, reagents, e.g., antibodies, that can distinguish aptamer. Aptamers are artificial oligonucleotides (DNA or between components of Gram-positive and Gram-negative 65 RNA) which bind to a wide variety of entities (e.g., metal bacteria can be developed using standard methods or are ions, Small organic molecules, proteins, and cells) with high commercially available (from, e.g., Santa Cruz, Biotechnol selectivity, specificity, and affinity. Aptamers can be isolated US 9,474,831 B2 25 26 from a large library of 10' to 10' random oligonucleotide PA IIL. Ralsonia RS-ILL, ADP-ribosylating toxin, Ralstonia sequences using an iterative in vitro selection procedure lectin, Clostridium hemagglutinin, botulinum toxin, tetanus often termed “systematic evolution of ligands by exponen toxin, cyanobacterial lectins, FimH. Gaf), PapG, Staphy tial enrichment” (SELEX). See, e.g., Cao, et al., Current lococcal enterotoxin B, toxin SSL11, toxin SSL5; fungal and Proteomics 2:31-40, 2005; Proske, et al., Appl. Microbiol. yeast lectins, e.g., Aleuria aurantia lectin, integrin-like lec Biotechnol. 69:367-374, 2005: Jayasena Clin. Chem. tin, Agaricus lectin, Sclerotium lectin, Xerocomus lectin, 45:1628-1650, 1999, each of which is incorporated herein Laetiporus lectin, Marasmius oreades agglutinin, agrocybe by reference. In general, SELEX may be used to generate galectin, coprinus galectin-2, Ig-like lectins, L-type lectins: aptamers against microorganisms including bacteria, fungi plant lectins, e.g., alpha-D-mannose-specific plant lectins, and parasites. For example, Cao, et al., describe using 10 amaranthus antimicrobial peptide, hevein, pokeweed lectin, SELEX and whole bacteria to generate a panel of DNA Urtica dioica UD, wheat germ WGA-1, WGA-2, WGA-3, aptamers configured to detect Staphylococcus aureus (in artocarpin, artocarpus hirsute AHL, banana lectin, Calsepa, Nucleic Acids Res., 37:4621-4.628, 2009). For Gram positive heltuba, jacalin, Maclura pomifera MPA, MornigaM, Parkia bacteria, teichoic acids and peptidoglycan will serve as lectins, abrin-a, abrus agglutinin, amaranthin, castor bean targets. For Gram negative bacteria, common lipopolysac 15 ricin B, ebulin, mistletoe lectin, TKL-1, cyanovirin-N charide moieties such as 2-keto-3-deoxyoctanate (KDO homolog, and various legume lectins; and viral lectins, e.g., antigen) will be targeted for aptamer development. Simi capsid protein, coat protein, fiber knob, hemagglutinin, and larly, for fungi, cell wall chitin will be used to select highly tailspike protein (see, e.g., E. Bettler, R. Loris, A. Imberty specific FRET-aptamers from a randomized DNA library. "3D-Lectin database: A web site for images and structural Other examples are described in Shangguan, et al., Proc. information on lectins' 3rd Electronic Glycoscience Con Natl. Acad. Sci. USA. 103: 11838-11843; Chen, et al., Bio ference, The internet and World WideWeb, 6-17 Oct. 1997: chem. Biophy's. Res. Commun. 357:743-748, 2007; Ulrich, et on the worldwide web at cermay.cnrs.fr/lectines, Sahly, et al., J. Biol. Chem. 277:20756-20762, 2002; and Low, et al., al., Infect. Immunity, 78:1322-1332, 2008, the content of Biochem. Biophys. Res. Commun., 378:701-705, 2009, each which is incorporated herein by reference. of which is incorporated herein by reference. 25 The at least one binding agent associated with the In an aspect, the at least one binding agent associated with sensor(s) includes but is not limited to, one or more artificial the sensor(s) include but is not limited to peptide-based binding substrates formed by the process of molecular aptamers configured to bind one or more components of a imprinting and configured to bind one or more components microorganism. Peptide-based aptamers are artificial pro of a microorganism. In the process of molecular imprinting, teins in which inserted peptides are expressed as part of the 30 a template, e.g., a whole microorganism or parts thereof, is primary sequence of a structurally stable protein. See, e.g., combined with functional monomers which, upon cross Crawford, et al., Brief Funct. Genomic Proteomic 2:72-79, linking, form a polymer matrix that surrounds the template. 2003, which is incorporated herein by reference. Peptide See Alexander, et al., J. Mol. Recog. 19:106-180, 2006, based aptamers can be generated by Screening a target which is incorporated herein by reference. Removal of the microorganism or parts thereof against yeast two-hybrid 35 template leaves a stable cavity in the polymer matrix that is libraries, yeast expression libraries, bacterial expression complementary in size and shape to the template. In an libraries and/or retroviral libraries. Peptide-based aptamers aspect, functional monomers of acrylamide and ethylene can have binding affinities comparable to antibodies. glycol dimethacrylate can be mixed with a microorganism or In an aspect, the at least one binding agent associated with parts thereof, in the presence of a photoinitiator and ultra the sensor(s) includes but is not limited to lectins configured 40 violet irradiation used to cross-link the monomers. The to bind one or more components of a microorganism. While resulting polymer can be crushed or ground into Smaller the term “lectin' was originally used to define agglutinins pieces and washed to remove the microorganism or parts involved in the agglutination process, the term “lectin' is thereof, leaving a particulate matrix material capable of currently used more generally to include Sugar-binding binding the microorganism. For example, Cohen et al., proteins. Lectins are able to recognize specific carbohydrate 45 describe using whole cell imprinting in-sol-gel imprinted structures such that even oligosaccharides with identical films to generate a bacterial sensor (m, Int. J. Mol. Sci., Sugar compositions can be distinguished or separated. Some 11:1236-1252, 2010). Examples of other functional mono lectins will bind only to structures with mannose or glucose mers, cross-linkers and initiators may be used to generate an residues, while others may recognize only galactose resi artificial binding substrate are provided. See, e.g., U.S. Pat. dues. Some lectins require that the particular Sugar is in a 50 No. 7,319,038: Alexander, et al., J. Mol. Recognit. 19:106 terminal non-reducing position in the oligosaccharide, while 180, 2006, each of which is incorporated herein by refer others can bind to Sugars within the oligosaccharide chain. ence. In a further aspect, hydrogels may be used for molecu AS Such, specific lectins can be used to distinguish various lar imprinting. See, e.g., Byrne et al., “Molecular imprinting microorganisms based on the composition and pattern of cell within hydrogels”. Advanced Drug Delivery Reviews, 54. surface carbohydrates. For example, Serra, et al., describe 55 149-161, 2002, which is incorporated herein by reference. the use of lectins as binding agents in piezoelectric biosen Other examples of synthetic binders are provided. See, e.g., sors capable of detecting and quantifying Staphylococcus U.S. Pat. Nos. 6,255,461; 5,804,563; 6,797,522; 6,670,427; aureus (m, Anal. Bioanal. Chem., 391:1853-1860, 2008). and 5,831,012; and U.S. Patent Application 20040018508: Examples of lectins include, but are not limited to, algal and Ye and Haupt, Anal Bioanal Chem. 378: 1887-1897, lectins, e.g., b-prism lectin; animal lectins, e.g., tachylectin 60 2004; Peppas and Huang, Pharm Res. 19:578-587 2002, 2, C-type lectins, C-type lectin-like, calnexin-calreticulin, each of which is incorporated herein by reference. capsid protein, chitin-binding protein, ficolins, fucollectin, Reservoirs H-type lectins, 1-type lectins, sialoadhesin, siglec-5, siglec In an aspect, the catheter includes at least one anti 7, micronemal protein, P-type lectins, pentrxin, b-trefoil, microbial agent reservoir configured to deliver one or more galectins, congerins, selenocosmia huwena lectin-I, Hcgp 65 anti-microbial agents to one or more anti-microbial regions 39, Ym1; bacterial lectins, e.g., Pseudomonas PA-IL, Bur of the body structure of the catheter. The at least one kholderia lectins, chromobacterium CV-IIL, Pseudomonas anti-microbial agent reservoir can be positioned in one or US 9,474,831 B2 27 28 more sites in at least one of the outer surface of the body ence). The actuation layer is defined by micro-resistors, structure, the inner surface of the body structure, embedded which once actuated, rapidly and locally heat a contained in the body structure itself, or combinations thereof. In an fluid to generate bubbles. The increase in pressure caused by aspect, the at least one anti-microbial agent reservoir is in the bubbles ruptures the membrane and jets the contained communication with one or more sensors. In an aspect, the drug solution out of the device, allowing for rapid drug reservoir is configured for controllable delivery of one or delivery. more anti-microbial agents in response to a signal from a In an embodiment, the system includes one or more sensor indicative of the presence of a microorganism. In an computer-readable media (e.g., drives, interface Sockets, aspect, the catheter includes a single anti-microbial agent Universal Serial Bus (USB) ports, memory card slots, input/ reservoir with multiple outlets for delivery of one or more 10 output components (e.g., graphical user interface, display, anti-microbial agents to one or more anti-microbial regions. keyboard, keypad, trackball, joystick, touch-screen, mouse, In an aspect, the catheter includes multiple anti-microbial Switch, dial, etc.)). agent reservoirs with one or more outlets for delivery of one In an embodiment, the computer-readable media is con or more anti-microbial agents to one or more anti-microbial figured to accept signal-bearing media. In an embodiment, a regions. In an aspect, the catheter includes one or more 15 program for causing the system to execute any of the anti-microbial agent reservoirs embedded in one or more disclosed methods can be stored on, for example, a com pores in the catheter body structure. See, e.g., U.S. Pat. No. puter-readable recording medium, a signal-bearing medium, 7.575,593, which is incorporated herein by reference. or the like. Examples of signal-bearing media include, In an aspect, the at least one anti-microbial-agent reser among others, a recordable type medium Such as magnetic voir includes at least one outlet with a release mechanism tape, floppy disk, hard disk drive, Compact Disc (CD), operably connected to one or more sensors for controllable Digital Video Disk (DVD). Blu-Ray Disc, digital tape, delivery of an anti-microbial agent. The release mechanism computer memory, etc., and transmission type medium can include but is not limited to a valve, a Switch, a plug, a (digital and/or analog). Other non-limiting examples of cap, or a membrane. In an aspect, the anti-microbial-agent signal bearing media include, for example, DVD-ROM, reservoir includes a valve for controllable delivery of an 25 DVD-RAM, DVD+RW, DVD-RW, DVD-R, DVD+R, CD anti-microbial agent. Various examples of micro Valves or ROM, Super Audio CD, CD-R, CD+R, CD+RW, CD-RW, microelectromechanical systems (MEMS) valves for con Video Compact Discs, Super Video Discs, flash memory, trolling fluid flow in micro devices have been described. magnetic tape, magneto-optic disk, MINIDISC, non-volatile See, e.g., Luckevich M. Valve World, May 2007, pp. 79-83: memory card, EEPROM, optical disk, optical storage, Givrad T K., et al., Proceedings of BIOMed2008, 3. Fron 30 RAM, ROM, system memory, web server, etc. tiers in Biomedical Devices Conference. Jun. 18-20, 2008, In an aspect, the at least one anti-microbial agent reservoir Irvine, Calif., USA: U.S. Pat. Nos. 6,612,535; 7,124,773, can be configured to include a release mechanism that is a each of which is incorporated herein by reference. natural and/or synthetic stimulus-responsive hydrogel or In an aspect, the at least one anti-microbial-agent reser polymer which changes confirmation rapidly and reversibly voir can include at least one outlet covered with a removable 35 in response to environmental stimuli Such as, for example, membrane. The membrane can be responsive to a directly temperature, pH, ionic strength, electrical potential, light, applied stimulus (e.g., an applied Voltage or potential) or to magnetic field or ultrasound. See, e.g., U.S. Pat. No. 5.226, a change in the local environment of the device (e.g., local 902; and Stubbe, et al., Pharmaceutical Res., 21:1732-1740, pH change), or any of a number of other stimuli including 2004, each of which is incorporated herein by reference. among other things heat, light (e.g., laser), and magnetic 40 Examples of polymers are described in U.S. Pat. Nos. field. See, e.g., U.S. Pat. No. 6,808.522; Grayson, R. et al., 5,830,207; 6,720,402; and 7,033,571, each of which is Proceedings of IEEE 92:6-21, 2004, which are each incor incorporated herein by reference. For example, a hydrogel or porated herein by reference. As an example, the at least one other polymer or other Smart material may be used as an anti-microbial-agent reservoir can be an array of microres environmentally sensitive actuator to control flow of an ervoirs on a microchip in which each aliquot of one or more 45 agent out of an implantable device as described in U.S. Pat. anti-microbial agents is contained in its own reservoir and Nos. 6,416,495; 6,571,125; and 6,755,621, each of which is capped by an environmentally sensitive material. In an incorporated herein by reference. As such, the at least one aspect, the microreservoirs can be capped with a gold anti-microbial agent reservoir can incorporate a hydrogel or membrane which is weakened and ruptured by electro other polymer that modulates delivery of one or more chemical dissolution in response to application of an anode 50 anti-microbial agents in response to a trigger from a sensor. Voltage to the membrane in the presence of chloride ions, The anti-microbial agent reservoirs can include one or resulting in release of contents of the microreservoir as more target-responsive microparticles attached to the cath described in U.S. Pat. No. 5,797,898 and in Prescott, et al., eter device in at least one of a plurality of regions and Nat. Biotech., 24:437-438, 2006, each of which is incorpo configured to release one or more anti-microbial agent upon rated herein by reference. 55 interaction with a microorganism. The one or more target Alternatively, the microreservoirs can be capped by a responsive microparticles can include one or more binding temperature sensitive material which can be ruptured in elements incorporated into the microparticles and config response to selective application of heat to one or more of ured to bind at least one microorganism component. the reservoirs as described in U.S. Pat. No. 6,669,683, which Examples of binding elements include but are not limited to is incorporated herein by reference. For example, Elman, et 60 antibodies, aptamers, oligonucleotides, protein nucleic al., describe a multi-layered temperature-responsive drug acids, receptors, ligands, lectins, synthetic binding moieties, delivery system that includes a reservoir layer containing a molecular imprinting, or combinations thereof. Binding of a drug Solution; a membrane layer that hermetically seals the microorganism to the microparticles changes the properties drug reservoir, and from where the drug is ejected; and an of the microparticle and allows for release of an encapsu actuation layer, where bubbles are formed in response to 65 lated anti-microbial agent. For example, Yang et al. describe localized heat application (in, Biomedical Microdevices, target-responsive microparticles which include a target 11:625-631, 2009, which is incorporated herein by refer specific aptamer, two additional overlapping oligonucle US 9,474,831 B2 29 30 otides linked to polymerized acrylamide, and an encapsu Further non-limiting examples of anti-microbial agents lated material. Binding of a target to the target-specific include one or more pore-forming antimicrobial peptides. aptamer disrupts the interaction of the overlapping oligo Antimicrobial peptides represent an abundant and diverse nucleotides causing aggregates of polymerized acrylamide group of molecules that are naturally produced by many to separate from one another and allowing for release of the tissues and cell types in a variety of invertebrate, plant and encapsulated material. See, e.g., Yang et al., J. Am. Chem. animal species. The amino acid composition, amphipathic Soc., 130:6320-6321, 2008; and Gu, et al., Proc. Natl. Acad. ity, cationic charge and size of antimicrobial peptides allow Sci., USA, 105:2586-2591, 2008, each of which is incorpo them to attach to and insert into microbial membrane rated herein by reference. In another example, Miyata, et al., bilayers to form pores leading to cellular disruption and describe target-responsive hydrogels prepared by molecular 10 death. More than 800 different antimicrobial peptides have imprinting in which ligands reactive with a target, such as, been identified or predicted from nucleic acid sequences, a for example, lectins and/or antibodies, are conjugated with subset of which have are available in a public database (see, acrylate and polymerized with acrylamide to form a target e.g., Wang & Wang, Nucleic Acids Res. 32: D590-D592, responsive hydrogel (Proc. Natl. Acad. Sci., USA, 103: 1190 2004); on the worldwide web at asp. unmc.edu/AP/main 1193, 2006, which is incorporated herein by reference). 15 php, which is incorporated herein by reference). More The one or more microparticles can include temperature specific examples of antimicrobial peptides include, but are responsive microparticles configured to release an encapsu not limited to, anionic peptides, e.g., maximin H5 from lated anti-microbial agent in response to changes in tem amphibians, Small anionic peptides rich in glutamic and perature. In this instance, the change in temperature can aspartic acids from sheep, cattle and humans, and dermcidin include elevated endogenous temperature of the Subject from humans; linear cationic alpha-helical peptides, e.g., either globally due to a fever or locally due to inflammation, cecropins (A), andropin, moricin, ceratotoxin, and melittin ischemia, or neoplastic tissue. The change in temperature from insects, cecropin P1 from Ascaris nematodes, magainin can also include application of an energy source to the (2), dermaseptin, bombinin, brevinin-1, esculentins and catheter to induce a localized increase in temperature. Tem buforin II from amphibians, pleurocidin from skin mucous perature-responsive microparticles can include thermally 25 secretions of the winter flounder, seminalplasmin, BMAP, sensitive lipid-based and/or polymer-based micelles. The SMAP (SMAP29, ovispirin), PMAP from cattle, sheep and micelles can be configured to encapsulate one or more pigs, CAP18 from rabbits and LL37 from humans; cationic anti-microbial agents and remain stable until a critical peptides enriched for specific amino acids, e.g., praline solution temperature (LCST) has been reached. For containing peptides including abaecin from honeybees, pra example, micelles fabricated from poly(N-isopropylacryl 30 line- and arginine-containing peptides including apidaecins amide-co-N,N-dimethylacrylamide)-b-poly(D.L-lactide-co from honeybees, drosocin from Drosophila, pyrrhocoricin glycolide) are stable at 37° C. but begin to release their from European sap-sucking bug, bactenicins from cattle contents at a LCST of 39° C. See, e.g., Liu, et al., Mol. (Bac7), sheep and goats and PR-39 from pigs, praline- and BioSyst., 1:158-165, 2005, which is incorporated herein by phenylalanine-containing peptides including prophenin reference. Temperature-responsive micelles composed of 35 from pigs, glycine-containing peptides including hymenop N-(2-hydroxypropyl) methyl acrylamide (lactate) and taecin from honeybees, glycine- and praline-containing pep optionally polyethylene glycol have also been described. tides including coleoptericin and holotricin from beetles, See, e.g., U.S. Pat. No. 7,425,581, which is incorporated tryptophan-containing peptides including indolicidin from herein by reference. Examples of other polymers for use in cattle, and Small histidine-rich salivary polypeptides, includ generating temperature-responsive microparticles include 40 ing histatins from humans and higher primates; anionic and but are not limited to poly(N-(3-ethoxypropyl)acrylamide), cationic peptides that contain cysteine and from disulfide dimethylaminoethyl methacrylate, ethylene glycol dimeth bonds, e.g., peptides with one disulphide bond including acrylate, and N-isopropyl acrylamide. See, e.g., U.S. Pat. brevinins, peptides with two disulfide bonds including No. 6,451,429, which is incorporated herein by reference. alpha-defensins from humans (HNP-1. HNP-2, cryptidins), Anti-Microbial Agents 45 rabbits (NP-1) and rats, beta-defensins from humans Further non-limiting examples of anti-microbial agent (HBD1, DEFB118), cattle, mice, rats, pigs, goats and poul include compounds, molecules, or treatments that elicit a try, and rhesus theta-defensin (RTD-1) from rhesus monkey, biological response from any biological Subject. Further insect defensins (defensin A); and anionic and cationic non-limiting examples of anti-microbial agents include peptide fragments of larger proteins, e.g., lactoferricin from active agents (e.g., antimicrobial active agents), pharmaceu 50 lactoferrin, casocidin 1 from human casein, and antimicro ticals (e.g., a drug, a therapeutic compound, pharmaceutical bial domains from bovine alpha-lactalbumin, human hemo salts, and the like) non-pharmaceuticals (e.g., a cosmetic globin, lysozyme, and ovalbumin (see, e.g., Brogden, Nat. Substance, and the like), neutraceuticals, antioxidants, phy Rev. Microbiol. 3:238-250, 2005, which is incorporated tochemicals, homeopathic agents, and the like. Further non herein by reference). limiting examples of anti-microbial agents include peroxi 55 Further non-limiting examples of anti-microbial agents dases (e.g., haloperoxidases Such as chloroperoxidase, and include antibacterial drugs. Non-limiting examples of anti the like), oxidoreductase (e.g., myeloperoxidase, eosinophil bacterial drugs include beta-lactam compounds, such as peroxidase, lactoperoxidase, and the like) oxidases, and the penicillin, methicillin, nafcillin, oxacillin, cloxacillin, like. dicloxacillin, amplicillin, ticarcillin, amoxicillin, carbenicil Further non-limiting examples of anti-microbial agents 60 lin, and piperacillin; cephalosporins and cephamycins such include one or more pore-forming toxins. Non-limiting as cefadroxil, cefazolin, cephalexin, cephalothin, cephapi examples of pore-forming toxins include beta-pore-forming rin, cephradine, cefaclor, cefamandole, cefonicid, cefuroX toxins, e.g., hemolysin, Panton-Valentine leukocidin S. ime, cefprozil, loracarbef, ceforanide, cefoxitin, cefimeta aerolysin, Clostridial epsilon-toxin; binary toxins, e.g., Zole, cefotetan, cefoperaZone, cefotaxime, ceftazidine, anthrax, C. perfingens Iota toxin, C. difficile cytolethal 65 ceftizoxine, ceftriaxone, cefixime, cefpodoxime, proxetil, toxins; cholesterol-dependent cytolysins; pneumolysin; cefdinir, cefditoren, pivoxil, ceftibuten, moxalactam, and Small pore-forming toxins; and gramicidin A. cefepime; other beta-lactam drugs such as aztreonam, cla US 9,474,831 B2 31 32 Vulanic acid, Sulbactam, taZobactam, ertapenem, imipenem, vesicles, organogels, phospholipid surfactant vesicles, phos and meropenem; other cell wall membrane active agents pholipid Surfactant vesicles, transfersomes, Virosomes. Fur Such as Vancomycin, teicoplanin, daptomycin, fosfomycin, ther non-limiting examples of energy-sensitive carriers and bacitracin, and cycloserine; tetracyclines Such as tetracy the like include electrical energy-sensitive, light sensitive, cline, chlortetracycline, oxytetracycline, demeclocycline, pH-sensitive, ion-sensitive, Sonic energy sensitive, ultra methacycline, doxycycline, minocycline, and tigecycline; Sonic energy sensitive carriers. Further non-limiting macrollides Such as erythromycin, clarithromycin, azithro examples of energy-sensitive carriers and the like include mycin, and tellithromycin; aminoglycosides such as Strepto cavitationally actuated drug delivery carriers, acoustically mycin, neomycin, kanamycin, amikacin, gentamicin, actuated drug delivery carries, and the like. tobramycin, Sisomicin, and netilmicin; Sulfonamides such as 10 In an embodiment, the anti-microbial agent includes at Sulfacytine, Sulfisoxazole, silfamethizole, Sulfadiazine, Sul least one active agent that selectively targets bacteria. For famethoxazole, Sulfapyridine, and Sulfadoxine; fluoroquino example, in an embodiment, the anti-microbial agent lones Such as ciprofloxacin, enoxacin, gatifloxacin, gemi includes at least one bacteriophage that, for example, selec floxacin, levofloxacin, lomefloxacin, moxifloxacin, tively targets bacteria. Bacteriophages generally comprise norfloxacin, and ofloxacin; antimycobacteria drugs such as 15 an outer protein hull enclosing genetic material. The genetic isoniazid, rifampin, rifabutin, rifapentine, pyrazinamide, material can be ssRNA, dsRNA, ssDNA, or dsDNA. Bac ethambutol, ethionamide, capreomycin, clofazimine, and teriophages are generally smaller than the bacteria they dapsone; and miscellaneous antimicrobials such as colis destroy, and range from about 20 nm to about 200 nm. timethate Sodium, methenamine hippurate, methenamine Non-limiting examples of bacteriophages include T2, T4, mandelate, metronidazole, mupirocin, nitrofurantoin, poly T6, phiX-174, MS2, and the like. In an embodiment, the myxin B, clindamycin, choramphenicol, quinupristin-dalfo bacteriophage includes at least one engineered enzymati pristin, lineZolid, spectinomycin, trimethoprim, pyrimeth cally active bacteriophage. For example, particular enzy amine, and trimethoprim-sulfamethoxazole. matically active bacteriophage sets assist in dispersing bio Further non-limiting examples of anti-microbial agents films. See U.S. Patent App. Pub. No. 20090155215, which include antifungal agents. Non-limiting examples of anti 25 is incorporated herein by reference. fungal agents include anidulafungin, amphotericin B, Among antimicrobial agent compositions, examples butaconazole, butenafine, caspofungin, clotrimazole, econ include, but are not limited to, diluted solutions of NaCl, azole, fluconazole, flucytosine griseofulvin, itraconazole, hypochlorous acid solutions (HAS), oxidative reduction ketoconazole, miconazole, micafungin, naftifine, natamycin, potential aqueous compositions, STERILOX TX (PuriCore nystatin, oxiconazole, Sulconazole, terbinafine, terconazole, 30 Inc.), STERILOX Solutions (PuriCore Inc.), MICROCYN tioconazole, tolnaftate, and/or Voriconazole. (Nofil Corp.), Superoxidized aqueous compositions, Super In an embodiment, the anti-microbial agents include, but oxidized water, Superoxide dismutase compositions, physi are not limited to, oxidizing chemicals suitable to disrupt or ologically balanced ionized acidic Solutions, and the like. destroy cell membranes. For example, some oxidizing Further non-limiting examples of antimicrobial agent com chemicals may withdraw electrons from a cell membrane 35 positions may be found in, for example, the following causing it to, for example, become destabilized. Destroying documents (the contents of each of which is incorporated the integrity of cell membranes of, for example, a pathogen herein by reference): U.S. Pat. Nos. 7.276.255 (issued Oct. may lead to cell death. 2, 2007), 7,183,048 (issued Feb. 27, 2007), 6,506,416 (is Further non-limiting examples of anti-microbial agents sued Jan. 14, 2003), 6,426,066 (issued Jul. 30, 2002), and include antiseptics and disinfectants. Non-limiting examples 40 5,622,848 (Apr. 22, 1997); and U.S. Patent Nos. 2007/ of antiseptics and disinfectants include acetic acid, acrisor 0196357 (published Aug. 23, 2007), 2007/0173755 (pub cin, aluminum acetate, alcohols (e.g., ethanol, isopropanol, lished Jul. 26, 2007), and 2005/0142157 (published Jun. 30, benzyl alcohol, phenylethyl alcohol), aldehydes (e.g., form 2005). aldehyde, glutaraldehyde), benzoic acid, boric acid, butyl In an aspect, the type of anti-microbial agent delivered paraben, chlorhexidine gluconate, chlorine sodium 45 and the spatial and temporal sequence of delivery is tailored hypochlorite, hexachlorophene, iodine, povidone-iodine, to the catheter for the presence and/or development of drug phenols, oxidizing agents (e.g., hydrogen peroxide), para resistant microorganisms. For example, the antibiotic naf bens (e.g., butylparaben, ethylparaben, methylparaben, pro cillin is a preferred first line of defense against methicillin pylparaben), phenylmercuric acetate, phenylmercuric sensitive Staphylococcus aureus MSSA). Other antibiotics nitrate, potassium permanganate, propylene oxide, pyrithi 50 used to treat MSSA include but are not limited to cefazolin, one Zinc, and quaternary ammonium (e.g., benzalkonium clindamycin, and/or dicloxacillin. However, methicillin-re chloride, cetylpyridinum chloride, benzethonium chloride), sistant Staphylococcus aureus MRSA no longer responds nitrofuraZone, selenium sulfide, silver nitrate, and silver to nafcillin and may require treatment with other anti Sulfadiazine. microbial agents, including among other things Vancomycin, Non-limiting examples of carriers include any matrix that 55 telavancin (a synthetic derivative of Vancomycin), allows for transport of for example, a disinfecting agent trimethoprim-sulfamethoxazole (for some strains of across any tissue, cell membranes, and the like of a biologi MRSA), minocycline, linezolid, quinupristin/dalfopristin, cal Subject, or that is suitable for use in contacting a daptomycin, and/or tigecycline. See, e.g., Herchline, biological subject, or that allows for controlled release “Staphylococcal Infections. eMedicine, updated Jan. 8, formulations of the compositions disclosed herein. Further 60 2010, accessed May 24, 2010 (emedicine.medscape.com), non-limiting examples of carriers include at least one of the content of which is incorporated herein by reference. In creams, liquids, lotions, emulsions, diluents, fluid ointment a recent study of 182 bacterial isolates from ICU patients bases, gels, organic and inorganic solvents, degradable or infected with coagulase-negative Staphylococcus, 95% were non-degradable polymers, pastes, salves, vesicle, and the resistant to penicillin, 86% were resistant to oxacillin, 48% like. Further non-limiting examples of carriers include 65 were resistant to erythromycin, 42% were resistant to clin cyclic oligosaccharides, ethasomes, hydrogels, liposomes, damycin, 54% were resistant to gentamicin, 66% were micelle, microspheres, nisomes, non-ionic Surfactant resistant to ciprofloxacin, and 0% were resistant to Vanco US 9,474,831 B2 33 34 mycin. In this same study, multiresistance was commonly when irradiated with UV light. See, Greene, Materials seen: 21% of the isolates were resistant to six tested anti Today, vol. 9, no. 11, p. 15 (2006), which is incorporated biotics, 34% to at least five tested antibiotics and 59% were herein by reference. resistant to at least four of the seven tested antibiotics. See, In an embodiment, at least one of the inner Surface or e.g., Agvald-Ohman, et al., Crit. Care, 8:R42-R47, 2004, outer surface of the body structure includes graphene film which is incorporated herein by reference. configured to be Superhydrophobic (contact angle of about In an embodiment, the anti-microbial agent delivered 160 degrees) to superhydrophilic (contact angle of about 0 from one or more anti-microbial regions or reservoirs degrees), by manipulating the roughness of the Surface. includes at least one D-amino acid. For example, it has been In an embodiment, at least one anti-microbial region 10 includes at least one self-cleaning coating, or other coating. reported that a factor including at least one of D-leucine, In an embodiment, at least one anti-microbial region D-methionine, D-tyrosine, or D-tryptophan is capable of includes at least one surface structure composition or depo breaking down biofilms, and is capable of preventing bio sition. In an embodiment, the Surface structure includes at film formation. In particular, biofilm formation by Staphly least one Substrate manufactured to include nanoscale topo coccus aureus and Pseudomonas aeruginosa were inhibited. 15 graphic anti-microbial features. See, for example, Kolodkin-Gal, et al., SCIENCE Vol. 328, Further non-limiting examples of coatings include Supe pp. 627-629 (2010), which is incorporated herein by refer rhydrophobic conducting polypyrrole films, coating, or CCC. components that are electrically switchable between an Among the one or more coatings, functionalized surfaces, oxidized State and a neutral state, resulting in reversibly Surface treatments, immuno-stimulating coatings, and the switchable superhydrophobic and superhydrophilic proper like, examples include, among other things, polymeric com ties (see, e.g., Lahann et al., A Reversibly Switching Surface, positions that resist bacterial adhesion, antimicrobial coat 299 (5605): 371-374 (2003) 21:47-51 (2003), the contents of ing, coatings that controllably release antimicrobial agents, each of which is incorporated herein by reference); coatings quaternary ammonium silane coatings, chitosan coatings, including electrically isolatable fluid-support structures (see, and the like. Further non-limiting examples of coatings, 25 e.g., U.S. Pat. No. 7,535,692 (issued May 19, 2009), the functionalized Surfaces, Surface treatments, immuno-stimu contents of each of which is incorporated herein by refer lating coatings, and the like may be found in, for example, ence); coatings including a plurality of Volume-tunable the following documents (the content of each of which is nanostructures (see, e.g., U.S. Patent Publication No. 2008/ incorporated herein by reference): U.S. Pat. Nos. 7,348,021 0095,977 (published Apr. 24, 2008), the contents of each of (issued Mar. 25, 2008), 7.217,425 (issued May 15, 2007), 30 which is incorporated herein by reference); coatings includ 7,151,139 (issued Dec. 19, 2006), and 7,143,709 (issued ing re-entrant Surface structures (see, e.g., Tuteja et al., Dec. 5, 2006). In an embodiment, at least a portion of an Robust Omniphobic Surfaces, Epub 2008 Nov. 10, 105(47): inner or an outer surface of the implantable device includes 18200-5 (2008), the contents of each of which is incorpo one or more self-cleaning coating materials. Examples of rated herein by reference); coatings including Superhydro self-cleaning coating (e.g., Lotus Effect) materials include, 35 phobic conducting polypyrrole materials, coatings including but are not limited to titanium dioxide, superhydrophobic Zwitterionic polymers (see, e.g., Cheng et al., A Switchable materials, carbon nanotubes with nanoscopic paraffin coat Biocompatible Polymer Surface with Self-Sterilizing and ing, or the like. Further non-limiting examples of self Nonfouling Capabilities, Angew. Chem. Int. Ed. 8831-8834 cleaning (e.g., non fouling) coating materials include anti (2008), the contents of each of which is herein by reference); microbial, and nonfouling Zwitterionic polymers, 40 or the like. Zwitterionic Surface forming materials, Zwitterionic poly Among active agents, examples include, but are not mers, poly(carboxybetaine methacrylate) (pCBMA), poly limited to, adjuvants, allergens, analgesics, anesthetics, anti (carboxybetaine acrylic amide) (pCBAA), poly(oligo(ethyl bacterial agents, antibiotics, antifungals, anti-inflammatory ene glycol) methyl ether methacrylate) (pOEGMA), poly agents (e.g., nonsteroidal anti-inflammatory drugs), antimi (N,N-dimethyl-N-(ethoxycarbonylmethyl)-N-2'- 45 crobials, antioxidants, antipyretics, anti-tumor agents, anti (methacryloyloxy)ethyl-ammonium bromide), cationic virals, bio-control agents, biologics or bio-therapeutics, che pC8NMA, switchable pCBMA-1 C2, pCBMA-2, and the motherapy agents, disinfecting agents, energy-actuatable like. See, e.g., WO 2008/083390 (published Jul. 10, 2008) active agents, immunogens, immunological adjuvants, (the contents of each of which is incorporated herein by immunological agents, immuno-modulators, immuno-re reference). 50 sponse agents, immuno-stimulators (e.g., specific immuno In an embodiment, at least one of the inner Surface or the stimulators, non-specific immuno-stimulators, or the like), outer surface of the body structure includes at least one immuno-Suppressants, non-pharmaceuticals (e.g., cosmetic high-aspect ratio polymer nanofibrillar structure (e.g., in the Substances, or the like), pharmaceuticals, protease inhibitors form of Stooped or crispated nanohairs). See, for example, or enzyme inhibitors, receptor agonists, receptor antago Kim, et al. Langmuir, Vol. 25, no. 16, pp. 8879-8882 (2009), 55 nists, active agents, tolerogens, toll-like receptor agonists, which is incorporated herein by reference. In an embodi toll-like receptor antagonists, vaccines, or combinations ment, the nanofibrillar surface can be controlled by oblique thereof. electronbeam irradiation, Such that the geometry of polymer Further non-limiting examples of active agents include nanohairs is tunable according to the tilting angle of the nonsteroidal anti-inflammatory drugs such as acemetacin, electron beam, the acceleration Voltage, and the exposure 60 aclofenac, aloxiprin, amtolimetin, aproxen, aspirin, azapro time. Id. paZone, benorilate, benoxaprofen, benzydamine hydrochlo In an embodiment, at least one of the inner Surface or the ride, benzydamine hydrochloride, bromfenal, bufexamac, outer surface of the body structure is switchable by exposure butibufen, carprofen, celecoxib, choline salicylate, clonixin, to ultraviolet light. For example, a fluorinated diarylethene desoxysulindac, diflunisal, dipyone, droxicam, etodolac, molecule with two thiophene rings decorated with methoxy 65 etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, fen and methylated silane pendant groups undergo reversible tiazac, fepradinol, floctafenine, flufenamic acid, indometha photoisomerization between open and closed ring forms cin, indoprofen, isoxicam, ketoralac, licofelone, lomoxicam, US 9,474,831 B2 35 36 loxoprofen, magnesium salicylate, meclofenamic acid, Wang, Nucleic Acids Res. 32:D590-D592, 2004): http:// meclofenamic acid, mefenamic acid, meloxicam, morniflu aps.unmc.edu/AP/main.php, which is incorporated herein by mate, niflumic acid, nimeSulide, oxaproZen, phenylbuta reference). More specific examples of antimicrobial peptides Zone, piketoprofen, piroxicam, pirprofen, priazolac, propy include, but are not limited to, anionic peptides, e.g., maxi phenaZone, produaZone, rofecoxib, Salalate, Salicylamide, min H5 from amphibians, Small anionic peptides rich in salicylic acid, sodium salicylate, Sodium thiosalicylate, glutamic and aspartic acids from sheep, cattle and humans, Sulindac. Suprofen, tenidap, tenoxicam, tiaprofenic acid, and dermcidin from humans; linear cationic alpha-helical tolimetin, tramadol, trolamine Salicylate, Zomepirac, or the peptides, e.g., cecropins (A), andropin, moricin, ceratotoxin, like. Further non-limiting examples of active agents include and melittin from insects, cecropin P1 from Ascaris nema energy (e.g., chemical energy, electrical resistance, laser 10 todes, magainin 2, dermaseptin, bombinin, brevinin-1, escu energy, terahertz energy, microwave energy, optical energy, lentins and buforin II from amphibians, pleurocidin from radio frequency energy, Sonic energy, thermal energy, ther skin mucous secretions of the winter flounder, seminalplas mal resistance heating energy or ultrasonic energy, or the min, BMAP, SMAP (SMAP29, ovispirin), PMAP from like)-actuatable active agents, and the like. cattle, sheep and pigs, CAP18 from rabbits and LL37 from In an embodiment, the active agent includes at least one 15 humans; cationic peptides enriched for specific amino acids, active agent that selectively targets bacteria. For example, in e.g., praline-containing peptides including abaecin from an embodiment, the active agent includes at least one honeybees, praline- and arginine-containing peptides includ bacteriophage that can, for example, selectively target bac ing apidaecins from honeybees, drosocin from Drosophila, teria. Bacteriophages generally comprise an outer protein pyrrhocoricin from European sap-sucking bug, bactenicins hull enclosing genetic material. The genetic material can be from cattle (Bac7), sheep and goats and PR-39 from pigs, ssRNA, dsRNA, ssDNA, or dsDNA. Bacteriophages are praline- and phenylalanine-containing peptides including generally Smaller than the bacteria they destroy generally prophenin from pigs, glycine-containing peptides including ranging from about 20 nm to about 200 nm. Non-limiting hymenoptaecin from honeybees, glycine- and praline-con examples of bacteriophages include T2, T4, T6, phiX-174. taining peptides including coleoptericin and holotricin from MS2, or the like). In an embodiment, the active agent 25 beetles, tryptophan-containing peptides including indolici includes at least one energy-actuatable agent that selectively din from cattle, and Small histidine-rich salivary polypep targets bacteria. For example, in an embodiment, the active tides, including histatins from humans and higher primates; agent includes at least one triplet excited-state photosensi anionic and cationic peptides that contain cysteine and from tizer that can, for example, selectively target bacteria. disulfide bonds, e.g., peptides with one disulphide bond Further non-limiting examples of active agents include 30 including brevinins, peptides with two disulfide bonds triplet excited-state photosensitizers, reactive oxygen spe including alpha-defensins from humans (HNP-1, HNP-2, cies, reactive nitrogen species, any other inorganic or cryptidins), rabbits (NP-1) and rats, beta-defensins from organic ion or molecules that include oxygen ions, free humans (HBD1, DEFB118), cattle, mice, rats, pigs, goats radicals, peroxides, or the like. Further non-limiting and poultry, and rhesus theta-defensin (RTD-1) from rhesus examples of active agents include compounds, molecules, or 35 monkey, insect defensins (defensin A); and anionic and treatments that elicit a biological response from any bio cationic peptide fragments of larger proteins, e.g., lactofer logical Subject. Further non-limiting examples of disinfect ricin from lactoferrin, casocidin 1 from human casein, and ing agents include active agents (e.g., antimicrobial active antimicrobial domains from bovine alpha-lactalbumin, agents), pharmaceuticals (e.g., a drug, a therapeutic com human hemoglobin, lysozyme, and ovalbumin (see, e.g., pound, pharmaceutical salts, or the like) non-pharmaceuti 40 Brogden, Nat. Rev. Microbiol. 3:238-250, 2005, which is cals (e.g., a cosmetic Substance, or the like), neutraceuticals, incorporated herein by reference). antioxidants, phytochemicals, homeopathic agents, and the Further non-limiting examples of active agents include like. Further non-limiting examples of disinfecting agents antibacterial drugs. Non-limiting examples of antibacterial include peroxidases (e.g., haloperoxidases such as chlorop drugs include beta-lactam compounds Such as penicillin, eroxidase, or the like), oxidoreductase (e.g., myeloperoxi 45 methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, dase, eosinophil peroxidase, lactoperoxidase, or the like) ampicillin, ticarcillin, amoxicillin, carbenicillin, and pipera oxidases, and the like. cillin; cephalosporins and cephamycins such as cefadroxil, Further non-limiting examples of active agents include cefazolin, cephalexin, cephalothin, cephapirin, cephradine, one or more pore-forming toxins. Non limiting examples of cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, pore-forming toxins include beta-pore-forming toxins, e.g., 50 loracarbef, ceforanide, cefoxitin, cefinetazole, cefotetan, hemolysin, Panton-Valentine leukocidin S. aerolysin, cefoperaZone, cefotaxime, ceftazidine, ceftizoxine, ceftriax Clostridial epsilon-toxin; binary toxins, e.g., anthrax, C. one, cefixime, cefpodoxime, proxetil, cefdinir, cefditoren, perfingens Iota toxin, C. difficile cytolethal toxins; choles pivoxil, ceftibuten, moxalactam, and cefepime; other beta terol-dependent cytolysins; pneumolysin; Small pore-form lactam drugs such as aztreonam, clavulanic acid, Sulbactam, ing toxins; and gramicidin A. 55 taZobactam, ertapenem, imipenem, and meropenem; other Further non-limiting examples of active agents include cell wall membrane active agents such as Vancomycin, one or more pore-forming antimicrobial peptides. Antimi teicoplanin, daptomycin, fosfomycin, bacitracin, and cyclos crobial peptides represent an abundant and diverse group of erine; tetracyclines such as tetracycline, chlortetracycline, molecules that are naturally produced by many tissues and oxytetracycline, demeclocycline, methacycline, doxycy cell types in a variety of invertebrate, plant and animal 60 cline, minocycline, and tigecycline; macrollides Such as species. The amino acid composition, amphipathicity, cat erythromycin, clarithromycin, azithromycin, and tellithro ionic charge and size of antimicrobial peptides allow them mycin; aminoglycosides Such as Streptomycin, neomycin, to attach to and insert into microbial membrane bilayers to kanamycin, amikacin, gentamicin, tobramycin, Sisomicin, form pores leading to cellular disruption and death. More and netilmicin; Sulfonamides such as Sulfacytine, Sulfisox than 800 different antimicrobial peptides have been identi 65 azole, silfamethizole, Sulfadiazine, Sulfamethoxazole, Sul fied or predicted from nucleic acid sequences, a Subset of fapyridine, and Sulfadoxine; fluoroquinolones such as cip which are available in a public database (see, e.g., Wang & rofloxacin, gatifloxacin, gemifloxacin, levofloxacin, US 9,474,831 B2 37 38 lomefloxacin, moxifloxacin, norfloxacin, and ofloxacin; includes energy-actuatable disinfecting agents, photoactive antimycobacteria drugs such as isoniazid, rifampin, rifabu agents, or a metabolic precursor thereof. In an embodiment, tin, rifapentine, pyrazinamide, ethambutol, ethionamide, the at least one energy-actuatable agent includes at least one capreomycin, clofazimine, and dapsone; and miscellaneous X-ray absorber. In an embodiment, the at least one energy antimicrobials such as colistimethate Sodium, methenamine actuatable agent includes at least one radiation absorber. hippurate, methenamine mandelate, metronidazole, mupiro The at least one active agent reservoir can include, for cin, nitrofurantoin, polymyxin B, clindamycin, choram example, among other things an acceptable carrier. In an phenicol, quinupristin-dalfopristin, lineZolid, spectrinomy embodiment, at least one active agent is carried by, encap cin, trimethoprim, pyrimethamine, and trimethoprim Sulated in, or forms part of an energy-sensitive (e.g., energy Sulfamethoxazole. 10 actuatable), carrier, vehicle, vesicle, pharmaceutical vehicle, Further non-limiting examples of active agents include pharmaceutical carrier, pharmaceutically acceptable vehicle, antifungal agents. Non-limiting examples of antifungal pharmaceutically acceptable carrier, or the like. agents include anidulafungin, amphotericin B, butacon Non-limiting examples of carriers include any matrix that azole, butenafine, caspofungin, clotrimazole, econazole, flu allows for transport of for example, a disinfecting agent conazole, flucytosine griseofulvin, itraconazole, ketocon 15 across any tissue, cell membranes, and the like of a biologi azole, miconazole, micafungin, naftifine, natamycin, cal Subject, or that is Suitable for use in contacting a nystatin, oxiconazole, Sulconazole, terbinafine, terconazole, biological subject, or that allows for controlled release tioconazole, tolnaftate, and/or Voriconazole. formulations of the compositions disclosed herein. Further Further non-limiting examples of active agents include non-limiting examples of carriers include at least one of anti-parasite agents. Non-limiting examples of anti-parasite creams, liquids, lotions, emulsions, diluents, fluid ointment agents include antimalaria drugs such as chloroquine, amo bases, gels, organic and inorganic solvents, degradable or diacquine, quinine, quinidine, mefloquine, primaquine, Sul non-degradable polymers, pastes, salves, vesicle, and the fadoxine-pyrimethamine, atovaquone-proguanil, chlo like. Further non-limiting examples of carriers include rproguanil-dapsone, proguanil, doxycycline, halofantrine, cyclic oligosaccharides, ethasomes, hydrogels, liposomes, lumefantrine, and artemisinins; treatments for amebiasis 25 micelle, microspheres, nisomes, non-ionic Surfactant Such as metronidazole, iodoquinol, paromomycin, dilox vesicles, organogels, phospholipid surfactant vesicles, phos anide furoate, pentamidine, Sodium Stibogluconate, emetine, pholipid Surfactant vesicles, transfersomes, Virosomes. Fur and dehydroemetine; and other anti-parasite agents such as ther non-limiting examples of energy-sensitive carriers and pentamidine, nitaZoxanide, Suramin, melarsoprol, eflornith the like include electrical energy-sensitive, light sensitive, ine, nifurtimox, clindamycin, albendazole, and timidazole. 30 pH-sensitive, ion-sensitive, Sonic energy sensitive, ultra Further non-limiting examples of active agents include ionic Sonic energy sensitive carriers. silver, (SilvaSorb(R), Medline Industries, Inc), anti-microbial In an embodiment, one or more active agents are carried silver compositions (Arglaes R., Medline Industries, Inc), or by energy-sensitive vesicles (e.g., energy-sensitive cyclic the like. Further non-limiting examples of active agents oligosaccharides, ethasomes, hydrogels, liposomes, include Superoxide-forming compositions. Further non-lim 35 micelles, microspheres, nisomes, non-ionic Surfactant iting examples of active agents include oxazolidinones, vesicles, organogels, phospholipid surfactant vesicles, trans gram-positive antibacterial agents, or the like. See, e.g., U.S. fersomes, Virosomes, and the like). In an embodiment, at Pat. No. 7,322,965 (issued Jan. 29, 2008), which is incor least one of the energy emitters is configured to provide porated herein by reference. energy of a character and for a time Sufficient to liberate at In an embodiment, the active agent includes one or more 40 least a portion of an active agent carried by the energy antimicrobial agents. In an embodiment, the antimicrobial sensitive vesicles. agent is an antimicrobial peptide. Amino acid sequence Among tracer agents, examples include one or more in information for a subset of these can be found as part of a Vivo clearance agents, magnetic resonance imaging agents, public database (see, e.g., Wang & Wang, Nucleic Acids Res. contrast agents, dye-peptide compositions, fluorescent dyes, 32:D590-D592, 2004): http://aps.unmc.edu/AP/main.php, 45 or tissue specific imaging agents. In an embodiment, the one which is incorporated herein by reference). Alternatively, a or more tracer agents include at least one fluorescent dye. In phage library of random peptides can be used to Screen for an embodiment, the one or more tracer agents include peptides with antimicrobial properties against live bacteria, indocyanine green. fungi and/or parasites. The DNA sequence corresponding to Formulations for Anti-Microbial Agents in Reservoirs an antimicrobial peptide can be generated ex vivo using 50 An anti-microbial agent delivered from one or more standard recombinant DNA and protein purification tech anti-microbial agent reservoirs can be administered alone or niques. in combination with one or more pharmaceutically accept In an embodiment, one or more of the active agent include able carriers, diluents, excipients, and/or vehicles such as, chemicals suitable to disrupt or destroy cell membranes. For for example, buffers, Surfactants, preservatives, solubilizing example, Some oxidizing chemicals can withdraw electrons 55 agents, isotonicity agents, and stablilizing agents as appro from a cell membrane causing it to, for example, become priate. In an embodiment, the anti-microbial agent can be destabilized. Destroying the integrity of cell membranes of carried by, encapsulated in, or forms part of an energy for example, a pathogen can lead to cell death. sensitive (e.g., energy-actuatable), carrier, vehicle, vesicle, Non-limiting examples of energy-actuatable active agents pharmaceutically vehicle, pharmaceutically carrier, pharma include radiation absorbers, light energy absorbers, X-ray 60 ceutically acceptable vehicle, pharmaceutically acceptable absorbers, photoactive agents, and the like. Non-limiting carrier, or the like. A “pharmaceutically acceptable' carrier, examples of photoactive agents include, but are not limited for example, may be approved by a regulatory agency of the to photoactive antimicrobial agents (e.g., eudistomin, pho state and/or Federal government such as, for example, the toactive porphyrins, photoactive TiO, antibiotics, silver United States Food and Drug Administration (US FDA) or ions, antibodies, nitric oxide, or the like), photoactive anti 65 listed in the U.S. Pharmacopeia or other generally recog bacterial agents, photoactive antifungal agents, and the like. nized pharmacopeia for use in animals, and more particu Further non-limiting examples of energy-actuatable agent larly in humans. Conventional formulation techniques gen US 9,474,831 B2 39 40 erally known to practitioners are described in Remington: cellulose ethers, cellulose and hydroxylated cellulose, The Science and Practice of Pharmacy, 20" Edition, Lip methyl cellulose and hydroxylated methyl cellulose, gums pincott Williams & White, Baltimore, Md. (2000), which is Such as guar, locust, karaya, Xanthan gelatin, and derivatives incorporated herein by reference in its entirety. thereof. Acceptable pharmaceutical carriers include, but are not As indicated in the Figures, in an embodiment, the device limited to, the following: Sugars, such as lactose, glucose includes at least one reservoir. In an embodiment, the and Sucrose; starches, such as corn starch and potato starch; reservoir includes, but is not limited to, at least one of a cellulose, and its derivatives. Such as sodium carboxymethyl metal, ceramic, glass, non-crystalline material, semiconduc cellulose, ethyl cellulose, cellulose acetate, and hydroxym tor, composite, or polymer. In an embodiment, the at least ethylcellulose; polyvinylpyrrolidone; cyclodextrin and amy 10 lose; powdered tragacanth; malt, gelatin, agar and pectin; one reservoir includes at least one active agent. In an talc; oils, such as mineral oil, polyhydroxyethoxylated castor embodiment, the at least one active agent is in the form of oil, peanut oil, cottonseed oil, safflower oil, sesame oil, olive a matrix including biodegradable material, or biocompatible oil, corn oil and soybean oil; polysaccharides, such as material. In certain instances, the release rate of the at least alginic acid and acacia; fatty acids and fatty acid derivatives, 15 one active agent can be regulated or controlled. In an Such as Stearic acid, magnesium and Sodium Stearate, fatty embodiment, the release rate of the at least one active agent acid amines, pentaerythritol fatty acid esters; and fatty acid is continuous, for example, by diffusion out or through a monoglycerides and diglycerides; glycols, such as propylene material. In an embodiment, the at least one reservoir glycol, polyols, such as glycerin, Sorbitol, mannitol and includes at least one biodegradable material. In an embodi polyethylene glycol; esters, such as ethyl oleate and ethyl ment, degradation of the at least one reservoir results in laurate; buffering agents, such as magnesium hydroxide, release of the contents of the at least one reservoir, for aluminum hydroxide and sodium benzoate/benzoic acid; example, by having at least a portion of the at least one water, isotonic saline; Ringer's Solution; ethyl alcohol; reservoir selectively degrade. In an embodiment, the device phosphate buffer solutions; other non-toxic compatible sub includes multiple reservoirs. In an embodiment, one or more stances employed in pharmaceutical compositions. 25 of the multiple reservoirs are selectively degraded in order In an aspect, the anti-microbial agent is incorporated into to regulate release of the contests thereof. the anti-microbial agent reservoir in a liquid form and One example of an active timed release device includes a diffuses or expels out of the reservoir once the release reservoir having a cap consisting of a thin film of conductive mechanism has been triggered. The anti-microbial agent can material deposited over the reservoir and capable of dissolv be formulated in a pharmaceutically acceptable liquid car 30 ing or disintegrating upon electrical conductivity. See, for rier. In an aspect, the liquid carrier or vehicle is a solvent or example, U.S. Patent App. Pub. No.: 20050149000, which is liquid dispersion medium comprising, for example, water, incorporated herein by reference. saline solution, ethanol, a polyol, vegetable oils, nontoxic At least a portion of the devices and/or processes glyceryl esters, and suitable mixtures thereof. The solubility described herein can be integrated into a data processing of an anti-microbial agent can be enhanced using solubility 35 system. A data processing system generally includes one or enhancers such as, for example, water, diols, such as pro more of a system unit housing, a video display device, pylene glycol and glycerol; mono-alcohols, such as ethanol, memory such as volatile or non-volatile memory, processors propanol, and higher alcohols; DMSO (dimethylsulfoxide); Such as microprocessors or digital signal processors, com dimethylformamide, N,N-dimethylacetamide: 2-pyrroli putational entities such as operating systems, drivers, done, N-(2-hydroxyethyl) pyrrolidone, N-methylpyrroli 40 graphical user interfaces, and applications programs, one or done, 1-dodecylazacycloheptan-2-one and other n-substi more interaction devices (e.g., a touch pad, a touch screen, tuted-alkyl-azacycloalkyl-2-ones and other n-substituted an antenna, etc.), and/or control systems including feedback alkyl-azacycloalkyl-2-ones (aZones). In some instances, it loops and control motors (e.g., feedback for detecting posi may be preferable to include isotonic agents such as, for tion and/or Velocity, control motors for moving and/or example, Sugars, buffers, sodium chloride or combinations 45 adjusting components and/or quantities). A data processing thereof. system can be implemented utilizing Suitable commercially In an aspect, the anti-microbial agent is incorporated into available components, such as those typically found in data the reservoir in a non-soluble form, either as one or more computing/communication and/or network computing/com dispersible particles or as an erodible form remaining in the munication systems. opened reservoir. For example, the anti-microbial agent can 50 FIGS. 1A, 1B, 2A, and 2B show various embodiments of be incorporated into the anti-microbial agent reservoir in a system 100 (e.g., a catheter system, an implantable cath solid form and formulated to slowly dissolve in a time eter system, an implantable system, an indwelling system, a dependent manner once in contact with the fluid environ partially implantable system, a fluid management system, or ment of a patient's tissue. The anti-microbial agent can be the like including an insertable device, partially implantable formulated in a slow release, controlled release, or extended 55 device, or implantable device) in which one or more meth release biodegradable composition that dissolves or breaks odologies or technologies can be implemented, such as, down in a time dependent manner. Examples of slow managing a transport of fluids, providing Surgical access, release, controlled release, or extended release compositions delivering therapeutics, as well as actively detecting, treat include but are not limited to hydrogels, polymers, gelled ing, or preventing an infection (e.g., an implant-associated and/or cross-linked water swellable polyolefins, polycarbon 60 infection, a hematogenous associated infection, an infection ates, polyesters, polyamides, polyethers, polyepoxides and present in tissue or biological fluid, a biofilm formation, a polyurethanes such as, for example, poly(acrylamide), poly microbial colonization, or the like), a biological sample (2-hydroxyethyl acrylate), poly(2-hydroxypropyl acrylate), abnormality (e.g., a cerebral spinal fluid abnormality, a poly(N-vinyl-2-pyrrolidone), poly(n-methylol acrylamide), hematological abnormality, a tissue abnormality, or the like), poly(diacetone acrylamide), poly(2-hydroxylethyl meth 65 or the like. In an embodiment, the system 100 has at least acrylate), poly(allyl alcohol). Other suitable polymers one component at least partially inserted into a biological include but are not limited to cellulose ethers, methyl subject 222. US 9,474,831 B2 41 42 In an embodiment, the system 100 is configured to, the surface of the body structure 104. In an embodiment, at among other things, reduce an in vivo concentration of an least one of the anti-microbial regions 202 is configured to infectious agent (e.g., microorganism) present in a biologi provide at least one anti-microbial property 204 of a char cal fluid (e.g., bodily fluid, blood, amniotic fluid, ascites, acter and for a time sufficient to inhibit adherence of at least bile, cerebrospinal fluid, interstitial fluid, pleural fluid, tran one extracellular matrix component to the Surface of the scellular fluid, or the like) managed by the system 100, or a body structure 104. In an embodiment, the extracellular biological sample 808 proximate one or more components of matrix component includes at least one of a protein, or the system 100. In an embodiment, the system 100 is glycosaminoglycan. In an embodiment, the at least one configured to provide antimicrobial therapy. anti-microbial property 204 includes at least one of nano The system 100 can include, among other things, at least 10 scale or micro-scale roughness. one insertable device 102. In an embodiment, the insertable In an embodiment, the anti-microbial agent includes at device 102 includes, among other things, a body structure least one of an anti-fungal agent, anti-parasitic agent, energy 104 having an outer surface 106 and an inner surface 108 emitter, photoactive material, thermal plasmonic structure, defining one or more fluid-flow passageways 110. In an thermal ridge, nanostructure, microstructure, Surface undu embodiment, the system 100 is configured to reduce the 15 lation, protease, amino acid, Surfactant, electricity, optical concentration of an infectious agent in the immediate vicin energy, plasmonic energy, bacteriophage, photoactive mate ity of an insertable device 102. For example, in an embodi rial, or antibiotic. In an embodiment, the bacteriophage ment, the system 100 is configured to controllably deliver includes an engineered enzymatically active bacteriophage. one or more anti-microbial agents to at least one of an inner In an embodiment, the anti-microbial agent includes at least surface 108 or an outer surface 106 of one or more fluid-flow two different bacteriophage sets. passageways 110 of an insertable device 102. In an embodiment, the antibiotic includes at least one of The insertable device 102 can include, among other azithromycin, clarithromycin, clindamycin, dirithromycin, things, one or more catheters 112. In an embodiment, the erythromycin, lincomycin, troleandomycin, cinoxacin, cip insertable device 102 is positioned to facilitate the admin rofloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxa istration of therapeutics (e.g., anti-microbial agents or other 25 cin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, therapeutic agents), nutraceuticals, intravenous fluids, blood ofloxacin, sparfloxacin, trovafloxacin, oxolinic acid, gemi products, parenteral nutrition, or the like. In an embodiment, floxacin, perfloxacin, imipenem-cilastatin, meropenem, the insertable device 102 is positioned to provide access for aztreonam, amikacin, gentamicin, kanamycin, neomycin, Surgical instruments. In an embodiment, the insertable netilmicin, streptomycin, tobramycin, paromomycin, teico device 102 is positioned to provide vascular access. In an 30 planin, Vancomycin, demeclocycline, doxycycline, meth embodiment, the insertable device 102 is positioned to acycline, minocycline, oxytetracycline, tetracycline, chlo facilitate drainage. rtetracycline, mafenide, sulfadizine, sulfacetamide, Among catheters 112, examples include, but are not Sulfadiazine, Sulfamethoxazole, Sulfasalazine, Sulfisoxazole, limited to, arterial catheters, dialysis catheters, drainage trimethoprim-sulfamethoxazole, sulfamethizole, linezolid, catheters, indwelling catheters, long term non-tunneled cen 35 quinopristin--dalfopristin, bacitracin, chloramphenicol, tral venous catheters, long term tunneled central venous colistemetate, fosfomycin, isoniazid, methenamine, metron catheters, mechanical catheters, peripheral venous catheters, idazol, mupirocin, nitrofurantoin, nitrofuraZone, novobio peripherally insertable central venous catheters, peritoneal cin, polymyxin B, spectinomycin, trimethoprim, collistin, catheters, pulmonary artery Swan-Ganz catheters, short cycloserine, capreomycin, ethionamide, pyrazinamide, para term central venous catheters, urinary catheters, ventricular 40 aminosalicyclic acid, erythromycin ethylsuccinate+Sulfisox catheters, and the like. In an embodiment, the body structure azole, penicillin, beta-lactamase inhibitor, methicillin, cefa 104 includes one or more catheters 112 each having a clor, cefamandole nafate, cefazolin, cefixime, cefinetazole, proximal portion 114, a distal portion 116, and at least one cefonioid, cefoperaZone, ceforanide, cefotainme, cefotaxime, fluid-flow passageway 110 extending therethrough. In an cefotetan, cefoxitin, cefpodoxime proxetil, ceftazidime, embodiment, one or more of the catheters 112 are configured 45 ceftizoxime, ceftriaxone, cefriaxone moxalactam, cefuroX for insertion into a body cavity, a duct, or a vessel of a ime, cephalexin, cephalosporin C, cephalosporin C sodium subject. In an embodiment, the system 100 can include, salt, cephalothin, cephalothin Sodium salt, cephapirin, among other things, one or more power sources 900. cephradine, cefuroximeaxetil, dihydratecephalothin, moxa In an embodiment, at least one of the anti-microbial lactam, loracarbef mafate, Amphotericin B, Carbol-Fuchsin, regions 202 is selectively actuatable 202a. In an embodi 50 Ciclopirox, Clotrimzole, Econazole, Haloprogin, Ketocon ment, at least one of the anti-microbial regions 202 is azole, Mafenide, Miconazole, Naftifine, Nystatin, Oxicon selectively actuatable between at least a first actuatable state azole Silver, Sulfadiazine, Sulconazole, Terbinatine, Tiocon and a second actuatable state. In an embodiment, at least one azole, Tolnaftate, Undecylenic acid, flucytosine, of the anti-microbial regions 202 is independently address miconazole, cephabam, beta-lactam, or cephalosporin. In an able 202b. In an embodiment, the insertable device 102 55 embodiment, the anti-microbial agent includes at least one includes one or more ports 118 configured to provide access of a macrollide, lincosamine, quinolone, fluoroquinolone, to, or from, an interior environment of at least one of the carbepenem, monobactam, aminoglycoside, glycopeptide, fluid-flow passageways 110. enzyme, tetracycline, Sulfonamide, rifampin, oxazoli In an embodiment, at least one of the anti-microbial donone, Streptogramin, or a synthetic moiety thereof. In an regions 202 is configured to provide at least one anti 60 embodiment, the anti-microbial agent includes at least one microbial property 204 of a character and for a time suffi Surfactant or amino acid. In an embodiment, the amino acid cient to inhibit microbial growth or microbial adherence to includes at least one D-amino acid. In an embodiment, the at least one of the anti-microbial regions 202 of the body anti-microbial agent includes at least one of a ceramic, structure 104. In an embodiment, at least one of the anti Super-oxide forming compound, enzyme, or polymer. In an microbial regions 202 is configured to provide at least one 65 embodiment, the anti-microbial agent includes at least one anti-microbial property 204 of a character and for a time metal, or salt thereof. In an embodiment, the enzyme Sufficient to inhibit at least one of microbial aggregation on includes at least one of DNAse, protease, glucosidase, or US 9,474,831 B2 43 44 endopeptidase. In an embodiment, the ceramic includes bound to the porous material 209. In an embodiment, the Zeolite, optionally with silver ions exchanged onto internal hydrophobic polycations include at least one of N-alkylated acidic sites of the Zeolite. In an embodiment, the anti poly 14-vinylpyridine, hexyl-poly 14-vinylpyridine, or microbial agent includes polytetrafluoroethylene. In an N-hexylated-methylated high molecular weight polyethyl embodiment, the anti-microbial agent includes at least one 5 enimine. In an embodiment, the porous material 209 of Group B Streptococci phage lysin, aminoglycoside, car includes at least one of cotton, wool, nylon, or polyester. bapenem, cephlasporin, fluoroquinolone, glycylcycline, In an embodiment, the insertable device 102 includes one macrollide, monobactam, penicillin, polypeptide, Sulfona or more catheters 112 configured for directly detecting or mide, tetracycline, metronidazole, rifampin, pyrazinamide, monitoring mechanical, physical, or biochemical functions nitrofurantoin, quinupristin-dalfopristin, spectinomycin, 10 associated with a biological Subject, draining or collecting telithromycin, Vancomycin, lineZolid, isoniazid, fosfomycin, body fluids; providing access to an interior of a biological ethambutol, daptomycin, clindamycin, or chloramphenicol. Subject; or distending at least one fluid-flow passageway In an embodiment at least one of the anti-microbial regions 110; as well as for administering therapeutics, nutraceuti 202 includes at least one of silver, copper, Zirconium, cals, intravenous fluids, nutrition, or the like. In an embodi diamond, rubidium, platinum, gold, nickel, lead, cobalt, 15 ment, the insertable device 102 includes one or more at least potassium, zinc, bismuth, tin, cadmium, chromium, alumi partially implantable catheters 112. In an embodiment, the num, calcium, mercury, thallium, gallium, strontium, insertable device 102 includes one or more ports 118 con barium, lithium, magnesium, oxides, hydroxides, or salts figured to provide access to, or from, an interior environ thereof. ment of at least one of the fluid-flow passageways 110. In an In an embodiment, an insertable device 102 includes a embodiment, the insertable device 102 includes one or more body structure 104 having an outer surface 106 and an inner biocompatible materials, biodegradable materials, poly surface 108 defining one or more fluid-flow passageways meric materials, thermoplastics, silicone materials (e.g., 110; one or more anti-microbial regions 202 including at polydimethysiloxanes), polyvinyl chloride materials, silk, least one D-amino acid coating on at least one of the outer biodegradable polymer, hydrogel, latex rubber materials, or surface 106, inner surface 108, or embedded in the body 25 the like. structure 104. In an embodiment, the D-amino acid includes In an embodiment, an at least partially implantable fluid at least one of D-leucine, D-methionine, D-tyrosine, or management system includes: a catheter assembly having a D-tryptophan. In an embodiment, an insertable device 102 body structure 104 including at least an outer surface 106 includes a body structure 104 having an outer surface 106 and an inner surface 108 defining one or more fluid-flow and an inner surface 108 defining one or more fluid-flow 30 passageways 110; and a plurality of selectively actuatable passageways 110; one or more selectively actuatable anti anti-microbial regions 202a configured to deliver at least microbial regions 202a including at least one anti-microbial one anti-microbial agent to at least a portion of one or more reservoir 208 including at least one D-amino acid, the of the outer surface 106, the inner surface 108, or embedded anti-microbial reservoir 208 configured to deliver at least in the internal body structure 104. one D-amino acid to at least one of the outer surface 106 35 Further non-limiting examples of catheters 112, shunts, inner surface 108, or internal body structure 104. medical ports, insertable devices, implantable devices, In an embodiment, at least one of the anti-microbial implantable or insertable device assemblies, or components regions 202 includes at least one of black silica, or hydro thereof, may be found in, for example the following docu genated diamond. In an embodiment, at least one of the ments (the contents of each of which is incorporated herein anti-microbial regions includes at least one electroactive 40 by reference): U.S. Pat. Nos. 7,524.298 (issued Apr. 28, polymer. In an embodiment, at least one of the anti-micro 2009), 7,390,310 (issued Jun. 24, 2008), 7,334,594 (issued bial regions includes at least one of polyvinyl chloride, Feb. 26, 2008), 7.309,330 (issued Dec. 18, 2007), 7,226,441 polyester, polyethylene, polypropylene, ethylene, or poly (issued Jun. 5, 2007), 7,118,548 (issued Oct. 10, 2006), olefin; or homopolymers or copolymers thereof. 6,932,787 (issued Aug. 23, 2005), 6,913,589 (issued Jul. 5, In an embodiment, at least one of the anti-microbial 45 2005), 6,743,190 (issued Jun. 1, 2004), 6,585,677 (issued regions 202 includes an anti-microbial property 204 selec Jul. 1, 2003); and U.S. Patent Publication Nos. 2009/ tive for at least one of a single phylum of microorganism, 0118661 (published May 7, 2009), 2009/0054824 (pub single genus of microorganism, single strain of microorgan lished Feb. 26, 2009), 2009/0054827 (published Feb. 26, ism, or single microorganism. In an embodiment, the at least 2009), 2008/0039768 (published Feb. 14, 2008), and 2006/ one anti-microbial property 204 is selected based on 50 0.004317 (published Jan. 5, 2006). expected microorganism presence or actual microorganism In an embodiment, the one or more anti-microbial regions presence proximate the body structure 104. In an embodi 202 can take a variety of shapes, configurations, or geom ment, at least one anti-microbial property 204 is selected etries, including, but not limited to, cylindrical, conical, based on expected microorganism response to at least one planar, parabolic, regular or irregular forms. In an embodi other anti-microbial region 202 of the body structure 104. 55 ment, a plurality of anti-microbial regions 202 are config In an embodiment, the body structure 104 of the insertable ured as bands on at least one of the outer surface 106, the device 102 includes at least one porous material 209. In an inner surface 108, or embedded in the body structure 104 of embodiment, at least one of the anti-microbial regions 202 the device 102. The one or more anti-microbial regions 202 includes at least one porous material 209. In an embodiment, can also form a variety of patterns 109 (e.g., spatial or the at least one porous material 209 is configured to capture 60 temporal patterns). Such as, repeating pattern, non-repeating at least one microorganism proximate to at least one of the pattern, graduating pattern, blocking pattern, or partially inner surface 108 or the outer surface 106 of the body repeating pattern. In an embodiment, the at least one spatial structure 104. In an embodiment, the at least one porous pattern or temporal pattern is derived from information material 209 is further configured to retain a captured relating to the type of microorganism expected to be present microorganism. In an embodiment, the porous material 209 65 proximate the body structure 104. In an embodiment, the at includes hydrophobic polycations bound thereto. In an least one spatial pattern or temporal pattern is based at least embodiment, the hydrophobic polycations are covalently in part on information relating to at least one of the type of US 9,474,831 B2 45 46 microorganism previously detected on at least one anti refractive index sensor, biomass sensor, electrochemical microbial region of the body structure 104. In an embodi sensor, fluid-flow sensor, or electronic sensor. ment, the blocking pattern is configured such that it forms In an embodiment, the sensor 302 is configured to detect the sole pathway to another pattern on the body structure (e.g., assess, calculate, evaluate, determine, gauge, measure, 104. In an embodiment, multiple anti-microbial regions 202 monitor, quantify, resolve, sense, or the like) at least one are formed from a single Substrate or structure. Non-limiting characteristic (e.g., a spectral characteristic, a spectral sig examples of anti-microbial regions 202 include at least one nature, a physical quantity, a relative quantity, an environ anti-microbial Surface property 204 (e.g., anti-microbial mental attribute, a physiologic characteristic, or the like) protruding elements 206 (e.g., anti-microbial nanostructures associated with a biological Subject 222. In an embodiment, 206a, etc.), anti-microbial polymers, anti-microbial metals, 10 the sensor 302 is configured to detect (e.g., assess, calculate, anti-microbial agents, etc., anti-microbial reservoir 208 evaluate, determine, gauge, measure, monitor, quantify, including at least one anti-microbial agent, or the like). In an resolve, sense, or the like) at least one characteristic (e.g., a embodiment, the one or more anti-microbial regions 202 spectral characteristic, a spectral signature, a physical quan include at least one structure, agent, or other anti-microbial tity, a relative quantity, an environmental attribute, a physi surface property 204 suitable for directing at least one 15 ologic characteristic, or the like) a microbial component. In microorganism toward or away from a particular location of an embodiment, the microbial component includes at least the insertable device 102. In an embodiment, the anti one a lipid, peptide, lipopolysaccharide, flagellin, lipote microbial agent is formulated to be released or activated ichoic acid, peptidoglycan, nucleic acid (e.g., DNA, double over time. stranded RNA, etc), unmethylated CpG motifs, polypeptide, In an embodiment, at least one of the anti-microbial protein, glycolipid, proteoglycan, lipoprotein, glycoprotein, regions 202 is actuatable 202a. In an embodiment, the glycosaminoglycan, polysaccharide, glycopeptides, metal actuatable anti-microbial region 202a is configured to loprotein, enzyme, carbohydrate, cytokine, microbial cell release at least one anti-microbial agent based at least in part membrane, microbial cell receptor, pathogen-associated on at least one detected microbial component associated molecular pattern, or other microbial component. with the biological sample 808. In an embodiment, at least 25 In an embodiment, the sensor 302 is configured to detect one of the anti-microbial regions 202 is actuatable by the (e.g., assess, calculate, evaluate, determine, gauge, measure, presence of at least one microorganism (e.g., bacteria, fungi, monitor, quantify, resolve, sense, or the like) at least one etc.). In an embodiment, the at least one microorganism characteristic (e.g., a spectral characteristic, a spectral sig includes at least one of Staphylococcus, Pseudomonas, or nature, a physical quantity, a relative quantity, an environ Escherichia bacteria. In an embodiment, the at least one 30 mental attribute, a physiologic characteristic, or the like) of microorganism includes at least one of Candida, or Saccha a microbial component proximate the body structure 104. In romyces. an embodiment, the sensor 302 is configured to detect (e.g., In an embodiment, the actuatable anti-microbial region assess, calculate, evaluate, determine, gauge, measure, 202a is configured for reversible activation. In an embodi monitor, quantify, resolve, sense, or the like) at least one ment, the at least one actuatable anti-microbial region 202a 35 characteristic (e.g., a spectral characteristic, a spectral sig is configured for irreversible activation. In an embodiment, nature, a physical quantity, a relative quantity, an environ the actuatable anti-microbial region 202a is actuatable by at mental attribute, a physiologic characteristic, or the like) of least partial degradation of the body structure 104. the presence of at least one microorganism within at least In an embodiment, the insertable device 102 further one of the fluid-flow passageways 110. In an embodiment, comprises at least one light source 211. In an embodiment, 40 the sensor 302 is configured to detect (e.g., assess, calculate, the at least one light source 211 is coupled to at least one evaluate, determine, gauge, measure, monitor, quantify, anti-microbial region 202. In an embodiment, the at least resolve, sense, or the like) at least one characteristic (e.g., a one light source 211 includes at least one of a light-emitting spectral characteristic, a spectral signature, a physical quan diode, ultraviolet light source, or infrared light source. tity, a relative quantity, an environmental attribute, a physi In an embodiment, the system 100 comprises a body 45 ologic characteristic, or the like) the presence of at least one structure 104 having an outer surface 106 and an inner microorganism proximate at least one of the anti-microbial surface 108 defining one or more fluid-flow passageways regions 202. In an embodiment, the sensor 302 is configured 110; at least one independently addressable and actively to detect (e.g., assess, calculate, evaluate, determine, gauge, controllable anti-microbial nanostructure 206a projecting measure, monitor, quantify, resolve, sense, or the like) at from at least one of the outer surface 106, or the inner 50 least one characteristic (e.g., a spectral characteristic, a surface 108 of the body structure 104; at least one sensor 302 spectral signature, a physical quantity, a relative quantity, an configured to detect one or more microorganisms present environmental attribute, a physiologic characteristic, or the proximate the body structure 104; and means for determin like) the presence of at least one microorganism proximate ing the presence of at least one microorganism proximate at one or more fluid-flow passageways 110. In an embodiment, least one of the independently addressable and actively 55 the sensor 302 is configured to detect (e.g., assess, calculate, controllable anti-microbial nanostructure 206a of the body evaluate, determine, gauge, measure, monitor, quantify, structure 104. In an embodiment, the system 100 further resolve, sense, or the like) at least one characteristic (e.g., a includes one or more instructions for determining the pres spectral characteristic, a spectral signature, a physical quan ence of at least one microorganism proximate at least one of tity, a relative quantity, an environmental attribute, a physi the independently addressable anti-microbial regions 202b 60 ologic characteristic, or the like) of the presence of at least of the body structure 104. one microorganism within the one or more fluid-flow pas Referring to FIGS. 2A and 2B, the system 100 can sageways 110 based on one or more flow characteristics. include, among other things, at least one sensor 302. In an In an embodiment, the sensor 302 is configured to per embodiment, the sensor 302 includes at least one of a form a real-time comparison of a measurand associated with plasmon sensor, pH sensor, temperature sensor, piezoelectric 65 a biological sample 808 proximate the insertable device 102 sensor, electrostrictive sensor, magnetostrictive sensor, bio to stored reference data and to generate a response 299 based chemical sensor, optical sensor, optical density sensor, on the comparison. In an embodiment, the sensor 302 is US 9,474,831 B2 47 48 configured to perform a comparison of a real-time detection or scintillation detector devices. In an embodiment, the associated with at least one anti-microbial region 202 of at sensor 302 includes one or more ultrasonic transducers. least one of the outer surface 106, or the inner surface 108 In an embodiment, the sensor 302 includes at least one of of the body structure 104, to the microbial marker informa an imaging spectrometer, a photo-acoustic imaging spec tion and to generate a response 299 based at least in part on trometer, a thermo-acoustic imaging spectrometer, and a the comparison. In an embodiment, the sensor 302 is con photo-acoustic/thermo-acoustic tomographic imaging spec figured to perform a comparison of a cumulative detection trometer. In an embodiment, the sensor 302 includes at least associated with at least one anti-microbial region 202 of at one of a thermal detector, a photovoltaic detector, or a least one of the outer surface 106 or the inner surface 108 of photomultiplier detector. the body structure 104 to the microbial marker information 10 In an embodiment, the sensor 302 includes one or more to generate a response 299 based at least in part on the density sensors. In an embodiment, the sensor 302 includes comparison. For example, the response 299 can include, one or more optical density sensors. In an embodiment, the among other things, activating an authorization protocol, sensor 302 includes one or more refractive index sensors. In activating an authentication protocol, activating a software an embodiment, the sensor 302 includes one or more fiber update protocol 333, activating a data transfer protocol 303, 15 optic refractive index sensors. or activating an anti-microbial region diagnostic protocol In an embodiment, the sensor 302 includes one or more 334. In an embodiment, the response 299 includes one or biosensors 303 (e.g., acoustic biosensors, amperometric more of a response 299 signal, control signal, or change in biosensors, calorimetric biosensors, optical biosensors, or delivery of at least one anti-microbial agent. In an embodi potentiometric biosensors). In an embodiment, the sensor ment, the response 299 includes one or more of sending 302 includes one or more fluid-flow sensors. In an embodi information associated with at least one of an authentication ment, the sensor 302 includes one or more differential protocol, an authorization protocol, an anti-microbial deliv electrodes, biomass sensors, immunosensors, or the like. In ery protocol, an activation protocol, an encryption protocol, an embodiment, the sensor 302 includes one or more one-, or a decryption protocol. two-, or three-dimensional photodiode arrays. In an embodiment, the sensor 302 is operably coupled to 25 In an embodiment, the system 100 includes one or more one or more computing devices 230. In an embodiment, at sensors 302. In an embodiment, the insertable device 102 least one computing device 230 is operably coupled to the includes one or more of the sensors 302. Non-limiting sensor 302 and configured to process an output associated examples of sensors 302 include acoustic wave sensors, with one or more sensor measurands. In an embodiment, at aptamer-based sensors, biosensors, blood Volume pulse sen least one computing device 230 is configured to concur 30 sors, cantilevers, conductance sensors, fluorescence sensors, rently or sequentially operate multiple sensors 302. In an force sensors, heat sensors (e.g., thermistors, thermocouples, embodiment, the sensor 302 includes a computing device or the like), high resolution temperature sensors, differential 230 configured to process sensor measurand information and calorimeter sensors, optical sensors, goniometry sensors, configured to cause the storing of the measurand information potentiometer sensors, resistance sensors, respiration sen in a data storage medium. In an embodiment, the sensor 302 35 sors, Sound sensors (e.g., ultrasound), Surface Plasmon includes an identification code and is configured to imple Band Gap sensor (SPRBG), physiological sensors, and the ment instructions addressed to the sensor 302 according to like. Further non-limiting examples of sensors 302 include the component identification code. affinity sensors, bioprobes, biostatistics sensors, enzymatic In an embodiment, the sensor 302 includes one or more sensors, in-situ sensors (e.g., in-situ chemical sensor), ion Surface plasmon resonance sensors. For example, in an 40 sensors, light sensors (e.g., visible, infrared, or the like), embodiment, the sensor 302 includes one or more localized microbiological sensors, microhotplate sensors, micron Surface plasmon resonance sensors. In an embodiment, the scale moisture sensors, nanosensors, optical chemical sen sensor 302 includes a light transmissive Support and a sors, single particle sensors, and the like. reflective metal layer. In an embodiment, the sensor 302 Further non-limiting examples of sensors 302 include includes a wavelength-tunable surface plasmon resonance 45 chemical sensors, cavitand-based Supramolecular sensors, sensor. In an embodiment, the sensor 302 includes a surface nucleic acid sensors, deoxyribonucleic acid sensors (e.g., plasmon resonance microarray sensor having a wavelength electrochemical DNA sensors, or the like), supramolecular tunable metal-coated grating. In an embodiment, the sensor sensors, and the like. In an embodiment, at least one of the 302 includes a Surface plasmon resonance microarray sensor sensors 302 is configured to detect or measure the presence having an array of micro-regions configured to capture 50 or concentration of specific target chemicals (e.g., blood target molecules. components, biological sample component, cerebral spinal In an embodiment, the sensor 302 includes one or more fluid component, infectious agents, infection indication electrochemical transducers, optical transducers, piezoelec chemicals, inflammation indication chemicals, diseased tis tric transducers, or thermal transducers. For example, in an Sue indication chemicals, biological agents, molecules, ions, embodiment, the sensor 302 includes one or more transduc 55 or the like). ers configured to detect acoustic waves associated with Further non-limiting examples of sensors 302 include changes in a biological mass present proximate a Surface of chemical transducers, ion sensitive field effect transistors the body structure 104. (ISFETs), ISFET pH sensors, membrane-ISFET devices In an embodiment, the sensor 302 includes one or more (MEMFET), microelectronic ion-sensitive devices, poten thermal detectors, photovoltaic detectors, or photomultiplier 60 tiometric ion sensors, quadruple-function ChemFET (chemi detectors. In an embodiment, the sensor 302 includes one or cal-sensitive field-effect transistor) integrated-circuit sen more charge-coupled devices, complementary metal-oxide sors, sensors with ion-sensitivity and selectivity to different semiconductor devices, photodiode image sensor devices, ionic species, and the like. Further non-limiting examples of whispering gallery mode (WGM) micro cavity devices, the one or more sensors 302 can be found in the following photoelectric device, wavelength-tunable surface plasmon 65 documents (the contents of each of which is incorporated resonance sensor, Surface plasmon resonance microarray herein by reference): U.S. Pat. Nos. 7,396,676 (issued Jul. 8, sensor having a wavelength-tunable metal-coating grating, 2008) and 6,831,748 (issued Dec. 14, 2004). US 9,474,831 B2 49 50 In an embodiment, the one or more sensors 302 include capture layer. In an embodiment, the sensor 302 includes a one or more acoustic transducers, electrochemical transduc biological molecule capture layer having an array of differ ers, photochemical transducer, optical transducers, piezo ent binding molecules that specifically bind one or more electrical transducers, or thermal transducers. For example, target molecules. In an embodiment, the sensor 302 includes in an embodiment, the one or more sensors 302 include one one or more computing devices 230 operably coupled to one or more acoustic transducers. In an embodiment, the one or or more sensors. For example, in an embodiment, the sensor more sensors 302 include one or more thermal detectors, 302 includes a computing device 230 operably coupled to photovoltaic detectors, or photomultiplier detectors. In an one or more surface plasmon resonance microarray sensors. embodiment, the one or more sensors 302 include one or In an embodiment, the sensor 302 is configured to detect more charge coupled devices, complementary metal-oxide 10 at least one attribute associated with a biological Subject semiconductor devices, photodiode image sensor devices, 222. In an embodiment, the at least one attribute includes at whispering gallery mode micro cavity devices, or Scintilla least one of physiological condition, genetic profile, pro tion detector devices. In an embodiment, the one or more teomic profile, genetic characteristic, proteomic character sensors 302 include one or more complementary metal istic, response to previous treatment, weight, height, medical oxide-semiconductor image sensors. 15 diagnosis, familial background, results of one or more In an embodiment, the one or more sensors 302 include medical tests, ethnic background, body mass index, age, one or more conductivity sensor. In an embodiment, the one presence or absence of at least one disease or condition, or more sensors 302 include one or more spectrometers. In species, ethnicity, race, allergies, gender, presence or an embodiment, the one or more sensors include one or more absence of at least one biological or chemical agent in the Bayer sensors. In an embodiment, the one or more sensors Subject, pregnancy status, lactation status, medical history, include one or more Foveon sensors. In an embodiment, the or blood condition. one or more sensors 302 include one or more density In an embodiment, the at least one characteristic associ sensors. In an embodiment, the one or more density sensors ated with a biological sample 808 proximate the insertable include one or more optical density sensors. In an embodi device 102 includes at least one of a transmittance, an energy ment, the one or more density sensors include one or more 25 frequency change, a frequency shift, an energy phase refractive index sensors. In an embodiment, the one or more change, or a phase shift. In an embodiment, the at least one refractive index sensors include one or more fiber optic characteristic includes at least one of a fluorescence, an refractive index sensors. intrinsic fluorescence, a tissue fluorescence, or a naturally In an embodiment, the one or more sensors 302 include occurring fluorophore fluorescence. In an embodiment, the one or more surface plasmon resonance sensors. In an 30 at least one characteristic includes at least one of an elec embodiment, the one or more sensors 302 are configured to trical conductivity, and electrical polarizability, or an elec detect target molecules. For example, surface-plasmon-reso trical permittivity. In an embodiment, the at least one char nance-based-sensors detect target molecules Suspended in a acteristic associated with a biological sample 808 proximate fluid, for example, by reflecting light off thin metal films in the insertable device 102 includes at least one of a thermal contact with the fluid. Adsorbing molecules cause changes 35 conductivity, a thermal diffusivity, a tissue temperature, or a in the local index of refraction, resulting in changes in the regional temperature. resonance conditions of the Surface plasmon waves. In an embodiment, the at least one characteristic associ In an embodiment, the one or more sensors 302 include ated with a biological sample 808 proximate the insertable one or more localized surface plasmon resonance sensors. In device 102 includes information related to metabolism or an embodiment, detection of target molecules includes 40 biological response to an anti-microbial agent or other monitoring shifts in the resonance conditions of the Surface anti-microbial surface property 204. plasmon waves due to changes in the local index of refrac In an embodiment, the at least one characteristic associ tion associates with adsorption of target molecules. In an ated with a biological sample 808 proximate the insertable embodiment, the one or more sensors 302 include one or device 102 includes at least one parameter associated with a more functionalized cantilevers. In an embodiment, the one 45 doppler optical coherence tomograph. (See, e.g., Li et al., or more sensors 302 include a light transmissive Support and Feasibility of Interstitial Doppler Optical Coherence a reflective metal layer. In an embodiment, the one or more Tomography for In vivo Detection of Microvascular sensors 302 include a biological molecule capture layer. In Changes During Photodynamic Therapy, Lasers in Surgery an embodiment, the biological molecule capture layer and Medicine 38(8):754-61. (2006), which is incorporated includes an array of different binding molecules that spe 50 herein by reference; see, also U.S. Pat. No. 7,365,859 cifically bind one or more target molecules. In an embodi (issued Apr. 29, 2008), which is incorporated herein by ment, the one or more sensors 302 include a Surface plasmon reference). resonance microarray sensor having an array of micro In an embodiment, the at least one characteristic associ regions configured to capture target molecules. ated with a biological sample 808 proximate the insertable In an embodiment, the one or more sensors 302 include 55 device 102 includes spectral signature information associ one or more acoustic biosensors, amperometric biosensors, ated with an implant device. For example, in an embodi calorimetric biosensors, optical biosensors, or potentiomet ment, the at least one characteristic associated with a bio ric biosensors. In an embodiment, the one or more sensors logical sample 808 proximate the insertable device 102 302 include one or more fluid flow sensors. In an embodi includes implant device spectral signature information asso ment, the one or more sensors 302 include one or more 60 ciated with at least one of a bio-implants, (e.g., bioactive differential electrodes. In an embodiment, the one or more implants, facial implants, buttock implants, breast implants, sensors 302 include one or more biomass sensors. In an cochlear implants, dental implants, neural implants, ortho embodiment, the one or more sensors 302 include one or pedic implants, ocular implants) prostheses, implantable more immunosensors. electronic device, implantable medical devices, and the like. In an embodiment, the sensor 302 is operably coupled to 65 Further non-limiting examples of implant devices include a microorganism colonization biomarker array. In an replacements implants (e.g., artificial joint implants, or the embodiment, the sensor 302 includes a biological molecule like Such as knee, shoulder, wrists elbow, or hip replace US 9,474,831 B2 51 52 ments implants, or the like), Subcutaneous drug delivery characteristic of a biological sample 808 proximate the devices (e.g., implantable pills, drug-eluting stents, or the insertable device 102 includes at least one of an electro like), shunts (e.g., cardiac shunts, lumbar-peritoneal shunts, magnetic energy absorption parameter, an electromagnetic cerebrospinal fluid shunts, cerebral shunts, pulmonary energy emission parameter, an electromagnetic energy scat shunts, portosystemic shunts, portacaval shunts, or the like), tering parameter, an electromagnetic energy reflectance stents (e.g., coronary stents, peripheral vascular stents, pro parameter, or electromagnetic energy depolarization param static stents, ureteral stents, vascular stents, or the like), eter. In an embodiment, the at least one characteristic urological catheters, central lines, Surgical drains, biological includes at least one of an absorption coefficient, an extinc fluid flow controlling implants, and the like. Further non tion coefficient, and a scattering coefficient. limiting examples of implant device include artificial hearts, 10 In an embodiment, the at least one characteristic of a endoscopes, valves (e.g., heart valves), Surgical drains, biological sample 808 proximate the insertable device 102 stomach partition clip, artificial prosthetics, catheters, con includes at least one parameter associated with an infection tact lens, mechanical heart valves, Subcutaneous sensors, marker (e.g., an infectious agent marker), an inflammation urinary catheters, vascular catheters, and the like. marker, an infective stress marker, a systemic inflammatory In an embodiment, the at least one characteristic includes 15 response syndrome marker, or a sepsis marker. Non-limiting at least one parameter associated with a medical state (e.g., examples of infection makers, inflammation markers, and medical condition, disease state, disease attributes, etc.). the like may be found in, for example, Imam et al., Inflammation is a complex biological response to insults that Radiotracers for Imaging of Infection and Inflammation—A can arise from, for example, chemical, traumatic, or infec Review, World J. Nucl. Med. 40-55 (2006), which is incor tious stimuli. It is a protective attempt by an organism to porated herein by reference. Non-limiting characteristics isolate and eradicate the injurious stimuli as well as to associated with an infection marker, an inflammation initiate the process of tissue repair. The events in the marker, an infective stress marker, a systemic inflammatory inflammatory response are initiated by a complex series of response syndrome marker, or a sepsis marker include at interactions involving inflammatory mediators, including least one of an inflammation indication parameter, an infec those released by immune cells and other cells of the body. 25 tion indication parameter, a diseased State indication param Histamines and eicosanoids Such as prostaglandins and eter, or a diseased tissue indication parameter. leukotrienes act on blood vessels at the site of infection to In an embodiment, the at least one characteristic of a localize blood flow, concentrate plasma proteins, and biological sample 808 proximate the insertable device 102 increase capillary permeability. includes at least one of tissue water content, oxy-hemoglo Chemotactic factors, including certain eicosanoids, 30 bin concentration, deoxyhemoglobin concentration, oxygen complement, and especially cytokines known as chemok ated hemoglobin absorption parameter, deoxygenated hemo ines, attract particular leukocytes to the site of infection. globin absorption parameter, tissue light scattering Other inflammatory mediators, including some released by parameter, tissue light absorption parameter, hematological the Summoned leukocytes, function locally and systemically parameter, or pH level. to promote the inflammatory response. Platelet activating 35 In an embodiment, the at least one characteristic includes factors and related mediators function in clotting, which aids a physiological characteristic of the biological Subject 222. in localization and can trap pathogens. Certain cytokines, Physiological characteristics Such as, for example pH can be interleukins and TNF, induce further trafficking and extrava used to assess blood flow, a cell metabolic state (e.g., sation of immune cells, hematopoiesis, fever, and production anaerobic metabolism, or the like), the presence of an of acute phase proteins. Once signaled. Some cells and/or 40 infectious agent, a disease state, and the like. Among physi their products directly affect the offending pathogens, for ological characteristics examples include, but are not limited example by inducing phagocytosis of bacteria or, as with to, at least one of a temperature, a regional or local tem interferon, providing antiviral effects by shutting down perature, a pH, an impedance, a density, a sodium ion level. protein synthesis in the host cells. a calcium ion level, a potassium ion level, a glucose level. Oxygen radicals, cytotoxic factors, and growth factors can 45 a lipoprotein level, a cholesterol level, a triglyceride level, a also be released to fight pathogen infection or to facilitate hormone level, a blood oxygen level, a pulse rate, a blood tissue healing. This cascade of biochemical events propa pressure, an intracranial pressure, a respiratory rate, a vital gates and matures the inflammatory response, involving the statistic, and the like. local vascular system, the immune system, and various cells In an embodiment, the at least one characteristic includes within the injured tissue. Under normal circumstances, 50 at least one of a temperature, a pH, an impedance, a density, through a complex process of mediator-regulated pro-in a sodium ion level, a calcium ion level, a potassium ion flammatory and anti-inflammatory signals, the inflammatory level, a glucose level, a lipoprotein level, a cholesterol level, response eventually resolves itself and subsides. For a triglyceride level, a hormone level, a blood oxygen level. example, the transient and localized Swelling associated a pulse rate, a blood pressure, an intracranial pressure, and with a cut is an example of an acute inflammatory response. 55 a respiratory rate. In an embodiment, the at least one However, in certain cases resolution does not occur as characteristic includes at least one hematological parameter. expected. Prolonged inflammation, known as chronic In an embodiment, the hematological parameter is associ inflammation, leads to a progressive shift in the type of cells ated with a hematological abnormality. present at the site of inflammation and is characterized by In an embodiment, the at least one characteristic of the simultaneous destruction and healing of the tissue from the 60 biological sample 808 proximate the insertable device 102 inflammatory process, as directed by certain mediators. includes at least one hematological parameter. Non-limiting Rheumatoid arthritis is an example of a disease associated examples of hematological parameters include an albumin with persistent and chronic inflammation. level, a blood urea level, a blood glucose level, a globulin Non-limiting Suitable techniques for optically measuring level, a hemoglobin level, erythrocyte count, a leukocyte a diseased state may be found in, for example, U.S. Pat. No. 65 count, or the like. In an embodiment, the infection marker 7,167,734 (issued Jan. 23, 2007), which is incorporated includes at least one parameter associated with a red blood herein by reference. In an embodiment, the at least one cell count, a lymphocyte level, a leukocyte count, a myeloid US 9,474,831 B2 53 54 count, an erythrocyte sedimentation rate, or a C-reactive Thromb. Vasc. Biol. 2002; 22: 1929-1935 (2002); Kal protein level. In an embodiment, the at least one character chenko et al., J. of Biomed. Opt. 11(5):050507 (2006). istic includes at least one parameter associated with a In an embodiment, the one or more imaging probes cytokine plasma level or an acute phase protein plasma include at least one carbocyanine dye label. In an embodi level. In an embodiment, the at least one characteristic ment, the sensor 302 is configured to determine at least one includes at least one parameter associated with a leukocyte characteristic associated with one or more imaging probes level. attached, targeted to, conjugated, bound, or associated with In an embodiment, the at least one characteristic of a at least one biomarker or biological sample component (e.g. biological sample 808 proximate the insertable device 102 biological tissue component, or biological fluid component, includes a spectral parameter associated with a biofilm 10 etc.). specific tag. In an embodiment, the at least one characteristic In an embodiment, the one or more imaging probes includes at least one of an optical density, opacity, refrac include at least one of a fluorescent agen, quantum dot, tivity, absorbance, fluorescence, or transmittance. In an radio-frequency identification transponder, X-ray contrast embodiment, the at least one characteristic includes at least agent, or molecular imaging probe. one of an inflammation indication parameter, infection indi 15 Further non-limiting examples of imaging probes include cation parameter, diseased State indication parameter, or fluorescein (FITC), indocyanine green (ICG), and rhod diseased tissue indication parameter. In an embodiment, the amine B. Non-limiting examples of other fluorescent dyes at least one characteristic includes at least one of an elec for use in fluorescence imaging include a number of red and tromagnetic energy absorption parameter, electromagnetic near infrared emitting fluorophores (600-1200 nm) includ energy emission parameter, electromagnetic energy scatter ing cyarine dyes such as Cy5, Cy5.5, and Cy7 (Amersham ing parameter, electromagnetic energy reflectance param Biosciences, Piscataway, N.J., USA) or a variety of Alexa eter, or electromagnetic energy depolarization parameter. In Fluor dyes such as Alexa Fluor 633, Alexa Fluor 635, Alexa an embodiment, the at least one characteristic includes at Fluor 647, Alexa Fluor 660, Alexa Fluor 680, Alexa Fluor least one of an absorption coefficient, extinction coefficient, 700, Alexa Fluor 750 (Molecular Probes-Invitrogen, Carls scattering coefficient, or fluorescence coefficient. In an 25 bad, Calif., USA; see, also, U.S. Patent Pub. No. 2005/ embodiment, the at least one characteristic includes at least 0171434 (published Aug. 4, 2005) (the contents of each of one of parameter associated with at least one of a biomarker, which is incorporated herein by reference), and the like. infection marker, inflammation marker, infective stress Further non-limiting examples of imaging probes include marker, or sepsis marker. IRDye800, IRDye700, and IRDye680 (LI-COR, Lincoln, In an embodiment, the at least one characteristic includes 30 Nebr., USA), NIR-1 and 1C5-OSu (Dejindo, Kumamotot, at least one of an electromagnetic energy phase shift param Japan), LaJolla Blue (Diatron, Miami, Fla., USA), FAR eter, an electromagnetic energy dephasing parameter, and an Blue, FAR-Green One, and FAR-Green Two (Innosense, electromagnetic energy depolarization parameter. In an Giacosa, Italy), ADS 790-NS, ADS 821-NS (American Dye embodiment, the at least one characteristic includes at least Source, Montreal, Calif.), NIAD-4 (ICx Technologies, one of an absorbance, a reflectivity, and a transmittance. In 35 Arlington, Va.), and the like. Further non-limiting examples an embodiment, the at least one characteristic includes at of fluorophores include BODIPY-FL, europium, green, yel least one of a refraction and a scattering. low and red fluorescent proteins, luciferase, and the like. In an embodiment, the sensor 302 is configured to deter Quantum dots of various emission/excitation properties can mine at least one characteristic associated with one or more be used as imaging probes. See, e.g., Jaiswal, et al. Nature biological markers or biological components (e.g., cerebro 40 Biotech. 21:47-51 (2003) (the contents of each of which is spinal fluid components, blood components, or the like). In incorporated herein by reference). Further non-limiting an embodiment, the sensor 302 is configured to determine at examples of imaging probes include those including anti least one characteristic associated with a biological sample bodies specific for leukocytes, anti-fibrin antibodies, mono proximate the insertable device 102. In an embodiment, the clonal anti-diethylene triamine pentaacetic acid (DTPA), sensor 302 is configured to determine a spatial dependence 45 DTPA labeled with Technetium-99m ("TC), and the like. associated with the least one characteristicassociated with a Further non-limiting examples of biomarkers include biological sample. In an embodiment, the sensor 302 is high-sensitivity C-reactive protein (hs-CRP), cardiac tro configured to determine a temporal dependence associated ponin T (cTnT), cardiac troponin I (cTnI), N-terminal-pro with the least one characteristic associated with a biological B-type matriuretic peptide (NT-proBNP), D-dimer, P-selec sample. In an embodiment, the sensor 302 is configured to 50 tin, E-selectin, thrombin, interleukin-10, fibrin monomers, concurrently or sequentially determine at least one spatial phospholipid microparticles, creatine kinase, interleukin-6. dependence associated with the least one characteristic tumor necrosis factor-alpha, myeloperoxidase, intracellular associated with a biological sample, and at least one tem adhesion molecule-1 (ICAM1), vascular adhesion molecule poral dependence associated with the least one characteristic (VCAM), matrix metalloproteinase-9 (MMP9), ischemia associated with a biological sample. 55 modified albumin (IMA), free fatty acids, choline, soluble In an embodiment, the sensor 302 is configured to deter CD40 ligand, insulin-like growth factor, (see, e.g., Giannit mine at least one spectral parameter associated with one or sis, et al. Risk stratification in pulmonary embolism based on more imaging probes (e.g., chromophores, fluorescent biomarkers and echocardiography. Circ. 112:1520-1521 agents, fluorescent marker, fluorophores, molecular imaging (2005), Barnes, et al., Novel biomarkers associated with probes, quantum dots, radio-frequency identification tran 60 deep venous throbosis. A comprehensive review. Biomarker sponders (RFIDS), X-ray contrast agents, or the like). In an Insights 2:93-100 (2008); Kamphuisen, Can anticoagulant embodiment, the sensor 302 is configured to determine at treatment be tailored with biomarkers in patients with least one characteristic associated with one or more imaging venous thromboembolism? J. Throm. Haemost. 4:1206-1207 probes attached, targeted to, conjugated, bound, or associ (2006); Rosalki, et al., Cardiac biomarkers for detection of ated with at least one inflammation markers. See, e.g., the 65 myocardial infarction. Perspectives from past to present. following documents (the contents of each of which is Clin. Chem. 50:2205-2212 (2004): Apple, et al., Future incorporated herein by reference): Jaffer et al., Arterioscler. biomarkers for detection of ischemia and risk Stratification US 9,474,831 B2 55 56 in acute coronary syndrome, Clin. Chem. 51:810-824 sample 808 within the biological subject 222. In an embodi (2005), each of which is incorporated herein by reference). ment, the sensor 302 is configured to detect at least one of In an embodiment, the sensor 302 is configured to detect an energy absorption profile and an energy reflection profile a spectral response 299 (e.g., an emitted energy, a remitted of a region within a biological Subject 222. energy, an energy absorption profile, energy emission pro 5 In an embodiment, the sensor 302 is configured to detect file, or the like) associated with a biomarker. Among bio a spectral response 299 from a biological sample 808 of a marker examples include, but are not limited to, one or more biological Subject 222. Blood is a tissue composed of Substances that are measurable indicators of a biological among other components, formed elements (e.g., blood cells state and can be used as indicators of normal disease state, Such as erythrocytes, leukocytes, thrombocytes, or the like) pathological disease state, and/or risk of progressing to a 10 Suspend in a matrix (plasma). The heart, blood vessels (e.g., pathological disease state. In some instances, a biomarker arteries, arterioles, capillaries, veins, Venules, or the like), can be a normal blood component that is increased or and blood components, make up the cardiovascular system. decreased in the pathological state. A biomarker can also be The cardiovascular system, among other things, moves a Substance that is not normally detected in biological oxygen and other gases, as well as other biochemical agents sample 808 (e.g. a biological fluid, or tissue), but is released 15 to and from cells and tissues, maintains homeostasis by into circulation because of the pathological State. In some stabilizing body temperature and pH, and helps fight dis instances, a biomarker can be used to predict the risk of CaSCS. developing a pathological state. For example, plasma mea In an embodiment, the sensor 302 is configured to detect Surement of lipoprotein-associated phospholipase A2 (Lp at least one of an emitted energy and a remitted energy PLA2) is approved by the U.S. Food & Drug Administration associated with a portion of a cardiovascular system. In an (FDA) for predicting the risk of first time stroke. embodiment, the sensor 302 is configured to detect at least In other instances, the biomarker can be used to diagnose one of an emitted energy and a remitted energy associated an acute pathological state. For example, elevated plasma with one or more blood components within a biological levels of S-100b, B-type neurotrophic growth factor subject 222. In an embodiment, the sensor 302 is configured (BNGF), von Willebrand factor (vWF), matrix metallopro 25 to detect at least one of an emitted energy and a remitted teinase-9 (MMP-9), and monocyte chemoattractant pro energy associated with one or more formed elements within tein-1 (MCP-1) are highly correlated with the diagnosis of a biological subject 222. In an embodiment, the sensor 302 stroke (see, e.g., Reynolds, et al., Early biomarkers of stroke. is configured to detect spectral information associated with Clin. Chem. 49:1733-1739 (2003), which is incorporated one or more of one or more blood components. In an herein by reference). 30 embodiment, the sensor 302 is configured to detect at least In an embodiment, the sensor 302 is configured to detect one of an emitted energy and a remitted energy associated at least one characteristic associated with one or more with a real-time change in one or more parameters associ biological sample components. In an embodiment, the at ated with at least one blood component within a biological least one characteristic includes at least one of absorption subject 222. In an embodiment, the sensor 302 is configured coefficient information, extinction coefficient information, 35 to detect an energy absorption of one or more blood com or scattering coefficient information associated with the at ponents. least one molecular probe. In an embodiment, the at least Non-limiting examples of detectable blood components one characteristic includes spectral information indicative of include erythrocytes, leukocytes (e.g., basophils, granulo at least one of rate of change, accumulation rate, aggregation cytes, eosinophils, monocytes, macrophages, lymphocytes, rate, or rate of change associated with at least one physical 40 neutrophils, or the like), thrombocytes, acetoacetate, parameter associated with a biological sample component. acetone, acetylcholine, adenosine triphosphate, adrenocor In an embodiment, the sensor 302 is configured to detect ticotrophic hormone, alanine, albumin, aldosterone, alumi spectral information associated with a real-time change in num, amyloid proteins (non-immunoglobulin), antibodies, one or more parameters associated with a biological sample apolipoproteins, ascorbic acid, aspartic acid, bicarbonate, 808 (e.g., biological tissue or fluid). For example, in an 45 bile acids, bilirubin, biotin, blood urea, nitrogen, bradykinin, embodiment, the sensor 302 is configured to detect at least bromide, cadmium, calciferol, calcitonin (ct), calcium, car one of an emitted energy and a remitted energy associated bon dioxide, carboxyhemoglobin (as HbcO), cell-related with a real-time change in one or more parameters associ plasma proteins, cholecystokinin (pancreozymin), choles ated with a biological sample 808 within one or more terol, citric acid, citrulline, complement components, coagul anti-microbial regions of an insertable device 102. In an 50 lation factors, coagulation proteins, complement compo embodiment, the sensor 302 includes one or more transduc nents, c-peptide, c-reactive protein, creatine, creatinine, ers configured to detect Sound waves associated with cyanide, 11-deoxycortisol, deoxyribonucleic acid, dihy changes in a biological sample 808 present proximate at drotestosterone, diphosphoglycerate (phosphate), or the like. least one of the outer surface 106 or the inner surface 108 of Further non-limiting examples of detectable blood com the body structure 104. 55 ponents include dopamine, enzymes, epidermal growth fac In an embodiment, the sensor 302 is configured to detect tor, epinephrine, ergothioneine, erythrocytes, erythropoietin, at least one of an emitted energy and a remitted energy. In folic acid, fructose, furosemide glucuronide, galactoglyco an embodiment, the sensor 302 is configured to detect at protein, galactose (children), gamma-globulin, gastric least one of an emitted energy and a remitted energy inhibitory peptide, gastrin, globulin, C-1-globulin, C-2- associated with a biological Subject 222. In an embodiment, 60 globulin, C-globulins, B-globulins, glucagon, glucosamine, the sensor 302 is configured to detect an optical energy glucose, immunoglobulins (antibodies), lipase p, lipids, absorption profile of a target sample, a portion of a tissue, or lipoprotein (Sr 12-20), lithium, low-molecular weight pro portion of a biological sample 808 (e.g., biological tissue or teins, lysine, lysozyme (muramidase), O-2-macroglobulin, fluid) within the biological subject 222. In an embodiment, Y-mobility (non-immunoglobulin), pancreatic polypeptide, the sensor 302 is configured to detect an excitation radiation 65 pantothenic acid, para-aminobenzoic acid, parathyroid hor and an emission radiation associated with a portion of a mone, pentose, phosphorated, phenol, phenylalanine, phos target sample, a portion of a tissue, or portion of a biological phatase, acid, prostatic, phospholipid, phosphorus, prealbu US 9,474,831 B2 57 58 min, thyroxine-binding, proinsulin, prolactin (female), Among miscellaneous trace components examples include, prolactin (male), proline, prostaglandins, prostate specific but are not limited to, Varcinoembryonic antigen, angio antigen, protein, protoporphyrin, pseudoglobulin I. pseudo tensinogen, and the like. globulin II, purine, pyridoxine, pyrimidine nucleotide, pyru In an embodiment, the sensor 302 is configured to detect vic acid, CCL5 (RANTES), relaxin, retinol, retinol-binding a spectral response 299 associated with a real-time change in protein, riboflavin, ribonucleic acid, secretin, serine, sero one or more parameters associated with at least one biologi tonin (5-hydroxytryptamine), silicon, Sodium, Solids, Soma cal sample 808 component (e.g., a cerebrospinal fluid com totropin (growth hormone), Sphingomyelin, Succinic acid, ponent). Non-limiting examples of detectable cerebrospinal Sugar, Sulfates, inorganic, Sulfur, taurine, testosterone (fe fluid components include adenosine deaminase, albumin, 10 calcium, chloride, C-reactive protein, creatine kinase, crea male), testosterone (male), triglycerides, triiodothyronine, tinine, cystatin C, cytokines, glucose, hydrogencarbonate, tryptophan, tyrosine, urea, uric acid, water, miscellaneous immunoglobulin G, interleukins, lactate, lactate dehydroge trace components, and the like. nase, lipids, lymphocytes, monocytes, mononuclear cells, Non-limiting examples of C-globulins examples include myelin basic protein, neuron-specific enolase, potassium, C.1-acid glycoprotein, C.1-antichymotrypsin, C.1-antitrypsin, 15 proteins, S-100 protein, Small molecules, sodium, B-micro C.1B-glycoprotein, C.1-fetoprotein, C.1-microglobulin, C.1T globulin, and the like. glycoprotein, C2HS-glycoprotein, C.2-macroglobulin, 3.1 S In an embodiment, the sensor 302 is in optical commu Leucine-rich C2-glycoprotein, 3.8 S histidine-rich C2-gly nication along an optical path with at least one of the energy coprotein, 4 S C2, C1-C.1-glycoprotein, 8S C-3-glycoprotein, emitters 220. In an embodiment, one or more of the energy 9.5 S C1-glycoprotein (serum amyloid P protein), Corticos emitters 220 are configured to direct an in vivo generated teroid-binding globulin, ceruloplasmin, GC globulin, hap pulsed energy stimulus along an optical path for a duration toglobin (e.g., Type 1-1, Type 2-1, or Type 2-2), inter-C.- sufficient to interact with one or more regions within the trypsin inhibitor, pregnancy-associated C2-glycoprotein, biological subject 222 and for a duration sufficient for a serum cholinesterase, thyroxine-binding globulin, transcor portion of the in vivo generated pulsed energy stimulus to tin, Vitamin D-binding protein, Zn-C2-glycoprotein, and the 25 reach a portion of the sensor 302 that is in optical commu like. Among B-Globulins, examples include, but are not nication along the optical path. In an embodiment, one or limited to, hemopexin, transferrin, B2-microglobulin, more of the energy emitters 220 are configured to direct 32-glycoprotein I. B2-glycoprotein II, (C3 proactivator), optical energy along an optical path for a duration Sufficient 32-glycoprotein III, C-reactive protein, fibronectin, preg to interact with one or more regions within the biological nancy-specific B1-glycoprotein, ovotransferrin, and the like. 30 Subject 222 and with at least a portion of the optical energy Among immunoglobulins examples include, but are not sensor 302. In an embodiment, one or more of the energy limited to, immunoglobulin G (e.g., IgG, IgG, IgG, IgGs. emitters 220 are configured to emit a pulsed optical energy IgG), immunoglobulin A (e.g., IgA, IgA, IgA), immuno stimulus along an optical path for a duration Sufficient to globulin M, immunoglobulin D, immunoglobulin E. K. interact with a sample received within the one or more Bence Jones protein, Y Bence Jones protein, JChain, and the 35 fluid-flow passageways 110; such that a portion of the pulsed like. optical energy stimulus is directed to a portion of the sensor Among apolipoproteins examples include, but are not 302 that is in optical communication along the optical path. limited to, apolipoprotein A-I (HDL), apolipoprotein A-II As indicated in FIG. 3, in an embodiment, the at least one (HDL), apolipoprotein C I (VLDL), apolipoprotein C-II, anti-microbial region 202 including at least one anti-micro apolipoprotein C-III (VLDL), apolipoprotein E, and the like. 40 bial agent is configured to release the anti-microbial agent Among Y-mobility (non-immunoglobulin) examples over time. In an embodiment, the anti-microbial agent include, but are not limited to, 0.6 S Y2-globulin, 2 S includes a microbial tactic agent. In an embodiment, the Y2-globulin, basic Protein B2, post-y-globulin (Y-trace), and microbial tactic agent includes at least one chemotactic the like. Among low-molecular weight proteins examples agent. In an embodiment, the at least one microbial tactic include, but are not limited to, lysozyme, basic protein B1, 45 agent includes at least one attractant or repellant Surface basic protein B2, 0.6 S Y2-globulin, 2 S Y2-globulin, post property. In an embodiment, the repellant Surface property is y-globulin, and the like. located proximate to a protected site 310. In an embodiment, Among complement components examples include, but the repellant surface property encircles a protected site 310. are not limited to, C1 esterase inhibitor, C1q component, C1r In an embodiment, the protected site 310 or the destructive component, C1s component, C2 component, C3 component, 50 site 305 includes at least one of a port 118, or sensor 302. C3a component, C3b-inactivator, C4 binding protein, C4 In an embodiment, the insertable device 102 comprises a component, C4a component, C4-binding protein, C5 com body structure 104 having an outer surface 106 and an inner ponent, C5a component, C6 component, C7 component, C8 surface 108 defining one or more fluid-flow passageways component, C9 component, factor B, factor B (C3 proacti 110; a plurality of anti-microbial regions 202 arranged in at vator), factor D, factor D (C3 proactivator convertase), 55 least one pattern 109 (e.g., spatial pattern or temporal factor H, factor H (BiH), properdin, and the like. Among pattern), one or more of the anti-microbial regions 202 coagulation proteins examples include, but are not limited included on at least one of the outer surface 106 or the inner to, antithrombin III, prothrombin, antihemophilic factor surface 108, or embedded in the body structure 104. (factor VIII), plasminogen, fibrin-stabilizing factor (factor In an embodiment, the system 100 is configured to XIII), fibrinogen, thrombin, and the like. 60 compare an input associated with at least one characteristic Among cell-related plasma proteins examples include, but associated with a biological sample 808 proximate the are not limited to, fibronectin, B-thromboglobulin, platelet insertable device 102 (e.g., received within one or more factor-4, serum Basic Protease Inhibitor, and the like. fluid-flow passageways 110, proximate (e.g., on or near) a Among amyloid proteins (Non-Immunoglobulin) examples surface of the body structure 104, or the like) to a database include, but are not limited to, amyloid-Related apoprotein 65 258 of stored reference values, and to generate a response (apoSAA1), AA (FMF) (ASF), AA (TH) (AS), serum amy 299 based in part on the comparison. In an embodiment, the loid P component (9.5 S 7C1-glycoprotein), and the like. response 299 includes at least one of a visual representation, US 9,474,831 B2 59 60 audio representation (e.g., alarm, audio waveform represen modulates with a detected heart beat of the biological tation of a tissue region, or the like), haptic representation, Subject 222 to a target value associated with a spectral or tactile representation (e.g., tactile diagram, tactile display, model. tactile graph, tactile interactive depiction, tactile model (e.g., In an embodiment, the system 100 is configured to multidimensional model of an infected tissue region, or the 5 compare the measurand associated with the biological Sub like), tactile pattern (e.g., refreshable Braille display), tac ject 222 to the threshold value associated with a spectral tile-audio display, tactile-audio graph, or the like). In an model and to generate a real-time estimation of an infection embodiment, the response 299 includes generating at least state based on the comparison. In an embodiment, the one of a visual, audio, haptic, or tactile representation of system 100 is configured to compare an input associated 10 with at least one characteristic associated with, for example, biological sample 808 spectral information (e.g., biological a biological sample proximate an insertable device 102 to a fluid spectral information, tissue spectral information, fat database 258 of stored reference values, and to generate a spectral information, muscle spectral information, bone response 299 based in part on the comparison. spectral information, blood component spectral information, As described in FIG. 7, the system 100 can include, biomarker spectral information, infectious agent spectral 15 among other things, one or more data structures (e.g., information, and the like). In an embodiment, the response physical data structures) 260. In an embodiment, a data 299 includes generating at least one of a visual, audio, structure 260 includes information associated with at least haptic, or tactile representation of at least one physical or one parameter associated with a tissue water content, an biochemical characteristic associated with a biological Sub oxy-hemoglobin concentration, a deoxyhemoglobin concen ject 222. tration, an oxygenated hemoglobin absorption parameter, a In an embodiment, the response 299 includes initiating deoxygenated hemoglobin absorption parameter, a tissue one or more treatment protocols. In an embodiment, the light scattering parameter, a tissue light absorption param response 299 includes activating one or more sterilization eter, a hematological parameter, a pH level, or the like. The protocols. In an embodiment, the response 299 includes system 100 can include, among other things, at least one of initiating at least one treatment regimen. In an embodiment, 25 inflammation indication parameter data, infection indication the response 299 includes delivering an energy stimulus. In parameter data, diseased tissue indication parameter data, or an embodiment, the response 299 includes delivering an the like configured as a data structure 260. In an embodi active agent (e.g., anti-microbial agent). In an embodiment, ment, a data structure 260 includes information associated the response 299 includes concurrently or sequentially deliv with least one parameter associated with a cytokine plasma ering an energy stimulus and an active agent (e.g., anti 30 concentration or an acute phase protein plasma concentra tion. In an embodiment, a data structure 260 includes microbial agent). information associated with a disease state of a biological In an embodiment, the response 299 includes at least one subject 222. In an embodiment, a data structure 260 includes of a response signal, a control signal, a change to a steril measurement data. In an embodiment, the computing device izing stimulus parameter (e.g., an electrical sterilizing stimu 35 230 includes a processor 232 configured to execute instruc lus, electromagnetic sterilizing stimulus, acoustic sterilizing tions, and a memory 250 that stores instructions configured stimulus, or thermal sterilizing stimulus), or the like. In an to cause the processor 232 to generate a second response embodiment, the response 299 includes at least one of a from information encoded in a data structure 260. change in an excitation intensity, change in an excitation In an embodiment, an insertable device 102 includes: a frequency, change in an excitation pulse frequency, change 40 body structure 104 having an outer surface 106 and an inner in an excitation pulse ratio, change in an excitation pulse surface 108 defining one or more fluid-flow passageways intensity, change in an excitation pulse duration time, 110; at least one anti-microbial region 202 configured to change in an excitation pulse repetition rate, or the like. deliver at least one anti-microbial agent to one or more areas In an embodiment, the response 299 includes at least one of at least one of the outer surface 106, the inner surface 108 of activating an authorization protocol 300, activating an 45 or embedded in the internal body structure 104; a sensor 302 authentication protocol 301, activating a Software update configured to detect at least one microbial component proxi protocol 333, activating a data transfer protocol 303, or mate at least one of the outer surface 106 or the inner surface activating an infection sterilization diagnostic protocol 3.04. 108 of the body structure 104; and one or more computer In an embodiment, the response 299 includes sending infor readable memory media 262 having microbial marker infor mation associated with at least one of an authentication 50 mation configured as a data structure 260, the data structure protocol 301, authorization protocol 300, delivery protocol 260 including a characteristic information section having 305, activation protocol 306, encryption protocol 307, or characteristic microbial information representative of the 308 decryption protocol. presence of at least one microorganism proximate at least In an embodiment, the system 100 is configured to one of the outer surface 106 or the inner surface 108 of the compare an input associated with a biological Subject 222 to 55 body structure 104, or the interior of the fluid-flow passage a database 258 of stored reference values, and to generate a way 110. response 299 based in part on the comparison. In an embodi In an embodiment, the at least one sensor 302 is operably ment, the system 100 is configured to compare an output of associated with at least one of the anti-microbial regions one or more of the plurality of logic components and to 202. In an embodiment, the at least one sensor 302 is determine at least one parameter associated with a cluster 60 configured to detect the presence of at least one microor centroid deviation derived from the comparison. In an ganism proximate at least one of the inner surface 108 or the embodiment, the system 100 is configured to compare a outer surface 106 of the one or more fluid-flow passageways measurand associated with the biological Subject 222 to a 110. In an embodiment, the at least one sensor 302 is threshold value associated with a spectral model and to configured to detect the presence of at least one microor generate a response 299 based on the comparison. In an 65 ganism within the one or more fluid-flow passageways 110 embodiment, the system 100 is configured to generate the based on one or more flow characteristics. In an embodi response 299 based on the comparison of a measurand that ment, the at least one sensor 302 is configured to detect a US 9,474,831 B2 61 62 location associated with the presence of at least one micro In an embodiment, the data structure 260 includes at least organism. In an embodiment, the at least one sensor 302 is one of psychosis state marker information, psychosis trait configured to detect at least one microbial component. In an marker information, or psychosis indication information. In embodiment, the at least one sensor 302 includes a microbial an embodiment, the data structure 260 includes at least one component capture layer. In an embodiment, the microbial of psychosis state indication information, psychosis trait capture layer includes an array of different binding mol indication information, or predisposition for a psychosis ecules that specifically bind one or more components of at indication information. In an embodiment, the data structure least one microorganism. 260 includes at least one of infection indication information, The system 100 can include, among other things, one or inflammation indication information, diseased State indica 10 tion information, or diseased tissue indication information. more computer-readable memory media (CRMM) 262 hav In an embodiment, a data structure 260 includes biologi ing biofilm marker information configured as a data struc cal sample spectral information. In an embodiment, the data ture 260. In an embodiment, the data structure 260 includes structure 260 includes one or more heuristically determined a characteristic information section having characteristic parameters associated with at least one in vivo or in vitro microbial component information representative of the pres 15 determined metric. For example, information associated ence of at least one microorganism proximate at least one of with a biological sample 808 can be determined by one or the outer surface 106 or the inner surface 108 of the body more in vivo or in vitro technologies or methodologies structure 104. In an embodiment, the data structure 260 including, for example, high-resolution proton magnetic includes infection marker information. In an embodiment, resonance spectroscopy, nanoprobe nuclear magnetic reso the data structure 260 includes biofilm marker information. nance spectroscopy, in vivo micro-dialysis, flow cytometry, In an embodiment, the data structure 260 includes biological or the like. Non-limiting examples of heuristics include a mass information associated with the presence of at least one heuristic protocol, heuristic algorithm, threshold informa microorganism proximate at least one of the inner Surface tion, a threshold level, a target parameter, or the like. The 108 or the outer surface 106 of the body structure 104. In an system 100 can include, among other things, a means 276 for embodiment, the data structure 260 includes a characteristic 25 generating one or more heuristically determined parameters information section having characteristic microbial meta associated with at least one in vivo or in vitro determined bolic information associated with the presence of at least one metric including one or more data structures 260. The microorganism proximate at least one of the inner Surface system 100 can include, among other things, a means 460 for 108, or the outer surface 106 of the body structure 104. In generating a response 299 based on a comparison, of a an embodiment, the data structure 260 includes a character 30 detected at least one of an emitted energy and a remitted istic information section having characteristic cell Surface energy to at least one heuristically determined parameter, information associated with the presence of at least one including one or more data structures 260. microorganism proximate at least one of the inner Surface In an embodiment, a data structure 260 includes one or 108, or the outer surface 106 of the body structure 104. more heuristics. In an embodiment, the one or more heuris In an embodiment, the data structure 260 includes a 35 tics include a heuristic for determining a rate of change characteristic information component including metabolite associated with at least one physical parameter associated information associated with a microorganism presence. In with a biological sample 808. For example, in an embodi an embodiment, the data structure 260 includes a character ment, the one or more heuristics include a heuristic for istic information component including temporal metabolite determining the presence of an infectious agent. In an information or spatial metabolite information associated 40 embodiment, the one or more heuristics include a heuristic with a microorganism presence. In an embodiment, the data for determining at least one dimension of an infected tissue structure 260 includes a characteristic information compo region. In an embodiment, the one or more heuristics include nent including oxygen concentration gradient information a heuristic for determining a location of an infection. In an associated with a microorganism presence. In an embodi embodiment, the one or more heuristics include a heuristic ment, the data structure 260 includes a characteristic infor 45 for determining a rate of change associated with a biochemi mation component including pH information associated cal marker within the one or more fluid-flow passageways with a microorganism presence. In an embodiment, the data 110. structure 260 includes a characteristic information compo In an embodiment, the one or more heuristics include a nent including nutrient information associated with a micro heuristic for determining a biochemical marker aggregation organism presence. In an embodiment, the data structure 260 50 rate. In an embodiment, the one or more heuristics include includes a characteristic information component including a heuristic for determining a type of biochemical marker. In spectral information associate with a biofilm-specific tag. an embodiment, the one or more heuristics include a heu In an embodiment, the data structure 260 includes a ristic for generating at least one initial parameter. In an characteristic information component including optical den embodiment, the one or more heuristics include a heuristic sity information. In an embodiment, the data structure 260 55 for forming an initial parameter set from one or more initial includes a characteristic information component including parameters. In an embodiment, the one or more heuristics opacity information. In an embodiment, the data structure include a heuristic for generating at least one initial param 260 includes a characteristic information component includ eter, and for forming an initial parameter set from the at least ing refractivity information. In an embodiment, the data one initial parameter. In an embodiment, the one or more structure 260 includes a characteristic information compo 60 heuristics include at least one pattern classification and nent including characteristic infection marker spectral infor regression protocol. mation. In an embodiment, the data structure 260 includes a In an embodiment, a data structure 260 includes infor characteristic information component including characteris mation associated with at least one parameter associated tic infective stress marker spectral information. In an with a tissue water content, an oxy-hemoglobin concentra embodiment, the data structure 260 includes a characteristic 65 tion, a deoxyhemoglobin concentration, an oxygenated information component including characteristic sepsis hemoglobin absorption parameter, a deoxygenated hemo maker spectral information. globin absorption parameter, a tissue light scattering param US 9,474,831 B2 63 64 eter, a tissue light absorption parameter, ahematological lipopolysaccharide, enzyme, lipid, peptide, polypeptide, parameter, a pH level, or the like. The system 100 can protein, organic, or inorganic molecule. In an embodiment, include, among other things, at least one of inflammation the at least one chemorepellent includes at least one of a indication parameter data, infection indication parameter hormone, oxide, peroxide, alcohol, or aldehyde. In an data, diseased tissue indication parameter data, or the like embodiment, the at least one chemorepellent includes at configured as a data structure 260. In an embodiment, a data least one of an inorganic salt, amino acid, or chemokine. In structure 260 includes information associated with least one an embodiment, the at least one microbial destructive site parameter associated with a cytokine plasma concentration 305 includes at least one anti-microbial agent. or an acute phase protein plasma concentration. In an In an embodiment, the insertable device 102 includes at embodiment, a data structure 260 includes information 10 least one microbial destructive site 305. In an embodiment, associated with a disease state of a biological Subject 222. In at least one of the anti-microbial regions 202 includes at an embodiment, a data structure 260 includes measurement least one gradient 312 (Such as a temporal gradient, spatial data. gradient, or chemical gradient). In an embodiment, at least The system 100 can include, among other things, one or one of the anti-microbial regions 202 includes at least one more computer-readable media drives 264, interface Sock 15 gradient 312 of self-assembled monolayers including at least ets, Universal Serial Bus (USB) ports, memory card slots, one alkanethiol. In an embodiment, the at least one and the like, and one or more input/output components 266 alkanethiol includes HS(CH) (OCH2CH)OH. Such as, for example, a graphical user interface 268, a In an embodiment, the insertable device 102 includes one display, a keyboard 270, a keypad, a trackball, a joystick, a or more power sources 900. In an embodiment, the power touch-screen, a mouse, a Switch, a dial, and the like, and any Source 900 is electromagnetically, magnetically, acousti other peripheral device. In an embodiment, the system 100 cally, optically, ultrasonically, inductively, electrically, or includes one or more user input/output components 266 that capacitively coupled to the body structure 104. In an operably couple to at least one computing device 230 to embodiment, the power source 900 is coupled to at least one control (electrical, electromechanical, Software-imple of the anti-microbial regions 202, a computing device 230, mented, firmware-implemented, or other control, or combi 25 or a sensor 302. Non-limiting examples of power sources nations thereof) at least one parameter associated with the 900 include one or more button cells, chemical battery cells, energy delivery associated with one or more of the anti a fuel cell, secondary cells, lithium ion cells, micro-electric microbial regions 202. patches, nickel metal hydride cells, silver-zinc cells, capaci In an embodiment, the system 100 includes one or more tors, Super-capacitors, thin film secondary cells, ultra-ca instructions that when executed on at least one computing 30 pacitors, zinc-air cells, or the like. Further non-limiting device 230 cause the computing device 230 to generate at examples of power sources 900 include one or more gen least one output to a user. In an embodiment, the at least one erators (e.g., electrical generators, thermo energy-to-electri computing device 230 is remote to the insertable device. In cal energy generators, mechanical-energy-to-electrical an embodiment, the at least one output includes at least one energy generators, micro-generators, nano-generators, or the of a treatment protocol, identification of a detected micro 35 like) Such as, for example, thermoelectric generators, piezo organism, status of the insertable device 102, or location of electric generators, electromechanical generators, biome a detected microorganism. In an embodiment, the user chanical-energy harvesting generators, and the like. In an includes at least one entity 555. In an embodiment, the at embodiment, the power source 900 includes at least one least one entity 555 includes at least one person or computer. rechargeable power source 701. In an embodiment, the In an embodiment, the at least one output includes output to 40 power source 900 is carried by the catheter device 102. In an a user readable display. In an embodiment, the user readable embodiment, the catheter device 102 can include, among display is operably coupled to the insertable device 102. In other things, at least one of a battery, a capacitor, and a an embodiment, the at least one output is in real-time. In an mechanical energy store (e.g., a spring, a flywheel, or the embodiment, the at least, one output is associated with like). In an embodiment, the power source 900 comprises at historical information. In an embodiment, the user readable 45 least one rechargeable power source 701. In an embodiment, display includes a human readable display. In an embodi the insertable device 102 is configured to receive power ment, the user readable display includes one or more active from an ex vivo power source. In an embodiment, the power displays. In an embodiment, the user readable display receiver 701 is configured to receive power from an in vivo includes one or more passive displays. In an embodiment, power source (e.g., thermoelectric generator, piezoelectric the user readable display includes one or more of a numeric 50 generator, electromechanical systems generator, alternating format, graphical format, or audio format. current nanogenerator, biomechanical-energy harvesting In an embodiment, the attractant Surface property is generator, etc.). located distal to a protected site 310. In an embodiment, the The system 100 can include, among other things, a attractant Surface property is configured to direct one or plurality of selectively actuatable anti-microbial regions more microorganisms away from a protected site 310. In an 55 202a. For example, in an embodiment, the catheter device embodiment, the attractant Surface property is configured to 102 includes a plurality of selectively actuatable anti-mi direct one or more microorganisms toward a destructive site crobial regions 202a that define one or more portions of the 305. In an embodiment, the at least one microbial tactic body structure 104. In an embodiment, at least a portion of agent includes at least one chemoattractant or chemorepel the outer surface 106 of the body structure 104 includes one lant. In an embodiment, the chemoattractant includes at least 60 or more of the plurality of selectively actuatable anti one of a carbohydrate, glycopeptides, proteoglycan, glyco microbial regions 202a. In an embodiment, at least a portion lipid, enzyme, lipopolysaccharide, lipid, peptide, polypep of the inner surface 108 of the body structure 104 includes tide, protein, organic, or inorganic molecule. In an embodi one or more of the plurality of selectively actuatable anti ment, the at least one chemoattractant includes at least one microbial regions 202a. of glucose, formyl peptide, or chemokine. In an embodi 65 In an embodiment, the insertable device 102 comprises a ment, the at least one chemorepellent includes at least one of body structure 104 having an outer surface 106 and an inner a carbohydrate, glycopeptides, proteoglycan, glycolipid, surface 108 defining one or more fluid-flow passageways US 9,474,831 B2 65 66 110, the body structure 104 having a plurality of actuatable protocol information (e.g., FDA regulatory compliance pro anti-microbial regions 202a that are selectively actuatable tocol information, or the like), regulatory use protocol between at least a first actuatable state and a second actu information, authentication protocol information, authoriza atable state; and one or more sensors 302 configured to tion protocol information, delivery regimen protocol infor detect at least one microbial component in a biological mation, activation protocol information, encryption protocol sample 808 proximate at least one of the outer surface 106 information, decryption protocol information, treatment pro or the inner surface 108 of the body structure 104. In an tocol information, or the like. In an embodiment, a database embodiment, the one or more sensors 302 are configured to 258 includes at least one of energy stimulus control delivery detect one or more microorganisms present proximate to the information, energy emitter 220 control information, power body structure 104. 10 control information, anti-microbial region 202 control infor In an embodiment, the insertable device 102 comprises a mation, or the like. In an embodiment, a database 258 body structure 104 defining one or more fluid-flow passage includes at least one spatial or temporal information asso ways 110; the body structure 104 including one or more ciated with anti-microbial region activation, anti-microbial selectively actuatable anti-microbial regions 202a including agent delivery, anti-microbial protruding element actuation, at least one anti-microbial agent, the one or more selectively 15 or other anti-microbial surface property 204 employed. actuatable anti-microbial regions 202a configured to direct In an embodiment, the system 100 is configured to at least one anti-microbial agent to one or more areas of at compare an input associated with at least one characteristic least one of the outer surface 106 of the body structure 104, associated with a biological subject 222 to a database 258 of the inner surface 108 of the body structure 104, or embedded stored reference values, and to generate a response 299 in the internal body structure 104; and one or more sensors based in part on the comparison. In an embodiment, the 302 configured to detect at least one microbial component system 100 is configured to compare an input associated proximate one or more areas of the body structure 104. with at least one physiological characteristic associated with In an embodiment, an insertable device 102 comprises a a biological subject 222 to a database 258 of stored reference body structure 104 having an outer surface 106 and an inner values, and to generate a response 299 based in part on the surface 108 defining one or more fluid-flow passageways 25 comparison. 110; at least one actively controllable anti-microbial nano In an embodiment, the at least one characteristic associ structure 206a projecting from at least one of the outer ated with a biological subject 222 includes real-time surface 106, or the inner surface 108, and at least one sensor detected information associated with a biological sample 302 configured to detect one or more microorganisms pres 808 (e.g., tissue, biological fluid, infections agent, bio ent proximate the body structure 104. 30 marker, or the like) proximate an insertable device 102. In an In an embodiment, an anti-microbial region 202 is con embodiment, the at least one characteristic associated with figured to provide at least one of an energy stimulus 350 a biological subject 222 includes a measurand detected at a (e.g., electromagnetic energy stimulus 350a, electrical plurality of time intervals. In an embodiment, the at least one energy stimulus 350b, acoustic energy stimulus 350c, or characteristic associated with a biological Subject 222 thermal energy stimulus 350d). In an embodiment, the 35 includes real-time detected information associated with a plurality of selectively actuatable anti-microbial regions biological sample 808 (e.g., a biological fluid) received 202a are configured to deliver at least one of a spatially within one or more fluid-flow passageways 110. collimated energy stimulus 350e: spatially focused energy Referring again to FIG. 3, the system 100 can include, stimulus 350f temporally patterned energy stimulus 350g: among other things, a plurality of actuatable anti-microbial or spaced-apart patterned energy stimulus 350h. 40 regions 202a that are selectively actuatable between at least As shown in FIG. 8, the system 100 can include, among a first anti-microbial state and a second anti-microbial state. other things, one or more databases 258. In an embodiment, For example, in an embodiment, an insertable device 102 a database 258 includes spectral information configured a includes a body structure 104 having an outer surface 106 physical data structure 790. In an embodiment, a database and an inner surface 108 defining one or more fluid-flow 258 includes at least one of inflammation indication param 45 passageways 110; and one or more actuatable anti-microbial eter data 776a, infection indication parameter data 776b, regions 202a configured to direct at least one anti-microbial diseased tissue indication parameter data 776c, or the like. In agent to one or more anti-microbial regions 202 proximate an embodiment, a database 258 includes at least one of at least one of the outer surface 106 or inner surface 108 of absorption coefficient data 776d, extinction coefficient data the body structure 104. In an embodiment, the one or more 776e, scattering coefficient data 776f, or the like. In an 50 actuatable anti-microbial regions 202a are configured to embodiment, a database 258 includes at least one of stored alter at least one anti-microbial property 204 in response 299 reference data 776g (e.g., infection marker data, inflamma to detection of at least one microorganism. In an embodi tion marker data, infective stress marker data, systemic ment, the one or more actuatable anti-microbial regions inflammatory response syndrome data, sepsis marker data, 202a are selectively actuatable between at least a first or the like). 55 anti-microbial State and a second anti-microbial state. In an In an embodiment, a database 258 includes information embodiment, a plurality of actuatable anti-microbial regions associated with a disease state of a biological Subject 222. In 202a are configured to actuate between the at least first an embodiment, a database 258 includes measurement data. anti-microbial state and the second anti-microbial state in In an embodiment, a database 258 includes at least one of response 299 to a detected microorganism. In another psychosis state indication information, psychosis trait indi 60 example, the anti-microbial nanostructure 206a is actively cation information, or predisposition for a psychosis indi controllable. In an embodiment, the at least one actively cation information. In an embodiment, a database 258 controllable anti-microbial nanostructure 206a is configured includes at least one of infection indication information, for cyclical activation. In an embodiment, the cyclical inflammation indication information, diseased State indica activation includes cyclical activation of a spaced-apart tion information, or diseased tissue indication information. 65 distribution or a temporally patterned distribution. In an In an embodiment, a database 258 includes at least one of embodiment, the at least one actively controllable anti cryptographic protocol information, regulatory compliance microbial nanostructure 206a is configured for patterned US 9,474,831 B2 67 68 activation (e.g., spatial or temporal pattern). In an embodi The system 100 can include, among other things, a ment, the at least one actively controllable anti-microbial plurality of independently addressable anti-microbial nanostructure 206a is configured to be randomly or nonran regions 202b. In an embodiment, the plurality of indepen domly activated. In another example, the system 100 dently addressable anti-microbial regions 202b is disposed includes an actively controllable circuit configured to deliver along a longitudinal axis of the insertable device 102. In an in vivo an external stimulus to one or more anti-microbial embodiment, the independently addressable anti-microbial regions 202 of the body structure 104 for a character and regions 202b are configured to direct an anti-microbial time sufficient to actuate from the first anti-microbial state to property 204 to one or more regions proximate at least one the second anti-microbial state. In an embodiment, one or of the outer surface 106 or the inner surface 108 of the body more actuatable anti-microbial regions are configured to 10 structure 104. In an embodiment, the plurality of indepen actuate at least one of electrochemically, electromagneti dently addressable anti-microbial regions 202b includes at cally, photochemically, acoustically, magnetically, or elec least one actuatable anti-microbial property 204. In an tro-optically between the first actuatable state and second embodiment, the system 100 further includes circuitry 602 actuatable state. In an embodiment, the one or more actu 15 (as shown in FIG. 6), configured for determining the pres atable anti-microbial regions 202a are controllably actu ence of at least one microorganism proximate at least one of atable between an active state and a passive state. In an a plurality of independently addressable anti-microbial embodiment, the one or more actuatable anti-microbial regions 202b of the body structure 104. In an embodiment, regions 202a are controllably actuatable between an active the at least one actuatable anti-microbial property 204 is state and a passive state based at least in part on detected configured to be actuated by at least one of a program, or the information from one or more sensors 302. In an embodi presence of at least one microorganism. ment, one or more actuatable anti-microbial regions 202a In an embodiment, the system 100 includes actuating are selectively actuatable between at least one first actu means 272 for concurrently or sequentially actuating two or atable state and a second actuatable state via at least one more of the anti-microbial regions 202. In an embodiment, Switch 118. 25 the actuating means 272 includes one or more switches 218. With continued reference to FIG. 3, the system 100 can In an embodiment, the one or more switches 218 are include, among other things, at least one computing device operably coupled to one or more computing devices 230. In 230 including one or more processors (e.g., a microproces an embodiment, the one or more switches 218 are configured sors), central processing units (CPUs) 234, a digital signal to increase or decrease the release of at least one anti processors (DSPs) 236, an application-specific integrated 30 microbial agent from the one or more selectively actuatable circuits (ASICs) 238, a field programmable gate arrays anti-microbial regions 202a. (FPGAs) 240, or other controllers 388, or the like, or any In an embodiment, the one or more Switches 218 include combinations thereof, and can include discrete digital or at least one acoustically active material 218g. In an embodi analog circuit elements or electronics, or combinations ment, the one or more switches 218 include at least one of thereof. The system 100 can include, among other things, 35 an electro-mechanical switch 218a, electrochemical switch one or more field programmable gate arrays having a 218b, electrical switch 218c, electro-optic switch 218d. plurality of programmable logic components. The system acousto-optic switch 218e, or optical switch 218?. 100 can include, among other things, one or more an In an embodiment, the actuating means 272 includes at application specific integrated circuits having a plurality of least one computing device 230 operably coupled to one or predefined logic components. 40 more Switches 218. In an embodiment, the actuating means In an embodiment, the processor 232 is configured to 272 includes at least one optical antifuse. In an embodiment, control activation or actuation of at least one anti-microbial the actuating means 272 includes a movable component region 202. In an embodiment, the processor 232 is config having an optical energy reflecting Substrate. In an embodi ured to be responsive to at least one sensor 302 of the system ment, the movable component is actuated by an electromag 100. In an embodiment the computing device 230 comprises 45 netic energy stimulus generated by one or more energy at least one controller 388. In an embodiment, at least one emitters 220, and configured to guide an optical energy computing device 230 is operably coupled to one or more along at least one of the anti-microbial regions 202 when anti-microbial regions 202. In an embodiment, one or more actuated. In an embodiment, the actuating means 272 is of the anti-microbial regions 202 are configured for selective configured to concurrently or sequentially actuate two or actuation via one or more computing devices 230. In an 50 more of the independently addressable energy or selectively embodiment, the controller 388 is configured to actuate one actuatable anti-microbial regions 202a. or more independently addressable anti-microbial regions Anti-microbial regions 202 forming part of the insertable 202b. In an embodiment, the controller 388 is configured to device 102, can take a variety of forms, configurations, and actuate at least one or more independently addressable geometrical patterns including for example, but not limited anti-microbial regions 202b in response to detected infor 55 to, a one-, two-, or three-dimensional arrays, a pattern 109 mation from at least one sensor 302. In an embodiment, the comprising concentric geometrical shapes, a pattern com controller 388 is configured to actuate one or more inde prising rectangles, squares, circles, triangles, polygons, any pendently addressable anti-microbial regions 202b in regular or irregular shapes, or the like, or any combination response to at least one of a scheduled program, external thereof (as shown in FIGS.5A and 5B). command, history of a previous presence of a microorgan 60 In an embodiment, at least one of the actuatable anti ism, expected presence of microorganisms, expected pres microbial regions 202a includes at least one anti-microbial ence of a particular microorganism, or history of a previous reservoir 208 actuatable by the presence of at least one actuation. In an embodiment, the system 100 includes actu microorganism proximate at least one of the actuatable ating means (e.g., Switch, etc.) for concurrently or sequen anti-microbial regions 202a. In an embodiment, the one or tially actuating two or more of the plurality of independently 65 more actuatable anti-microbial regions 202a are configured addressable anti-microbial regions 202b determined to have to deliver at least one anti-microbial agent in a spatially a microorganism present proximate to the same. patterned distribution. In an embodiment, the one or more US 9,474,831 B2 69 70 actuatable anti-microbial regions 202a are configured to In an embodiment, the diameter of the at least one actively deliver at least one anti-microbial agent in a temporally controllable anti-microbial nanostructure 206a is at least patterned distribution. about 0.5 nm, at least about 1 nm, at least about 5 nm, at least In an embodiment, the actively controllable anti-micro about 10 nm, at least about 15 nm, at least about 20 nm, at bial nanostructure 206a is movable. In an embodiment, the least about 25 nm, at least about 30 nm, at least about 35 nm, movable anti-microbial nanostructure 206a includes at least at least about 40 nm, at least about 45 nm, at least about 50 one micro-electromechanical structure. In an embodiment, nm, at least about 55 nm, at least about 60 nm, at least about the movable anti-microbial nanostructure 206a includes at 65 nm, at least about 70 nm, at least about 75 nm, at least least one electroactive polymer. In an embodiment, the about 80 nm, at least about 85 nm, at least about 90 nm, at movable anti-microbial nanostructure 206a is configured to 10 least about 95 nm, at least about 100 nm, at least about 110 deflect one or more microorganisms. In an embodiment, the nm, at least about 120 nm, at least about 130 nm, at least movable anti-microbial nanostructure 206a is configured to about 150 nm, at least about 160 nm, at least about 170 nm, extend or contract. In an embodiment, the movable anti at least about 180 nm, at least about 190 nm, at least about microbial nanostructure 206a is configured to increase or 200 nm, or any value therebetween or greater. decrease the spacing between two or more nanostructures 15 In an embodiment, the spacing between components of an 206a. In an embodiment, the movable anti-microbial nano anti-microbial region 202 is such that a single microorgan structure 206a is configured to move in at least one of ism can fit (or complete an electrical circuit) therein. rotation, torsion, compression, axial, radial, or lateral move In an embodiment, the depth of the at least one actively ment. controllable anti-microbial nanostructure 206a is at least In an embodiment, the distance between at least two about 0.25um, at least about 0.5um, at least about 1 um, at anti-microbial nanostructures 206a is less than or equal to least about 5um, at least about 10 Jum, at least about 15um, about 0.01 um, about 0.05um, about 1.0 um, about 2.0 um, at least about 20 m, at least about 25 um, at least about 30 about 3.0 um, about 4.0 um, about 5.0 um, about 6.0 um, um, at least about 35um, at least about 40 um, at least about about 7.0 um, about 8.0 um, about 9.0 um, about 10.0 um, 45 um, at least about 50 um, at least about 55 um, at least about 11.0 um, about 12.0 um, about 13.0 Lim, about 14.0 25 about 60 um, at least about 65um, at least about 70 um, at um, about 15.0 um, about 16.0 um, about 17.0 m, about least about 75um, at least about 80 um, at least about 85 um, 18.0 um, about 19.0 um, about 20.0 Lum. at least about 90 um, at least about 95um, at least about 100 In an embodiment, the actively controllable anti-micro um, at least about 110 um, at least about 120 um, at least bial nanostructure 206a includes at least one of silver, about 130 um, at least about 150 lum, at least about 160 um, copper, rubidium, platinum, gold, nickel, lead, cobalt, potas 30 at least about 170 um, at least about 180 um, at least about sium, zinc, bismuth, tin, cadmium, chromium, aluminum, 190 um, at least about 200 um, or any value therebetween or calcium, mercury, thallium, gallium, strontium, barium, greater. lithium, magnesium, oxides, hydroxides, or salts thereof. In In an embodiment, the actively controllable anti-micro an embodiment, the at least one actively controllable anti bial nanostructure 206a includes at least one electrically microbial nanostructure 206a includes at least one of gra 35 actuatable contact. In an embodiment, the actively control phene, black silica, hydrogenated diamond, Zirconium, or lable anti-microbial nanostructure 206a includes at least two diamond. In an embodiment, the at least one actively con electrically actuatable contacts. In an embodiment, the at trollable anti-microbial nanostructure 206a includes at least least two electrically actuatable contacts are differentially one of polyvinyl chloride, polyester, polyethylene, polypro chargeable. In an embodiment, the at least two electrically pylene, ethylene, polyolefin, acrylic, polycarbonate, or sili 40 actuatable contacts are arranged in a static charge pattern. In cone, or homopolymers or copolymers thereof. In an an embodiment, the at least two electrically actuatable embodiment, the at least one actively controllable anti contacts are arranged in a dynamic charge pattern. In an microbial nanostructure 206a includes at least one of poly embodiment, the at least one electrically actuatable contact tetrafluoroethylene or polydimethylsiloxane elastomer. can be locally charged based on detection of at least one In an embodiment, the at least one actively controllable 45 microbe present proximate the at least one electrically anti-microbial nanostructure 206a includes a plurality of actuatable contact. In an embodiment, the at least two nanostructures 206a configured in at least one spatial pat electrically actuatable contacts are spaced Such that the tern. In an embodiment, the at least one spatial or temporal presence of a microbe conducts current via the at least two pattern 109 includes at least one of a repeating pattern, electrically actuatable contacts. In an embodiment, the at non-repeating pattern, or partially repeating pattern. In an 50 least one anti-microbial nanostructure 206a includes at least embodiment, the at least one spatial pattern is derived from one photoactive material. In an embodiment, the photoactive information relating to the type of microorganism expected material includes at least one photocatalyst. In an embodi to be present proximate the body structure 104. ment, the photoactive material includes titanium dioxide. In an embodiment, the spacing between at least two In an embodiment, the plurality of actuatable anti-micro actively controllable anti-microbial nanostructures 206a 55 bial regions 202a are actively controllable, via one or more includes a space of at least about 1 um, at least about 5um, computing device 230, between the at least first anti-micro at least about 10 um, at least about 15 um, at least about 20 bial state and the second anti-microbial state. um, at least about 25 at least about 30 um, at least about 35 The system 100 can include, among other things, one or um, at least about 40 um, at least about 45um, at least about more actively controllable reflective or transmissive com 50 um, at least about 55 um, at least about 60 m, at least 60 ponents configured to outwardly transmit or internally about 65 um, at least about 70 um, at least about 75 um, at reflect an energy stimulus propagated therethrough. In an least about 80 um, at least about 85 um, at least about 90 um, embodiment, an insertable device 102 includes one or more at least about 95 um, at least about 100 um, at least about 110 actively controllable reflective or transmissive components um, at least about 120 um, at least about 130 um, at least configured to outwardly transmit or internally reflect an about 150 lum, at least about 160 um, at least about 170 um, 65 energy stimulus propagated therethrough. at least about 180 um, at least about 190 um, at least about In an embodiment, one or more actuatable anti-microbial 200 um, or any space therebetween or greater than. regions 202a are selectively actuatable between at least a US 9,474,831 B2 71 72 first transmissive state and a second transmissive state via at tially hydrophobic state and a substantially hydrophilic state. least one acoustically active material. In an embodiment, In an embodiment, the one or more fluid-flow passageways one or more of plurality of actuatable anti-microbial regions 110 includes a Surface region that is energetically actuatable 202a are selectively actuatable between at least a first between at least a first hydrophilic state and a second transmissive state and a second transmissive state via at least hydrophilic state. In an embodiment, at least one of the one electro-mechanical Switch. In an embodiment, one or fluid-flow passageways 110 includes a surface region that is more of plurality of actuatable anti-microbial regions 202a energetically actuatable between a hydrophobic state and a are selectively actuatable between at least a first transmis hydrophilic state. In an embodiment, at least one of the sive state and a second transmissive state via at least one fluid-flow passageways 110 includes a Surface region having electro-optic Switch. In an embodiment, one or more of the 10 a material that is switchable between a Zwitterionic state and actuatable anti-microbial regions 202a are selectively actu a non-Zwitterionic state. atable between at least a first transmissive state and a second In an embodiment, the one or more fluid-flow passage transmissive state via at least one acousto-optic Switch. In an ways 110 includes at least one of an anti-microbial coating. embodiment, one or more of the actuatable anti-microbial In an embodiment, at least one of the fluid-flow passageways regions 202a are selectively actuatable between at least a 15 110 includes an anti-microbial coating. In an embodiment, at first transmissive state and a second transmissive state via at least one of the fluid-flow passageways 110 includes a least one optical Switch. Surface region that is energetically actuatable between an The system 100 can include, among other things, a anti-microbial state. In an embodiment, at least one anti computing device 230 operably coupled to one or more of microbial coating is configured for time-release of at least the actuatable anti-microbial regions 202a. In an embodi one anti-microbial agent. In an embodiment, the coating ment, the controller 388 is configured to cause a change includes at least one of an anti-microbial agent, electroactive between an at least first anti-microbial state and a second polymer, petroleum jelly, silver gel, Surfactant, alcohol gel. anti-microbial state based on detected information from the or other coating. In an embodiment, the coating includes at one or more sensors 302. In an embodiment, the controller least one expandable material. In an embodiment the 388 is programmable. 25 expandable material is actively controllable. In an embodi In an embodiment, the insertable device 102 includes one ment, the expandable material is configured to physically or more computing devices 230 operably coupled to one or dislocate at least one microorganism on at least one of the more of the actuatable anti-microbial regions 202a. In an inner surface 108 or outer surface 106 of the body structure embodiment, at least one of the computing devices 230 is 104. In an embodiment, the at least one expandable material configured to cause a change between the at least a first 30 is configured to expand in at least one longitudinal or anti-microbial State and a second anti-microbial state based transverse motion. on detected information from the one or more sensors 302. In an embodiment, an insertable device 102 includes a In an embodiment, at least one computing device 230 is body structure 104 having an outer surface 106 and an inner configured to actuate one or more of the actuatable anti surface 108 defining one or more fluid-flow passageways microbial regions 202a between the at least first anti 35 110; one or more anti-microbial regions 202 including at microbial state and the second anti-microbial state based on least one anti-microbial coating actuatable by the presence a comparison of a detected characteristic associated with the of at least one microorganism, and configured to actively biological sample 808 proximate at least one of the outer elute at least one anti-microbial agent proximate to at least surface 106 or the inner surface 108 of the body structure one of the outer surface 106 or the inner surface 108 of the 104. For example, in an embodiment, the one or more 40 body structure 104. sensors 302 are configured to detect at least one character In an embodiment, an insertable device 102 includes a istic associated with one or more anti-microbial regions 202 body structure 104 having an outer surface 106 and an inner proximate at least one of the outer surface 106 or the inner surface 108 defining one or more fluid-flow passageways surface 108 of the body structure 104; and at least one 110; one or more anti-microbial regions 202 including at controller 388 operably coupled to one or more of the 45 least one anti-microbial reservoir 208 including at least one spaced-apart release ports 118a and configured to actuate anti-microbial agent, the at least one anti-microbial reservoir one or more of the spaced-apart release ports 118a between 208 configured to deliver at least one anti-microbial agent an anti-microbial agent discharge state and an anti-microbial proximate to at least one of the outer surface 106 or the inner agent retention state based on a comparison of a detected surface 108 of the body structure 104. characteristic to stored reference data. 50 In an embodiment, the body structure 104 includes one or For example, in an embodiment the anti-microbial region more anti-microbial protruding elements 206 (e.g., nano 202 affects adhesion of for example, bacteria, or other structure, microstructure, nanoscale pillar, nanoscale ridge, microorganisms, and biofilm formation by changing at least high aspect ratio nanofibrillar structure, nanoscale projec one of a functional, structural, and chemical characteristic of tion, nanoscale irregularity, nanoscale elongation, nanoscale a surface on an insertable device 102. For example, adhesion 55 Valley, nanoscale trough, nanoscale spike (e.g., blunt tip may be affected by changing Surface morphology. It may spike, sharp tip spike, etc.), or the like) on at least one also be possible to modulate the adhesion and biofilm Surface. In an embodiment, the at least one anti-microbial formation by modulating at least one of the functional, nanostructure 206a includes at least one Surface portion that structural, or chemical characteristics of a Surface on an is energetically unstable. In an embodiment, the at least one insertable device 102. By modulating at least one of a 60 anti-microbial nanostructure 206a includes at least a portion functional, structural, or chemical characteristic of a Surface of a surface that is hydrophilic. In an embodiment, the at on an insertable device 102, the transport properties of a least one anti-microbial nanostructure 206a includes at least fluid exposed to the surface on an insertable device 102 may a portion of a surface that is hydrophobic. also be affected. In an embodiment, the anti-microbial protruding element In an embodiment, at least one of the fluid-flow passage 65 206 is produced by femtosecond laser pulses against a ways 110 includes one or more surface anti-microbial Substrate. In an embodiment, the Substrate includes at least regions that are energetically actuatable between a Substan one of a hydrophobic, superhydrophobic, or ultrahydropho US 9,474,831 B2 73 74 bic substrate. In an embodiment, the substrate includes one least one anti-microbial nanostructure 206a is configured to or more of a metal, ceramic, glass, non-crystalline material, increase at least one of microbial movement, microbial semiconductor, composite, or polymer. In an embodiment, attachment, microbial growth, or microbial persistence the polymer includes a diarylethene. In an embodiment, the proximate at least one surface of the body structure 104. In polymer includes at least one electrically conductive poly an embodiment, the at least one anti-microbial nanostructure mer. In an embodiment, the at least one electrically conduc 206a is configured to decrease at least one of microbial tive polymer includes at least one dopant. In an embodiment, movement, microbial attachment, microbial growth, or the at least one dopant includes at least one low surface microbial persistence proximate at least one Surface of the energy dopant. In an embodiment, the at least one dopant body structure 104. includes perfluorooctanesulfonate. In an embodiment, the at 10 In an embodiment, the insertable device 102 includes at least one electrically conductive polymer includes the at least one switchable surface 404. In an embodiment, the least one electrically conductive polymer includes at least switchable surface 404 is configured to alter the liquid-solid one of polythiophene, poly(p-phenylene), poly(aniline), contact angle of the at least one actuatable anti-microbial polyacetylene, poly(pyrrole), poly (N-methylpyrrole), poly nanostructure 206a. In an embodiment, the at least one (thiophene), poly(alkyl thiophene), poly(furan), poly(pyri 15 switchable surface 404 includes poly(dimethylsiloxane). In dine), poly(fluorene), poly(3-hexylthiophene), polynaphtha an embodiment, the switchable surface 404 is reversibly lene, poly(p-phenylene Sulfide), poly(aZulene), polyacene, switchable. In an embodiment, the switchable surface 404 is polycuinone.polystyrene Sulfonate, polyethylenedioxythio configured to alter at least one of the electrical charge, phene, poly(p-phenylene), poly(p-phenylene vinylene), chemical composition, polarizability, transparency, conduc polysulfone, poly(pyridine), poly(quinoxaline), polyanthra tivity, light absorption, osmotic potential, Zeta potential, quinone, poly(n-vinylcarbazole), poly(acene), or poly(het surface energy, coefficient of friction, or affinity for at least eroaromatic vinylene). one microbial component. In an embodiment, the at least In an embodiment, the liquid-Solid contact angle of the one switchable surface 404 is configured to switch from a Substrate is greater than about 0 degrees, greater than about first conformation state to a second conformation state in 5 degrees, greater than about 10 degrees, greater than about 25 response 299 to an external stimulus. In an embodiment, the 20 degrees, greater than about 30 degrees, greater than about at least one switchable surface 404 is switchable from a first 40 degrees, greater than about 50 degrees, greater than about state to a second state. In an embodiment, the second state 60 degrees, greater than about 70 degrees, greater than about inhibits anti-microbial presence proximate at least one Sur 80 degrees, greater than about 90 degrees, greater than about face of the insertable device 102. 100 degrees, greater than about 105 degrees, greater than 30 In an embodiment, the external stimulus includes at least about 110 degrees, greater than about 120 degrees, greater one microorganism. In an embodiment, the external stimulus than about 130 degrees, greater than about 140 degrees, includes at least one physical or chemical change proximate greater than about 150 degrees, greater than about 160 the switchable surface 404. In an embodiment, the at least degrees, greater than about 170 degrees, about 180 degrees, one external stimulus includes at least one of a change in or any value therebetween. 35 applied Voltage, change in temperature, change in pH, In an embodiment, a plurality of nanostructures 206a exposure to ultraviolet light, disruption to ultraviolet light, includes at least two nanostructures 206a oriented parallel to electromagnetic radiation, magnetic field, removal of a each other. In an embodiment, a plurality of nanostructures magnetic field, change in capacitance, change in electro 206a includes at least two nanostructures 206a oriented static charge, removal of electrostatic charge, exposure to a perpendicular to each other. In an embodiment, a plurality of 40 ligand, exposure to a solvent, or exposure to an ion. In an nanostructures 206a includes at least two nanostructures embodiment, the first conformation state and the second 206a with at least one topographical pattern. In an embodi conformation state differ in degree of hydrophobicity. In an ment, the plurality of anti-microbial nanostructures 206a embodiment, the second conformation state has a greater includes at least two different anti-microbial nanostructures liquid-Solid contact angle than the first conformation state. 206a. In an embodiment, the at least two different anti 45 In an embodiment, the at least one anti-microbial nano microbial nanostructures 206a include at least one different structure 206a is configured to be activated by at least one spatial property or temporal property (e.g. wettability). physical or chemical change on the Switchable surface 404. The wettability, or other surface properties can be con In an embodiment, the at least one anti-microbial nanostruc trolled by altering the density of the protruding elements. ture 206a is configured to be activated by at least one of a See e.g., Spori et al., Cassie-State Wetting Investigated by 50 change in applied voltage, change in temperature, change in Means of a Hole-to-Pillar Density Gradient, Langmuir, pH, exposure to ultraviolet light, disruption to ultraviolet 2010, 26 (12), pp. 9465-9473. In an embodiment, the anti light, electromagnetic radiation, magnetic field, removal of microbial nanostructure 206a is actuatable. In an embodi a magnetic field, change in capacitance, change in electro ment, the at least one anti-microbial nanostructure 206a static charge, removal of electrostatic charge, exposure to a includes at least one of a rough Surface or patterned surface. 55 ligand, exposure to a solvent, or exposure to an ion. In an In an embodiment, the rough Surface includes an engineered embodiment, the first conformation state and the second roughness index of from about 1 to about 100, wherein the conformation state differ in degree of hydrophobicity. In an roughness index includes the ratio of the actual Surface area embodiment, the second conformation state has a greater to the geometric Surface area. In an embodiment, the at least liquid-Solid contact angle than the first conformation state. one anti-microbial nanostructure 206a is configured to be 60 In an embodiment, the insertable device 102 includes at actuated by at least partial degradation of at least one least one photonic crystal. In an embodiment, the photonic component of the body structure 104. crystal includes at least one biopolymer. In an embodiment, In an embodiment, the at least one anti-microbial nano the photonic crystal includes at least one nanopatterned structure 206a is configured to modulate at least one of Surface. In an embodiment, the at least one photonic crystal microbial movement, microbial attachment, microbial 65 includes at least one embedded material. In an embodiment, growth, or microbial persistence proximate at least one that least one embedded material includes at least one of a surface of the body structure 104. In an embodiment, the at biological cell, enzyme, nucleic acid, detection material, US 9,474,831 B2 75 76 Small molecule, protein, peptide, polypeptide, amino acid, phy, X-ray lithography, LIGA techniques (e.g., X-ray lithog carbohydrate, lipid, therapeutic agent, electronic compo raphy, electroplating, and molding), conductive paint silk nent, or other material. In an embodiment, the at least one screen techniques, conventional pattering techniques, injec detection material includes at least one of a contrast agent, tion molding, conventional silicon-based fabrication meth or electronic identification device. In an embodiment, the at ods (e.g., inductively coupled plasma etching, wet etching, least one detection material includes at least one of a isotropic and anisotropic etching, isotropic silicon etching, radioactive substance, luminescent Substance, or odorous anisotropic silicon etching, anisotropic GaAs etching, deep Substance. In an embodiment, the detection material reactive ion etching, silicon isotropic etching, silicon bulk includes at least one of a diamagnetic particle, ferromagnetic micromachining, or the like), complementary-symmetry/ particle, paramagnetic particle, Super paramagnetic particle, 10 metal-oxide semiconductor (CMOS) technology, deep X-ray particle with altered isotope, or other magnetic particle. exposure techniques, and the like. Further examples of For example, in an embodiment, an insertable device 102 methodologies and technologies for making controllable comprises a body structure 104 having an outer surface 106 wettability components can found in the following docu and an inner surface 108 defining one or more fluid-flow ments (the contents of each of which is incorporated herein passageways 110; wherein at least one of the outer Surface 15 by reference): Feng et al., Reversible Super-hydrophobicity 106 or the inner surface 108 of the body structure 104 to Super-hydrophilicity Transition of Aligned ZnO Nanorod includes at least one anti-microbial nanostructure 206a. In Films, J. Am. Chem. Soc., 126, 62-63 (2004), Lin et al., an embodiment, an insertable device 102 comprises a body Electrically Tunable Wettability of Liquid Crystal/Polymer structure 104 including at least one anti-microbial nano Composite Films, Optics Express 16(22): 17591-598 structure 206a. In an embodiment, an insertable device 102 (2008), Spori et al., Cassie-State Wetting Investigated by comprises a body structure 104 having an outer surface 106 Means of a Hole-to-Pillar Density Gradient, Langmuir, and an inner surface 108 defining one or more fluid-flow 2010, 26 (12), pp. 9465-9473 Wang et al., Photoresponsive passageways 110; wherein at least one of the outer Surface Surfaces with Controllable Wettability, Journal of Photo 106, or the inner surface 108 of the body structure 104 chemistry and Photobiology C: Photochemistry Reviews, includes at least one actuatable anti-microbial nanostructure 25 8(1): 18-29 (2007), U.S. Pat. No. 6,914.279 (issued Jul. 5, 206a. In an embodiment, an insertable device 102 comprises 2005), and U.S. Patent Publication No. 2008/0223717 (pub a body structure 104 including at least one actuatable lished Sep. 18, 2008). anti-microbial nanostructure 206a. The wettability of a substrate can be determined using In an embodiment, the one or more anti-microbial regions various technologies and methodologies including contact 202 are configured to photochemically actuate between the 30 angle methods, the Goniometer method, the Whilemy first wettability state and the second wettability state in the method, the Sessile drop technique, or the like. Wetting is a presence of an ultraviolent energy. In an embodiment, the process by which a liquid interacts with a solid. Wettability one or more anti-microbial regions 202 are configured to (the degree of wetting) is determined by a force balance actuate between the first wettability state and the second between adhesive and cohesive force and is often charac wettability State in the presence of an applied potential. In an 35 terized by a contact angle. The contact angle is the angle embodiment, the one or more anti-microbial regions 202 are made by the intersection of the liquid/solid interface and the UV-manipulatable between the first wettability and the sec liquid/air interface. Alternatively, it is the angle between a ond wettability. Solid sample's Surface and the tangent of a droplet’s ovate In an embodiment, the one or more anti-microbial regions shape at the edge of the droplet. Contact angle measure 202 are configured to photochemically actuate between a 40 ments provide a measure of interfacial energies and conveys substantially hydrophobic state and a substantially hydro direct information regarding how hydrophilic or hydropho philic state. In an embodiment, the one or more anti bic a surface is. For example, Superhydrophilic Surfaces microbial regions 202 are configured to electrically actuate have contact angles less than about 5, hydrophilic Surfaces between a substantially hydrophobic state and a substan have contact angles less than about 90°, hydrophobic sur tially hydrophilic state. In an embodiment, the one or more 45 faces have contact angles greater than about 90°, and Supe anti-microbial regions 202 include at least one ZnO nano rhydrophobic surfaces have contact angles greater than rod film, coating, or material that is UV-manipulatable about 150°. between a superhydrophobic state and superhydrophilic In an embodiment, the insertable device 102 includes a State. body structure 104 including one or more controllable In an embodiment, the one or more anti-microbial regions 50 wettability-components 804 having switchable wetting 202 are energetically controllably actuatable between a properties. In an embodiment, the insertable device 102 substantially hydrophobic state and a substantially hydro includes a body structure 104 including one or more con philic state. In an embodiment, the one or more anti trollable-wettability-components 804 that are energetically microbial regions 202 are energetically controllably actu actuatable between at least a first wettability and a second atable between at least a first hydrophilic state and a second 55 wettability. In an embodiment, the one or more controllable hydrophilic State. In an embodiment, the one or more wettability-components 804 are acoustically, chemically, anti-microbial regions 202 are energetically controllably electro-chemically, electrically, optically, thermally, or actuatable between a hydrophobic state and a hydrophilic photo-chemically actuatable between at least, a first wetta state. In an embodiment, the one or more anti-microbial bility and a second wettability. regions 202 include a material that is switchable between a 60 In an embodiment, the one or more controllable-wetta Zwitterionic state and a non-Zwitterionic State. bility-components 804 include at least one acousto-respon Controllable-wettability-components 804 can be made sive material. using a variety of methodologies and technologies includ In an embodiment, the one or more controllable-wetta ing, for example, spray pyrolysis, electro-deposition, elec bility-components 804 include at least one photo-responsive tro-deposition onto laser-drilled polymer molds, laser cut 65 material. Non-limiting examples of photo-responsive mate ting and electro-polishing, laser micromachining, rials include SnO, SnO, TiO, WO, ZnO, ZnO, and the photolithography, Surface micro-machining, soft lithogra like. In an embodiment, the one or more controllable US 9,474,831 B2 77 78 wettability-components 804 include at least one film, coat herein by reference): U.S. Pat. Nos. 7,348,021 (issued Mar. ing, or material including SnO, SnO, TiO, WO, ZnO, 25, 2008), 7,217,425 (issued May 15, 2007), 7,151,139 ZnO, or the like. In an embodiment, the one or more (issued Dec. 19, 2006), and 7,143,709 (issued Dec. 5, 2006). controllable-wettability-components 804 are UV-manipulat In an embodiment, at least a portion of an inner or an outer able between at least a first wettability and a second wetta- 5 surface of the insertable device 102 includes one or more bility. In an embodiment, the one or more controllable self-cleaning coating materials. Non limiting examples of wettability-components 804 include one or more ZnO nano self-cleaning coating (e.g., Lotus Effect) materials include rod films, coatings, or materials that are UV-manipulatable Superhydrophobic materials, carbon nanotubes with nano between a superhydrophobic state and superhydrophilic scopic paraffin coating, or the like. Further non-limiting state. In an embodiment, the one or more controllable 10 wettability-components 804 include at least one electro examples of self-cleaning (e.g., non fouling) coating mate chemically active material. Non-limiting examples of elec rials include antimicrobial, and nonfouling Zwitterionic trochemically active materials include electrochemically polymers, Zwitterionic Surface forming materials, Zwitteri active polymers (e.g., polyaniline, polyethylenethioxythio onic polymers, poly(carboxybetaine methacrylate) phene, conjugated polymer poly(3-hexylthiophene), or the 15 (pCBMA), poly(carboxybetaine acrylic amide) (pCBAA), like), and the like. poly(oligo(ethylene glycol) methyl ether methacrylate) (pO In an embodiment, the one or more controllable-wetta EGMA), poly(N,N-dimethyl-N-(ethoxycarbonylmethyl)-N- bility-components 804 include one or more superhydropho 2'-(methacryloyloxy)ethyl-ammonium bromide), cationic bic conducting polypyrrole films, coatings, or components pC8NMA, switchable pCBMA-1 C2, pCBMA-2, and the that are electrically switchable between an oxidized state like. See, e.g., WO 2008/083390 (published Jul. 10, 2008) and a neutral State, resulting in reversibly Switchable Supe (the contents of each of which is incorporated herein by rhydrophobic and Superhydrophilic properties. (See, e.g., reference). Lahann et al., A Reversibly Switching Surface, 299 (5605): Further non-limiting examples of coatings include Supe 371-374 (2003) 21:47-51 (2003), the contents of each of rhydrophobic conducting polypyrrole coatings that are elec which is incorporated herein by reference). In an embodi 25 trically switchable between an oxidized state and a neutral ment, the one or more controllable-wettability-components state, resulting in reversibly switchable superhydrophobic 804 include one or more electrically isolatable fluid-support and Superhydrophilic properties (see, e.g., Lahann et al. A structures. See, e.g., U.S. Pat. No. 7,535,692 (issued May Reversibly Switching Surface, 299 (5605): 371-374 (2003) 19, 2009), the contents of each of which is incorporated 21:47-51 (2003), the contents of each of which is incorpo herein by reference). 30 rated herein by reference); coatings including electrically In an embodiment, the one or more controllable-wetta isolatable fluid-support structures (see, e.g., U.S. Pat. No. bility-components 804 include a plurality of volume-tunable 7,535,692 (issued May 19, 2009), the contents of each of nanostructures 206a. See, e.g., U.S. Patent Publication No. which is incorporated herein by reference); coatings includ 2008/0095977 (published Apr. 24, 2008), the contents of ing a plurality of Volume-tunnable nanostructures (see, e.g., each of which is incorporated herein by reference). In an 35 U.S. Patent Publication No. 2008/0095,977 (published Apr. embodiment, the one or more controllable-wettability-com 24, 2008), the contents of each of which is incorporated ponents 804 include one or more tunable (electrically tun herein by reference); coatings including re-entrant Surface able) Superhydrophobic conducting polypyrrole films, coat structures (see, e.g., Tuteja et al., Robust Omniphobic Sur ings, or components. See, e.g., Krupenki et al. Electrically faces, Epub 2008 Nov. 10, 105(47): 18200-5 (2008), the Tunable Superhydrophobic Nanostructured Surfaces, Bell 40 contents of each of which is incorporated herein by refer Labs Technical Journal 10 (3):161-170 (2009), the contents ence); coatings including Superhydrophobic conducting of each of which is incorporated herein by reference). In an polypyrrole materials, coatings including Zwitterionic poly embodiment, the one or more controllable-wettability-com mers (see, e.g., Cheng et al., A Switchable Biocompatible ponents 804 include one or more electrically tunable crystal/ Polymer Surface with Self-Sterilizing and Nonfouling Capa polymer composites. In an embodiment, the one or more 45 bilities, Angew. Chem. Int. Ed. 8831-8834 (2008), the controllable-wettability-components 804 include a switch contents of each of which is incorporated herein by refer able surface 404. See e.g., Gras et al., Intelligent Control of ence); or the like. Surface Hydrophobicity, ChemPhysChem 8(14): 2036-2050 Further non-limiting examples of coating include reflec (2007). tive coatings, beam-splitter coatings, broadband multilayer In an embodiment, the insertable device 102 includes one 50 coatings, composite coatings, dielectric coatings, dielectric or more coatings (e.g., optically active coatings, reflective reflective coatings (e.g., dielectric high reflective coatings), coating, opaque coatings, transmissive coatings, etc.). In an grating waveguide coatings (e.g., high reflectivity grating embodiment, at least a portion of the body structure 104 waveguide coatings), IR reflective coatings, metallic reflec includes a Surface having a coating, coatings configured to tive coatings (e.g., metallic high reflective coatings), multi treat or reduce the concentration of an infectious agent in the 55 layer coatings, narrow or broadband coatings, optical coat immediate vicinity of the insertable device 102. ings, partial reflective coatings, polymeric coatings, single Non-limiting examples of coatings include anti-biofilm layer coatings, UV reflective coatings, UV-IR reflective activity coatings, coatings having self-cleaning properties, coatings, and the like, and combinations thereof. For coatings having self-cleaning or anti-bacterial activity, and example, in an embodiment, the insertable device 102 the like. 60 includes at least one of an outer internally reflective or an Further non-limiting examples coatings include poly inner internally reflective coating on the body structure 104. meric compositions that resist bacterial adhesion, antimicro For example, in an embodiment, at least a portion of an inner bial coatings, coatings that controllably release antimicro surface 108 or an outer surface 106 of the insertable device bial agents, quaternary ammonium silane coatings, chitosan 102 includes a coating configured to internally reflect at least coatings, and the like. Further non-limiting examples of 65 a portion of an emitted energy stimulus within an interior of coatings may be found in, for example, the following at least one of the fluid-flow passageways 110. In an documents (the contents of each of which is incorporated embodiment, at least a portion of the body structure 104 US 9,474,831 B2 79 80 includes at least one of an outer internally reflective coating least one anti-microbial agent proximate to at least one of the and an inner internally reflective coating. outer surface 106 or the inner surface 108 of the body The system 100 can include, among other things, one or structure 104. more reflective materials. In an embodiment, the insertable In an embodiment, an insertable device 102 comprises a device 102 includes a reflective material. For example, in an body structure 104 having an outer surface 106 and an inner embodiment, at least a portion of the body structure 104 surface 108 defining one or more fluid-flow passageways includes a reflective material. Non limiting examples of 110; one or more anti-microbial regions 202 of the body reflective materials include aluminum, aluminum oxide, structure 104 including at least one anti-microbial agent barium sulfate, chromium, copper, fluorine, germanium, reservoir 208, the reservoir 208 configured to release one or gold, hafnium dioxide, high refractive index materials, low 10 refractive index materials, magnesium fluoride, nickel, more anti-microbial agents to the one or more anti-microbial nickel-chromium platinum, quartz, rhodium, Sapphire, sili regions 202 of the body structure 104. In an embodiment, a con dioxide, silver, tantalum pentoxide, thorium fluorides, system 100 comprises an insertable device 102 including a titanium, titanium dioxide, titanium oxide, tungsten, yttrium body structure 104 having an outer surface 106 and an inner oxide, Zinc oxide, Zinc sulfide, Zirconium, Zirconium oxide, 15 surface 108 defining one or more fluid-flow passageways and the like, as well as compounds, composites, and mix 110; and one or more anti-microbial regions 202 proximate tures thereof. at least one of an outer surface 106, an inner surface 108, or For example, in an embodiment, at least a portion of the embedded in the internal body structure 104; the body insertable device 102 includes one or more coatings includ structure 104 including at least one anti-microbial agent ing at least one reflective material. In an embodiment, the reservoir 208 operably coupled to the one or more anti reflective material includes at least one of aluminum, barium microbial regions 202; and circuitry 604 configured for Sulfate, gold, silver, titanium dioxide, and Zinc oxide. In an operating the at least one anti-microbial agent reservoir 208. embodiment, the reflective material includes an ultraviolet In an embodiment, the system 100 comprises circuitry energy reflective material. In an embodiment, the ultraviolet 605 configured for operating at least one sensor 302 oper energy reflective material comprises a metallic film. In an 25 ably coupled to at least one of the anti-microbial regions embodiment, the ultraviolet energy reflective material com 202. In an embodiment, the system 100 comprises circuitry prises enhanced aluminum. In an embodiment, the ultravio 605 configured for operating at least one sensor 302 oper let energy reflective material comprises enhanced aluminum ably coupled to at least one of the at least one anti-microbial overcoated with at least one of magnesium fluoride, silicon agent reservoir 208. In an embodiment, the at least one dioxide, or silicon monoxide. In an embodiment, the ultra 30 sensor 302 is configured to detect information related to at violet energy reflective material comprises enhanced alumi least one microbial component. In an embodiment, the num overcoated with high phosphorous nickel. In an system 100 further comprises circuitry 606 configured for embodiment, the ultraviolet energy reflective material com operating one or more central processing units 234. prises barium sulfate. In an embodiment, a system 100 includes means for In an embodiment, at least a portion of the body structure 35 operating an insertable device 102, the insertable device 102 104 includes an optical material that permits the transmis including a body structure 104 having an outer surface 106 sion of at least a portion of an emitted energy stimulus from and an inner surface 108 defining one or more fluid-flow an interior of at least one of the fluid-flow passageways 110 passageways 110; and one or more anti-microbial regions to an exterior of at least one of the fluid-flow passageways 202 proximate at least one of an outer surface 106, an inner 110. In an embodiment, at least a portion of the body 40 surface 108 or embedded in the internal body structure 104; structure 104 includes an optical material that internally the body structure 104 including at least one anti-microbial reflects at least a portion of an emitted energy stimulus agent reservoir 208 operably coupled to the one or more present within an interior of at least one of the fluid-flow anti-microbial regions 202; and means 604 (as shown in passageways 110. In an embodiment, at least a portion of the FIG. 7) for operating the at least one anti-microbial agent body structure 104 includes an optical material that inter 45 reservoir 208. In an embodiment, the system 100 further nally reflects at least a portion of an emitted energy stimulus comprises means 605 for operating one or more sensor within an interior of at least one of the fluid-flow passage transmitters 445 or sensor receivers 444. ways 110, without Substantially permitting the transmission In an embodiment, the system 100 includes one or more of the emitted energy stimulus through an exterior of the computing devices 230 operably coupled to one or more body structure 104. In an embodiment, at least a portion of 50 sensors 302. In an embodiment, at least one computing the body structure 104 includes an optical material that device 230 is configured to process an output associated internally directs at least a portion of an emitted energy with one or more sensors 302. In an embodiment, the system stimulus along a Substantially longitudinal direction of at 100 includes one or more computing devices 230 configured least one of the fluid-flow passageways 110. In an embodi to concurrently or sequentially operate multiple sensors 302. ment, wherein at least a portion of the body structure 104 55 In an embodiment, the system 100 is configured to compare includes an optical material that internally directs at least a an input associated with at least one characteristic associated portion of an emitted energy stimulus along a substantially with a biological sample proximate an insertable device 102 lateral direction of at least one of the fluid-flow passageways to a data structure 260 including reference values, and to 110. generate a response 299 based in part on the comparison. In In an embodiment, an insertable device 102 comprises a 60 an embodiment, the system 100 is configured to compare an body structure 104 having an outer surface 106 and an inner input associated with at least one physiological characteris surface 108 defining one or more fluid-flow passageways tic associated with a biological Subject 222 to a data struc 110; at least one actuatable anti-microbial region 202a ture 260 including reference values, and to generate a including at least one anti-microbial reservoir 208 including response 299 based in part on the comparison. In an embodi at least one anti-microbial agent, the at least one actuatable 65 ment, the system 100 is configured to compare an input anti-microbial reservoir 208 actuatable by the presence of at associated with at least one characteristic associated with a least one microorganism and configured to actively elute at biological sample 808 proximate an insertable device 102 to US 9,474,831 B2 81 82 a data structure 260 including reference values, and to a physical data structure 260 and to generate a response 299 generate a response 299 based in part on the comparison. based at least in part on the comparison. In an embodiment, In an embodiment, at least one computing device 230 is one or more computing devices 230 are operably coupled to configured to perform a comparison of at least one detected at least one of the selectively actuatable anti-microbial characteristic to stored reference data, and to generate a regions 202a, and configured to actuate at least one of the response 299 based at least in part on the comparison. For selectively actuatable anti-microbial regions 202a in example, in an embodiment, at least one computing device response 299 to detected information from the one or more 230 is configured to perform a comparison of at least one sensors 302. characteristic associated with the biological sample 808 to Referring to FIGS. 4A, 4B, 5A, and 5B, in an embodi stored reference data, and to initiate a treatment protocol 10 ment, the plurality of selectively actuatable anti-microbial based at least in part on the comparison. In an embodiment, regions 202a are configured to provide a spatial or temporal at least one computing device 230 is configured to perform patterned 109 anti-microbial surface property 204. In an a comparison of a detected at least one of the emitted optical embodiment, the plurality of selectively actuatable anti energy or the remitted optical energy from the region microbial regions 202a are configured to deliver an anti proximate the body structure 104 to reference spectral 15 microbial agent of a dose Sufficient (e.g., of character and for information, and to cause an emission of an energy stimulus a duration Sufficient, of Sufficient strength or duration, etc.) from one or more energy emitters 220 to at least one of the to provide a spatial or temporal patterned 109 anti-microbial outer surface 106 and the inner surface 108 of the body surface of the body structure 104. structure 104. In an embodiment, one or more computing In an embodiment, the insertable device 102 comprises a devices 230 are communicatively coupled to one or more body structure 104 having an outer surface 106, and an inner sensors 302 and configured to actuate a determination of the surface 108 defining one or more fluid-flow passageways at least one characteristic associated with a biological speci 110; wherein at least one of the outer surface 106, or the men proximate a surface of the insertable device 102. inner surface 108 of the body structure 104 includes at least In an embodiment, a computing device 230 is configured one anti-microbial nanostructure 206a. to compare a measurand associated with the biological 25 In an embodiment, the insertable device 102 comprises a subject 222 to a threshold value associated with a tissue body structure 104 including at least one anti-microbial spectral model and to generate a response 299 based on the nanostructure 206a. In an embodiment, the insertable device comparison. In an embodiment, a computing device 230 is 102 comprises a body structure 104 having an outer surface configured to compare an input associated with at least one 106 and an inner surface 108 defining one or more fluid-flow characteristic associated with, for example, a biological 30 passageways 110; wherein at least one of the outer Surface sample proximate an insertable device 102 to a database 258 106, or the inner surface 108 of the body structure 104 of stored reference values, and to generate a response 299 includes at least one actuatable anti-microbial nanostructure based in part on the comparison. 206a. The response 299 can include, among other things, at least In an embodiment, the insertable device 102 comprises a one of a response signal, an absorption parameter, an extinc 35 body structure 104 including at least one actuatable anti tion parameter, a scattering parameter, a comparison code, a microbial nanostructure 206a. comparison plot, a diagnostic code, a treatment code, an As indicated in FIG. 7, in an embodiment, a catheter alarm response, and a test code based on the comparison of system 100 comprises a body structure 104 having an outer a detected optical energy absorption profile to characteristic surface 106 and an inner surface 108 defining one or more spectral signature information. In an embodiment, the 40 fluid-flow passageways 110; and a plurality of selectively response 299 includes at least one of a display, a visual actuatable anti-microbial regions 202a configured to direct representation (e.g., a visual depiction representative of the at least one anti-microbial agent to one or more areas of at detected (e.g., assessed, calculated, evaluated, determined, least one of the outer surface 106 of the body structure 104, gauged, measured, monitored, quantified, resolved, sensed, the inner surface 108 of the body structure 104, or embedded or the like) information) component, a visual display of at 45 in the internal body structure; and circuitry 602 configured least one spectral parameter, and the like. In an embodiment, for determining the presence of at least one microorganism the response 299 includes a visual representation indicative proximate to one or more areas of the body structure 104. In of a parameter associated with an infection present in a an embodiment, the circuitry 602 configured for determining region of a biological sample proximate one or more sensors the presence of at least one microorganism includes at least 302. In an embodiment, the response 299 includes a gener 50 one sensor 302 operably coupled to a microorganism bio ating a representation (e.g., depiction, rendering, modeling, marker array. In an embodiment, the circuitry 602 config or the like) of at least one physical parameter associated with ured for determining the presence of at least one microor a biological specimen. ganism includes at least one of an electrochemical In an embodiment, at least one computing device 230 is transducer 602a, optical transducer 602b, biochemical trans configured to perform a comparison of the at least one 55 ducer 602c, ultrasonic transducer 602d, piezoelectric trans characteristic associated with the microbial component from ducer 602e, or thermal transducer 602f. In an embodiment, an anti-microbial region 202 proximate at least one of the the circuitry 602 configured for determining the presence of outer surface 106 or the inner surface 108 of the body at least one microorganism includes at least one thermal structure 104 to stored reference data, and to initiate a detector 602g, photovoltaic detector 602h or photomultiplier treatment protocol based at least in part on the comparison, 60 detector 602i. or deliver at least one anti-microbial agent to at least one of In an embodiment, the transcutaneous energy transfer the outer surface 106 or the inner surface 108 of the body system 914 is electromagnetically, magnetically, acousti structure 104. cally, optically, inductively, electrically, or capacitively In an embodiment, the computing device 230 is config coupleable to an in vivo power Supply. In an embodiment, ured to perform a comparison of a real-time measurand 65 the transcutaneous energy transfer system 914 includes at associated with a region proximate the insertable device 102 least one electromagnetically coupleable power supply 916, to infection marker or biomarker information configured as magnetically coupleable power Supply 918, acoustically US 9,474,831 B2 83 84 coupleable power supply 920, optically coupleable power transcutaneous energy transfer system 914 is electromag supply 922, inductively coupleable power supply 924, elec netically, magnetically, acoustically, optically, inductively, trically coupleable power supply 926, or capacitively electrically, or capacitively coupled to at least one of the coupleable power supply 928. In an embodiment, the energy anti-microbial regions 202 (e.g., selectively actuatable anti transcutaneous transfer system 914 is configured to wire microbial regions 202a), computing device 230, or sensor lessly receive power from a remote power supply 930. For 3O2. example, in an embodiment the power source 900 includes In an embodiment, the transcutaneous energy transfer at least one biological-Subject powered generator 704. In an system 914 is configured to transfer power from at least one embodiment, the power source 900 includes a thermoelec of an in vivo or an ex vivo power source to the catheter tric generator 706. In an embodiment, the power source 900 10 device 102. In an embodiment, the transcutaneous energy includes a piezoelectric generator 708. In an embodiment, transfer system 914 is configured to transfer power to the the power source 900 includes a MEMS generator 710. In an catheter device 102 and to recharge a power source 900a embodiment, the power source 900 includes a biomechani within the catheter device 102. cal energy harvesting generator 712. In an embodiment, the circuitry 602 configured to deter In an embodiment, the power source 900 is configured to 15 mine the microorganism presence includes at least one wirelessly receive power from a remote power supply 930. sensor 302. In an embodiment, the circuitry 602 configured In an embodiment, the catheter device 102 includes one or to determine the microorganism presence includes at least more power receivers 932 configured to receive power from one sensor 302 having a component identification code and an in vivo or ex vivo power source. In an embodiment; the configured to implement instructions addressed to the sensor power source 900 is configured to wirelessly receive power 302 according to the component identification code. In an via at least one of an electrical conductor or an electromag embodiment, the circuitry 602 configured to determine the netic waveguide. In an embodiment, the power source 900 microorganism presence includes at least one sensor 302 includes one or more power receivers 932 configured to operably coupled to a microorganism colonization bio receive power from an in vivo or ex vivo power source. In marker array. an embodiment, the in vivo power source includes at least 25 In an embodiment, the circuitry 602 configured to deter one of a thermoelectric generator, a piezoelectric generator, mine the microorganism presence includes biofilm marker a microelectromechanical systems generator, or a biome information configured as a physical data structure. In an chanical-energy harvesting generator. embodiment, the physical data structure includes a charac In an embodiment, the catheter device 102 includes one or teristic information section having characteristic microbial more generators configured to harvest mechanical energy 30 colonization spectral information representative of the pres from for example, acoustic waves, mechanical vibration, ence of a microbial colonization proximate the insertable blood flow, and the like. For example, in an embodiment, the device 102. power source 900 includes at least one of a biological The system 100 can include, among other things, circuitry Subject (e.g., human)-powered generator 904, a thermoelec 604 configured to obtain information. In an embodiment, the tric generator 906, piezoelectric generator 908, electrome 35 circuitry 604 configured to obtain information includes chanical generator 910 (e.g., a microelectromechanical circuitry 604 configured to obtain information associated systems (MEMS) generator, or the like), biomechanical with a delivery of the optical energy. In an embodiment, the energy harvesting generator 912, and the like. circuitry 604 configured to obtain information includes In an embodiment, the biological-Subject-powered gen circuitry 604 configured to obtain at least one of a command erator 904 is configured to harvest thermal energy generated 40 stream, a Software stream, and a data stream. by the biological Subject. In an embodiment, the biological The system 100 can include, among other things, circuitry subject-powered generator 904 is configured to harvest 606 configured to store information. In an embodiment, the energy generated by the biological Subject using at least one circuitry 606 configured to store information includes one or of a thermoelectric generator 906, piezoelectric generator more data structures. 908, electromechanical generator 910 (e.g., a microelectro 45 The system 100 can include, among other things, circuitry mechanical systems (MEMS) generator, or the like), bio 608 configured to provide information. In an embodiment, mechanical-energy harvesting generator 912, and the like. the circuitry 608 configured to provide information includes For example, in an embodiment, the biological-Subject circuitry 608 configured to provide having infection marker powered generator 904 includes one or more thermoelectric information. In an embodiment, the circuitry 608 configured generators 906 configured to convertheat dissipated by the 50 to provide information includes circuitry 608 configured to biological Subject into electricity. In an embodiment, the provide status information. In an embodiment, the circuitry biological-subject-powered generator 904 is configured to 608 configured to provide information includes circuitry 608 harvest energy generated by any physical motion or move configured to provide information regarding the detection of ment (e.g., walking) by biological Subject. For example, in at least one of the emitted optical energy or the remitted an embodiment, the biological-Subject-powered generator 55 optical energy. In an embodiment, the circuitry 608 config 904 is configured to harvest energy generated by the move ured to provide information includes circuitry 608 config ment of a joint within the biological Subject. In an embodi ured to detect at least one delivered anti-microbial agent, or ment, the biological-subject-powered generator 904 is con other anti-microbial protruding elements 206 actuated. figured to harvest energy generated by the movement of a The system 100 can include, among other things, circuitry fluid (e.g., biological fluid) within the biological subject. 60 610 configured to perform a comparison of the determined The system 100, can include, among other things, a at least one characteristic associated with the biological transcutaneous energy transfer system 914. In an embodi sample 808 proximate the insertable device 102 to stored ment, the catheter device 102 includes a transcutaneous reference data following the delivery of the anti-microbial energy transfer system 914. For example, in an embodiment, surface property 204. The insertable device 102 can include, the catheter device 102 includes one or more power receiv 65 among other things, circuitry 602 configured to generate a ers 932 configured to receive power from at least one of an response 299 based at least in part on the comparison. The in vivo or an ex vivo power source. In an embodiment, the circuitry 602 configured to perform a comparison can US 9,474,831 B2 85 86 include, among other things, one or computing devices 230 anti-microbial regions 202 are configured to direct at least a configured to perform a comparison of the at least one portion of a first anti-microbial property 204 along a Sub characteristic associated with the biological sample 808 stantially lateral 122 direction in a first region of at least one proximate the insertable device 102 stored reference data of the fluid-flow passageways 110 and configured to direct following delivery of the anti-microbial agent, and to gen- 5 at least a portion of a second anti-microbial property 204 erate a response 299 based at least in part on the comparison. along a Substantially lateral 122 direction in a second region In an embodiment, the insertable device 102 includes one of the one or more fluid-flow passageways 110, the second or more anti-microbial regions 202a that form part of a region different from the first region. In an embodiment, the surface along a longitudinal direction 120 of a fluid-flow one or more anti-microbial regions 202a are configured to passageway 110. In an embodiment, the insertable device 10 direct at least a portion of a first anti-microbial property 204 102 includes one or more anti-microbial regions 202a that along a Substantially longitudinal 120 direction in a first form part of a Surface along a lateral direction 122 of a region of at least one of the fluid-flow passageways 110 and fluid-flow passageway 110. In an embodiment, the insertable configured to direct at least a portion of a second anti device 102 includes one or more anti-microbial regions 202a microbial property 204 along a substantially longitudinal that form part of a surface along a helical direction 124 of 15 120 direction in a second region of the one or more fluid a fluid-flow passageway 110. In an embodiment, the one or flow passageways 110, the second region different from the more anti-microbial regions 202a are configured to laterally, first region. In an embodiment, the one or more anti 122 internally direct, longitudinally 120 internally direct, or microbial regions 202a are configured to externally direct at helically 124 internally direct at least a portion of at least one least a portion of an anti-microbial property 204. In an anti-microbial property 204 within an interior of at least one 20 embodiment, the one or more anti-microbial regions 202a of the fluid-flow passageways 110. In an embodiment, the are configured to direct at least a portion of a first anti one or more anti-microbial regions 202a are configured to microbial property 204 along a substantially helical 124 direct at least a portion of at least one anti-microbial direction in a first region of at least one of the fluid-flow property 204 in peristaltic movement along one or more passageways 110 and configured to direct at least a portion fluid-flow passageways 110. In an embodiment, at least one 25 of a second anti-microbial property 204 along a Substantially anti-microbial nanostructure 206a extends substantially lon helical 124 direction in a second region of the one or more gitudinally 120 along at least one of the fluid-flow passage fluid-flow passageways 110, the second region different ways 110. In an embodiment, at least one of the anti from the first region. microbial nanostructures 206a extends substantially In an embodiment, a plurality of anti-microbial regions laterally 122 within at least one of the fluid-flow passage- 30 202, are disposed along the one or more fluid-flow passage ways 110. In an embodiment, at least one of the anti ways 110. In an embodiment, a plurality of anti-microbial microbial nanostructures 206a extends substantially heli regions 202 are configured to form at least a portion of at cally 124 along at least one of the fluid-flow passageways least one of the inner surface 108 or outer surface 106 of the 110. body structure 104. In an embodiment, at least one of the In an embodiment, at least one of the anti-microbial 35 anti-microbial regions 202 on the inner surface 108 of the regions 202a extends Substantially longitudinally 120 along body structure 104 is different than at least one of the at least one of the fluid-flow passageways 110. In an anti-microbial regions 202 on the outer surface 106 or embodiment, at least one of the anti-microbial regions 202a embedded in the body structure 104. In an embodiment at extends substantially laterally 122 within at least one of the least one of the anti-microbial regions 202 on the outer fluid-flow passageways 110. In an embodiment, at least one 40 surface 106 of the body structure 104 is different than at least of the anti-microbial regions 202a extends substantially one of the anti-microbial regions 202 on the inner surface helically 124 within at least one of the fluid-flow passage 108 or embedded in the body structure 104. In an embodi ways 110. In an embodiment, at least one of the anti ment, at least one of the anti-microbial regions 202 embed microbial regions 202a extends substantially laterally 122 ded in the body structure 104 is different than at least one of along a first portion of the body structure 104 and a different 45 the anti-microbial regions 202 on the outer surface 106 or one of the one or more anti-microbial regions 202a extends the inner surface 108 of the body structure 104. Substantially laterally 122 along a second portion of the The system 100 includes, among other things, circuitry body structure 104. In an embodiment, at least one of the 601 configured for obtaining information. In an embodi anti-microbial regions 202a extends substantially helically ment, the circuitry 601 configured for obtaining information 124 along a first portion of the body structure 104 and a 50 includes circuitry 601 configured for obtaining information different one of the anti-microbial regions 202a extends associated with delivery of at least one anti-microbial agent. Substantially helically along a second portion of the body In an embodiment, the circuitry 601 configured for obtaining structure 104. In an embodiment, at least one of the anti information includes circuitry 601 configured for obtaining microbial regions 202a extends Substantially longitudinally at least one of a command stream, Software stream, or data 120 along a first portion of the body structure 104 and a 55 Stream. different one of the anti-microbial regions 202a extends The system 100 includes, among other things, circuitry Substantially longitudinally 120 along a second portion of 603 configured for providing information. In an embodi the body structure 104. ment, the circuitry 603 configured for providing information In an embodiment, one or more anti-microbial regions includes circuitry 603 configured for providing microbial 202a are configured to direct at least one first anti-microbial 60 marker information. In an embodiment, the circuitry 603 property 204 or anti-microbial agent along a substantially configured for providing information includes circuitry 603 lateral 122 direction in one or more anti-microbial regions configured for providing status information. In an embodi 202 of at least one of the fluid-flow passageways 110 and ment, the circuitry 603 configured for providing information configured to direct at least one second anti-microbial prop includes circuitry 603 configured for providing information erty 204 along a substantially longitudinal 120 direction in 65 regarding the detection of at least one microbial component one or more anti-microbial regions 202 of at least one of the proximate to at least one of the outer surface 106 or the inner fluid-flow passageways 110. In an embodiment, one or more surface 108 of the body structure 104. In an embodiment, the US 9,474,831 B2 87 88 circuitry 601 configured for obtaining information further anti-microbial agent) from one or more anti-microbial includes circuitry 603 configured for providing information. regions 202. In an embodiment, the control circuitry 602 is The transcutaneous energy transfer system 914 can configured to control delivery of at least one active agent include, among other things, an inductive power Supply. In (including an anti-microbial agent) from at least one active an embodiment, the inductive power Supply includes a agent reservoir (e.g., anti-microbial agent reservoir 208). In primary winding operable to produce a varying magnetic an embodiment, the at least one anti-microbial agent reser field. The catheter device 102 can include, among other voir 208 includes an electricity storage device 701. In an things, a secondary winding electrically coupled to one or embodiment, the at least one electricity storage device 701 more energy emitters 220 for providing a Voltage to bio is rechargeable and electricity can be reloaded into the logical sample proximate the catheter device 102 in response 10 storage device 701. In an embodiment, at least one comput 299 to the varying magnetic field of the inductive power ing device 230 is operably coupled to one or more selec Supply. In an embodiment, the transcutaneous energy trans tively actuatable anti-microbial region 202a and configured fer system 914 includes a secondary coil configured to to control at least one of a delivery regimen, spatial distri provide an output Voltage ranging from about 10 volts to bution, or temporal distribution associated with the delivery about 25 volts. In an embodiment, the transcutaneous energy 15 of the active agent. In an embodiment, the one or more transfer system 914 is configured to manage a duty cycle computing devices 230 are configured to actuate at least one associated with emitting an effective amount of the steril selectively actuatable anti-microbial regions 202a in izing energy stimulus from one or more energy emitters 220. response to a scheduled program, an external command, a In an embodiment, the transcutaneous energy transfer sys history of a previous microbial presence, a signal, data point, tem. 914 is configured to transfer power to the catheter or a history of a previous actuation. In an embodiment, the device 102 and to recharge a power source 900 within the one or more computing devices 230 are configured to catheter device 102. control delivery of at least one anti-microbial agent from an In an embodiment, the insertable device 102 is, for anti-microbial reservoir 208 of the anti-microbial region example, wirelessly coupled to a computing device 230 that 202. communicates with the insertable device 102 via wireless 25 In an embodiment, the system 100 includes at least one communication. Non-limiting examples of wireless commu computing device 230 communicably coupled to one or nication include optical connections, ultraviolet connec more anti-microbial regions 202, and optionally configured tions, infrared, BLUETOOTHR, Internet connections, to control at least one parameter associated with selectively radio, network connections, and the like. actuating one or more anti-microbial regions 202. The system 100 can include, among other things, one or 30 In an embodiment, the plurality of selectively actuatable more memories 250 that, for example, store instructions or anti-microbial regions 202a are configured to provide a data, for example, volatile memory (e.g., Random Access spatial or temporal patterned 109 anti-microbial surface Memory (RAM) 252, Dynamic Random Access Memory property 204 at least a first region 406 and a second region (DRAM), or the like), non-volatile memory (e.g., Read 408 different from the first region 406. For example, in an Only Memory (ROM) 254, Electrically Erasable Program 35 embodiment, the second region 408 includes at least one of mable Read-Only Memory (EEPROM), Compact Disc a spectral power distribution (SPD), an irradiance (I), or a Read-Only Memory (CD-ROM), or the like), persistent peak power (P.) different from the first region 406. In an memory, or the like. Further non-limiting examples of one or embodiment, the second region 408 includes at least one of more memories 250 include Erasable Programmable Read an illumination intensity, peak emission wavelength, or Only Memory (EPROM), flash memory, and the like. Vari 40 pulse frequency different from the first region 406. In an ous components of the insertable device 102 (e.g., memories embodiment, the second region 408 includes at least one of 250, processors 232, or the like) can be operably coupled to an intensity, phase, or polarization different from the first each other via one or more instruction 775, data 776, or region 406. In an embodiment, the second region 408 power buses 256. includes at least one of a frequency, repetition rate, or Referring to FIG. 6, the system 100 can include, among 45 bandwidth different from the first region 406. In an embodi other things, circuitry 602 configured to determine a micro ment, the second region 408 includes at least one of an organism presence in one or more anti-microbial regions energy-emitting pattern, ON-pulse duration, or OFF-pulse 202 in proximity to the insertable device 102, for example, duration different from the first region 406. In an embodi proximate at least one of the outer surface 106 or the inner ment, the second region 408 includes at least one of an surface 108 of the body structure 104. Circuitry 602 can 50 emission intensity, emission phase, emission polarization, or include one or more components operably coupled (e.g., emission wavelength different from the first region 406. In communicatively coupled, electromagnetically, magneti an embodiment, the second region has at least one different cally, acoustically, optically, inductively, electrically, capaci anti-microbial property 204 (e.g., structure, agent, reservoir, tively coupleable, or the like) to each other. In an embodi etc.) different from the first region 406. For example, in an ment, circuitry 602 includes one or more remotely located 55 embodiment, the second region 408 includes at least one of components. In an embodiment, remotely located compo an anti-microbial protruding element 206 (e.g., nanostruc nents are operably coupled via wireless communication. In ture 206a, or other element) different than the first region an embodiment, remotely located components are operably 406. In an embodiment, the second region 408 includes at coupled via one or more receivers 444, transmitters 445, least one of an anti-microbial agent that is different than the transceivers 446, and the like. 60 first region 406. In an embodiment, the system 100 includes control cir The system 100 can include, among other things, one or cuitry 602 operably coupled to the one or more anti more modules optionally operable for communication with microbial regions 202. In an embodiment, the system 100 one or more input/output components 266, that are config includes control circuitry 602 operably coupled to the active ured to relay user output and/or input. In an embodiment, a agent assemblies 800 (e.g., anti-microbial regions 202). In 65 module includes one or more instances of electrical, elec an embodiment, the control circuitry 602 is configured to tromechanical, Software-implemented, firmware-imple control delivery of at least one active agent (including an mented, or other control devices. For example, in an US 9,474,831 B2 89 90 embodiment, the insertable device 102, includes a controller device 102 including a body structure 104 having an outer 388 operably coupled to the sensor 302. In an embodiment, surface 106 and an inner surface 108 defining one or more the at least one controller 388 is configured to be responsive fluid-flow passageways 110; and one or more anti-microbial to the detected presence of at least one microorganism by the regions 202 proximate at least one of an outer surface 106, at least one sensor 302. Such devices include one or more an inner surface 108, or embedded in the internal body instances of memory 250, computing devices 230, ports, structure 104; the body structure 104 including at least one valves, fuses, antifuses, antennas, power, or other Supplies; anti-microbial agent reservoir 208 operably coupled to the logic modules or other signaling modules; gauges or other one or more anti-microbial regions 202; and one or more Such active or passive detection components; program instructions for operating the at least one anti-microbial instructions, or piezoelectric transducers, shape memory 10 agent reservoir 208. In an embodiment, the system 100 elements, micro-electro-mechanical system (MEMS) ele further comprises one or more instructions for operating one ments, or other actuators. In an embodiment, the controller or more sensor receivers 444 or sensor transmitters 445. In 388 is configured to activate at least one independently an embodiment, the signal-bearing medium 777 includes a addressable and actively controllable anti-microbial nano computer-readable medium. In an embodiment, the signal structure 202a in response 299 to detected information from 15 bearing medium 777 includes a recordable medium or a at least one sensor 302. In an embodiment, the controller 388 communications medium. is configured to activate at least one independently address In an embodiment, the system 100 includes a signal able and actively controllable anti-microbial nanostructure bearing medium 777 bearing: a body structure 104 having an 206a in response 299 to at least one of a scheduled program, outer surface 106 and an inner surface 108 defining one or external command, history of a previous presence of a more fluid-flow passageways 110; at least one independently microorganism, or history of a previous activation. In an addressable and actively controllable anti-microbial nano embodiment, the system 100 further comprises circuitry 602 structure 206a; and one or more instructions for controlling configured for determining the presence of at least one the at least one independently addressable and actively microorganism proximate the body structure 104 Subsequent controllable anti-microbial nanostructure 206a of the body to a first round of activation of at least one independently 25 structure 104. addressable and actively controllable anti-microbial nano In an embodiment, an insertable device system 100, structure 206a. In an embodiment, the system 100 further comprises a body structure 104 having an outer surface 106 comprises circuitry 602 configured for altering the type of and an inner surface 108 defining one or more fluid-flow response 299 of an independently addressable and actively passageways 110; at least one independently addressable controllable anti-microbial nanostructure 202a based on the 30 and actively controllable anti-microbial nanostructure 206a determination of the presence of at least one microorganism projecting from at least one of the outer surface 106, or the proximate the body structure 104 Subsequent to a first round inner surface 108 of the body structure 104; and circuitry of activation. In an embodiment, the system 100 further configured 602 for determining the presence of at least one comprises electrically activating means (e.g., Switches 118, microorganism on at least one of the independently address etc.) for concurrently or sequentially electrically activating 35 able and actively controllable anti-microbial nanostructure two or more of the at least one independently addressable 206a of the body structure 104. and actively controllable anti-microbial nanostructure 202a In an embodiment, the system 100 includes at least one determined to have at least one microorganism present receiver 444 configured to acquire information based at least thereon. in part on a detected microbial component (e.g. microbial The computer-readable media drive 264 or memory slot 40 marker information). In an embodiment, the at least one can be configured to accept signal-bearing medium 777 receiver 444 is configured to acquire instructions. In an (e.g., computer-readable memory media, computer-readable embodiment, the at least one receiver 444 is configured to recording media, or the like). In an embodiment, a program acquire information based at least in part on whether a for causing the system 100 to execute any of the disclosed detected microbial component from one or more regions methods can be stored on, for example, a computer-readable 45 proximate at least one of the outer surface 106 or the inner recording medium (CRMM) 262, or other signal-bearing surface 108 of the body structure 104 satisfies a target medium 777. Non-limiting examples of signal-bearing condition. In an embodiment, the at least one receiver 444 is media 777 include a recordable type medium such as a configured to acquire information associated with delivery magnetic tape, floppy disk, a hard disk drive, a Compact of at least one anti-microbial agent. In an embodiment, the Disc (CD), a Digital Video Disk (DVD), Blu-Ray Disc, a 50 at least one receiver 444 is configured to receive one or more digital tape, a computer memory, or the like, as well as signals (e.g., acoustic signal, electromagnetic signal, optical transmission type medium Such as a digital and/or an analog signal, infrared signal, radio signal, radio frequency signal, communication medium (e.g., a fiber optic cable, a wave microwave signal, ultrasonic signal, or biochemical signal). guide, a wired communications link, a wireless communi In an embodiment, the at least one receiver 444 is configured cation link (e.g., transmitter 445, receiver 444, transmission 55 to receive one or more signals according to one or more logic, reception logic, etc.), etc.). Further non-limiting schedules. In an embodiment, the at least one receiver 444 examples of signal-bearing media 777 include, but are not is configured to receive one or more signals in response 299 limited to, DVD-ROM, DVD-RAM, DVD+RW, DVD-RW, to detection of at least one microbial component. In an DVD-R, DVD+R, CD-ROM, Super Audio CD, CD-R, CD" embodiment, the at least one receiver 444 is configured to R, CD" RW, CD-RW, Video Compact Discs, Super Video 60 receive one or more signals in response 299 to one or more Discs, flash memory, magnetic tape, magneto-optic disk, queries. In an embodiment, the at least one receiver 444 is MINIDISC, non-volatile memory card, EEPROM, optical configured to acquire data, or acquire software. In an disk, optical storage, RAM, ROM, system memory, web embodiment, the at least one receiver 444 is configured to server, and the like. receive stored reference data. In an embodiment, the at least For example, in an embodiment, the system 100 includes 65 one receiver 444 is configured to receive data from one or a signal-bearing medium 777 bearing: one or more instruc more distal sensors 302. In an embodiment, the at least one tions for operating an insertable device 102, the insertable receiver 444 is configured to receive stored reference data. US 9,474,831 B2 91 92 In an embodiment, the system 100 includes at least one biological subject 222 to stored reference data, and to transmitter 445 configured to send information based at least generate a response 299 based at least in part on the in part on historical action taken with regard to at least one comparison. anti-microbial region 202. In an embodiment, the historical As indicated in FIG. 8, in an embodiment, the system 100 action taken includes at least one of activation or response includes a cryptographic logic component 221. In an 299 to at least one microorganism. In an embodiment, the at embodiment, the cryptographic logic component 221 is least one transmitter 445 is configured to send a request for configured to implement at least one cryptographic process transmission of at least one of data, command, authorization, or cryptographic logic. In an embodiment, the cryptographic update, or code. In an embodiment, the system 100 includes logic component 221 is configured to implement one or 10 more processes associated with at least one of a crypto circuitry 601 configured for obtaining information; and graphic protocol, decryption protocol, or encryption proto circuitry 603 configured for providing information. In an col. In an embodiment, the cryptographic logic component embodiment, the at least one transmitter 445 is configured to 221 is configured to implement one or more processes transmit one or more signals (e.g., acoustic signal, electro associated with at least one of a regulatory compliance magnetic signal, optical signal, infrared signal, radio signal, 15 protocol, regulatory use protocol, or authentication protocol. radio frequency signal, microwave signal, ultrasonic signal, In an embodiment, the cryptographic logic component 221 or biochemical signal). In an embodiment, the at least one is configured to implement one or more processes associated transmitter 445 is configured to transmit one or more signals with at least one of an authorization protocol, activation according to one or more schedules. In an embodiment, the protocol, or treatment regimen protocol. In an embodiment, at least one transmitter 445 is configured to transmit one or the cryptographic logic component 221 is configured to more signals in response 299 to detection of at least one generate information associated with at least one of an microbial component. In an embodiment, the at least one authentication protocol, authorization protocol, delivery of transmitter 445 is configured to transmit in response 299 to at least one anti-microbial agent protocol, activation proto the status of at least one of the level of anti-microbial agent col, encryption protocol, or decryption protocol. In an in the reservoir 208, or release of the at least one anti 25 embodiment, the cryptographic logic component 221 is microbial agent from the reservoir 208. In an embodiment, configured to generate information associated with at least the at least one transmitter 445 is configured to transmit one one of an authorization instruction, authentication instruc or more signals in response 299 to one or more queries. In tion, prescription dosing instruction, anti-microbial agent an embodiment, the at least one transmitter 445 is configured administration instruction, or prescribed regimen instruc to transmit one or more encrypted signals. 30 tion. In an embodiment the cryptographic logic component In an embodiment, the system 100 comprises: a signal 221 is configured to generate information associated with at bearing medium 777 bearing: a body structure 104 having an least one of an instruction stream, encrypted data stream, outer surface 106 and an inner surface 108 defining one or authentication data stream, or authorization data stream. In more fluid-flow passageways 110; at least one independently an embodiment, the cryptographic logic component 221 is addressable and actively controllable anti-microbial nano 35 configured to generate information associated with at least structure 206a; and one or more instructions for determining one of an activation code, error code, command code, or the presence of at least one microorganism on at least one of authorization code. In an embodiment, the cryptographic the independently addressable and actively controllable anti logic component 221 is configured to generate information microbial nanostructure 206a of the body structure 104. associated with at least one of a cryptographic protocol, In an embodiment, the system 100 includes signal-bearing 40 decryption protocol, encryption protocol, regulatory com media 777 in the form of one or more logic devices (e.g., pliance protocol, or regulatory use protocol. programmable logic devices, complex programmable logic In an embodiment, the insertable device 102 includes at device, field-programmable gate arrays, application specific least one outer internally reflective coating 708 on a body integrated circuits, or the like) comprising, for example, a structure 104 defining the one or more fluid-flow passage data structure 260 including one or more look-up tables. The 45 ways 110. In an embodiment, the insertable device 102 system 100 can include, among other things, signal-bearing includes at least one inner internally reflective coating 709 media 777 having sample information (e.g., biological on a body structure 104 defining the one or more fluid-flow sample 808 information, reference information, characteris passageways 110. tic spectral information, or the like) configured as a data In an embodiment, the system 100 is configured to initiate structure 260. In an embodiment, the data structure 260 50 one or more medical protocols 399 (e.g. clinical trial pro includes at least one of psychosis state indication informa tocol, diagnostic protocol, treatment protocol, etc.). In an tion, psychosis trait indication information, or predisposition embodiment, the system 100 is configured to initiate at least for a psychosis indication information. In an embodiment, one medical protocol 399 based on a detected spectral event. the data structure 260 includes at least one of infection In an embodiment, the system 100 is configured to initiate indication information, inflammation indication informa 55 at least one medical protocol 399 based on a detected tion, diseased State indication information, or diseased tissue biomarker event. In an embodiment, the system 100 is indication information. configured to initiate at least one medical protocol 399 based Many of the disclosed embodiments can be electrical, on a detected infection. In an embodiment, the system 100 electromechanical, Software-implemented, firmware-imple is configured to initiate at least one medical protocol 399 mented, or other otherwise implemented, or combinations 60 based on a detected a fluid vessel abnormalities (e.g., an thereof. Many of the disclosed embodiments can be software obstruction), a detected biological sample 808 abnormality or otherwise in memory, such as one or more executable (e.g., cerebrospinal fluid abnormalities, hematological instruction sequences or Supplemental information as abnormalities, components concentration or level abnor described herein. For example, in an embodiment, the insert malities, flow abnormalities, or the like), a detected biologi able device 102 can include, among other things, one or 65 cal parameter, or the like. more computing devices 230 configured to perform a com In an embodiment, the system 100 can include, among parison of the at least one characteristic associated with the other things, one or more active agent assemblies 800 US 9,474,831 B2 93 94 (including but not limited to, anti-microbial reservoirs 208). salicylic acid, sodium salicylate, Sodium thiosalicylate, In an embodiment, the insertable device 102 includes at least Sulindac. Suprofen, tenidap, tenoxicam, tiaprofenic acid, one active agent assembly 800 including one or more tolmetin, tramadol, trolamine Salicylate, Zomepirac, or the anti-microbial reservoir 208. In an embodiment, the at least like. one anti-microbial reservoir 208 is actuatable by the pres Further non-limiting examples of active agents include ence of at least one microorganism. In an embodiment, the energy-actuatable active agents (e.g., chemical energy, elec anti-microbial reservoir 208 is configured for at least one of trical resistance, laser energy, terahertz energy, microwave active or passive delivery of the at least one anti-microbial energy, optical energy, radio frequency energy, acoustic agent. In an embodiment, the at least one anti-microbial energy, thermal energy, thermal resistance heating energy, or reservoir 208 is configured for time-release of at least one 10 ultrasonic energy actuatable active agents, or the like) and anti-microbial agent. the like. In an embodiment, an insertable device 102 includes a In an embodiment, the active agent includes at least one body structure 104 having an outer surface 106 and an inner active agent that selectively targets bacteria. For example, in surface 108 defining one or more fluid-flow passageways an embodiment, the active agent includes at least one 110; one or more anti-microbial regions 202 of the body 15 bacteriophage that can, for example, selectively target bac structure 104 including at least one selectively actuatable teria. Bacteriophages generally comprise an outer protein anti-microbial agent reservoir 208 configured to be actu hull enclosing genetic material. The genetic material can be atable by the presence of at least one microorganism, and ssRNA, dsRNA, ssDNA, or dsDNA. Bacteriophages are configured to actively deliver one or more anti-microbial generally smaller than the bacteria they destroy generally agents to the one or more anti-microbial regions 202 of the ranging from about 20 nm to about 200 nm. Non-limiting body structure 104. examples of bacteriophages include T2, T4, T6, phiX-174. In an embodiment, the active agent assembly 800 is MS2, or the like). In an embodiment, the active agent configured to deliver one or more active agents from the at includes at least one energy-actuatable agent that selectively least one active agent reservoir (e.g., anti-microbial agent targets bacteria. For example, in an embodiment, the active reservoir 208) to one or more anti-microbial regions proxi 25 agent includes at least one triplet excited-state photosensi mate the body structure 104. For example, in an embodi tizer that can, for example, selectively target bacteria. ment, the insertable device 102 includes one or more active Further non-limiting examples of active agents include agent assemblies 800 configured to deliver at least one triplet excited-state photosensitizers, reactive oxygen spe active agent from the at least one anti-microbial reservoir cies, reactive nitrogen species, any other inorganic or 208 to at least one of a region proximate an outer surface 108 30 organic ion or molecules that include oxygen ions, free and a region proximate an inner surface 110 of the insertable radicals, peroxides, or the like. Further non-limiting device 102. examples of active agents include compounds, molecules, or In an embodiment, the anti-microbial reservoir 208 treatments that elicit a biological response from any bio includes at least one active agent composition. Non-limiting logical Subject 222. Further non-limiting examples of dis examples of active agents include adjuvants, allergens, 35 infecting agents include therapeutic agents (e.g., antimicro analgesics, anesthetics, antibacterial agents, antibiotics, anti bial therapeutic agents), pharmaceuticals (e.g., a drug, a fungals, anti-inflammatory agents (e.g., nonsteroidal anti therapeutic compound, pharmaceutical salts, or the like) inflammatory drugs), antimicrobials, anti-parasitic, antioxi non-pharmaceuticals (e.g., a cosmetic Substance, or the dants, antipyretics, anti-tumor agents, antivirals, bio-control like), neutraceuticals, antioxidants, phytochemicals, homeo agents, biologics or bio-therapeutics, chemotherapy agents, 40 pathic agents, and the like. Further non-limiting examples of disinfecting agents, energy-actuatable active agents, anti disinfecting agents include peroxidases (e.g., haloperoxi clotting factor, vaccine, Small molecule, nutraceutical, Vita dases such as chloroperoxidase, or the like), oxidoreductase min, mineral, anti-microbial agent, immunogens, immuno (e.g., myeloperoxidase, eosinophil peroxidase, lactoperoxi logical adjuvants, immunological agents, immuno dase, or the like) oxidases, and the like. modulators, immuno-response agents, immuno-stimulators 45 Further non-limiting examples of active agents include (e.g., specific immuno-stimulators, non-specific immuno one or more pore-forming toxins. Non limiting examples of stimulators, or the like), immuno-Suppressants, non-phar pore-forming toxins include beta-pore-forming toxins, e.g., maceuticals (e.g., cosmetic Substances, or the like), phar hemolysin, Panton-Valentine leukocidin S. aerolysin, maceuticals, protease inhibitors or enzyme inhibitors, Clostridial epsilon-toxin; binary toxins, e.g., anthrax, C. receptor agonists, receptor antagonists, therapeutic agents, 50 perfingens lota toxin, C. difficile cytolethal toxins; choles tolerogens, toll-like receptor agonists, toll-like receptor terol-dependent cytolysins; pneumolysin; Small pore-form antagonists, vaccines, or combinations thereof. ing toxins; and gramicidin A. Further non-limiting examples of active agents include Further non-limiting examples of active agents include nonsteroidal anti-inflammatory drugs such as acemetacin, one or more pore-forming antimicrobial peptides. Antimi aclofenac, aloxiprin, amtolimetin, aproxen, aspirin, azapro 55 crobial peptides represent an abundant and diverse group of paZone, benorilate, benoxaprofen, benzydamine hydrochlo molecules that are naturally produced by many tissues and ride, benzydamine hydrochloride, bromfenal, bufexamac, cell types in a variety of invertebrate, plant and animal butibufen, carprofen, celecoxib, choline salicylate, clonixin, species. The amino acid composition, amphipathicity, cat desoxysulindac, diflunisal, dipyone, droxicam, etodolac, ionic charge and size of antimicrobial peptides allow them etofenamate, etoricoxib, felbinac, fenbufen, fenoprofen, fen 60 to attach to and insert into microbial membrane bilayers to tiazac, fepradinol, floctafenine, flufenamic acid, indometha form pores leading to cellular disruption and death. More cin, indoprofen, isoxicam, ketoralac, licofelone, lomoxicam, than 800 different antimicrobial peptides have been identi loxoprofen, magnesium salicylate, meclofenamic acid, fied or predicted from nucleic acid sequences, a Subset of meclofenamic acid, mefenamic acid, meloxicam, morniflu which are available in a public database (see, e.g., Wang & mate, niflumic acid, nimeSulide, oxaproZen, phenylbuta 65 Wang, Nucleic Acids Res. 32:D590-D592, 2004): http:// Zone, piketoprofen, piroxicam, pirprofen, priazolac, propy aps.unmc.edu/AP/main.php, the contents of each of which is phenaZone, produaZone, rofecoxib, Salalate, Salicylamide, incorporated herein by reference). US 9,474,831 B2 95 96 More specific examples of antimicrobial peptides include, tin, rifapentine, pyrazinamide, ethambutol, ethionamide, among others, anionic peptides, e.g., maximin H5 from capreomycin, clofazimine, and dapsone; and miscellaneous amphibians, Small anionic peptides rich in glutamic and antimicrobials such as colistimethate sodium, methenamine aspartic acids from sheep, cattle and humans, and dermcidin hippurate, methenamine mandelate, metronidazole, mupiro from humans; linear cationic alpha-helical peptides, e.g., cin, nitrofurantoin, polymyxin B, clindamycin, choram cecropins (A), andropin, moricin, ceratotoxin, and melittin phenicol, quinupristin-dalfopristin, lineZolid, spectrinomy from insects, cecropin P1 from Ascaris nematodes, magainin cin, trimethoprim, pyrimethamine, and trimethoprim 2, dermaseptin, bombinin, brevinin-1, esculentins and bufo Sulfamethoxazole. rin II from amphibians, pleurocidin from skin mucous Further non-limiting examples of active agents include secretions of the winter flounder, seminalplasmin, BMAP, 10 antifungal agents. Non-limiting examples of antifungal SMAP (SMAP29, ovispirin), PMAP from cattle, sheep and agents include anidulafungin, amphotericin B, butacon pigs, CAP18 from rabbits and LL37 from humans; cationic azole, butenafine, caspofungin, clotrimazole, econazole, flu peptides enriched for specific amino acids, e.g., praline conazole, flucytosine griseofulvin, itraconazole, ketocon containing peptides including abaecin from honeybees, pra azole, miconazole, micafungin, naftifine, natamycin, line- and arginine-containing peptides including apidaecins 15 nystatin, oxiconazole, Sulconazole, terbinafine, terconazole, from honeybees, drosocin from Drosophila, pyrrhocoricin tioconazole, tolnaftate, and/or Voriconazole. from European sap-sucking bug, bactenicins from cattle Further non-limiting examples of active agents include (Bac7), sheep and goats and PR-39 from pigs, praline- and anti-parasite agents. Non-limiting examples of anti-parasite phenylalanine-containing peptides including prophenin agents include antimalaria drugs such as chloroquine, amo from pigs, glycine-containing peptides including hymenop diacquine, quinine, quinidine, mefloquine, primaquine, Sul taecin from honeybees, glycine- and praline-containing pep fadoxine-pyrimethamine, atovaquone-proguanil, chlo tides including coleoptericin and holotricin from beetles, rproguanil-dapsone, proguanil, doxycycline, halofantrine, tryptophan-containing peptides including indolicidin from lumefantrine, and artemisinins; treatments for amebiasis cattle, and Small histidine-rich salivary polypeptides, includ Such as metronidazole, iodoquinol, paromomycin, dilox ing histatins from humans and higher primates; anionic and 25 anide furoate, pentamidine, Sodium Stibogluconate, emetine, cationic peptides that contain cysteine and from disulfide and dehydroemetine; and other anti-parasite agents such as bonds, e.g., peptides with one disulphide bond including pentamidine, nitaZoxanide, Suramin, melarsoprol, eflornith brevinins, peptides with two disulfide bonds including ine, nifurtimox, clindamycin, albendazole, and tinidazole. alpha-defensins from humans (HNP-1. HNP-2, cryptidins), Further non-limiting examples of active agents include ionic rabbits (NP-1) and rats, beta-defensins from humans 30 silver, (SilvaSorb(R), Medline Industries, Inc), anti-microbial (HBD1, DEFB118), cattle, mice, rats, pigs, goats and poul silver compositions (Arglaes R., Medline Industries, Inc), or try, and rhesus theta-defensin (RTD-1) from rhesus monkey, the like. Further non-limiting examples of active agents insect defensins (defensin A); and anionic and cationic include Superoxide-forming compositions. Further non-lim peptide fragments of larger proteins, e.g., lactoferricin from iting examples of active agents include oxazolidinones, lactoferrin, casocidin 1 from human casein, and antimicro 35 gram-positive antibacterial agents, or the like. See, e.g., U.S. bial domains from bovine alpha-lactalbumin, human hemo Pat. No. 7,322,965 (issued Jan. 29, 2008), which is incor globin, lysozyme, and ovalbumin (see, e.g., Brogden, Nat. porated herein by reference. Rev. Microbiol. 3:238-250, 2005, which is incorporated In an embodiment, the active agent includes one or more herein by reference). antimicrobial agents. In an embodiment, the antimicrobial Further non-limiting examples of active agents include 40 agent is an antimicrobial peptide. Amino acid sequence antibacterial drugs. Non-limiting examples of antibacterial information for a subset of these can be found as part of a drugs include beta-lactam compounds such as penicillin, public database (see, e.g., Wang & Wang, Nucleic Acids Res. methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, 32:D590-D592, 2004): http://aps.unmc.edu/AP/main.php, ampicillin, ticarcillin, amoxicillin, carbenicillin, and pipera which is incorporated herein by reference). Alternatively, a cillin; cephalosporins and cephamycins such as cefadroxil, 45 phage library of random peptides can be used to Screen for cefazolin, cephalexin, cephalothin, cephapirin, cephradine, peptides with antimicrobial properties against live bacteria, cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, fungi and/or parasites. The DNA sequence corresponding to loracarbef, ceforanide, cefoxitin, cefimetazole, cefotetan, an antimicrobial peptide can be generated ex vivo using cefoperaZone, cefotaxime, ceftazidine, ceftizoxine, ceftriax standard recombinant DNA and protein purification tech one, cefixime, cefpodoxime, proxetil, cefdinir, cefditoren, 50 niques. pivoxil, ceftibuten, moxalactam, and cefepime; other beta In an embodiment, one or more of the active agent include lactam drugs such as aztreonam, clavulanic acid, Sulbactam, chemicals suitable to disrupt or destroy cell membranes. For taZobactam, ertapenem, imipenem, and meropenem; other example, Some oxidizing chemicals can withdraw electrons cell wall membrane active agents such as Vancomycin, from a cell membrane causing it to, for example, become teicoplanin, daptomycin, fosfomycin, bacitracin, and cyclos 55 destabilized. Destroying the integrity of cell membranes of erine; tetracyclines such as tetracycline, chlortetracycline, for example, a pathogen can lead to cell death. oxytetracycline, demeclocycline, methacycline, doxycy In an embodiment, the insertable device 102 includes one cline, minocycline, and tigecycline; macrollides such as or more active agent assemblies 800 configured to deliver at erythromycin, clarithromycin, azithromycin, and tellithro least one active agent from the at least one reservoir 208 to mycin; aminoglycosides such as Streptomycin, neomycin, 60 at least one of a region proximate an outer Surface 106 or an kanamycin, amikacin, gentamicin, tobramycin, sisomicin, inner surface 108 of the insertable device 102. In an embodi and netilmicin; Sulfonamides such as Sulfacytine, Sulfisox ment, at least one of the active agent assemblies 800 is azole, silfamethizole, Sulfadiazine, Sulfamethoxazole, Sul configured to deliver one or more active agents in a spatially fapyridine, and Sulfadoxine; fluoroquinolones such as cip or temporally patterned distribution. In an embodiment, at rofloxacin, gatifloxacin, gemifloxacin, levofloxacin, 65 least one of the active agent assemblies 800 is configured to lomefloxacin, moxifloxacin, norfloxacin, and ofloxacin; deliver one or more active agents in a temporally patterned antimycobacteria drugs such as isoniazid, rifampin, rifabu distribution. In an embodiment, the insertable device 102 US 9,474,831 B2 97 98 includes a plurality of spaced-apart-release-ports 118a active antibacterial agents, photoactive antifungal agents, adapted to deliver one or more active agents in a spatially and the like. Further non-limiting examples of energy patterned distribution. In an embodiment, the insertable actuatable agent includes energy-actuatable disinfecting device 102 includes a plurality of spaced apart controllable agents, photoactive agents, or a metabolic precursor thereof. release ports 118a adapted to deliver one or more active In an embodiment, the at least one energy-actuatable agent agents in a spatially patterned distribution. includes at least one X-ray absorber. In an embodiment, the In an embodiment, the insertable device 102 includes a at least one energy-actuatable agent includes at least one release system 799. radiation absorber. In an embodiment, the insertable device 102 includes at In an embodiment, the active agent assembly 800 is least one computing device 230 operably coupled to one or 10 configured to deliver at least one energy-actuatable disin more of the plurality of spaced-apart-release-ports 118a and fecting agent from at least one reservoir 208 to a biological configured to actuate one or more of the plurality of spaced sample 808 proximate the insertable device 102. In an apart-release-ports between an active agent discharge state embodiment, the insertable device 102 includes one or more and an active agent retention state. In an embodiment, a active agent assemblies 800 configured to deliver at least computing device 230 is operable to actuate one or more of 15 one energy-actuatable disinfecting agent from the at least the plurality of spaced-apart-release-ports 118a between an one active agent reservoir 208 to a biological sample 808 active agent discharge state and an active agent retention proximate at least one surface of the insertable device 102. state based on a comparison of a detected characteristic to In an embodiment, at least one of the active agent assemblies stored reference data. 800 is configured to deliver at least one energy-actuatable In an embodiment, the computing device 230 is operably disinfecting agent in a spatially patterned distribution. In an coupled to the active agent assembly and configured to embodiment, the active agent assembly 800 is configured to actively control one or more of the plurality of spaced-apart deliver at least one energy-actuatable steroid to biological release-ports 118a. In an embodiment, at least one comput sample 808 proximate the at least one outer surface 108 of ing device 230 is operably coupled to one or more of the the insertable device 102. spaced-apart controllable-release ports 118a and configured 25 The at least one active agent reservoir 208 can include, to control at least one of a port release rate, a port release among other things, an acceptable carrier. In an embodi amount, and a port release pattern associated with a delivery ment, at least one active agent is carried by, encapsulated in, of the one or more active agents. In an embodiment, at least or forms part of an energy-sensitive (e.g., energy-actu one processor 232 is operably coupled to the active agent atable), carrier, vehicle, vesicle, pharmaceutical vehicle, assembly 800 (e.g., an anti-microbial reservoir 208) and 30 pharmaceutical carrier, pharmaceutically acceptable vehicle, configured to control at least one of a port release rate, a port pharmaceutically acceptable carrier, or the like. release amount, and a port release pattern associated with the Non-limiting examples of carriers include any matrix that delivery of the one or more active agents from the at least allows for transport of a disinfecting agent across any tissue, one active agent reservoir 208 to an interior of the one or cell membranes, and the like of a biological subject 222, or more fluid-flow passageways 110. 35 that is Suitable for use in contacting a biological Subject 222, In an embodiment, a computing device 230 is operably or that allows for controlled release formulations of the coupled to the active agent assembly 800 and configured to compositions disclosed herein. Further non-limiting control at least one of an active agent delivery rate, an active examples of carriers include at least one of creams, liquids, agent delivery amount, an active agent delivery composi lotions, emulsions, diluents, fluid ointment bases, gels, tion, a port release rate, a port release amount, and a port 40 organic and inorganic solvents, degradable or non-degrad release pattern. able polymers, pastes, salves, vesicle, and the like. Further In an embodiment, at least one computing device 230 is non-limiting examples of carriers include cyclic oligosac operably coupled to one or more of the plurality of spaced charides, ethasomes, hydrogels, liposomes, micelle, micro apart-release-ports 118a and configured to actuate one or spheres, nisomes, non-ionic Surfactant vesicles, organogels, more of the plurality of spaced-apart-release-ports 118a 45 phospholipid surfactant vesicles, phospholipid surfactant between an active agent discharge state and an active agent vesicles, transfersomes, Virosomes. Further non-limiting retention state. In an embodiment, the insertable device 102 examples of energy-sensitive carriers and the like include includes one or more active agent assemblies 800 including electrical energy-sensitive, light sensitive, pH-sensitive, ion one or more active agent reservoir 208 configured to deliver sensitive, acoustic energy sensitive, ultrasonic energy sen at least one active agent from the at least one active agent 50 sitive carriers. (e.g., anti-microbial agent) reservoir 208 to at least one of a In an embodiment, one or more active agents are carried region proximate an outer Surface 108 and a region proxi by energy-sensitive vesicles (e.g., energy-sensitive cyclic mate an inner surface 110 of the insertable device 102. oligosaccharides, ethasomes, hydrogels, liposomes, In an embodiment, the insertable device 102 includes one micelles, microspheres, nisomes, non-ionic Surfactant or more active agent assemblies 800 configured to deliver 55 vesicles, organogels, phospholipid surfactant vesicles, trans one or more disinfecting agents. In an embodiment, the fersomes, Virosomes, and the like). In an embodiment, at insertable device 102 includes one or more active agent least one of the energy emitters 220 is configured to provide assemblies 800 configured to deliver at least one energy energy of a dose sufficient to liberate at least a portion of an actuatable agent from at least one reservoir 208 to, for active agent carried by the energy-sensitive vesicles. example, an interior of one or more fluid-flow passageways 60 In an embodiment, the insertable device 102 includes one 110. Non-limiting examples of energy-actuatable active or more biological sample compartment 708. In an embodi agents include radiation absorbers, light energy absorbers, ment, the insertable device 102 includes one or more active X-ray absorbers, photoactive agents, and the like. Non agent assemblies 800 configured to receive one or more limiting examples of photoactive agents include, but are not biological samples 808. In an embodiment, the biological limited to photoactive antimicrobial agents (e.g., eudis 65 sample compartment 708 is placed under the scalp of a user. tomin, photoactive porphyrins, photoactive TiO, antibiot In an embodiment, the biological sample compartment 708 ics, silver ions, antibodies, nitric oxide, or the like), photo is configured to allow for the removal of biological sample US 9,474,831 B2 99 100 with a syringe. In an embodiment, the biological sample stimulus. In an embodiment, the one or more fluid-flow compartment 708 includes a sensor 302 configured to detect, passageways 110 include a photoactive agent configured to for example, bacteria, cancer cells, blood, or proteins of a emit ultraviolet light energy in the presence of an electrical fluid sample received within. In an embodiment, the sensor potential. In an embodiment, the one or more fluid-flow 302 is operably coupled to the at least one biological sample 5 passageways 110 include a photoactive agent having one or compartment 708 (e.g., operably coupled to at least one more photoabsorption bands in the visible region of the selectively actuatable anti-microbial agent reservoir 208). In electromagnetic spectrum. an embodiment, the biological sample compartment 708 is Various methods for reducing, inhibiting, or eliminating configured to allow the injection or introduction of antibi growth or adherence of at least one microorganism are otics for cerebrospinal fluid infection or chemotherapy 10 disclosed herein, each of which can utilize additional steps medication. In an embodiment, the biological sample com disclosed, for example in FIGS. 9-28, or throughout the partment 708 includes circuitry configured to detect at least specification. For example, as depicted in FIG. 9, a method one physical quantity, environmental attribute, or physi 1500 includes activating 1501 at least one anti-microbial ologic characteristic associated with, for example, a shunt region of a plurality of anti-microbial regions of at least one ing process. In an embodiment, the sensor 302 is configured 15 of an outer Surface, an inner Surface, or embedded in a body to detect at least one microorganism proximate at least one structure of an insertable device, the body structure defining anti-microbial nanostructure 206a. In an embodiment, the one or more fluid-flow passageways, based on an automati sensor 302 is configured to detect at least one microorganism cally detected biomarker associated with at least one micro proximate at least one anti-microbial region 202a. In an organism. In an embodiment, 1510 wherein activating the at embodiment, the at least one sensor 302 is operably asso- 20 least one anti-microbial region includes activating a spatially ciated with at least one anti-microbial nanostructure 206a or temporally patterned anti-microbial region in at least one within at least one of the fluid-flow passageways 110. In an of the plurality of anti-microbial regions of the body surface. embodiment, the at least one sensor 302 is configured to In an embodiment 1520 wherein activating the at least one detect at least one microorganism in one or more fluid-flow anti-microbial region is based at least in part on one or more passageways 110 based at least in part on one or more flow 25 of a detected fluorescence, detected impedance, detected characteristics. optical reflectance, detected thermal transfer, or detected In an embodiment, a plurality of the selectively actuatable microbial component. In an embodiment 1530 wherein anti-microbial regions 202a form at least one spatial or activating the at least one anti-microbial region is initiated at temporal pattern extending over at least a portion of the body least one of prior to, during, or Subsequent to insertion of the structure 104. In an embodiment, the selectively actuatable 30 insertable device into a biological Subject. In an embodiment anti-microbial region 202a (optionally including an anti 1540 wherein activating the at least one anti-microbial microbial reservoir 208) are capable of at least one of region is based at least in part on one or more of current independent or dependent actuation. biomarker information, previous biomarker information, or In an embodiment, the insertable device 102 includes one previous activation events. In an embodiment 1550 the or more active agent assemblies 800 configured to deliver at 35 method is implemented by at least one computing device. In least one tracer agent from at least one reservoir 208. In an an embodiment 1555 the method further comprises gener embodiment, the insertable device 102 includes one or more ating at least one output to a user. In an embodiment 1560 active agent assemblies 800 including one or more tracer wherein the at least one output includes at least one of a agent reservoir 208 configured to deliver at least one tracer treatment protocol, identification of a detected microorgan agent. In an embodiment, the one or more active agent 40 ism, status of the insertable device, or location of a detected assemblies 800 are configured to deliver one or more tracer microorganism. In an embodiment 1570 wherein the at least agents. Non-limiting examples of tracer agents include one one output occurs in real-time. In an embodiment 1580 or more in vivo clearance agents, magnetic resonance imag wherein the at least one output is associated with historical ing agents, contrast agents, dye-peptide compositions, fluo information. In an embodiment 1590 the user includes at rescent dyes, or tissue specific imaging agents. In an 45 least one entity. In an embodiment 1591 the at least one embodiment, the one or more tracer agents include at least entity includes at least one person or computer. In an one fluorescent dye. In an embodiment, the one or more embodiment 1592, the at least one output includes output to tracer agents include indocyanine green. a user readable display. In an embodiment 1593 the user In an embodiment, active agent assembly 800 is further readable display includes a human readable display. In an configured to concurrently or sequentially deliver one or 50 embodiment 1594 the user readable display includes at leat more tracer agents and one or more energy-actuatable dis one of a passive display or active display. In an embodiment infecting agents. In an embodiment, the active agent assem 1599 the user readable display is coupled to the insertable bly 800 is further configured to deliver one or more tracer device. agents for indicating the presence or concentration of one or As depicted in FIG. 10, a method 1600 includes 1610 more energy-actuatable disinfecting agents in at least a 55 actuating at least one anti-microbial region of a plurality of region proximate the insertable device 102. In an embodi anti-microbial regions configured to direct at least one ment, the active agent assembly 800 is further configured to anti-microbial agent to one or more areas of at least one of deliver one or more tracer agents for indicating the response an outer Surface, an inner Surface, or internally embedded in of the one or more energy-actuatable disinfecting agents to a body structure of an insertable device, the body structure energy emitted from the one or more energy-emitting emit- 60 defining one or more fluid-flow passageways, in response to ters 302. an in vivo detected microbial component associated with a In an embodiment, one or more fluid-flow passageways biological sample proximate to one or more areas of the 110 include a photoactive agent. In an embodiment, one or body structure. more fluid-flow passageways 110 include a photoactive As depicted in FIG. 11, a method 1700 includes 1705 coating material. In an embodiment, one or more fluid-flow 65 automatically comparing one or more characteristics com passageways 110 include a photoactive agent configured to municated from an inserted insertable device to stored emit ultraviolet light energy in the presence of an energy reference data, the one or more characteristics including at US 9,474,831 B2 101 102 least one of information associated with microbial marker surface of the insertable device. In an embodiment 1940 information; and information associated with at least one initiating the treatment protocol includes activating at least microbial component detected proximate to at least one of one of an authorization protocol, authentication protocol, or an outer surface or inner surface of the insertable device, or anti-microbial agent delivery protocol, based at least in part information associated with a fluid received within one or on the automatically detected signal associated with at least more fluid-flow passageways of the inserted insertable one microbial component. device; and initiating a treatment protocol based at leastin As depicted in FIG. 14, a method 2000, includes 2005 a part on the comparison. In an embodiment 1710 automati method implemented by at least one computing device. In an cally comparing the one or more characteristics communi embodiment 2010, the method further comprises generating cated from an inserted insertable device to stored reference 10 data includes comparing, via circuitry forming part of the at least one output to a user. In an embodiment 2020, the at inserted insertable device, one or more characteristics com least one output includes at least one output to a user municated from the inserted insertable device to stored readable display. In an embodiment 2030 the at least one reference data. In an embodiment 1720 initiating the treat output includes at least one of a treatment protocol, identi ment protocol includes generating a spatially patterned 15 fication of a detected microorganism, status of the insertable distribution of at least one anti-microbial agent released device, or location of a detected microorganism. In an from at least one anti-microbial region of the device. In an embodiment 2040 the user includes at least one entity. In an embodiment 1730 initiating the treatment protocol includes embodiment 2050 the at least one entity includes at least one delivering a dose of at least one anti-microbial agent based person or computer. In an embodiment 2060 the at least one at least in part on the comparison. In an embodiment 1740 output includes at least one output to a user readable display. initiating the treatment protocol includes concurrently or In an embodiment 2070 the user readable display includes a sequentially delivering two or more anti-microbial agents to human readable display. In an embodiment 2080 the user at least one of the outer surface, or the inner surface of the readable display includes one or more active displays. In an body structure of the insertable device, based at least in part embodiment 2090, the user readable display includes one or on the comparison. In an embodiment 1750 initiating the 25 more passive displays. In an embodiment 2094 the at least treatment protocol includes activating at least one of an one output occurs in real-time. In an embodiment 2095 the authorization protocol, authentication protocol, or anti-mi user readable display includes one or more of a numeric crobial agent delivery protocol based at least in part on the format, graphical format, or audio format. In an embodiment comparison. 2096 the signal includes at least one of a fluorescent signal, As depicted in FIG. 12, a method 1800 includes activating 30 impedance signal, optical signal, thermal signal, biochemi at least one activatable anti-microbial region including at cal signal, or electrochemical signal. In an embodiment least one anti-microbial reservoir configured to actively 2097, selectively releasing the at least one anti-microbial elute at least one anti-microbial agent proximate at least one agent is initiated at least one of prior to, during, or Subse of the outer surface or the inner surface of the body structure quent to insertion of the insertable device into a biological of the device, based at least in part on detecting the presence 35 subject. In an embodiment 2098 the at least one output is of at least one microorganism proximate to one or more associated with historical information. In an embodiment areas of the body structure. 2099 the user readable display is coupled to the insertable As depicted in FIG. 13, a method 1900 includes 1905 device. selectively releasing at least one anti-microbial agent from As depicted in FIG. 15, a method 2100 includes 2110 an anti-microbial agent reservoir operably coupled to one or 40 selectively actuating one or more anti-microbial regions so more anti-microbial regions proximate at least one of an as to partially release at least one anti-microbial agent outer surface, inner surface, or embedded in the internal through at least one of an outer Surface or an inner Surface body structure of an insertable device, the insertable device of the catheter assembly in response to real-time, detected including a body structure having an outer Surface and an information associated with the presence of a microbial inner Surface defining one or more fluid-flow passageways, 45 component proximate one or more regions of at least one of in response to an automatically detected signal associated an outer Surface or inner Surface of the catheter assembly. with the at least one microbial component proximate at least As depicted in FIG. 16, a method 2200 includes 2210 one of the outer surface or inner surface of the insertable activating via control circuitry at least one actively control device, or present in the fluid-flow passageway. In an lable anti-microbial nanostructure of at least one of the outer embodiment 1910, selectively releasing at least one anti 50 Surface or the inner Surface in a body structure of an microbial agent from an anti-microbial agent reservoir oper insertable device. In an embodiment 2215 the body structure ably coupled to one or more anti-microbial regions includes defines one or more fluid-flow passageways, based on at concurrently or sequentially releasing at least one first least one of an automatically detected biomarker, temporal anti-microbial agent from an anti-microbial agent reservoir randomness, or a heuristically determined parameter asso operably coupled to a first anti-microbial region, and releas 55 ciated with at least one microorganism. In an embodiment ing at least one second anti-microbial agent from an anti 2220 wherein activating the at least one actively controllable microbial agent reservoir operably coupled to a second anti-microbial nanostructure includes electrically activating anti-microbial agent reservoir. a spatially patterned anti-microbial nanostructure. In an In an embodiment 1920, releasing the at least one anti embodiment 2230 activating the at least one actively con microbial agent includes releasing the anti-microbial agent 60 trollable anti-microbial nanostructure includes electrically at a dose sufficient to modulate an activity of the detected activating a temporally patterned anti-microbial nanostruc microorganism in response to the automatically detected ture. In an embodiment 2240 the actuation is based at least signal associated with at least one microbial component. In in part on detection of at least one microorganism. In an an embodiment 1930, the method further comprises initiat embodiment 2250 the actuation is based at least in part on ing a treatment protocol in response to the automatically 65 a schedule. In an embodiment 2260 the actuation is based at detected signal associated with at least one microbial com least in part on a command from an implant. In an embodi ponent proximate at least one of the outer Surface or inner ment 2270 the actuation is based at least in part on a US 9,474,831 B2 103 104 command from one or more sensors. In an embodiment 2280 between the first actuatable anti-microbial state and the the actuation is based at least in part on an external com second actuatable anti-microbial State in response to a mand. detected presence of at least one microbial component. In an As depicted in FIG. 17, a method 2300 includes 2305 embodiment 2620, the first actuatable anti-microbial state activating the at least one actively controllable anti-micro includes a first adsorption affinity, and the second actuatable bial nanostructure includes activating a spatially patterned anti-microbial state includes a second adsorption affinity. In anti-microbial nanostructure based on at least one charac an embodiment 2630, actuating between the at least one of teristic. In an embodiment 2310, the at least one character the first actuatable anti-microbial state or the second actu istic includes at least one detected characteristic including atable anti-microbial state includes at least one of a change one or more of a detected fluorescence, detected impedance, 10 in at least one of hydrophilicity, hydrophobicity, electrical detected optical reflectance, detected thermal transfer, charge, chemical composition, polarizability, transparence, detected change in conductance, detected change in index of conductivity, light absorption, osmotic potential, Zeta poten refraction, detected pH, or detected microbial component of tial, Surface energy, coefficient of friction, or tackiness. In an at least one microorganism. In an embodiment 2320 acti embodiment 2640, actuating the at least one actively con vating the at least one actively controllable anti-microbial 15 trollable anti-microbial nanostructure includes actuating a nanostructure is initiated at least one of prior to, during, or spatially patterned anti-microbial nanostructure based on at subsequent to insertion of the insertable device into a least one of detected fluorescence, detected impedance, biological subject. In an embodiment 2330, the method detected optical reflectance, detected thermal transfer, includes electrically activating a computing device to detected change in conductance, detected change in index of execute the method. In an embodiment 2340 the method refraction, detected pH, or detected microbial component. In further comprises generating at least one output to a user. In an embodiment 2650, the actuation is based at least in part an embodiment 2350 generating at least one output to the on a schedule, command from an implant, command from user includes electrically activating at least one of a treat one or more sensors, or external command. In an embodi ment protocol, identification of a detected microorganism, ment 2660, the method further comprises generating at least status of the insertable device, or location of a detected 25 one output to a user. microorganism. In an embodiment 2360 generating at least As depicted in FIG. 21, a method 2700 includes 2705 one output to the user includes generating at least one output actuating at least one independently addressable and actu to at least one entity. In an embodiment 2365 the at least one atable anti-microbial region, the at least one independently entity includes at least one person or computer. In an addressable and actuatable anti-microbial region included in embodiment 2370 the at least one output includes at least 30 at least one of the outer surface or the inner surface of a body one output to a user readable display. In an embodiment structure of an insertable device, the body structure defining 2380 the user readable display includes one or more active one or more fluid-flow passageways, based at least in part on displays. In an embodiment 2390 the user readable display an automatically detected biomarker or a heuristically deter includes one or more passive displays. In an embodiment mined parameter associated with at least one microorgan 2395 the user readable display includes one or more of a 35 ism. numeric format, graphical format, or audio format. As depicted in FIG. 22, a method 2800 includes 2805 As depicted in FIG. 18, a method 2400 includes 2405 the actuating one or more anti-microbial regions of an insertable heuristically determined parameter includes at least one of a device between at least a first actuatable anti-microbial state threshold level or target parameter. In an embodiment 2410 and a second actuatable anti-microbial state in response to a the heuristically determined parameter includes at least one 40 detected presence of at least one microbial component heuristic protocol determined parameter or heuristic algo proximate at least one of the one or more anti-microbial rithm determined parameter. regions of an insertable device. In an embodiment 2810, As depicted in FIG. 19, a method 2500 includes 2505 actuating includes reversibly actuating between the first activating via control circuitry at least one independently actuatable anti-microbial state and the second actuatable addressable and actively controllable anti-microbial nano 45 anti-microbial State in response to a detected presence of at structure projecting from at least one of the outer Surface or least one microbial component. In an embodiment 2820 the the inner surface of a body structure of an insertable device, first actuatable anti-microbial state includes a first adsorp the body structure defining one or more fluid-flow passage tion affinity, and the second actuatable anti-microbial State ways, based on at least one of an automatically detected includes a second adsorption affinity. In an embodiment biomarker or a heuristically determined parameter associ 50 2830, actuating between the at least one of the first actu ated with at least one microorganism. In an embodiment atable anti-microbial state or the second actuatable anti 2506 activating the at least one actively controllable anti microbial State includes at least one of a change in at least microbial nanostructure includes activating a spatially pat one of hydrophilicity, hydrophobocity, electrical charge, terned anti-microbial nanostructure. In an embodiment 2507 chemical composition, polarizability, transparence, conduc activating the at least one actively controllable anti-micro 55 tivity, light absorption, osmotic potential, Zeta potential, bial nanostructure includes activating a temporally patterned Surface energy, coefficient of friction, or tackiness. anti-microbial nanostructure. As depicted in FIG. 23, a method 2900 includes actuating As depicted in FIG. 20, a method 2600 includes 2605 at least one anti-microbial region of a plurality of anti actuating at least one anti-microbial region between a first microbial regions configured to direct at least one anti anti-microbial state and a second anti-microbial state, the at 60 microbial agent to one or more areas of at least one of an least one anti-microbial region included in at least one of the outer Surface, an inner Surface, or internally embedded in a outer surface or the inner surface of a body structure of an body structure of an insertable device, the body structure insertable device, the body structure defining one or more defining one or more fluid-flow passageways, in response to fluid-flow passageways, based at least in part on an auto an in vivo detected microbial component associated with a matically detected biomarker or a heuristically determined 65 biological sample proximate to one or more areas of the parameter associated with at least one microorganism. In an body structure. In an embodiment 2905, actuating the at embodiment 2610, actuating includes reversibly actuating least one anti-microbial region including actuating at least US 9,474,831 B2 105 106 one spatially patterned or temporally patterned anti-micro least in part on detection of at least one microorganism. In bial region in at least one of the plurality of anti-microbial an embodiment 3220 actuating the one or more anti-micro regions of the body surface. In an embodiment 2906, actu bial regions is based at least in part on a schedule. In an ating the at least one anti-microbial region is based at least embodiment 3230 actuating the one or more anti-microbial in part on at least one of a detected fluorescence, detected regions is based at least in part on a command from an impedance, detected optical reflectance, detected thermal implant. In an embodiment 3240 actuating the one or more transfer, or detected microbial component. In an embodi anti-microbial regions is based at least in part on a command ment 2907, actuating the at least one anti-microbial region from one or more sensors. In an embodiment 3250, actuating is initiated at least one of prior to, during, or Subsequent to the one or more anti-microbial regions is based at least in insertion of the insertable device into a biological subject. In 10 part on an external command. In an embodiment 3260, an embodiment 2908 actuating the at least one anti-micro actuating the one or more anti-microbial regions includes bial region is based at least in part on one or more of current actuating a spatially patterned anti-microbial region based biomarker information, previous biomarker information, or on a detected fluorescence. In an embodiment 3270, actu previous actuation events. ating the one or more anti-microbial regions includes acti As depicted in FIG. 24, a method 3000 includes 3010 15 Vating a spatially patterned anti-microbial region based on a activating the at least one actively controllable anti-micro detected impedance. In an embodiment 3280 actuating the bial nanostructure is based at least in part on detection of at one or more anti-microbial regions includes actuating a least one microorganism. In an embodiment 3020, activating spatially patterned anti-microbial region based on a detected the at least one actively controllable anti-microbial nano optical reflectance. structure is based at least in part on a schedule. In an As depicted in FIG. 27, a method 3300 includes 3310 embodiment 3030, activating the at least one actively con actuating the one or more anti-microbial regions includes trollable anti-microbial nanostructure is based at least on actuating a spatially patterned anti-microbial region based part on a command from an implant. In an embodiment on a detected thermal transfer. In an embodiment 3320 3040, activating the at least one actively controllable anti actuating the one or more anti-microbial regions includes microbial nanostructure is based at least in part on a com 25 actuating a spatially patterned anti-microbial region based mand from one or more sensors. In an embodiment 3050, on a detected change in conductance. In an embodiment activating the at least one actively controllable anti-micro 3330 actuating the one or more anti-microbial regions bial nanostructure is based at least in part on an external includes actuating a spatially patterned anti-microbial region command. In an embodiment 3060, activating the at least based on a detected change in index of refraction. In an one actively controllable anti-microbial nanostructure 30 embodiment 3340 actuating the one or more anti-microbial includes activating a spatially patterned anti-microbial nano regions includes actuating a spatially patterned anti-micro structure based on a detected fluorescence. In an embodi bial region based on a detected pH. In an embodiment 3350 ment 3070, activating the at least one actively controllable actuating the one or more anti-microbial regions includes anti-microbial nanostructure includes activating a spatially actuating a spatially patterned anti-microbial region based patterned anti-microbial nanostructure based on a detected 35 on a detected microbial component of at least one microor impedance. In an embodiment 3080 activating the at least ganism. In an embodiment 3360 actuating the one or more one actively controllable anti-microbial nanostructure anti-microbial regions includes electrically activating a includes activating a spatially patterned anti-microbial nano computing device to execute the method. In an embodiment structure based on a detected optical reflectance. 3370 actuating the one or more anti-microbial regions is As depicted in FIG. 25, a method 3100 includes 3110 40 initiated at least one of prior to, during, or Subsequent to activating the at least one actively controllable anti-micro insertion of the insertable device into a biological subject. bial nanostructure includes activating a spatially patterned As depicted in FIG. 28, a method 3400 includes 3401 anti-microbial nanostructure based on a detected thermal actuating at least one actuatable anti-microbial region transfer. In an embodiment 3120 activating the at least one including at least one anti-microbial reservoir configured to actively controllable anti-microbial nanostructure includes 45 actively elute at least one anti-microbial agent proximate at activating a spatially patterned anti-microbial nanostructure least one of the outer surface or the inner surface of the body based on a detected change in conductance. In an embodi structure of the device, based at least in part on detecting the ment 3130, activating the at least one actively controllable presence of at least one microorganism proximate to one or anti-microbial nanostructure includes activating a spatially more areas of the body structure. patterned anti-microbial nanostructure based on a detected 50 As depicted in FIG. 29, a method 3500 includes 3510 at change in index of refraction. In an embodiment 3140. least one anti-microbial region including one or more of an activating the at least one actively controllable anti-micro anti-microbial agent, or anti-microbial nanostructure. In an bial nanostructure includes activating a spatially patterned embodiment 3520 the anti-microbial agent includes at least anti-microbial nanostructure based on a detected pH. In an one surfactant or amino acid. In an embodiment 3530 the embodiment 3150, activating the at least one actively con 55 amino acid includes at least one D-amino acid. In an trollable anti-microbial nanostructure includes activating a embodiment 3540 the anti-microbial agent includes at least spatially patterned anti-microbial nanostructure based on a one of an anti-fungal agent, anti-parasitic agent, bacterio detected microbial component of at least one microorgan phage, or antibiotic. In an embodiment 3550 the anti ism. In an embodiment 3160, activating the at least one microbial agent includes at least one enzymatically active actively controllable anti-microbial nanostructure includes 60 bacteriophage. In an embodiment 3560, the antibiotic electrically activating a computing device to execute the includes at least one of azithromycin, clarithromycin, clin method. In an embodiment 3170, activating the at least one damycin, dirithromycin, erythromycin, lincomycin, trolean actively controllable anti-microbial nanostructure is initiated domycin, cinoxacin, ciprofloxacin, enoxacin, gatifloxacin, at least one of prior to, during, or Subsequent to insertion of grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, the insertable device into a biological subject. 65 nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trova As depicted in FIG. 26, a method 3200 includes 3210 floxacin, oxolinic acid, gemifloxacin, perfloxacin, imi actuating the one or more anti-microbial regions based at penemi-cilastatin, meropenem, aztreonam, amikacin, gen US 9,474,831 B2 107 108 tamicin, kanamycin, neomycin, netilmicin, Streptomycin, to achieve the desired functionality. Specific examples of tobramycin, paromomycin, teicoplanin, Vancomycin, deme operably coupleable include, but are not limited to, physi clocycline, doxycycline, methacycline, minocycline, oxytet cally mateable and/or physically interacting components, racycline, tetracycline, chlortetracycline, mafenide, Sul and/or wirelessly interactable, and/or wirelessly interacting fadizine, Sulfacetamide, Sulfadiazine, Sulfamethoxazole, components, and/or logically interacting, and/or logically SulfaSalazine, Sulfisoxazole, trimethoprim-Sulfamethox interactable components. azole, Sulfamethizole, lineZolid, quinopristin--dalfopristin, In an embodiment, one or more components may be bacitracin, chloramphenicol, colistemetate, fosfomycin, iso referred to herein as “configured to,” “configurable to.” niazid, methenamine, metronidazol, mupirocin, nitrofuran “operable/operative to,” “adapted/adaptable.” “able to.” toin, nitrofuraZone, novobiocin, polymyxin B, spectinomy 10 “conformable/conformed to.” etc. Such terms (e.g., “con cin, trimethoprim, collistin, cycloserine, capreomycin, figured to') can generally encompass active-state compo ethionamide, pyrazinamide, para-aminosalicyclic acid, nents and/or inactive-state components and/or standby-state erythromycin ethylsuccinate+Sulfisoxazole, penicillin, beta components, unless context requires otherwise. lactamase inhibitor, methicillin, cefaclor, cefamandole The foregoing detailed description has set forth various nafate, cefazolin, cefixime, cefinetazole, cefonioid, cefop 15 embodiments of the devices and/or processes via the use of eraZone, ceforanide, cefotainme, cefotaxime, cefotetan, block diagrams, flowcharts, and/or examples. Insofar as cefoxitin, cefpodoxime proxetil, ceftazidime, ceftizoxime, Such block diagrams, flowcharts, and/or examples contain ceftriaxone, cefriaxone moxalactam, cefuroxime, cepha one or more functions and/or operations, it will be under lexin, cephalosporin C, cephalosporin C Sodium salt, cepha stood by the reader that each function and/or operation lothin, cephalothin Sodium salt, cephapirin, cephradine, within Such block diagrams, flowcharts, or examples can be cefuroximeaxetil, dihydratecephalothin, moxalactam, lorac implemented, individually and/or collectively, by a wide arbef mafate, Amphotericin B, Carbol-Fuchsin, Ciclopirox, range of hardware, software, firmware, or virtually any Clotrimzole, Econazole, Haloprogin, Ketoconazole, combination thereof. Further, the use of “Start,” “End' or Mafenide, Miconazole, Naftifine, Nystatin, Oxiconazole Sil “Stop' blocks in the block diagrams is not intended to ver, Sulfadiazine, Sulconazole, Terbinatine, Tioconazole, 25 indicate a limitation on the beginning or end of any functions Tolnaftate. Undecylenic acid, flucytosine, miconazole or in the diagram. Such flowcharts or diagrams may be incor cephalosporin. porated into other flowcharts or diagrams where additional As depicted in FIG. 30, a method 3600 includes 3610 an functions are performed before or after the functions shown anti-microbial agent including at least one of a macrollide, in the diagrams of this application. In an embodiment, lincosamine, quinolone, fluoroquinolone, carbepenem, 30 several portions of the subject matter described herein is monobactam, aminoglycoside, glycopeptide, enzyme, tetra implemented via Application Specific Integrated Circuits cycline, sulfonamide, rifampin, oxazolidonone, strepto (ASICs), Field Programmable Gate Arrays (FPGAs), digital gramin, or a synthetic moiety thereof. In an embodiment signal processors (DSPs), or other integrated formats. How 3620, the anti-microbial agent includes at least one of a ever, some aspects of the embodiments disclosed herein, in metal, ceramic, Super-oxide forming compound, or polymer. 35 whole or in part, can be equivalently implemented in inte In an embodiment 3630, the anti-microbial agent includes at grated circuits, as one or more computer programs running least one of polyvinyl chloride, polyester, polyethylene, on one or more computers (e.g., as one or more programs polypropylene, ethylene, polyolefin, homopolymers or running on one or more computer systems), as one or more copolymers thereof. In an embodiment 3640, the anti programs running on one or more processors (e.g., as one or microbial agent includes polytetrafluoroethylene. In an 40 more programs running on one or more microprocessors), as embodiment 3650, at least one of the plurality of anti firmware, or as virtually any combination thereof, and that microbial regions includes at least one of silver, copper, designing the circuitry and/or writing the code for the Zirconium, diamond, rubidium, platinum, gold, nickel, lead, software and or firmware would be well within the skill of cobalt, potassium, zinc, bismuth, tin, cadmium, chromium, one of skill in the art in light of this disclosure. In addition, aluminum, calcium, mercury, thallium, gallium, strontium, 45 the mechanisms of the subject matter described herein are barium, lithium, magnesium, oxides, hydroxides, or salts capable of being distributed as a program product in a thereof. In an embodiment 3660, the at least one of the variety of forms, and that an illustrative embodiment of the plurality of anti-microbial regions includes at least one of an subject matter described herein applies regardless of the electroactive polymer, hydrogenated diamond, or black particular type of signal-bearing medium used to actually silica. 50 carry out the distribution. Non-limiting examples of a sig The herein described subject matter sometimes illustrates nal-bearing medium include the following: a recordable type different components contained within, or connected with, medium such as a floppy disk, a hard disk drive, a Compact different other components. It is to be understood that such Disc (CD), a Digital Video Disk (DVD), a digital tape, a depicted architectures are merely examples, and that in fact, computer memory, etc.; and a transmission type medium many other architectures can be implemented that achieve 55 Such as a digital and/or an analog communication medium the same functionality. In a conceptual sense, any arrange (e.g., a fiber optic cable, a waveguide, a wired communica ment of components to achieve the same functionality is tions link, a wireless communication link (e.g., transmitter, effectively “associated such that the desired functionality is receiver, transmission logic, reception logic, etc.), etc.). achieved. Hence, any two components herein combined to While particular aspects of the present subject matter achieve a particular functionality can be seen as “associated 60 described herein have been shown and described, it will be with each other such that the desired functionality is apparent to the reader that, based upon the teachings herein, achieved, irrespective of architectures or intermedial com changes and modifications can be made without departing ponents. Likewise, any two components so associated can from the subject matter described herein and its broader also be viewed as being “operably connected, or “operably aspects and, therefore, the appended claims are to encom coupled, to each other to achieve the desired functionality, 65 pass within their scope all such changes and modifications as and any two components capable of being so associated can are within the true spirit and scope of the subject matter also be viewed as being “operably coupleable,” to each other described herein. In general, terms used herein, and espe US 9,474,831 B2 109 110 cially in the appended claims (e.g., bodies of the appended What is claimed is: claims) are generally intended as "open terms (e.g., the 1. An insertable device system, comprising: term “including should be interpreted as “including among a body structure having an outer Surface and an inner other things,” the term “having should be interpreted as Surface defining one or more fluid-flow passageways; “having at least,” the term “includes should be interpreted 5 at least one independently addressable and actively con as “includes but is not limited to.” etc.). Further, if a specific trollable anti-microbial nanostructure including a nano number of an introduced claim recitation is intended. Such fiber of a surface switchable between a Zwitterionic an intent will be explicitly recited in the claim, and in the state and a non-Zwitterionic state and projecting from at absence of Such recitation no such intent is present. For least one of the outer surface or the inner surface of the example, as an aid to understanding, the following appended 10 body structure; and claims may contain usage of the introductory phrases “at circuitry operably coupled to the nanofiber and configured least one' and "one or more' to introduce claim recitations. to activate the nanofiber based on at least one signal However, the use of such phrases should not be construed to from a sensor configured to determine the presence of imply that the introduction of a claim recitation by the at least one microorganism on at least one of the indefinite articles “a” or “an limits any particular claim 15 independently addressable and actively controllable containing such introduced claim recitation to claims con anti-microbial nanostructure of the body structure. taining only one Such recitation, even when the same claim 2. The insertable device system of claim 1, further includ includes the introductory phrases “one or more' or “at least ing a controller operably coupled to the at least one sensor, one' and indefinite articles such as “a” or “an” (e.g., “a” the controller configured to actuate at least one of the and/or “an should typically be interpreted to mean “at least independently addressable and actively controllable anti one' or “one or more); the same holds true for the use of microbial nanostructure in response to at least one of a definite articles used to introduce claim recitations. In addi scheduled program, external command, history of a previous tion, even if a specific number of an introduced claim presence of a microorganism, or history of a previous recitation is explicitly recited. Such recitation should typi activation. cally be interpreted to mean at least the recited number (e.g., 25 3. The insertable device system of claim 1, further includ the bare recitation of “two recitations, without other modi ing circuitry configured for determining the presence of at fiers, typically means at least two recitations, or two or more least one microorganism on the body structure Subsequent to recitations). Furthermore, in those instances where a con a first round of activation of the at least one independently vention analogous to “at least one of A, B, and C, etc. is addressable and actively controllable anti-microbial nano used, in general Such a construction is intended in the sense 30 Structure. of the convention (e.g., “a system having at least one of A, 4. The insertable device system of claim 3, wherein the B, and C would include but not be limited to systems that circuitry configured for determining the presence of at least have A alone, B alone, C alone, A and B together, A and C one microorganism includes at least one sensor including an together, B and C together, and/or A, B, and C together, etc.). identification code. In those instances where a convention analogous to “at least 35 5. The insertable device system of claim 4, wherein the at one of A, B, or C, etc. is used, in general Such a construc least one sensor is configured to implement instructions tion is intended in the sense of the convention (e.g., “a addressed to the at least one identification code. system having at least one of A, B, or C would include but 6. The insertable device system of claim 3, wherein the not be limited to systems that have A alone, B alone, C alone, circuitry configured for determining the presence of at least A and B together, A and C together, B and C together, and/or 40 one microorganism includes at least one sensor operably A, B, and C together, etc.). Typically a disjunctive word coupled to a microorganism biomarker array. and/or phrase presenting two or more alternative terms, 7. The insertable device system of claim 3, wherein the whether in the description, claims, or drawings, should be circuitry configured for determining the presence of at least understood to contemplate the possibilities of including one one microorganism includes at least one of an electrochemi of the terms, either of the terms, or both terms unless context 45 cal transducer, optical transducer, biochemical transducer, dictates otherwise. For example, the phrase “A or B will be ultrasonic transducer, piezoelectric transducer, or thermal typically understood to include the possibilities of “A” or transducer. B Or A and B. 8. The insertable device system of claim 3, wherein the With respect to the appended claims, the operations circuitry configured for determining the presence of at least recited therein generally may be performed in any order. 50 one microorganism includes at least one thermal detector, Also, although various operational flows are presented in a photovoltaic detector, or photomultiplier detector. sequence(s), it should be understood that the various opera 9. The insertable device system of claim 3, wherein the tions may be performed in orders other than those that are circuitry configured for determining the presence of at least illustrated, or may be performed concurrently. Examples of one microorganism includes at least one of a density sensor, Such alternate orderings includes overlapping, interleaved, 55 refractive index sensor, Surface plasmon resonance sensor, interrupted, reordered, incremental, preparatory, Supplemen biomass sensor, electrochemical sensor, fluid-flow sensor, or tal, simultaneous, reverse, or other variant orderings, unless biochemical sensor. context dictates otherwise. Furthermore, terms like “respon 10. The insertable device system of claim 3, wherein the sive to.” “related to,” or other past-tense adjectives are circuitry configured for determining the presence of at least generally not intended to exclude such variants, unless 60 one microorganism includes a microbial component capture context dictates otherwise. layer. While various aspects and embodiments have been dis 11. The insertable device system of claim 10, wherein the closed herein, other aspects and embodiments are contem microbial component capture layer includes an array of plated. The various aspects and embodiments disclosed different binding molecules that specifically bind one or herein are for purposes of illustration and are not intended to 65 more components on at least one microorganism. be limiting, with the true scope and spirit being indicated by 12. The insertable device system of claim 1, further the following claims. including circuitry configured for altering the type of US 9,474,831 B2 111 112 response of the independently addressable and actively 27. The insertable device system of claim 26, wherein the controllable anti-microbial nanostructure based on the deter at least one independently addressable and actively control mination of the presence of at least one microorganism on lable anti-microbial nanostructure is configured to be actu the body structure subsequent to a first round of activation. ated by the presence of at least one microorganism. 13. The insertable device system of claim 1, further 5 28. An insertable device system, comprising: including electrically activating means for concurrently or a computer-recordable medium bearing: sequentially electrically activating two or more of the at a body structure having an outer Surface and an inner least one independently addressable and actively control Surface defining one or more fluid-flow passageways; lable anti-microbial nanostructure determined to have at at least one independently addressable and actively con least one microorganism present thereon. 10 14. The insertable device system of claim 1, further trollable anti-microbial nanostructure including a nano including at least one computing device. fiber of a surface switchable between a Zwitterionic 15. The insertable device system of claim 14, wherein the state and a non-Zwitterionic state; and at least one computing device is remote to the insertable one or more instructions for controlling the at least one device. 15 independently addressable and actively controllable 16. The insertable device system of claim 14, further anti-microbial nanostructure of the body structure. including one or more instructions that when executed on 29. A method of reducing microbial growth of at least a the at least one computing device cause the at least one portion of an insertable device, comprising: computing device to generate at least one output to a user. activating via control circuitry at least one independently 17. The insertable device system of claim 16, wherein the addressable and actively controllable anti-microbial at least one output includes at least one of a treatment nanostructure including a nanofiber of a Surface Swit protocol, identification of a detected microorganism, status chable between a Zwitterionic state and a non-Zwitte of the insertable device, or location of a detected microor rionic state and projecting from at least one of the outer ganism. surface or the inner surface of a body structure of an 18. The insertable device system of claim 16, wherein the 25 insertable device, the body structure defining one or user includes at least one entity. more fluid-flow passageways, based on at least one of 19. The insertable device system of claim 18, wherein the an automatically detected biomarker or a heuristically at least one entity includes at least one person or computer. determined parameter associated with at least one 20. The insertable device system of claim 16, wherein the microorganism. at least one output includes output to a user readable display. 30 30. The method of claim 29, wherein activating the at 21. The insertable device system of claim 20, wherein the least one actively controllable anti-microbial nanostructure user readable display includes a human readable display. includes activating a spatially patterned anti-microbial nano 22. The insertable device system of claim 20, wherein the Structure. user readable display includes one or more active displayS. 31. The method of claim 29, wherein activating the at 23. The insertable device system of claim 20, wherein the 35 least one actively controllable anti-microbial nanostructure user readable display includes one or more passive displayS. includes activating a temporally patterned anti-microbial 24. The insertable device system of claim 20, wherein the nanoStructure. user readable display includes one or more of a numeric 32. The method of dam 29, wherein activating the at least format, graphical format, or audio format. one actively controllable anti-microbial nanostructure 25. An insertable device system, comprising: 40 includes activating a spatially patterned anti-microbial nano a body structure having an outer Surface and an inner structure based on at least one of detected fluorescence, Surface defining one or more fluid-flow passageways; detected impedance, detected optical reflectance, detected at least one independently addressable and actively con thermal transfer, detected change in conductance, or trollable anti-microbial nanostructure including a nano detected change in index of refraction. fiber of a surface switchable between a Zwitterionic 45 33. The method of claim 29, wherein activating the at state and a non-Zwitterionic state and projecting from at least one actively controllable anti-microbial nanostructure least one of the outer surface or the inner surface of the includes activating a spatially patterned anti-microbial nano body structure; structure based on a detected pH. at least one sensor configured to detect one or more 34. The method of claim 29, wherein activating the at microorganisms present on the body structure; and 50 least one actively controllable anti-microbial nanostructure means for determining the presence of at least one micro includes activating a spatially patterned anti-microbial nano organism on at least one of the independently address structure based on a detected microbial component of at able and actively controllable anti-microbial nanostruc least one microorganism. ture of the body structure. 35. The method of claim 29, wherein activating the at 26. An insertable device system, comprising: 55 least one actively controllable anti-microbial nanostructure a computer-recordable medium bearing: is initiated at least one of prior to, during, or Subsequent to a body structure having an outer Surface and an inner insertion of the insertable device into a biological subject. Surface defining one or more fluid-flow passageways; 36. The method of claim 29, wherein the method includes at least one independently addressable and actively con electrically activating a computing device to execute the trollable anti-microbial nanostructure including a nano 60 method. fiber of a surface switchable between a Zwitterionic 37. The method of claim 29, further including generating state and a non-Zwitterionic state and; and at least one output to a user. one or more instructions for determining the presence of 38. The method of claim 37, wherein generating at least at least one microorganism on at least one of the at least one output to the user includes electrically activating at least one independently addressable and actively control 65 one of a treatment protocol, identification of a detected lable anti-microbial nanostructure of the body struc microorganism, status of the insertable device, or location of ture. a detected microorganism. US 9,474,831 B2 113 114 39. The method of claim 37, wherein generating at least one output to the user includes generating at least one output to at least one entity. 40. The method of claim 37, wherein the at least one entity includes at least one person or computer. 41. The method of claim 37, wherein the at least one output includes at least one output to a user readable display. 42. The method of claim 41, wherein the user readable display includes a human readable display. 43. The method of claim 41, wherein the user readable 10 display includes one or more active displays. 44. The method of claim 41, wherein the user readable display includes one or more passive displays. 45. The method of claim 41, wherein the user readable display includes one or more of a numeric format, graphical 15 format, or audio format. k k k k k