(12) United States Patent (10) Patent No.: US 6,500,323 B1 Chow Et Al
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USOO650O323B1 (12) United States Patent (10) Patent No.: US 6,500,323 B1 Chow et al. (45) Date of Patent: Dec. 31, 2002 (54) METHODS AND SOFTWARE FOR 5,869,004 A 2/1999 Parce et al. DESIGNING MICROFLUIDIC DEVICES 5,876,675 A 3/1999 Kennedy 5,880,071 A 3/1999 Parce et al. (75) Inventors: Andrea W. Chow, Los Altos, CA (US); 5,882,465 A 3/1999 McReynolds Anne R. Kopf-Sill, Portola Valley, CA 5,885.470 A 3/1999 Parce et al. 5,942,443 A 8/1999 Parce et al. (US); Calvin Y. H. Chow, Portola 5,948.227 A 9/1999 Dubrow Valley, CA (US) 5,955,028 A 9/1999 Chow 5,957,579 A 9/1999 Kopf-Sill et al. (73) Assignee: Caliper Technologies Corp., Mountain 5,958.203 A 9/1999 Parce et al. View, CA (US) 5,958,694. A 9/1999 Nikiforov 5,959,291 A 9/1999 Jensen (*) Notice: Subject to any disclaimer, the term of this 5,964.995 A 10/1999 Nikiforov et al. patent is extended or adjusted under 35 5,965,001. A 10/1999 Chow et al. U.S.C. 154(b) by 0 days. (List continued on next page.) (21) Appl. No.: 09/277,367 FOREIGN PATENT DOCUMENTS WO WO96O4547 2/1996 (51) Int. Cl. .......................... G01N 27.447; B01L 300 W WE so (52) U.S. Cl. ........................ 204/450; 204/453; 422/100 (58) Field of Search ................................. 204/450, 451, OTHER PUBLICATIONS 204/454, 453, 600, 601, 602, 604; 422/70, Culbertson et al. (“Dispersion Sources for Compact Geom 99, 100, 702/19, 22 etries on Microchips", Anal. Chem. 1998, 70,3781-3789), Sep.1998.* (56) References Cited (List continued on next page.) U.S. PATENT DOCUMENTS Primary Examiner Jill Warden 4,390,403 A 6/1983 Batchelder Assistant Examiner Ab Noguerola 4,908,112 A 3/1990 Pace (74) Attorney, Agent, or Firm Matthew B. Murphy; 5,126,022 A 6/1992 Soane et al. Andrew L. Filler 5,498.392 A 3/1996 Wilding et al. 5,571,410 A 11/1996 Swedberg et al. (57) ABSTRACT 5,585,069 A 12/1996 Zanzucchi et al. - 0 5,593.838 A 1/1997 Zanzucchi et al. Methods and Systems for designing optimized fluidic chan 5,603,351 A 2/1997 Cherukuri et al. nel networks for performing different analytical operations, 5,635,358 A 6/1997 Wilding et al. which include the Steps of Selecting a driving force, identi 5,637.469 A 6/1997 Wilding et al. fying at least a first reaction parameter, and designing the 5,699,157 A 12/1997 Parce channel network by determining channel lengths and croSS 5,750,015 A 5/1998 Soane et al. Sectional dimensions that are optimized for the reaction 58OO.6905,779,868 A 9/19987/1998 ChowParce etet al.al. requirementsts in viView orfth une selectedlected driving fIorce. PrefPreferre d 5,842,787.2Y- - - 2 A 12/1998 Kopf-Sill et al. C thods are used to design9. integrated9. microScale fluidic 5,846,727 A * 12/1998 Soper et al. ................... 435/6 Systems. 5,852.495 A 12/1998 Parce 5,858.804 A * 1/1999 Zanzucchi et al. .......... 436/536 23 Claims, 14 Drawing Sheets 200 N US 6,500,323 B1 Page 2 U.S. PATENT DOCUMENTS Cohen, C.B. et al., “A Microchip-Based Enzyme Assay for 5,965,410 A 10/1999 Chow et al. Protein Kinase A.” Anal. Chem. (1999) 273:89–97. 5,972,187 A 10/1999 Parce et al. Dasgupta, P.K. et al., “Electroosmosis: A Reliable Fluid 5,976,336 A 11/1999 Dubrow et al. Propulsion System for Flow Injection Analysis,” Anal. 5,989.402 A 11/1999 Chow et al. Chem. (1994) 66:1792–1798. 6,001.231 A 12/1999 Kopf-Sill 6,004,515 A 12/1999 Parce et al. Doshi, M.R. et al., “Three Dimensional Laminar Dispersion 6,011,252 A 1/2000 Jensen in Open and Closed Rectangular Conduits,” Chem. Eng. Sci. 6,012.902 A 1/2000 Parce (1978) 33:795-804. 6,062,261 A 5/2000 Jacobson et al. ........... 137,827 Guell, D.C. et al., “Taylor Dispersion in Conduits of Large 6,136,272 A * 10/2000 Weigl et al. ............. 422/82.05 Aspect Ratio,” Chem. Eng. Comm. (1987) 58:231-244. OTHER PUBLICATIONS Jacobson, S.C. et al., “Fused Quartz Substrates for Micro Papautsky et al. (“Microchannel fluid behavior using chip Electrophoresis,” Anal. Chem. (1995) 67:2059-2063. micropolar fluid theory”, Proc. IEEE Annu. Int. Workshop Manz, A. et al., “ElectrooSmotic pumping and electro Micro Electro Mech. Syst., 11th, 544–549, 1998), 1998.* phoretic Separations for miniaturized chemical analysis SyS Shoji et al. (“Mrcroflow devices and systems”, J. Micro tems,” J. Micromech. Microeng. (1994) 4:257-265. mech. Microeng. 4 (Sep. 1994) 157-171), Sep. 1998.* Ramsey, J.M. et al., “Microfabricated chemical measure pp. 115-117 of “A Dictionary of Electrochemistry”, Davies ment systems.” Nature Med. (1995) 1:1093–1096. et al., John Wiley & Sons, 1976.* Seiler, K. et al., “Planar Glass Chips for Capillary Electro Mastrangelo, C.H. et al., “Microfabricated Devices for phoresis: Repetitive Sample Injection, Quantitation, and Genetic Diagnostics”, Proc. of IEEE (1998) Separation Efficiency,” Anal. Chem. (1993) 65:1481–1488. 86(8):17691787. Shoji, S. et al., “Microflow devices and systems”, J. Micro Seiler, K. et al., “Electroosmotic Pumping and Valveless mech. Microeng. (1994) 4:157–171. Control of Fluid Flow Within a Manifold of Capillaries on Aris, R. “ON The dispersion of a solute in a fluid flowing a Glass Chip,” Anal. Chem. (1994) 66:3485-3491. through a tube,” Proc. Roy. Soc. London (1956) Taylor, G. et al., “Dispersion of soluble matter in solvent A235:67-77. flowing slowly through a tube,” Proc. Roy. Soc. London Chatwin, P.C. et al., “The effect of aspect ratio on longitu (1953) 219A:186-203. dinal diffusivity in rectangular channels,” J. Fluid Mech. (1982) 120:347–358. * cited by examiner U.S. Patent Dec. 31, 2002 Sheet 1 of 14 US 6,500,323 B1 Fig. 1B U.S. Patent Dec. 31, 2002 Sheet 2 of 14 US 6,500,323 B1 Attach to capillary element Fig. 1C U.S. Patent Dec. 31, 2002 Sheet 3 of 14 US 6,500,323 B1 1 1 1 from 0.9 0.8 O.7 O6 O.5 50 1OO 150 200 Time (s) Fig. 1D U.S. Patent Dec. 31, 2002 Sheet 4 of 14 US 6,500,323 B1 200 N 220 Fig. 2B U.S. Patent Dec. 31, 2002 Sheet 5 of 14 US 6,500,323 B1 Fig. 2C U.S. Patent Dec. 31, 2002 Sheet 6 of 14 US 6,500,323 B1 11 1O : 9 8 7 5 4. HHHH 3 H 2 . th HA . ". AirAs Hill R O 1 - 1. L- . ... I | | 1.4-l ---- 1-1-1-1-1 r 11. 1- L. I I-1---- | - 1OO 200 300 400 500 600 700 8OO 900 Seconds Fig. 2D 10% Ficoll/Fluo-3 1 OO 1000 104 Conc. (nM) Fig. 2E U.S. Patent Dec. 31, 2002 Sheet 7 of 14 US 6,500,323 B1 3OO Fig. 3A U.S. Patent Dec. 31, 2002 Sheet 8 of 14 US 6,500,323 B1 Fig. 3B U.S. Patent Dec. 31, 2002 Sheet 9 of 14 US 6,500,323 B1 7OOOOO — 650000 6OOOOO 55OOOO - 500000 450000 81nM 40nM buffer control 162nM 400000 - 65OnM 325nM 1.3 M 350000 3OOOOO 25OOOC 20000c --- -- -- Ha-Hm 21 O 31 O 410 51O 610 710 810 910 1010 1110 Time (seconds) Fig. 3C U.S. Patent Dec. 31, 2002 Sheet 10 of 14 US 6,500,323 B1 \ 402 404 1410 412 414 Fig. 4A U.S. Patent Dec. 31, 2002 Sheet 11 of 14 US 6,500,323 B1 Fig. 4B U.S. Patent Dec. 31, 2002 Sheet 12 of 14 US 6,500,323 B1 measured calculated Stage Number Fig. 4C U.S. Patent Dec. 31, 2002 Sheet 13 of 14 US 6,500,323 B1 120 measured calculated 1 OO 8 O 6 O 4 O 20 Stage Number Fig. 4D U.S. Patent Dec. 31, 2002 Sheet 14 of 14 US 6,500,323 B1 - 500 (c) 514 510 506 as Figure 5A ? 500 -516 518 520 522 FIXED REMOVABLE PROCESSOR MEMORY STORAGE STORAGE 532 r 524 (1 526 DSPLAY ADAPTER SOUND CARD 5O2 508 510 528 -530 DisplayDISPLAY KEYBOARD MOUSE SPEAKERS INTERFACENETWORK Figure 5B US 6,500,323 B1 1 2 METHODS AND SOFTWARE FOR given analysis while operating within the first, Second, and DESIGNING MICROFLUIDIC DEVICES third parameters. Another aspect of the present invention is a computer implemented process for designing channel networks for BACKGROUND OF THE INVENTION performing a desired analytical operation. A Selected driving Microfluidic devices have gained interest as a potential force is input into a computer to be used in performing the avenue for increasing throughput, accuracy and automat analytical operation of at least one reaction requirement. The ability of chemical, biochemical and biological analyses computer comprises appropriate programming for calculat while reducing instrument and reagent costs, Space ing first, Second and third lengths for first, Second and third requirements, and the like. Typically, Such Systems employ interconnected channel Segments, and at least one croSS integrated channel networks disposed in Solid Substrates. Sectional dimension of the first, Second and third channel Analytical reagents are transported through the conduits, Segments. The first, Second and third lengths and the at least mixed, diluted, Separated and analyzed.