USOO8574660B2

(12) United States Patent (10) Patent No.: US 8,574,660 B2 Weaver et al. (45) Date of Patent: Nov. 5, 2013

(54) ARTICLES HAVING NON-FOULING 6,358,557 B1 3/2002 Wang et al. SURFACES AND PROCESSES FOR 6,395,800 B1 5, 2002 Jones et al. PREPARING THE SAME WITHOUT 8:53: 533 S5 a. ALTERING BULK PHYSICAL PROPERTIES 6,534,268 B1 3/2003 Kawai et al. (75) Inventors: Douglas J. K. Weaver, Cambridge, MA 6,711,879 B2 3/2004 Korteweg et al. (US); Jun Li, Cambridge, MA (US); 7,087,658 B2 8, 2006 Swan et al. Zheng Zhang, Cambridge, MA (US); 75.3 E: 5399, SR al. al AbbVy N. . Deleault,eleault, Cambridge,Ulambridge, MA 7,238,4264 - w B2 7/2007 Jiangawhney et al. et al. (US); Eric W. Marchese, Cambridge, 7.276.286 B2 10/2007 Chapman et al. MA (US); Phu C. Nguyen, Cambridge, 7,306.625 B1 12/2007 Stratford et al. MA (US); Chad C. Huval, Cambridge 7.431,888 B2 10/2008 Frechet et al. R. s s 2001/0050749 A1 12/2001 Watanabe MA (US); Michael A. Bouchard, 2003/0021823 A1 1/2003 Landers et al. Cambridge, MA (US); Arthur J. Coury, 2003/0143335 A1 7/2003 Qiu et al. Cambridge, MA (US); Christopher R. 2004/0256232 Al 12/2004 Jiang et al. 2006/0217285 A1 9, 2006 DeStarac (73) Assignee: Semprus Biosciences Corporation, 2007/00482492007, 0104891 A1 3,5/2007 2007 YE. blood saet al. Boston, MA (US) 2007/025.4006 A1 11/2007 Loose et al. 2008. O181861 A1 7/2008 Jiang et al. (*) Notice: Subject to any disclaimer, the term of this 2008, 0255.305 A1 10, 2008 Brook et al. patent is extended O adjusted under 35 2009. O155335 A1* 6, 2009 O'Shaughnessey et al. . 424/423 U.S.C. 154(b) by 210 days. 2009/O197791 A1 8, 2009 BalaStreet al. (Continued) (21) Appl. No.: 13/156,904 FOREIGN PATENT DOCUMENTS (22) Filed: Jun. 9, 2011 WO O3,OOO433 A1 1, 2003 (65) Prior Publication Data WO 2007/OO2493 A2 1, 2007 (Continued) US 2011/0305909 A1 Dec. 15, 2011 OTHER PUBLICATIONS Related U.S. Application Data Odian, G., Polymerization Mechanism. Types of Polymers and Poly merizations, p. 6-7. (60) Provisional application No. 61/353,200, filed on Jun. Bell, C.; Peppas, N., Biomedical membranes from hydrogels and 9, 2010. interpolymer complexes. Biopolymers II 1995, 122, 125-175. Chapman, R. G.; Ostuni, E.; Liang, M. N.; Meluleni, G.; Kim, E.; (51) Int. Cl Yan, L.; Pier, G.; Warren, H. S.; Whitesides, G. M., Polymeric Thin A. iL 3/00 2006.O1 Films That Resist the Adsorption of Proteins and the Adhesion of ( .01) Bacteria. Langmuir 2001, 17 (4), 1225-1233. (52) U.S. Cl. Cheng, G.; Li, G.; Xue, H.; Chen, S.; Bryers, J. D.; Jiang, S. Zwit USPC ...... 427/2.25; 424/423: 530/423: 530/326; terionic carboxybetaine polymer Surfaces and their resistance to 530/327 long-term biofilm formation. Biomaterials 2009, 30 (28), 5234-40. Cheng. G.; Zhang, Z. Chen, S.; Bryers, J. D., Jiang, S., Inhibition of (58) Field of Classification Search bacterial adhesion and biofilm formation on Zwitterionic Surfaces. USPC ...... 427/2.25; 424/423 Biomaterials 2007, 28 (29), 4192-4199. See application file for complete search history. Du, H.; Chandaroy, P.; Hui, S.W. Grafted poly-(ethylene glycol) on lipid surfaces inhibits protein adsorption and cell adhesion. (56) References Cited Biochimica et Biophysica Acta (BBA)-Biomembranes 1997, 1326 (2), 236-248. U.S. PATENT DOCUMENTS (Continued) 4,098,728 A 7, 1978 Rosenblatt Primary Examiner — Dah-Wei Yuan 4,211,227 A 7, 1980 Anderson et al. Assistant Examiner — Andrew Bowman 4,480,011 A 10, 1984 Durand et al. 4,636,208 A 1, 1987 Rath (74) Attorney, Agent, or Firm — Bryan Cave LLP 4,877,864 A 10/1989 Wang et al. (57) ABSTRACT 5,002,794. A 3, 1991 Ratner et al. 5,013,649 A 5/1991 Wang et al. Processes are described herein for preparing medical devices 5, 180,375 A 1/1993 Feibus and other articles having a low-fouling Surface on a substrate 5.453,467 A 9, 1995 Bamford et al. comprising a polymeric Surface. The polymeric Surface mate 5,661,007 A 8/1997 Wozney et al. rial may possess a range of polymeric backbones and Sub 5,688,678 A 11/1997 Hewicket al. stituents while providing the articles with a highly efficient, 5,739,236 A 4, 1998 Bowers et al. biocompatible, and non-fouling Surface. The processes 5,844,016 A 12/1998 Sawhney et al. involve treating the substrate to reduce the concentration of 5,866,113 A 2f1999 Hendriks et al. chemical species on the surface of or in the substrate without 5.997,895 A 12/1999 Narotam et al. altering the bulk physical properties of the device or article, 6,054,504 A 4/2000 Dalla Riva Toma and thereafter forming a grafted polymer layer on the treated 6,150,459 A 1 1/2000 Mayes et al. Substrate Surface. 6,177,406 B1 1/2001 Wang et al. 6,200,338 B1* 3/2001 Solomon et al...... 623, 1.34 28 Claims, No Drawings US 8,574,660 B2 Page 2

(56) References Cited Keiji Fujimoto. Y.T., Hiroyuki Inoue, Yoshito Ikada, Ozone-induced graft polymerization onto polymer surface. J Polym Sci A Polym U.S. PATENT DOCUMENTS Chem 1993, 31, 1035-1043. Kildal, K.; Olafsen, K.; Stori, A., Peroxide-initiated grafting of 20090311301 A1 12/2009 Kleiner et al. acrylamide on to polyethylene Surfaces. Journal of Applied Polymer 2010.0035074 A1 2/2010 Cohen et al. Science 1992, 44 (11), 1893-1898. 2010, 0072642 A1 3/2010 Broad et al. Liu, P-S.; Chen, Q.: Liu, X.;Yuan, B.; Wu, S.-S.; Shen, J.; Lin, S.-C., 2010.009916.0 A1 4/2010 Jiang et al. Grafting of Zwitterion from Cellulose Membranes via ATRP for Improving Blood Compatibility. Biomacromolecules 2009, 10 (10), FOREIGN PATENT DOCUMENTS 2809-2816. WO 2007/024393 A2 3, 2007 Massia, S. P.; Stark, J., Immobilized RGD peptides on surface WO 2007/095393 A2 8, 2007 grafted dextran promote biospecific cell attachment. J Biomed Mater WO 2008/006911 A2 1, 2008 Res 2001, 56 (3), 390-9. WO 2008/O19381 A2 2, 2008 Michel, R.; Pasche, S.; Textor, M. Castner, D. G., Influence of PEG WO 2008.083390 A2 T 2008 Architecture on Protein Adsorption and Conformation. Langmuir WO 2009-079664 A1 6, 2009 2005, 21 (26), 12327-12332. WO 2009/085096 A2 T 2009 Sakharov AM. M. L., Skibida IP. Catalytic oxidative deformylation of polyethylene glycols with the participation of molecular oxygen. OTHER PUBLICATIONS Kinet Catal 2001, 42, 662-668. Feng, W.; Brash, J.; Zhu, S., Atom-Transfer Radical Grafting Poly Villa-Diaz, L. G.; Nandivada, H.; Ding, J.; Nogueira-de-Souza, N. merization of 2-Methacryloyloxyethyl Phosphorycholine from Sili C.; Krebsbach, P. H.; O'Shea, K. S.; Lahann, J.; Smith, G. D., Syn con Wafer Surfaces. Journal of Polymer Science Part A: Polymer thetic polymer coatings for long-term growth of human embryonic Chemistry 2004, 42, 2931-2942. stem cells. Nat Biotechnol 2010, 28 (6), 581-3. Goda, T., Konno, T.: Takai, M.; Moro, T.: Ishihara, K., Biomimetic West, S. L.; Salvage, J. P. Lobb, E.J.; Armes, S. P.; Billingham, N.C.; phosphorylcholine polymer grafting from polydimethylsiloxane Sur Lewis, A. L.; Hanlon, G. W.; Lloyd, A. W., The biocompatibility of face using photo-induced polymerization. Biomaterials 2006, 27 crosslinkable copolymer coatings containing Sulfobetaines and (30), 5151-60. phosphobetaines. Biomaterials 2004, 25 (7-8), 1195-1204. Harder, P.; Grunze, M.; Dahint, R.; Whitesides, G. M.; Laibinis, P. E., Wozney, J. M.; Rosen, V.: Celeste, A.J.; Mitsock, L. M.; Whitters, M. Molecular Conformation in Oligo(ethylene glycol)-Terminated Self J.; Kriz, R. W.; Hewick, R. M.; Wang, E. A., Novel regulators of bone formation: molecular clones and activities. Science 1988, 242 Assembled Monolayers on Gold and Silver Surfaces Determines (4885), 1528-1534. Their Ability to Resist Protein Adsorption. The Journal of Physical Yuan, Y.; Ai, F. Zang, X. Zhuang, W.; Shena, J., Lin, S., Chemistry B 1998, 102 (2), 426-436. Polyurethane vascular catheter surface grafted with Zwitterionic Haynie, S. L.; Crum, G. A.; Doele, B. A., Antimicrobial activities of Sulfobetaine monomer activated by ozone. Colloids and Surfaces B: amphiphilic peptides covalently bonded to a water-insoluble resin. Biointerfaces 35. Antimicrobial Agents and Chemotherapy 1995, 39 (2), 301-307. Yuan, J.; Chen, L., Jiang, X. Shen, J., Lin, S., Chemical graft poly Ignatova et al., Combination of Electrografting and Atom-Transfer merization of Sulfobetaine monomer on polyurethane Surface for Radical Polymerization for Making the Stainless Steel Surface Anti reduction in platelet adhesion. Colloids Surf B Biointerfaces 2004, bacterial and Protein Antiadhesive. Langmuir 2005, 22 (1), 255-262. 39(1-2), 87-94. Ishihara, K.; Iwasaki, Y.; Ebihara, S.; Shindo, Y.; Nakabayashi, N., Yuan, J.; Zhang, J.; Zhou, J.;Yuan, Y. L.; Shen, J.; Lin, S.C., Platelet Photoinduced graft polymerization of 2-methacryloyloxyethyl adhesion onto segmented polyurethane Surfaces modified by phosphorylcholine on polyethylene membrane Surface for obtaining carboxybetaine. J Biomater Sci Polym Ed 2003, 14 (12), 1339-49. blood cell adhesion resistance. Colloids Surf B Biointerfaces 2000, Yuan, Y.; Ai. F.; Zhang, X.; Shen, J.; Lin, S. Grafting Sulfobetaine 18 (3-4), 325-335. monomer onto the segmented poly(ether-urethane) Surface to Yuan, J.; Zhang, J.; Zang, X. Shen, J.; Lin, S., Improvement of blood improve hemocompatibility. J Biomaterial Sci Polym Ed 2002, 13, compatibility on cellulose membrane Surface by grafting betaines. 1081-92. Colloids and Surfaces B: Biointerfaces 30. Yuan.Y.; Zhang, J.; Ai, F.Yuan, J.; Zhou, J.; Shen, J.; Lin, S., Surface Jiang, Y.; Rongbing, B., Ling, T., Jian, S.; Sicong, L., Blood compat modification of SPEC films by ozone induced graft copolymerization ibility of polyurethane Surface grafted copolymerization with to improve hemocompatibility. Colloids and Surfaces B: Biointerfaces 2003, 29, 247-256. Sulfobetaine monomer. Colloids Surf B Biointerfaces 2004, 36 (1), Zhang, V., Cheng, Yang, Xue, Jiang. Nonfouling Behavior of 27-33. Polycarboxybetaine-Grafted Surfaces: Structural and Environmental Jin, Z.; Feng, W.; Beisser, K. Zhu, S.; Sheardown, H.; Brash, J. L., Effects—Biomacromolecules (ACS Publications). Protein-resistant polyurethane prepared by Surface-initiated atom Biomacromolecules (Web): Sep. 12, 2008, 10, 2686-92. transfer radical graft polymerization (ATRgP) of water-soluble poly Zhang, Z.; Chen, S.; Chang.Y.; Jiang, S., Surface grafted Sulfobetaine mers: effects of main chain and side chain lengths of grafts. 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(56) References Cited Salim, M. et al., Studies of electroosmotic flow and the effects of OTHER PUBLICATIONS protein adsorption in plasma-polymerized microchannel Surfaces, Electrophoresis, 2009, 30, 1877-1887. Vermette, P. et al., Tissue Engineering Intelligence Unit 6, Biomedi cal Applications of Polyurethanes, Chapter 7, 2001, 175-211. * cited by examiner US 8,574,660 B2 1. 2 ARTICLES HAVING NON-FOULING Although advances have been made in biomolecule-resis SURFACES AND PROCESSES FOR tant polymer coatings generally, various flaws can be present PREPARING THE SAME WITHOUT in the surface structure of biocompatible materials, both glo ALTERING BULK PHYSICAL PROPERTIES bally and at particular locations and regions of the Surface (whether a non-polymeric Substrate Surface, a polymeric Sub FIELD OF THE INVENTION strate or polymer Substrate coating). Such flaws may be the result of improper handling or artifacts of the manufacturing The present invention generally relates to articles of manu or polymerization process, or may be present on a substrate facture, Such as medical devices, having a non-fouling Sur Surface prior to polymer growth and/or deposition. Regard face comprising a grafted polymer layer. The Surface resists 10 less of their source, such flaws can substantially limit the the adhesion of biological material. The present invention effectiveness of conventional polymer coatings and poly also relates to processes for preparing Such articles. meric Substrate Surfaces. For instance, increased or decreased BACKGROUND OF THE INVENTION protein adsorption may result from changes in one or more of 15 the specific chemical, morphological, and physical properties Many different materials have been investigated to resist of the Substrate or Substrate coating. In general, the present non-specific protein adsorption. Chemistries utilized for this invention is directed to processes for preparing articles hav purpose include, but are not limited to: polyethers (e.g., poly ing improved surfaces that will serve as Substrates for non ethylene glycol), polysaccharides Such as dextran, hydro fouling grafted polymer layers. philic polymers such as polyvinylpyrrolidone or hydroxy ethyl-methacrylate, heparin, intramolecular Zwitterions or SUMMARY OF THE INVENTION mixed charge materials, and hydrogen bond accepting groups such as those described in U.S. Pat. No. 7,276,286. The ability Among the various aspects of the present invention is the of these materials in preventing protein adsorption varies provision of medical devices and other articles having a low greatly between the chemistries. Of these materials, only a 25 fouling Surface on a substrate comprising a polymeric Sur few resist fouling to the degree required for short-term in vivo face. The polymeric Surface material may possess a range of application. However, the few materials appropriate for short polymeric backbones and Substituents while providing the term application, when used for longer periods of time in articles with a highly efficient, biocompatible, and non-foul complex media or in vivo, exhibit significant fouling or other ing Surface. degradation, making them unsuitable for long-term applica 30 Among the various aspects of the present invention may be tions. Furthermore, surfaces coated with materials that resist noted the provision of processes for preparing an article hav in vivo degradation are often susceptible to a noticeable ing a low-fouling surface on a substrate comprising a poly decrease in fouling resistance over time. meric Surface. Also noted are the provision of articles, such as WO 2007/02493 describes grafting sulfobetaine and car medical devices, having a non-fouling Surface comprising a boxybetaine from self-assembled monolayers on gold Sub 35 grafted polymeric material. strates or from silyl groups on glass Substrates using atom One aspect of the present invention is directed to a process transfer radical polymerization (ATRP). Gold and glass are for preparing an article having a low-fouling Surface on a not appropriate substrates for many medical devices used in Substrate, the Substrate having a Surface comprising a poly vivo. Self-assembled monolayers, such as thiol-based mono meric material. The process comprises (a) treating the Sub layers, may be unstable since the thiol group is not stably 40 strate surface to improve surface characteristics without sig bound to the substrate. nificantly altering the bulk physical properties of the article U.S. Pat. No. 6,358,557 to Wang et al. describes the graft and (b) forming a grafted polymer layer on the treated Sub polymerization of Substrate surfaces, but not with a high strate Surface. In accordance with this embodiment, the density of a highly non-fouling polymeric material. Athermal treated Surface and the grafted polymer layer, in combination, initiator is used to initiate polymerization, typically at tem 45 constitute a low-fouling Surface having a fibrinogen adsorp peratures greater than 85°C. Such temperatures are generally tion of less than about 125 ng/cm in a fibrinogen binding not suitable for many medical devices. Such as thin-walled assay in which the low-fouling surface is incubated for 60 polyurethane catheters. Further, the “salt out' method minutes at 37° C. in a composition containing 70 ug/mL described is generally not suitable for grafting polymers such fibrinogen derived from human plasma and 1.4 ug/mL I-125 as Zwitterionic polymers. 50 radiolabeled fibrinogen. In one embodiment, the treated Sur Jian et al., Colloids and Surfaces B: Biointerfaces 28, 1-9 face and the grafted polymer layer, in combination, constitute (2003) describes the surface modification of segmented poly a low-fouling Surface having a fibrinogen adsorption of less (ether urethane) by grafting Sulfobetaine Zwitterionic mono than about 90 ng/cm in a fibrinogen binding assay in which mer, but not with a high density of non-fouling material. The the modified surface is incubated for 60 minutes at 37°C. in resulting materials are not sufficiently non-fouling to be use 55 a solution containing 70 ug/mL fibrinogen derived from ful in medical device applications. human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. Resistance of protein fouling in biocompatible solid Sur In another embodiment, the treated surface and the grafted faces can play an important role in a range of technological polymer layer, in combination, constitute a modified Surface disciplines, including biotechnology, medicine, food pro having a fibrinogen adsorption of less than about 70 ng/cm in cessing, and pharmaceutical applications, to name a few. It is 60 a fibrinogen binding assay in which the modified Surface is well known, for example, that protein adsorption and bacte incubated for 60 minutes at 37°C. in a solution containing 70 rial adhesion and colonization can result in infection and ug/mL fibrinogen derived from human plasma and 1.4 ug/mL Subsequent failure of implanted medical devices. Incidences I-125 radiolabeled fibrinogen. In another embodiment, the of protein adsorption and fouling can be minimized by chang treated Surface and the grafted polymer layer, in combination, ing the physical and/or chemical properties of the biomaterial 65 constitute a modified surface having a fibrinogen adsorption Surface. This may include, for example, the employment of of less than about 50 ng/cm in a fibrinogen binding assay in polymeric Substrate Surfaces that are resistant to biomaterials. which the modified surface is incubated for 60 minutes at 37° US 8,574,660 B2 3 4 C. in a solution containing 70Lug/mL fibrinogen derived from monomer or monomeric unit bearing an anion or other human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. anionic species, e.g., a group that is present in a negatively Another aspect of the present invention is directed to an charged State or in a non-charged state, but in the non-charged article of manufacture comprising a polymeric Substrate hav state is capable of becoming negatively charged, e.g., upon ing a surface and a grafted polymeric Surface on the Substrate 5 removal of an electrophile (e.g., a proton (H+), for example in Surface, the Substrate having a process aid concentration of a pH dependent manner) or a protecting group (e.g., a car less than about 0.1%, wherein the treated surface and the boxylic acid ester), or the addition of a nucleophile. In certain grafted polymer layer, in combination, constitute a low-foul instances, the group is Substantially negatively charged at an ing Surface having a fibrinogen adsorption of less than about approximately physiological pH but undergoes protonation 125 ng/cm in a fibrinogen binding assay in which the low 10 and becomes substantially neutral at a weakly acidic pH. The fouling surface is incubated for 60 minutes at 37° C. in a non-limiting examples of Such groups include carboxyl composition containing 70 ug/mL fibrinogen derived from groups, barbituric acid and derivatives thereof, Xanthine and human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. derivatives thereof, boronic acids, phosphinic acids, phos In each of the foregoing aspects and embodiments of the phonic acids, sulfinic acids, Sulfonic acids, phosphates, and invention, preferably the article (i) is other than a non-luminal 15 Sulfonamides. polyurethane rod and (ii) has a length greater than 5 centime Anionic species or Anionic moiety: unless otherwise indi ters when the article is a double lumen catheter. cated, an “Anionic species' oran “Anionic moiety' is a group, Other objects and features will be in part apparent and in residue or molecule that is present in a negatively charged or part pointed out hereinafter. non-charged State, but in the non-charged state is capable of becoming negatively charged, e.g., upon removal of an elec ABBREVIATIONS AND DEFINITIONS trophile (e.g., a proton (H+), for example in a pH dependent manner) or other protecting group (e.g., a carboxylic acid The following definitions and methods are provided to ester), or the addition of a nucleophile. In certain instances, better define the present invention and to guide those of ordi the group, residue or molecule is substantially negatively nary skill in the art in the practice of the present invention. 25 charged at an approximately physiological pH but undergoes Unless otherwise noted, terms are to be understood according protonation and becomes Substantially neutral at a weakly to conventional usage by those of ordinary skill in the relevant acidic pH. art. Antibiofilm activity: unless otherwise indicated, “antibio When introducing elements of the present invention or the film activity” may be quantified, for example, using a stan preferred embodiment(s) thereof, the articles “a,” “an,” “the 30 dard continuous flow assay. In one such assay, samples may and “said are intended to mean that there are one or more of be pre-incubated with 50% fetal bovine serum for 18-20 the elements. The terms "comprising,” “including” and “hav hours at 120 RPM at 37°C. Following preincubation, samples ing are intended to be inclusive and mean that there may be are then exposed to a subculture of bacteria via a modified additional elements other than the listed elements. CDC (mCDC) to make a bacterial suspension of 10°Cfu/mL Aliphatic: unless otherwise indicated, “aliphatic' or “ali 35 in 1xRBS. The reactor is run in batch mode for 2 hours at 37° phatic group” means an optionally Substituted, non-aromatic C. with agitation. Thereafter, the samples are transferred to a hydrocarbon moiety. The moiety may be, for example, linear, fresh reactor a suitable growth media for where flow of the branched, or cyclic (e.g., mono or polycyclic Such as fused, sterile media (8 mL/min) runs 20-23 hours with agitation. In bridging, or spiro-fused polycyclic), or a combination one preferred embodiment, the bacterial strain is Staphylo thereof. Unless otherwise specified, aliphatic groups contain 40 coccus epidermidis (S. epidermidis, ATCC 35984), and the 1-20 carbon atoms. growth media used is 1:10 Tryptic soy broth (TSB)+0.25 Alkyl: unless otherwise indicated, the alkyl groups wt % glucose. In an alternate preferred embodiment, the described herein are preferably lower alkyl containing from bacterial strain is Escherichia coli (E. coli, ATCC 25922) and one to eight carbon atoms in the principal chain and up to 20 the growth media is M63 media supplemented with 1 mM carbon atoms. They may be linear, branched or cyclic and 45 MgSO, 0.2% glucose, and 0.5% casamino acids. After incu include methyl, ethyl, propyl, butyl, hexyl and the like. bation, the samples are rinsed five times in 100 mL of 1xPBS Amino: unless otherwise indicated, the term "amino” as to remove bacteria not tightly attached. Then, accumulated used herein alone or as part of another group denotes the bacteria on materials are macroscopically rated for biofilm moiety —NR'R' wherein R', and R are independently Surface coverage and are removed by Sonication in a new hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocy 50 solution of PBS and the total number of bacterial cells quan clo. tified through dilution plating. Preferably at least a 1, 2, 3 or Ammonium: unless otherwise indicated, the term "ammo 4 log reduction in bacterial count is found on the article with nium' as used herein alone or as part of another group denotes the non-fouling polymer layer relative to a reference Sub the moiety - N'R'R'R' wherein R, R and Rare indepen strate, that is, the same or an otherwise functionally equiva dently hydrogen, hydrocarbyl, substituted hydrocarbyl or 55 lent Substrate lacking the non-fouling polymer layer. An heterocyclo. article that has a 1 log reduction in adhered bacteria relative to Amide or Amido: unless otherwise indicated, the "amide' a reference substrate is said to have antibiofilm activity of 1 or "amido’ moieties represent a group of the formula log. An article that has a 2 log reduction in adhered bacteria —CONR'R' wherein R' and Rare as defined in connection relative to a reference substrate is said to have antibiofilm with the term “amino.” “Substituted amide.” for example, 60 activity of 2 log, and so forth. refers to a group of the formula—CONR'R' wherein at least Antimicrobial: unless otherwise indicated, “antimicro one of R' and R are other than hydrogen. “Unsubstituted bial refers to molecules and/or compositions that kill (i.e., amido.” for example, refers to a group of the formula microbicidal), inhibit the growth of (i.e., microbistatic), and/ —CONR'R'', wherein R' and Rare each hydrogen. or prevent fouling by, microorganisms including bacteria, Anionic Monomer, Anionic Monomeric Unit or Anionic 65 yeast, fungi, mycoplasma, viruses or virus infected cells, Repeat Unit: unless otherwise indicated, an "anionic mono and/or protozoa. Antimicrobial activity with respect to bac mer.” "anionic monomeric unit' or “anionic repeat unit is a teria may be quantified, for example, using a standard assay. US 8,574,660 B2 5 6 In one such assay, samples may be pre-incubated with 50% example, a bioactive agent can be an amino acid, antimicro fetal bovine serum for 18-20 hours at 120 RPM at 37° C. bial peptide, immunoglobulin, an activating, signaling or sig Following pre-incubation, samples are placed in Staphyllo nal amplifying molecule, including, but not limited to, a pro coccus aureus (S. aureus, ATCC 25923) which has been tein kinase, a cytokine, a chemokine, an interferon, tumor diluted from an overnight culture to a planktonic concentra necrosis factor, growth factor, growth factor inhibitor, hor tion of 1-3x10 CFU/mL in 1% tryptone soy broth (TSB) mone, enzyme, receptor-targeting ligand, gene silencing diluted in 1xRBS or other suitable media. Samples are incu agent, ambisense, antisense, an RNA, a living cell, cohesin, bated with bacteria for 24-26 hrs with agitation (120 rpm) at laminin, fibronectin, fibrinogen, osteocalcin, osteopontin, or 37°C. The concentration of TSB or other media can vary with osteoprotegerin. Bioactive agents can be aptamers, proteins, the organism being used. After incubation, the samples are 10 glycoproteins, peptides, oligliopeptides, polypeptides, poly placed in 3 mL PBS for 5 min at 240 RPM at 37°C. to remove mers, inorganic compounds, organometallic compounds, bacteria not tightly attached to the material. Then, accumu organic compounds or any synthetic or natural, chemical or lated bacteria on materials are removed by Sonication in a new biological compound. solution of PBS and the total number of bacterial cells are Biocompatibility: unless otherwise indicated, “biocompat quantified through dilution plating. Preferably at least a 1, 2, 15 ibility” is the ability of a material to perform with an appro 3 or 4 log reduction in bacterial count occurs relative to priate host response in a specific situation. This can be evalu colonization on a reference Substrate, that is, the same or an ated using International Standard ISO 10993. Biocompatible otherwise functionally equivalent Substrate lacking the non compositions described herein are preferably substantially fouling polymer layer. A surface that has a lower bacterial non-toxic. count on it than the reference substrate may be said to reduce Biological fluids: unless otherwise indicated, “biological microbial colonization. fluids' are fluids produced by organisms containing proteins Antimicrobial peptide (AmP): unless otherwise indicated, and/or cells, as well as fluids and excretions from microbes. “antimicrobial peptide' (or “AmP) refers to oligopeptides, This includes, but is not limited to, blood, saliva, urine, cere polypeptides, or peptidomimetics that kill (i.e., are microbi broSpinal fluid, tears, semen, lymph, ascites, sputum, bone cidal) or inhibit the growth of (i.e., are microbistatic) micro 25 marrow, synovial fluid, aqueous humor, cerumen, organisms including bacteria, yeast, fungi, mycoplasma, broncheoalveolar lavage fluid, prostatic fluid, cowper's fluid viruses or virus infected cells, and/or protozoa. or pre-ejaculatory fluid, Sweat, fecal matter, cyst fluid, pleural Anti-thrombogenic: unless otherwise indicated, “anti and peritoneal fluid, chyme, chyle, bile, intestinal fluid, pus, thrombogenic’ refers to the ability of a composition to resist sebum, Vomit, mucosal Secretion, stool water, pancreatic thrombus formation. Anti-thrombogenic activity can be 30 juice, lavage fluids from sinus cavities, bronchopulmonary evaluated using an ex-Vivo flow loop model of thrombosis. aspirates, or any derivative thereof (e.g., serum, plasma). Briefly, up to 10 liters of fresh blood are collected from a Block Copolymer: unless otherwise indicated, a “block single animal (bovine). This blood is heparinized to prevent copolymer comprises two or more homopolymer or copoly coagulation, filtered to remove particulates, and autologous mer subunits linked by covalent bonds. Block copolymers radio-labeled platelets are added. Within eight hours after 35 with two or three distinct blocks are called diblock copoly blood harvesting, coated and uncoated articles are placed in a mers and triblock copolymers, respectively. A schematic gen flow loop circuit, which pumps blood from a bath over the eralization of a diblock copolymer is represented by the for article and thenbackinto the bath. A second internal flow loop mula A,B,C...... -IX,Y,Z. . . . . wherein each letter circuit can be established for an article containing alumen by stands for a constitutional or monomeric unit, and wherein connecting the two ports of the article through a 2nd peristal 40 each Subscript to a constitutional unit represents the mole tic pump. The size of tubing into which the article is placed fraction of that unit in the particular block, the three dots and speed of the blood flow may be adjusted based on the size indicate that there may be more (there may also be fewer) of the article being tested. constitutional units in each block and m and n indicate the Aryl: unless otherwise indicated, the term “aryl' or “aryl molecular weight of each block in the diblock copolymer. As group' refers to optionally Substituted monocyclic, bicyclic, 45 Suggested by the schematic, in some instances, the number and tricyclic ring systems having a total of five to fourteen and the nature of each constitutional unit is separately con ring members, wherein at least one ring in the system is trolled for each block. The schematic is not meant and should aromatic and wherein each ring in the system contains three to not be construed to infer any relationship whatsoever between seven ring members. The terms “aryl or “ar as used herein the number of constitutional units or the number of different alone or as part of another group denote optionally Substituted 50 types of constitutional units in each of the blocks. Nor is the homocyclic aromatic groups, preferably monocyclic orbicy schematic meant to describe any particular number or clic groups containing from 6 to 12 carbons in the ring por arrangement of the constitutional units within a particular tion, such as phenyl, biphenyl, naphthyl, Substituted phenyl, block. In each block the constitutional units may be disposed substituted biphenyl or substituted naphthyl. Phenyl and sub in a purely random, an alternating random, a regular alternat stituted phenyl are the more preferred aryl. 55 ing, a regular block or a random block configuration unless Attached: unless otherwise indicated, two moieties or expressly stated to be otherwise. A purely random configura compounds are “attached if they are held together by any tion, for example, may have the non-limiting form: X-X-Y- interaction including, by way of example, one or more cova Z-X-Y-Y-Z-Y-Z-Z-Z . . . . A non-limiting, exemplary alter lent bonds, one or more non-covalent interactions (e.g., nating random configuration may have the non-limiting form: hydrogen bonds, ionic bonds, static forces, van der Waals 60 X-Y-X-Z-Y-X-Y-Z-Y-X-Z . . . . and an exemplary regular interactions, combinations thereof, or the like), or a combi alternating configuration may have the non-limiting form: nation thereof. X-Y-Z-X-Y-Z-X-Y-Z . . . . An exemplary regular block con Bioactive Agent/Active Agent/Biomolecule: unless other figuration may have the following non-limiting configura wise indicated, “bioactive agent' or “active agent” or “bio tion: . . . X-X-X-Y-Y-Y-Z-Z-Z-X-X-X. . . , while an exem molecule used herein synonymously, refers to any organic 65 plary random block configuration may have the non-limiting orinorganic therapeutic, prophylactic or diagnostic agent that configuration: ... X-X-X-Z-Z-X-X-Y-Y-Y-Y-Z-Z-Z-X-X-Z- actively or passively influences a biological system. For Z-Z-. . . . In a gradient polymer, the content of one or more US 8,574,660 B2 7 8 monomeric units increases or decreases in a gradient manner includes any increase in thickness to the Substrate or change from the a end of the polymer to the () end. In none of the in Surface chemical composition of the Substrate. preceding generic examples is the particular juxtaposition of Complex Media: unless otherwise indicated, “complex individual constitutional units or blocks or the number of media' refers to biological fluids or Solutions containing pro constitutional units in a block or the number of blocks meant teins or digests of biological materials. Examples include, but nor should they be construed as in any manner bearing on or are not limited to, cation-adjusted Mueller Hinton broth, tryp limiting the actual structure of block copolymers forming a tic soy broth, brain heart infusion, or any number of complex micelle described herein. As used herein, the brackets enclos media, as well as any biological fluid. ing the constitutional units are not meant and are not to be Copolymer: unless otherwise indicated, “copolymer construed to mean that the constitutional units themselves 10 refers to a polymer derived from two, three or more mono form blocks. That is, the constitutional units within the square meric species and includes alternating copolymers, periodic brackets may combine in any manner with the other consti copolymers, random copolymers, statistical copolymers and tutional units within the block, i.e., purely random, alternat block copolymers. ing random, regular alternating, regular block or random Cysteine: unless otherwise indicated, "cysteine' refers to block configurations. The block copolymers described herein 15 the amino acid cysteine or a synthetic analogue thereof, are, optionally, alternate, gradient or random block copoly wherein the analogue contains a free Sulfhydryl group. mers. In some embodiments, the block copolymers are den Degradation Products: unless otherwise indicated, “degra drimer, star or graft copolymers. dation products are atoms, radicals, cations, anions, or mol Branched: unless otherwise indicated, “branched’ refers to ecules other than water formed as the result of hydrolytic, a polymer structure in which a polymer chain divides into two oxidative, enzymatic, or other chemical processes. or more polymer chains. Dry Thickness: unless otherwise indicated, “Dry Thick Brushes/Polymer Brushes: unless otherwise indicated, ness, as used herein in connection with a polymer layer, shall “brushes' or “polymer brushes are used herein synony mean the thickness of the polymer layer using a scanning mously and refer to polymerchains that are bound to a Surface electron microscope (SEM). To measure dry thickness, the generally through a single point of attachment using graft 25 sample is freeze fractured for imaging by being Submerged in from techniques. The polymers can be end-grafted (attached liquid nitrogen then cracked with an ultra microtome blade. via a terminal group) or attached via a side chain or a position For metal substrates, they may be scored with a notch before in the polymer chain other than a terminal position. The a primer or the non-fouling polymer is applied to make freeze polymers can be linear or branched. For example, the polymer fracturing easier. The freeze fracturing should break the chains described herein can contain a plurality of side chains 30 article at a plane approximately orthogonal to the polymer that contain Zwitterionic groups. The side chains can consist modified surface in order to measure the thickness of the of a single non-fouling moiety or monomer and/or a non polymer layer normal to the substrate. The samples are sput fouling oligomer (e.g., 2-10 monomeric residues) or polymer ter coated in gold for 90 seconds using a sputter coater and (e.g., >10 monomeric residues). then imaged underhigh vacuum at 5 kV using an SE2 detector Carboxyammonium: unless otherwise indicated, a "car 35 under a Field Emission Scanning Electron Microscope boxyammonium moiety is a Zwitterionic moiety comprising (SEM). Exemplary microtome blades include the Leica carboxylate and ammonium functionality and includes, for Ultracut UCT Ultramicrotome, exemplary sputter coaters example, carboxyammonium monomers, carboxyammo include the Cressington 208HR, exemplary SEMs include the nium oligomers, carboxyammonium polymers, carboxyam Supraš5VP FESEM, Zeiss. Dry thickness may be approxi monium repeat units, and other carboxyammonium-contain 40 mated by analyzing intensity of chemical signals in the ing materials. Carboxybetaine monomers, oligomers, grafted polymer, for instance, through the use of ATR-FTIR. polymers, repeat units and other carboxybetaine materials are Fibrinogen Adsorption Assay: unless otherwise indicated, exemplary carboxyammonium moieties. a “Fibrinogen Adsorption Assay” is an assay used to assess Cationic Monomer, Cationic Monomeric Unit or Cationic the capacity of a Surface for fibrinogen. In the assay, test Repeat Unit: unless otherwise indicated, a "cationic mono 45 samples are placed in a suitable sized container, which may be mer.” “cationic monomeric unit' or “cationic repeat unit is a a 96-well manifold, microcentrifuge tube, or other container. monomer or a monomeric or repeat unit (the terms "mono The Volumes in the following are appropriate for a deep meric unit' and “repeat unit' being used interchangeably) 96-well plate, but may be scaled to properly cover a device bearing a cation or other cationic species, e.g., a moiety being tested. The samples are sterilized with 70% ethanol capable of having a positive charge upon addition of an elec 50 Solution for thirty minutes and the test groups run with an in trophile (e.g., a proton (H+) or an alkyl cation, for example in per run of 3-4. The sample container is blocked with 20 a pH dependent manner) or removal of a protecting group or mg/mL Bovine Serum Albumin (BSA) in 1xEBS for 1 hour at a nucleophile). 4°C., followed by three rinses with 1xPBS before samples Cationic species or Cationic Moiety: unless otherwise indi are added. The sample is exposed to a solution containing 70 cated, a “Cationic species” or a "Cationic Moiety” is a group, 55 ug/mL unlabeled human fibrinogen, 1.4 g/mL I-125 radio residue or molecule that is present in a positively charged or labeled human fibrinogen, 35-55 ug/mL BSA in water, non-charged State, but in the non charged State is capable of optionally tri-sodium citrate, and optionally sodium chloride. becoming positively charged, e.g., upon addition of an elec The BSA is a common agent co-lyophilized with the radio trophile (e.g., a proton (H+), for example in a pH dependent labeled fibrinogen. Optionally, the BSA and radiolabeled manner) or removal of a protecting group or a nucleophile. In 60 fibrinogen may have been dissolved from a lyophilized form certain instances, the group, residue or molecule is perma that contains tri-sodium citrate and Sodium chloride. The nently charged, e.g., comprises a quaternary nitrogen atom. samples are incubated for one hour at 37° C. on an orbital Coating: unless otherwise indicated, "coating refers to shaker at 150 RPM. The test solution is then removed and four any temporary, semi-permanent or permanent layer, or layers, 1-minute rinses with a 10 mM NaI and one 1-minute rinse treating or covering a surface. The coating may be a chemical 65 with 1xPBS is performed. The samples are loaded into a modification of the underlying substrate or may involve the gamma counter. The counter measures the radioactivity in addition of new materials to the surface of the substrate. It I-125 counts per minute for each sample and this data is used US 8,574,660 B2 10 to calculate the absolute fibrinogen adsorption or a percent carrying the polymer layer. R., refers to arithmetical mean reduction of the non-fouling polymer layer samples Versus a roughness of a surface, which measures the vertical devia reference Substrate, that is, the same or an otherwise func tions of a real surface from its ideal form. tionally equivalent Substrate lacking the non-fouling polymer Graft: unless otherwise indicated, the term 'graft, as used layer. The percent reduction is equal to: (1-non-fouling 5 herein in connection with a polymer, means the modification sample CPM/Average CPM of the reference substrate) of the surface of a material with a polymer by a 'graft-from'. * 100%. 'graft-through', or a 'graft-to” approach, or a combination Global Average Dry Thickness: unless otherwise indi thereof to form a grafted polymer. cated, “Global Average Dry Thickness.” as used herein in Graft-from method: unless otherwise indicated, the term connection with a polymer layer, shall mean the mean calcu 10 'graft-from, as used herein in connection with a method for lated by averaging the Local Average Dry Thickness of at the modification of a material with a polymer, shall mean the least 3, and preferably at least 5, representative locations in situ polymerization and growth of a polymer at the Surface spaced approximately evenly across the portion of the article of, or within a material. carrying the polymer layer. For example, if a polymer layer is Graft-from polymer: unless otherwise indicated, the term applied to the indwelling portion of a catheter, the represen 15 'graft-from polymer, as used herein, shall mean a polymer tative locations are approximately evenly spaced across the formed by a graft-from method. indwelling portion of the catheter. It is preferred to measure Graft-through method: unless otherwise indicated, the the thickness at representative points across the longest term 'graft-through as used herein in connection with a dimension of the portion of the article that is covered with the method for the modification of a material with a polymer, polymer layer. The standard deviation of the Global Average shall mean the in situ polymerization of monomers in the Dry Thickness is found by calculating the standard deviation neighborhood of the material that may polymerize through of the Local Average Dry Thickness across at least 5, and functional groups presented from the material Surface. For preferably at least 10, representative locations spaced example, the material may have vinyl groups presented from approximately evenly across the portion of the article carry the Surface through which polymerization occurs. ing the polymer layer. 25 Graft-through polymer: unless otherwise indicated, the Global Average Humidified Thickness: unless otherwise term 'graft-through polymer, as used herein, shall mean a indicated, “Global Average Humidified Thickness, as used polymer formed by a graft-through method. herein in connection with a polymer layer, shall mean the Graft-to method: unless otherwise indicated, the term mean calculated by averaging the Local Average Humidified 'graft-to.” as used herein in connection with a method for the Thickness of at least 3, and preferably at least 5, representa 30 modification of a material with a polymer shall mean the tive locations spaced approximately evenly across the portion modification of the surface of a material with a presynthe of the article carrying the polymer layer. For example, if a sized polymer polymer layer is applied to the indwelling portion of a cath Graft-to polymer: unless otherwise indicated, the term eter, the representative locations are approximately evenly 'graft-topolymer, as used herein, shall mean a grafted poly spaced across the indwelling portion of the catheter. It is 35 merformed by a graft-to method. preferred to measure the thickness at representative points Heteroalkyl: unless otherwise indicated, the term “het across the longest dimension of the portion of the article that eroalkyl means an alkyl group wherein at least one of the is covered with the polymer layer. The standard deviation of backbone carbon atoms is replaced with a heteroatom. the Global Average Humidified Thickness is found by calcu Heteroaryl: unless otherwise indicated, the term “het lating the standard deviation of the Local Average Humidified 40 eroaryl' means an aryl group wherein at least one of the ring Thickness across at least 5, and preferably at least 10, repre members is a heteroatom, and preferably 5 or 6 atoms in each sentative locations spaced approximately evenly across the ring. The heteroaromatic group preferably has 1 or 2 oxygen portion of the article carrying the polymer layer. atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogenatoms in the Global Average R. Surface Roughness: unless otherwise ring, and may be bonded to the remainder of the molecule indicated, “Global Average R. Surface Roughness, as used 45 through a carbon or heteroatom. Exemplary heteroaromatics herein in connection with a polymer layer, shall mean the include furyl, thienyl, pyridyl, oxazolyl pyrrolyl, indolyl, mean calculated by averaging the R. Surface roughness of at quinolinyl, or isoquinolinyl and the like. Exemplary Substitu least 5, and preferably at least 10, representative locations ents include one or more of the following groups: hydrocar spaced approximately evenly across the portion of the article byl, substituted hydrocarbyl, keto (i.e., =O), hydroxy, pro carrying the polymer layer. For example, if a polymer layer is 50 tected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, applied to the indwelling portion of a catheter, the represen aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, tative locations are approximately evenly spaced across the acetals, esters and ethers. indwelling portion of the catheter. It is preferred to measure Heteroatom: unless otherwise indicated, the term "heteroa the thickness at representative points across the longest tom' means an atom other than hydrogen or carbon, such as dimension of the portion of the article that is covered with the 55 a chlorine, iodine, bromine, oxygen, Sulfur, nitrogen, phos polymer layer. The standard deviation of the Global Average phorus, boron, arsenic, selenium or silicon atom. R. Surface Roughness is found by calculating the standard Heterocyclo: unless otherwise indicated, the terms “het deviation of the Local Average R. Surface Roughness erocyclo' and "heterocyclic” as used herein alone or as part of across at least 5, and preferably at least 10, representative another group denote optionally Substituted, fully saturated locations spaced approximately evenly across the portion of 60 or unsaturated, monocyclic or bicyclic, aromatic or nonaro the article carrying the polymer layer. matic groups having at least one heteroatom in at least one Global Average R. Surface Roughness: unless otherwise ring, and preferably 5 or 6 atoms in each ring. The heterocyclo indicated, “Global Average R. Surface Roughness” as used group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, herein in connection with a polymer layer shall mean the and/or 1 to 4 nitrogenatoms in the ring, and may be bonded to mean calculated by averaging the R. Surface roughness of at 65 the remainder of the molecule through a carbon or heteroa least 5, and preferably at least 10, representative locations tom. Exemplary heterocyclo include heteroaromatics such as spaced approximately evenly across the portion of the article furyl, thienyl, pyridyl, oxazolyl pyrrolyl, indolyl, quinolinyl, US 8,574,660 B2 11 12 or isoquinolinyl and the like. Exemplary Substituents include article that spans approximately 10-40 micrometers. The one or more of the following groups: hydrocarbyl, Substituted standard deviation of the Local Average Dry Thickness is hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, determined by calculating the standard deviation of the Dry alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, Thickness across at least 5, and more preferably at least 10, nitro, cyano, thiol, ketals, acetals, esters and ethers. representative locations spaced approximately evenly across Heterohydrocarbyl: unless otherwise indicated, the term a cross section of article that spans approximately 10-40 "heterohydrocarbyl means a hydrocarbyl group wherein at micrometers. least one of the chain carbon atoms is replaced with a het Local Average Humidified Thickness: unless otherwise erOatOm. indicated, “Local Average Humidified Thickness” is the Humidified Thickness: unless otherwise indicated, 10 mean Humidified Thickness calculated by averaging "humidified thickness, as used herein in connection with a Humidified Thickness measurements of at least 3, and pref polymer layer, shall mean the thickness of the polymer layer erably at least 5, representative locations spaced approxi using an environmental scanning electron microscope mately evenly across a cross section of the article that spans (ESEM and approximately 26% relative humidity). To mea approximately 10-40 micrometers. The standard deviation of sure humidified thickness, the sample is freeze fractured for 15 the Local Average Humidified Thickness may be determined imaging by being Submerged in liquid nitrogen then cracked by calculating the standard deviation of the Humidified with an ultra microtome blade. The freeze fracturing should Thickness across of at least 5, and preferably at least 10, break the article at a plane orthogonal to the polymer modified representative locations spaced approximately evenly across surface in order to measure the thickness of the polymer layer a cross section of article that spans approximately 10-40 normal to the Substrate. After fracturing, the samples are micrometers. soaked in water for at least one hour and then Submerged in Membrane-Targeting Antimicrobial Agent: unless other liquid nitrogen and fixed to a cold stage at -8°C. to -12°C. wise indicated, “membrane-targeting antimicrobial agent' The samples are then imaged using a VPSE detector at the refers to any antimicrobial agent that retains its bactericidal or highest resolvable humidity (approximately 26% or 81 Pa) bacteriostatic activity when immobilized on a substrate and under a Scanning Electron Microscope (SEM) with an Envi 25 can therefore be used to create an immobilized antimicrobial ronmental Scanning Electron Microscope (E-SEM). Exem Surface. In one embodiment, the membrane-targeting antimi plary microtome blades include the Leica Ultracut UCT crobial agent is an antimicrobial peptide, and in another Ultramicrotome, exemplary SEMs include the Supra55VP embodiment it is a quaternary ammonium compound or poly FESEM, Zeiss, and exemplary E-SEMs include the Zeiss C. EVO 55. 30 Non-Degradable: unless otherwise indicated, “non-de Hydrocarbon or Hydrocarbyl: unless otherwise indicated, gradable' refers to material compositions that do not react the terms “hydrocarbon” and “hydrocarbyl” as used herein significantly within a biological environment either hydro describe organic compounds or radicals consisting exclu lytically, reductively, enzymatically or oxidatively to cleave sively of the elements carbon and hydrogen. These moieties into Smaller or simpler components. include alkyl, alkenyl, alkynyl, and aryl moieties. These moi 35 Non-Fouling Composition/Non-Fouling Material/Non eties also include alkyl, alkenyl, alkynyl, and aryl moieties Fouling Polymer/Non-Fouling Polymer Layer: unless other Substituted with otheraliphatic or cyclic hydrocarbon groups, wise indicated, a “non-fouling composition' or “non-fouling Such as alkaryl, alkenaryl and alkynary1. Unless otherwise material' or “non-fouling polymer or “Non-fouling polymer indicated, these moieties preferably comprise 1 to 20 carbon layer” as used interchangeably herein, is a composition that atOms 40 provides or increases the protein resistance of a Surface of an Hydrophilic: unless otherwise indicated, “hydrophilic' article to which the composition is attached. For example, refers to solvents, molecules, compounds, polymers, mix when attached to a Substrate such a composition may resist tures, materials, or functional groups which have an affinity the adhesion of proteins, including blood proteins, plasma, for water. Such materials typically include one or more cells, tissue and/or microbes to the substrate relative to the hydrophilic functional groups, such as hydroxyl, Zwitteri 45 amount of adhesion to a reference Substrate, that is, the same onic, carboxy, amino, amide, phosphate, Sulfonyl, hydrogen or an otherwise functionally equivalent Substrate lacking the bond forming, and/or ether groups. composition. Preferably, a substrate surface will be substan Hydrophobic: unless otherwise indicated, “hydrophobic' tially non-fouling in the presence of human blood. Preferably refers to solvents, molecules, compounds, polymers, mix the amount of adhesion will be decreased 20%, 30%, 40%, tures, materials, or functional groups that are repelled by 50 50%. 60%, 70%, 80%, or more, for example, 85%, 90%, water. Such materials typically contain non-polar functional 95%, 99%, 99.5%, 99.9%, or more, relative to the reference groups. substrate. One particularly preferred measure of the non Immobilization/Immobilized: unless otherwise indicated, fouling character or protein resistance of a surface is the “immobilization' or “immobilized’ refers to a material or amount of fibrinogen adsorbed in a Fibrinogen Adsorption bioactive agent that is covalently or non-covalently attached 55 Assay as described herein. Preferably, the amount of directly or indirectly to a substrate. “Co-immobilization' adsorbed fibrinogen using the Fibrinogen Adsorption Assay refers to immobilization of two or more agents. described herein is <125 ng/cm, <90 ng/cm, <70 ng/cm, Initiator: unless otherwise indicated, “initiator” refers to a <50 ng/cm, <30 ng/cm, <20 ng/cm, <15 ng/cm, <12 Substance or a combination of Substances that can produce a ng/cm, <10 ng/cm, <8 ng/cm, <6 ng/cm, <4 ng/cm, <2 radical or other species under relatively mild conditions and 60 ng/cm, <1 ng/cm, <0.5 ng/cm, or <0.25 ng/cm. promote polymerization reactions. For example, redox pairs Non-Naturally Occurring Amino Acid: unless otherwise as described elsewhere herein may be an initiator. indicated, “non-naturally occurring amino acid refers to any Local Average Dry Thickness: unless otherwise indicated, amino acid that is not found in nature. Non-natural amino “Local Average Dry Thickness” is the mean Dry Thickness acids include any D-amino acids, amino acids with side calculated by averaging Dry Thickness measurements of at 65 chains that are not found in nature, and peptidomimetics. least 3, and preferably at least 5, representative locations Examples of peptidomimetics include, but are not limited to, spaced approximately evenly across a cross section of the b-peptides, g-peptides, and d-peptides; oligomers having US 8,574,660 B2 13 14 backbones which can adopt helical or sheet conformations, Standard silicon cantilever (Olympus AC160TS, spring con Such as compounds having backbones utilizing bipyridine stant 42 N/m) is employed for the measurement with an segments, compounds having backbones utilizing Solvopho AC/Tapping mode. The R. Surface roughness is calculated by bic interactions, compounds having backbones utilizing side the software (IGOR Pro) attached with the AFM machine. chain interactions, compounds having backbones utilizing Alternatively, the roughness can be measured using a stylus hydrogen bonding interactions, and compounds having back profilometer. For example, the sample Surface roughness can bones utilizing metal coordination. All of the amino acids in be measured by a Tencor P-16+ profilometer with a 60 degree, the human body, except glycine, exist as the D and L forms. 2 um diamond tip stylus. Preferably, an 800 um scan length is Nearly all of the amino acids occurring in nature are the chosen with 20 Lum/second scan rate, 50 Hz scan frequency, 10 and 2 ug loading force. At least three different sites are mea L-forms. D-forms of the amino acids are not found in the Sured for the same sample, and the Surface roughness is aver proteins of higher organisms, but are present in some lower aged from at least three samples. Alternatively, the R. Surface forms of life, such as in the cell walls of bacteria. They also roughness can be measured preferably by non-contact meth are found in some antibiotics, among them, streptomycin, ods, including using optical profilometers. For example, the actinomycin, bacitracin, and tetracycline. These antibiotics 15 sample surface roughness is measured by a optical profilo can kill bacterial cells by interfering with the formation of meter (Zeta Z20 or Olympus Lext OLS4000). Preferably a proteins necessary for viability and reproduction. Non-natu 3-D image is taken by the optical profilometer under a 50x rally occurring amino acids also include residues, which have objective lens, and the sample's Surface roughness is then side chains that resist non-specific protein adsorption, which measured along at least three different lines cross the image. may be designed to enhance the presentation of the antimi At least three different spots are measured and the surface crobial peptide in biological fluids, and/or polymerizable side roughness is averaged from at least three samples. In a pre chains, which enable the synthesis of polymer brushes using ferred example an Olympus LEXT OLS4000 3D Laser Mea the non-natural amino acid residues within the peptides as Suring Microscope is employed for roughness measurement monomeric units. and 3D imaging. A LEXT microscope utilizes low wave Polymer: unless otherwise indicated, “polymer includes 25 length optical technology with a 408 nm laser in combination natural and synthetic, homopolymers and copolymers com with confocal scanning. Samples to be measured are mounted prising multiple repeat units and, unless otherwise indicated, on a glass slide by double-sided tape. Digital 3-D images are may be linear, branched, or dendritic. Examples of copoly taken with the Olympus LEXT OLS4000 laser confocal mers include, but are not limited to, random copolymers and microscope (“LEXT) under an Olympus MPLAPON 50x block copolymers, Smart polymers, temperature responsive 30 objective lens. The digital images taken in this way have a (e.g., NIPAM), and pH responsive (e.g., pyridyl based) poly 256x256 um field area. The Z-direction repeatability for this CS. LEXT machine has been certified by Olympus to be less than Polypeptide/Peptide/Oligopeptide: unless otherwise indi 0.012 Lum. Preferably, to measure the roughness, at least three cated, “polypeptide.” “peptide.” and "oligopeptide' encom images are taken from each sample and the R roughness is pass organic compounds composed of amino acids, whether 35 calculated by using a 9 um cut-off length. natural, synthetic or mixtures thereof, that are linked together R. Surface Roughness: unless otherwise indicated, “R, chemically by peptide bonds. Peptides typically contain 3 or Surface Roughness' refers to root mean squared roughness of more amino acids, preferably more than 9 and less than 150, a Surface, which measures the Vertical deviations of a real more preferably less than 100, and most preferably between 9 surface from its ideal form. The roughness refers to surface and 51 amino acids. The polypeptides can be “exogenous.” or 40 micro-roughness which may be different than measurements "heterologous, i.e., production of peptides within an organ of large scale surface variations. Preferably, this may be mea ism or cell that are not native to that organism or cell. Such as sured using atomic force microscopy (MFP-3D, Asylum) human polypeptide produced by a bacterial cell. Exogenous across a field of approximately 1-30 um by 1-30 um, prefer also refers to Substances that are not native to the cells and are ably 20 um by 20 Lum. The sample is washed with purified added to the cells, as compared to endogenous materials, 45 water to remove surface salts and then air dried. Standard which are produced by the cells. The peptide bond involves a silicon cantilever (Olympus AC160TS, spring constant 42 single covalent link between the carboxyl group (oxygen N/m) is employed for the measurement with an AC/Tapping bearing carbon) of one amino acid and the amino nitrogen of mode. The R. Surface roughness is calculated by the Soft a second amino acid. Small peptides with fewer than about ten ware (IGOR Pro) attached with the AFM machine. Alterna constituent amino acids are typically called oligopeptides, 50 tively the roughness can be measured using a stylus profilo and peptides with more than ten amino acids are termed meter. For example, the sample Surface roughness can be polypeptides. Compounds with molecular weights of more measured by a Tencor P-16+ profilometer with a 60 degree, 2 than 10,000 Daltons (50-100 amino acids) are usually termed um diamond tip stylus. Preferably, an 800 um Scan length is proteins. chosen with 20 Lum/second scan rate, 50 Hz scan frequency, Quaternary Nitrogen: unless otherwise indicated, “quater 55 and 2 ug loading force. At least three different sites are mea nary nitrogen as used herein, refers to a nitrogenatom that is Sured for the same sample, and the Surface roughness is aver a member of a quaternary ammonium cation. aged from at least three samples. Alternatively, the R. Sur R. Surface Roughness: unless otherwise indicated, “R face roughness can be measured preferably by non-contact Surface Roughness' refers to arithmetical mean roughness of methods, including using optical profilometers. For example, a Surface, which measures the Vertical deviations of a real 60 the sample surface roughness is measured by a optical pro surface from its ideal form. The roughness refers to surface filometer (Zeta Z20 or Olympus Lext OLS4000). Preferably micro-roughness which may be different than measurements a 3-D image is taken by the optical profilometer under a 50x of large scale surface variations. Preferably, this may be mea objective lens, and the sample's Surface roughness is then sured using atomic force microscopy (AFM) (MFP-3D, Asy measured along at least three different lines cross the image. lum) across a field of approximately 1-30 um by 1-30 um, 65 At least three different spots are measured and the surface preferably 20 um by 20 lum. The sample is washed with roughness is averaged from at least three samples. In a pre purified water to remove surface salts and then air dried. ferred example an Olympus LEXT OLS4000 3D Laser Mea US 8,574,660 B2 15 16 Suring Microscope is employed for roughness measurements Stable: unless otherwise indicated, “stable, as used herein and 3D imaging. A LEXT microscope utilizes low wave in reference to a material, means that the material retains length optical technology with a 408 nm laser in combination functionality over extended periods of time. In one embodi with confocal scanning can be used for the measurement. ment, the referenced material retains at least 90% of a refer Samples to be measured are mounted on a glass slide by enced activity (or property) for at least 30 days at 37°C. in at double-sided tape. Digital 3-D images are taken with the least one of phosphate buffered saline containing protein, Olympus LEXT OLS4000 laser confocal microscope media, or serum, or in vivo. In one embodiment, the reference (“LEXT) under an Olympus MPLAPON 50x objective lens. material retains at least 80% of a referenced activity (or The digital images taken in this way have a 256x256 um field property) for at least 90 days at 37° C. in at least one of area. The Z-direction repeatability for this LEXT machine 10 has been certified by Olympus to be less than 0.012 um. To phosphate buffered saline containing protein, media, or measure the roughness, at least three images have been taken serum, or in vivo. In one embodiment, the referenced material from each sample and the R, roughness is calculated by retains at least 90% of the referenced activity (or property) for using a 9 um cut-off length. at least 30 days at 37° C. and at least 80% of the referenced Solvent Extractable Polymerization Initiator: unless other 15 activity (or property) for at least 90 days at 37°C. The refer wise indicated, “Solvent Extractable Polymerization Initia enced activity or property may include Surface contact angle, tor” refers to any compound capable of starting radical poly non-fouling, anti-thrombogenic, and/or antimicrobial activ merization that has been incorporated within the article, ity. wherein either the initiator or its degradation products may be Static Contact Angle: unless otherwise indicated, “Static extracted from the article using a Suitable solvent. In general, Contact Angle' is the angle at which a water/vapor interface extractions can use nonpolar or polar solvents. For example, meets a Substrate Surface at or near equilibrium conditions. extraction solvents such as water, acetone or ethanol; and/or The contact angle is measured by first soaking the samples other extraction solvents in which the solubility of the initia with pure ethanol for 5 minutes and washing with PBS three tor and/or its degradation products is at least 1 mg/L. The times. The samples are then soaked within PBS (150 mM, pH extraction should be carried out for a sufficient time such that 25 7.4) for 24 hours and washed three times with purified water. the change in concentration of the extract is not increasing Then the samples are dried under a flow of airfor 5 min before more than 5% per hour. Alternatively, extraction until the testing. A drop of purified water (e.g., 1 LL) is deposited on amount of extracted material in a Subsequent extraction is less the test Surface, the shape of the droplet is photographed by a than 10% of that detected in the initial extraction, or until microscope with a CCD camera using a video contact angle there is no analytically significant increase in the cumulative 30 extracted material levels detected. Extraction conditions system (e.g., VCA 2000, AST Inc.), and the contact angle is include: 37° C. for 72 h; 50° C. for 72 h; 70° C. for 24 h; 1219 then determined (using, for example, a VCA Optima XE). C. for 1 h. Extraction ratio includes 6 cm/mL surface area/ The size of the water droplet used to determine the contact Volume and/or 0.2 g sample/mL. In some instances, complete angle may vary depending upon the Substrate type and com dissolution of the substrate may be appropriate. Materials 35 position. For a 5 French device, for instance, an 0.1 uL drop of shall be cut into small pieces before extraction to enhance purified water may be used. Submersion in the extract media, for example, for polymeric Substantially Hemocompatible: unless otherwise indi substrates approximately 10 mmx50mm or 5mmx25mm are cated, “substantially hemocompatible” means that the com appropriate. The instrumentation used includes high-perfor position is Substantially non-hemolytic, in addition to being mance liquid chromatography-photo-diode array detection 40 non-thrombogenic and non-immunogenic, as tested by mass spectrometry (HPLC-PDA-MS) for organics analysis: appropriately selected assays for thrombosis, coagulation, gas chromatography-mass spectrometry (GC-MS) for organ and complement activation as described in ISO 10993-4. ics analysis; inductively coupled plasma-optical emission Substantially Non-Cytotoxic: unless otherwise indicated, spectroscopy or mass spectrometry (ICP-OES or ICP-MS) “substantially non-cytotoxic' refers to a composition that for metals analysis; and sometimes ion chromatography (IC) 45 does not Substantially change the metabolism, proliferation, for inorganics and ion analysis. Sometimes more advanced or viability of mammalian cells that contact the surface of the MS detectors such as time-of-flight (TOF) are used to obtain composition. These may be quantified by the International accurate mass information. Hexane and alcohol extractions Standard ISO 10993-5 which defines three main tests to are analyzed by GC-MS. Water and alcohol extractions are assess the cytotoxicity of materials including the extract test, analyzed by HPLC. The initiator or its degradation products 50 the direct contact test and the indirect contact test. may be quantified and/or detected in the substrate or grafted Substantially Non-Hemolytic Surface: unless otherwise polymer by the previously described methods. These include indicated, “substantially non-hemolytic surface” means that FTIR-ATR, electron spectroscopy for chemical analysis the composition does not lyse 50%, preferably 20%, more (ESCA, also called X-ray photoelectron spectroscopy, XPS), preferably 10%, even more preferably 5%, most preferably Secondary Ion Mass Spectrometry (SIMS), and surface-en 55 1%, of human red blood cells when the following assay is hanced Raman spectroscopy (SERS). For example, peroxide applied: a stock of 10% washed pooled red blood cells (Rock may be detected spectrophotometrically using any of the land Immunochemicals Inc, Gilbertsville, Pa.) is diluted to following three methods: the iodide method (oxidation of 0.25% with a hemolysis buffer of 150 mM. NaCl and 10 mM sodium iodide by peroxides in the presence of ferric chlo Tris at pH 7.0. A 0.5 cm antimicrobial sample is incubated ride), the DPPH method (treatment with 1,1-diphenyl-2-pic 60 with 0.75 mL of 0.25% red blood cell suspension for 1 hour at rylhydrazyl, a radical Scavenger, to decompose the peroX 37°C. The solid sample is removed and cells are spun down ides), or the peroxidase method (reduction with glutathione, at 6000 g, the supernatant is removed, and the OD414 mea catalyzed by glutathione peroxidase, followed by measuring sured on a spectrophotometer. Total hemolysis is defined by the coupled oxidation of NADPH in the presence of glu diluting 10% of washed pooled red blood cells to 0.25% in tathione reductase). See, for example, Fujimoto et al., Journal 65 sterile deionized (DI) water and incubating for 1 hour at 37° of Polymer Science Part A: Polymer Chemistry, Vol. 31, C., and 0% hemolysis is defined using a suspension of 0.25% 1035-1043 (1993). red blood cells in hemolysis buffer without a solid sample. US 8,574,660 B2 17 18 Substantially Non-Toxic: unless otherwise indicated, DETAILED DESCRIPTION OF THE INVENTION “Substantially non-toxic' means a Surface that is Substantially hemocompatible and Substantially non-cytotoxic. Medical devices and other articles comprise any of a wide Substituted/Optionally Substituted: unless otherwise indi range of materials. Certain of these materials, by virtue of cated, the term “substituted” and “optionally substituted their intrinsic characteristics, exhibit a greater resistance to means that the referenced group is or may be substituted with protein adsorption and cell/microorganism adhesion; for one or more additional Suitable group(s), which may be indi example, hydrophilic materials tend to exhibit less protein vidually and independently selected, for example, from adsorption than hydrophobic materials. acetals, acyl, acyloxy, alkenoxy, alkoxy, alkylthio, alkynoxy, Methods of manufacture can greatly affect the surface amido, amino, aryl, aryloxy, arylthio, azido, carbonyl, car 10 characteristics of an article and its resistance to protein boxamido, carboxyl, cyano, esters, ethers, hydrocarbyl, Sub adsorption and cell/microorganism adhesion. Manufacturing stituted hydrocarbyl, heterohydrocarbyl, substituted hetero methods may affect, for example, the porosity of a material, hydroalkyl, cycloalkyl, halogen, heteroalicyclic, heteroaryl, its roughness (micro-roughness and macro-roughness), hydroxy, isocyanato, isothiocyanato, ketals, keto, mercapto, incorporation of foreign-body inclusions that project from the nitro, perhaloalkyl, silyl, Sulfamoyl, Sulfate, Sulfhydryl, Sul 15 Surface of the material, and similar surface characteristics. fonamido, Sulfonate, Sulfonyl, Sulfoxido, thiocarbonyl, thio Each of these, and other factors, may increase the degree of cyanato, thiol, and/or the protected derivatives thereof. It will fouling that occurs at the article Surface, independent of any be understood that “substitution' or “substituted” includes further surface modification. This fouling can be cause by the implicit proviso that such Substitution is in accordance deposition of proteins, minerals, mammalian cells, or bacte with permitted valence of the substituted atom and the sub ria. In the clinical setting, deposition of biological materials stituent, and that the Substitution results in a stable com leading to thrombosis and bacterial biofilm are particularly pound, e.g., which does not spontaneously undergo transfor undesirable. mation Such as by rearrangement, cyclization, elimination, In accordance with one aspect of the present invention, etc. therefore, the surface characteristics of the surface of a medi Substrate: unless otherwise indicated, “substrate” refers to 25 cal device or other article substrate are improved as a result of the material from which a non-fouling polymer is grafted. the treatments described herein. In some embodiments, for Sulfoammonium: unless otherwise indicated, a 'sulfoam instance, the treatments reduce the Surface roughness of the monium moiety is a Zwitterionic moiety comprising Sulfate article substrate. In these and other embodiments, various low and ammonium functionality and includes, for example, Sul molecular weight species are reduced (or even Substantially foammonium monomers, Sulfoammonium oligomers, Sul 30 or completely removed). Such surface characteristics may be foammonium polymers, Sulfoammonium repeat units, and particularly acute when the Substrate surface is a polymeric other sulfoammonium-containing materials. Sulfobetaine material. These and other treatments may be carried out monomers, oligomers, polymers, repeat units, and other Sul before or during the formation of a grafted polymer layer on fobetaine materials are exemplary Sulfoammonium moieties. the surface of the substrate. Preferably, the treatments are Tether/Tethering Agent/Linker: unless otherwise indi 35 performed without altering various physical characteristics of cated, “tether or “tethering agent' or “linker as used herein the underlying bulk material(s). Without being bound to any synonymously, refers to any molecule, or set of molecules, or particular theory, it is believed that the surface treatments polymer used to covalently or non-covalently immobilize one described herein provide an improved polymeric (or other) or more non-fouling materials, one or more bioactive agents, Substrate surface for non-fouling grafted polymeric materials or combinations thereof on a material where the molecule 40 and methods. Advantageously, the Surface treatment pro remains as part of the final chemical composition. The tether cesses described herein do not substantially disturb or alter can be either linear or branched with one or more sites for the various physical properties of the bulk, nor do they sub immobilizing bioactive agents. The tether can be any length. stantially disturb or alter the various visual characteristics and However, in one embodiment, the tether is greater than 3 other characteristics of the Substrate. Among other physical angstroms in length. The tether may be non-fouling, such as 45 properties of the bulk, for example, the surface treatments a monomer, oligomer, or polymer or a non-fouling non-Zwit described herein do not substantially affect the size (includ terionic material. The tether may be immobilized directly on ing, e.g., length, width, height, Volume, diameter, etc.), duc the substrate or on a polymer, either of which may be non tility, flexural modulus, flexural strength, shear strength, spe fouling. cific modulus, tensile strength, yield strength, and the like. Undercoating Layer: unless otherwise indicated, “under 50 Visual and other characteristics that are not substantially coating layer” refers to any coating, or combination of coat affected by the surface treatments described herein include, ings, incorporated into a Substrate from which a non-fouling for example, color, marking clarity and legibility of printed polymer is grafted. indicia. Zwitterion/Zwitterionic Material: unless otherwise indi In a preferred embodiment, the Surface treatment processes cated, “Zwitterion' or “Zwitterionic material' refers to a mac 55 described herein do not substantially disturb or alter the vari romolecule, material, or moiety possessing both cationic and ous physical properties and visual characteristics of a catheter anionic groups. In most cases, these charged groups are bal device including, by way of example, one or more of the anced, resulting in a material with Zero net charge. catheter body length; extension line length; outer diameter Zwitterionic Polymers: unless otherwise indicated, “Zwit (body), at juncture hub; outer diameter (body), at distal tip; terionic polymers' may be homopolymers or copolymers and 60 roundness (body), at distal tip; cross-sectional area; lumen include both polyampholytes (e.g., polymers with the width; lumen height; wall thicknesses; septum width: cath charged groups on different monomer units) and polybetaine eter body color; extension line color; juncture hub color:luer (polymers with the anionic and cationic groups on the same color; marking clarity and legibility; distance marking orien monomer unit). Exemplary Zwitterionic polymers include tation; flow rate, gravity; flow rate, pumped; tensile strength, alternating copolymers, statistical copolymers, random 65 catheter body; elongation, catheter body; tensile strength, copolymers and block copolymers of two, three or more extension line; tensile strength, catheter body juncture hub OOCS. joint; tensile strength, extension line juncture hub joint; US 8,574,660 B2 19 20 tensile strength, extension line—luer joint, luer gauging (ISO Additionally, or alternatively, the conditions used in the 594-1); luer separation force (ISO 594-1); luer liquid leakage Surface modification with a non-fouling modification may (ISO 594-2); luer air leakage (ISO 594-2); luer stress crack migrate low molecular weight species, such as additives or ing (ISO 594-2); catheter leakage, air, catheter leakage, liq processing aids, to the Surface of the non-fouling Surface uid. Standard methods from the International Organization material. Representative conditions include aqueous expo for Standardization (ISO) and equipment for the evaluation of sure at 22-80° C. from 2-12 hours. Other treatment methods these various physical properties include, for example, involve a heat treatment of the substrate surface. dimensions (length): calibrated ruler, dimensions (cross-sec In one embodiment, the low molecular weight species that tional): noncontact measurement system; Gravity flow rate: may be present at the start of the surface modification are ISO 10555-3: Pumped flow rate: syringe pump set to 11.9 10 Sufficiently reduced through a treatment process So that they mL/min: Tensile testing: ISO 10555-1, ISO 10555-3: Luer are substantially undetectable at the surface of the substrate at testing: ISO 594-1, ISO 594-2; and Cather leakage: ISO the start of the polymer grafting of the non-fouling layer. In a 10555-1. further embodiment, the additives and/or low molecular In one aspect, the Surface treatments of the present inven 15 weight polymers present at the start of the Surface modifica tion reduces (or even completely removes) low molecular tion are sufficiently reduced through a treatment process So weight species on or in the Surface of the medical device or that they are substantially undetectable at the surface of the other article substrate. Such species may include, for non-fouling layer after the non-fouling Surface modification. example, discontinuous material phases (e.g., phase bound In one preferred embodiment, the surface treatment and the aries), Surface contamination or other mechanical or chemical Surface modification are performed in a single step. By way of defects in the surface of the article that could potentially example, one or more solvents used in a Surface treatment to otherwise serve as a site for a performance or modification dissolve or clean up low molecular weight species (e.g., addi failure. In one embodiment, the low molecular weight species tives, low molecular weight polymers, artifacts, and other is an additive or a low molecular weight polymer. Additives components) may also function to introduce a polymerization that may be reduced or substantially or completely removed 25 initiator into and/or onto the substrate surface by physio in accordance with the treatment processes described herein adsorption, allowing the Substrate to Swell and ultimately include, for example, inorganic and organic species. Low imbibing initiator into the substrate. This surface treatment/ molecular weight polymers may be present as a result of the imbibing process may optionally be accompanied by processing techniques and condition in the formation of the mechanical agitation (e.g., Sonication), for example, to pro Substrate and/or the underlying bulk material. In various 30 mote dissolution or removal of the substrate surface material embodiments, for example, low molecular weight species and/or to enhance the imbibing process. Suitable solvents may have a molecular weight of less than about 50,000 Dal include but are not limited to isopropanol and ethanol or tons, less than about 25,000 Daltons, less than about 15,000 solvent mixtures including one or both. As a result of the Daltons, less than about 10,000 Daltons, less thanabout 5,000 imbibing process, the imbibed substrate may contain about Daltons, or less than about 1,000 Daltons. In another aspect, 35 0.001% by weight initiator. In some embodiments, the the Surface treatments of the present invention improve (i.e., imbibed Substrate will contain greater amounts of initiator, reduce) Surface roughness of the Substrate. Among the Vari e.g., at least about 0.01% by weight. For example, in some ous Surface treatments contemplated in connection with the embodiments the imbibed substrate will contain at least about present invention, include heat treatments (that is, heating all 0.1% by weight. By way of further example, in some embodi or a portion of the article or substrate for a period of time, 40 ments the imbibed substrate will contain about 0.05% to resulting in a smoother, more homogeneous, or otherwise about 2% by weight initiator. By way of further example, in improved Surface), Solvent or reactant treatments that dis some embodiments the imbibed substrate will contain about solve or otherwise physically and/or chemically reduce or 0.1% to about 1% by weight initiator. By way of further remove material from the surface of or in the substrate, and example, in some embodiments the imbibed substrate will combinations of Such treatment methods. Physical agitation 45 contain about 0.2% to about 0.5% by weight initiator. By way or Sonication may also be applied during such treatments. of further example, in some embodiments the imbibed sub In general, the Substrate Surface regions may comprise a strate will contain about 1% to about 10% by weight initiator. combination of different species, the presence of which may Typically, however, the imbibed substrate will contain less adversely effect the grafting process. By way of example, than about 20% by weight initiator. many Substrates may include low molecular weight species, 50 In accordance with one aspect of the invention, the Surface Such as additives, in the form of processing aids such as waxes treatments of the present invention reduce the concentration and oils. For instance, process aids are often present in of low molecular weight species on the surface of or in the extruded materials and may be included in the material before substrate before (or during) the formation of the grafted poly extrusion or added during the extrusion process. These pro mer layer on the article. These and other treatments may also cess aids, in particular waxes, can be mobile within the Sub 55 have the added benefit of reducing roughness or otherwise strate depending on the conditions to which the Substrate is Smoothing the Substrate Surface. For example, in some exposed, which may be a function of temperature, time, and embodiments, the Surface of an article having a polymeric Solvent. Preferably, the processing aids that may be present in Surface is chemically, mechanically, thermally, and/or or on the substrate or substrate surface at the start of the chemomechanically treated to reduce the incidence and/or Surface modification are minimized through a treatment pro 60 the severity of surface species before the grafted polymer cess. Other additives that may be present in or on the substrate layer is formed. For example, the surface may be treated with Surface include dispersing agents, binders, cross-linking a solvent, acid, base, reactant, polishing agent, chelating agents, stabilizing agents, coloring agents, UV absorbent agent, or other moiety, or combinations thereof, that agents, charge adjusting agents, softening agents, anti-oxi smoothes the polymeric surface of the substrate and/or dants, pigments, flame retardants, scorch retarders, foaming 65 reduces the incidence or severity of material discontinuities agents, tackifiers, blowing agents, lubricants, UV-stabilizers, and/or contamination before the grafted polymer layer is impact modifiers, and the like. formed on the polymeric surface of the article. US 8,574,660 B2 21 22 Regardless of the treatment method employed, the treated fields, and/or electric and magnetic fields. The Surface struc Surface is a polymeric Surface having a relatively low Surface ture of a material, including atoms and molecules, is often roughness. In one embodiment, the treated Surface has a mobile in response to the outside environment. In response to global average R. Surface roughness of no more than 200 a hydrophobic environment (e.g., air), more hydrophobic nm. In another embodiment, the treated Surface has a global 5 (lower energy) components, for example the carbon back average R. Surface roughness of no more than 150 nm. In bone of poly(2-hydroxyethyl methacrylate), may migrate to another embodiment, the treated Surface has a global average the Surface of a material—a process that reduces interfacial R. Surface roughness of no more than 100 nm. In a preferred energy. In response to an aqueous environment, the Surface embodiment, the treated surface has a global average R. may reverse its structure and point polar (hydrophilic) surface roughness of no more than 50 nm. Preferably, the 10 groups, for example the hydroxyl groups of poly(2-hydroxy treated Surface has a global average R. Surface roughness of ethyl methacrylate), outward to interact with the polar water no more than 25 nm. Preferably, the treated surface has a molecules. It is thought that energy minimization drives this global average R. Surface roughness of no more than 10 nm. process. Segmented thermoplastic elastomers may exhibit In some embodiments, the treated surface will have a global structural heterogeneity on the molecular, domain, and on average R. Surface roughness of about 1 to 5. 15 large Scale, e.g., spherulitic texture. Domain structures in Regardless of the treatment method employed, the treated segmented polyurethanes may change their orientation when Surface is a polymeric Surface also having a relatively low stresses, such as elongation and annealing, are applied. In Surface density of defects having a size, i.e., a largest dimen some embodiments, it may be desirable to expose the sub Sion, greater than 0.5 micrometers. In some embodiments, the strate to conditions that alter the groups presented from the surface of the substrate from which the non-fouling material Surface before the non-fouling polymer is grafted. The Sur is to be grafted has a Surface defect density of defects having face composition can be estimated by using a combination of a size greater than about 0.5 micrometers that is less than 0.1 contact angles, ESCA (XPS), auger electron spectroscopy, defects/um. For example, the surface of the substrate from SIMS, ATR-FTIR, STM SEM, EDACS, and sum frequency which the non-fouling material is to be grafted may have a generation. Surface defect density of defects having a size greater than 25 Even if only a single phase is detectable on the article about 0.5 micrometers that is less than 0.05 defects/um. By Surface, it may be preferable to have a high purity of a single way of further example, the surface of the substrate from polymer on the Surface. For example, a pure polyurethane which the non-fouling material is to be grafted may have a surface may be preferable to one that contains both polyure Surface defect density of defects having a size greater than thane and an extrusion wax that are well mixed. The purity of about 0.5 micrometers that is less than 0.01 defects/um. By 30 the surface can be estimated by applying ATR-FTIR micros way of further example, the surface of the substrate from copy of the article surface relative to the desired single surface which the non-fouling material is to be grafted may have a material. Use ATR-FTIR, peak integration can be applied to Surface defect density of defects having a size greater than assess the relative quantities of two or more materials with about 0.5 micrometers that is less than 0.002 defects/um. By distinct infrared peaks. For instance, ethylene bis Stearamide way of further example, the surface of the substrate from 35 has a characteristic peak at 1639 cm and Tecoflex polyure which the non-fouling material is to be grafted may have a thane has a characteristic peak at 1693 cm. In some embodi Surface defect density of defects having a size greater than ments, it is preferable for the highest fractional component to about 0.5 micrometers that is less than 0.001 defects/um. account for more than 70% of the surface area. In further In one embodiment, the treated Surface is a polymeric embodiments, it is preferable for the highest fractional com Surface also having a high degree of chemical uniformity. The 40 ponent to account for more than 80% of the surface area. In chemical composition of the Surface may be mapped with a further embodiments, it is preferable for the highest fractional variety of surface analytics including FTIR-ATR microscopy, component to account for more than 90% of the surface area. EDAX mapping, and XPS. If an article has known heteroge In further embodiments, it is preferable for the highest frac neous components, such as barium Sulfate crystals in poly tional component to account for more than 95% of the surface urethane, the signals for individual components can be char 45 area. In further embodiments, it is preferable for the highest acterized as standards to aid in identifying the elements in the fractional component to account for more than 99% of the mixed composition. If a heterogeneous Surface is present with surface area. In further embodiments, it is preferable for the distinct chemical signals, a mapping tool can be applied and highestfractional component to account for more than 99.5% the approximate fractional composition of each phase on the of the surface area. In further embodiments, it is preferable for Surface can be determined. In some embodiments, it is pref 50 the highest fractional component to account for more than erable for the highest fractional phase to account for more 99.9% of the Surface area. than 70% of the surface area. In further embodiments, it is In one preferred embodiment, the treated surface is a poly preferable for the highestfractional phase to account for more meric Surface having relatively low surface roughness and a than 80% of the surface area. In further embodiments, it is relatively low Surface density of defects having a size greater preferable for the highestfractional phase to account for more 55 than 0.5 micrometers. For example, in one embodiment, the than 90% of the surface area. In further embodiments, it is treated Surface is a polymeric Surface having a global average preferable for the highestfractional phase to account for more R. Surface roughness of no more than 200 nm and a Surface than 95% of the surface area. In further embodiments, it is defect density of defects having a size greater than about 0.5 preferable for the highestfractional phase to account for more micrometers that is less than 0.1 defects/um: more prefer than 99% of the surface area. In further embodiments, it is 60 ably in this embodiment; the global average R. Surface preferable for the highestfractional phase to account for more roughness is no more than 150 nmi; still more preferably in than 99.5% of the surface area. In further embodiments, it is this embodiment; the global average R. Surface roughness preferable for the highestfractional phase to account for more is no more than 100 nm. For example, in one embodiment, the than 99.9% of the surface area. treated Surface is a polymeric Surface having a global average In some embodiments, it may be preferable to have certain 65 R. Surface roughness of no more than 50 nm and a Surface components or materials on the Surface by exposing the Sur defect density of defects having a size greater than about 0.5 face to a certain environment Such as vapors, solvents, stress micrometers that is less than 0.1 defects/um. By way of US 8,574,660 B2 23 24 further example, in one embodiment, the treated Surface has a 90% of the surface area. By way of further example, the global average R. Surface roughness of no more than 25 nm. surface of the substrate from which the non-fouling material and a surface defect density of defects having a size greater is to be grafted may have a surface defect density of defects than about 0.5 micrometers that is less than 0.1 defects/um. having a size greater than about 0.5 micrometers that is less By way of further example, in one embodiment, the treated than 0.002 defects/um and the highest fractional component Surface has a global average R. Surface roughness of no using ATR-FTIR peak integration accounts for more than more than 10 nm and a surface defect density of defects 95% of the surface area. By way of further example, the having a size greater than about 0.5 micrometers that is less surface of the substrate from which the non-fouling material than 0.1 defects/um. By way of further example, in one is to be grafted may have a surface defect density of defects embodiment, the treated Surface will have a global average 10 having a size greater than about 0.5 micrometers that is less R. Surface roughness of about 1 to 5 and a surface defect than 0.001 defects/um the highest fractional component density of defects having a size greater than about 0.5 using ATR-FTIR peak integration accounts for more than micrometers that is less than 0.1 defects/um. In each of the 99% of the surface area. In each of the foregoing examples foregoing examples and embodiments of this paragraph, the and embodiments of this paragraph, the highest fractional defect density may be even less, e.g., is less than 0.1 defects/ 15 component using ATR-FTIR peak integration accounts defect um, less than 0.05 defects/um, less than 0.01 defects/um, density may be even greater, e.g., more than 99.5% of the less than 0.002 defects/um, or even less than 0.001 defects/ surface area, or even more than 99.9% of the surface area. um for defects having a size greater than about 0.5 microme In one preferred embodiment, the treated surface is a poly terS. meric Surface having relatively low Surface roughness, a rela In one preferred embodiment, the treated surface is a poly tively low Surface density of defects having a size greater than meric Surface having a relatively low surface roughness and a 0.5 micrometers, and a relatively high purity of a single poly relatively high purity of a single polymer on the Surface. For mer on the Surface. For example, in one embodiment, the example, in one embodiment, the treated Surface is a poly treated Surface is a polymeric Surface having a global average meric Surface having a global average R. Surface roughness R. Surface roughness of no more than 50 nm, a Surface of no more than 50 nm and the highest fractional component 25 defect density of defects having a size greater than about 0.5 using ATR-FTIR peak integration accounts for more than micrometers that is less than 0.1 defects/um and the highest 70% of the surface area. By way of further example, in one fractional component using ATR-FTIR peak integration embodiment, the treated surface has a global average R. accounts for more than 70% of the surface area. By way of Surface roughness of no more than 25 nm and the highest further example, in one embodiment, the treated Surface has a fractional component using ATR-FTIR peak integration 30 global average R. Surface roughness of no more than 25 nm, accounts for more than 70% of the surface area. By way of a Surface defect density of defects having a size greater than further example, in one embodiment, the treated surface has a about 0.5 micrometers that is less than 0.1 defects/um and global average R. Surface roughness of no more than 10 nm. the highest fractional component using ATR-FTIR peak inte and the highest fractional component using ATR-FTIR peak gration accounts for more than 80% of the surface area. By integration accounts for more than 90% of the surface area. 35 way of further example, in one embodiment, the treated Sur By way of further example, in one embodiment, the treated face has a global average R. Surface roughness of no more Surface will have a global average R. Surface roughness of than 10 nm, a Surface defect density of defects having a size about 1 to 5 and the highest fractional component using greater than about 0.5 micrometers that is less than 0.1 ATR-FTIR peak integration accounts for more than 95% of defects/um and the highest fractional component using ATR the Surface area. In each of the foregoing examples and 40 FTIR peak integration accounts for more than 90% of the embodiments of this paragraph, the highest fractional com Surface area. By way of further example, in one embodiment, ponent using ATR-FTIR peak integration accounts defect the treated Surface will have a global average R. Surface density may be even greater, e.g., more than 99% of the roughness of about 1 to 5, a surface defect density of defects surface area, more than 99.5% of the surface area, or even having a size greater than about 0.5 micrometers that is less more than 99.9% of the surface area. 45 than 0.1 defects/um, and the highest fractional component In one preferred embodiment, the treated surface is a poly using ATR-FTIR peak integration accounts for more than meric Surface having a relatively low surface density of 95% of the surface area. In each of the foregoing examples defects having a size greater than 0.5 micrometers and a and embodiments of this paragraph, the defect density may be relatively high purity of a single polymer on the Surface. For even less, e.g., is less than 0.1 defects/um, less than 0.05 example, in Some embodiments, the Surface of the Substrate 50 defects/um, less than 0.01 defects/um, less than 0.002 from which the non-fouling material is to be grafted has a defects/um, or even less than 0.001 defects/um for defects Surface defect density of defects having a size greater than having a size greater than about 0.5 micrometers. By way of about 0.5 micrometers that is less than 0.1 defects/um and further example, in one embodiment, the treated Surface has a the highest fractional component using ATR-FTIR peak inte global average R. Surface roughness of no more than 25 nm. gration accounts for more than 70% of the surface area. By 55 and a surface defect density of defects having a size greater way of further example, in one embodiment, the surface of the than about 0.5 micrometers that is less than 0.1 defects/um. substrate from which the non-fouling material is to be grafted Similarly, in each of the foregoing examples and embodi may have a Surface defect density of defects having a size ments of this paragraph, the highest fractional component greater than about 0.5 micrometers that is less than 0.05 using ATR-FTIR peak integration accounts defect density defects/um and the highest fractional component using ATR 60 may be even greater, e.g., more than 99% of the Surface area, FTIR peak integration accounts for more than 80% of the more than 99.5% of the surface area, or even more than 99.9% Surface area. By way of further example, in one embodiment, of the surface area. the surface of the substrate from which the non-fouling mate Advantageously, the Surface treatment(s) described herein rial is to be grafted may have a surface defect density of improve the Surface characteristics and provide an improved defects having a size greater than about 0.5 micrometers that 65 polymeric Surface for a non-fouling grafted polymer layer. is less than 0.01 defects/um the highestfractional component Grafted polymer layers that are relatively uniform, that are using ATR-FTIR peak integration accounts for more than Sufficiently dense and/or branched, and/or are significantly US 8,574,660 B2 25 26 hydrophilic can significantly increase a materials resistance example, Suitable metallic materials include, but are not lim to protein adsorption and/or cell/microorganism contamina ited to, metals and alloys based on titanium, Such as unalloyed tion. titanium (ASTM F67) and titanium alloys, such as ASTM Substrates F1108, Ti-6Al-4V ELI (ASTM F136), Nitinol (ASTM In general, the Substrate comprises any of a wide range of 5 F2063), nickel titanium alloys, and thermo-memory alloy materials selected from, for example, one or more metals, materials; stainless steel (ASTM F138 and F139), tantalum ceramics, glasses, polymers, biological tissues (living or (ASTM F560), palladium, zirconium, niobium, molybde dead), woven and non-woven fibers, semi-metals, and com num, nickel-chrome, or certain cobalt alloys including Stel binations thereof. In one preferred embodiment, the substrate lite, cobalt-chromium (Vitallium, ASTM F75 and Wrought comprises a polymer. In these and other embodiments, the 10 cobalt-chromium (ASTM F90)), and cobalt-chromium Substrate may be a composite of two or more materials. Such nickel alloys such as ELGILOYR), PHYNOX(R), and HAS as two or more polymeric materials. For example, the Sub TELLOYOR). strate may comprise a polymeric coating over a metallic, In the embodiments in which a ceramic bulk material is ceramic, glass, polymeric, woven or non-woven fiber or semi coated or covered with a polymeric coat or overlay, for metal core. Alternatively, the Substrate may comprise a poly 15 example, Suitable ceramic materials include, but are not lim meric material throughout, i.e., from its surface and into its ited to, oxides, carbides, or nitrides of the transition elements bulk. By way of further example, the substrate may comprise Such as titanium oxides, hafnium oxides, iridium oxides, a polymeric coating. Overlying a metallic, ceramic, glass, chromium oxides, aluminum oxides, and Zirconium oxides. polymeric, woven or non-woven fiber or semi-metal core Silicon based materials, such as silica, may also be used. inner layer which, in turn, overlies a foam, metallic, ceramic, In one embodiment, the Substrate may include, in or on its glass, polymeric, woven or non-woven fiber or semi-metal Surface, a radiopaque material, for example, to aid in radio core. By way of another example, the Substrate may comprise graphic imaging. Illustrative examples of radiopaque materi a first polymeric material overlaying a second polymeric als include, but are not limited to, gold, barium salts (e.g., material. Preferably, the substrate is at least polymeric barium sulfate), bismuth salts (e.g., bismuth Subcarbonate), throughout or comprises a polymeric material above a bulk of 25 gold or gold foil, tantalum, ferritic particles, platinum, plati another (e.g., non-polymeric) material. In a particularly pre num-tungsten, platinum-iridium, palladium, rhodium, and ferred embodiment, the substrate is a polymeric material ionic or non-ionic contrasting agents such as diatrizoates, through the entire Substrate thickness. iodipamide, iohexyl, iopamidol, iothalamate, ioVersol, ioxag Suitable polymeric materials include, but are not limited late, and metrizamide, and combinations thereof. In certain to, polyamide, polyamine, polyanhydride, polyazine, poly 30 preferred embodiments, the radiopaque material is barium (carbonate), polyester, polyether, polyetheretherketone sulfate. (PEEK), polyguanidine, polyimide, polyketal, poly(ketone), In another particular embodiment, the substrate may polyolefin, poly(orthoester), polyphosphazine, polysaccha include, in or on its Surface, a colorant material, that is, a ride, polysiloxane, polysulfone, polyurea, polyurethane, material that provides an optical or visual effect, tint, or color halogenated polymer, silicone, aldehyde crosslinked resin, 35 to a material. Suitable colorant materials include, but are not epoxy resin, phenolic resin, latex, or a copolymer or blend limited to, dyes and pigments. Where the colorant is a dye, for thereof. Exemplary polymers include polystyrene and Substi example, the colorant may be generally soluble in a solvent or tuted polystyrenes, polyalkylenes, such as polyethylene and carrier material dispersed within the continuous phase. polypropylene, poly(urethane)S. polyacrylates and poly Where the colorant is a pigment, on the other hand, the pig methacrylates, polyacrylamides and polymethacrylamides, 40 ment material is typically an organic or inorganic, colored, polyesters, polysiloxanes, polyethers (including polyac white, or black material that is usually substantially insoluble etals), poly(orthoesters), poly(carbonates), poly(hydroxyal in a solvent or carrier system, and is likewise insoluble in the kanoate)s, polyfluorocarbons, PEEK, Teflon, silicones, continuous phase. epoxy resins, KEVLARR, NOMEX(R), DACRONR), Suitable dye colorant materials include direct dyes, Vat HYTREL(R), PEBAX(R), SURLYNR), nylon, polyalkenes, 45 dyes, Sulfur dyes, organic pigments, reactive dyes, disperse phenolic resins, PTFE, natural and synthetic elastomers, dyes, acid dyes, azoic dyes, synthetic dyes, basic dyes, fluo adhesives and sealants, polyolefins, polysulfones, polyacry rescent dyes, and phosphorescent dyes. Suitable pigment lonitrile, biopolymers such as polysaccharides and natural colorant materials include, by way of non-limiting example, latex copolymers thereof, and combinations thereof. In one pearlescent, metallic flake, cholesteric liquid crystal (CLC) embodiment the Substrate is a medical grade polyurethane or 50 pigments, ultramarine pigments, effect pigments, fluorescent CARBOTHANER), aliphatic polycarbonate-based polyure pigments, phosphorescent pigments, inorganic pigments, thanes, available from Lubrizol Corporation, blended with carbon black pigments, natural pigments, organic pigments, appropriate extrusion agents and plasticizers, possibly one mixed metal oxide pigments, iron oxide pigments, titanium already approved by the FDA or other appropriate regulatory dioxide pigments, Zinc oxide pigments, titanium oxide pig agency for use in vivo. In one preferred embodiment, the first 55 ments, organic azo pigments (such as azo lake pigments, material comprises a polyurethane polymer or copolymer insoluble azo pigments, condensed azo pigments, and chelate thereof. Preferred substrates are elastollan, pearlthane, des aZo pigments), organic polycyclic pigments (such as phtha mopan, estane, pellethane, irogan, exelast EC, laripur, car locyanine based pigments, anthraquinone based pigments, bothane, carbothane, isoplast, tecoflex, tecophilic, tecoplast, perylene based pigments, perinone based pigments, indigo tecothane, biomer (Ethicon), biospan, cardiothane 51 60 based pigments, quinacridone based pigments, dioxazine (aVothane), cardiomat, chronoflex AL, chronoflex AR, chro based pigments, isoindolinone based pigments, quinophtha noflex C, corplex, corethane, mitrathane, rimplast, toyobo lone based pigments, and diketopyrrolopyrrole (DPP) based TMS, vialon, enka PUR, comfeel ulcus, viasorb, bioclusive, pigments), dyeing lake pigments (such as lake pigments of blisterfilm, opsite, tegaderm, epigard, lyofoam, omiderm, acid or basic dyes), azine pigments; and the like. microthane, and Surethane. 65 In certain aspects, the Substrate may include, in or on its In the embodiments in which a metallic bulk material is Surface, polymeric colorant materials, which may addition coated or covered with a polymeric coat or overlay, for ally serve as a structural material of the substrate. One suit US 8,574,660 B2 27 28 able and non-limiting example is the class of poly(arylene illofacial implants, cosmetic implants, valves, appliances, ethynylene) (PAE) polymers, which are conjugated and scaffolding, Suturing material, needles, hernia repair meshes, stable Solid polymers that can fluoresce in orange, yellow, tension-free vaginal tape and vaginal slings, prosthetic neu green, and blue ranges, for example. Suitable examples of rological devices, tissue regeneration or cell culture devices, PAE fluorescent polymers include poly(p-phenylene), poly 5 dialyzer, cranial implants, Syringes, blood collection contain (p-phenyleneethynylene) (PPE) or poly(p-phenylenevi ers, scrotal implants, calve implants, buttock implants, nylene) and derivatives thereof, including those derivates extraocular implants, horn implants, Subdermal implants, having alkyl, alkyl phenyl, and alkoxy groups such as grafted transdermal implants, magnetic implants, medical devices PPE and dioctyl-PPE, or ternary benzothiadiazole-co containing microfluidics, blood based sensors used outside of alkyne-co-alkyne substituted backbones. Other suitable con 10 the body, nanoparticles used as sensors, IV catheter sheath, or jugated polymers include polythiophene and polyaniline, by other medical devices used within or in contact with the body way of example. or any portion of any of these. In another particular embodiment, the substrate includes The substrate may be in the form of, or form part of gels, one or more structure- and/or density-enhancing agents liquids, films, coatings, particles (nanoparticles, micropar including, for example, metals, ceramics, carbon fibers, nano 15 ticles, or millimeter diameter beads), fibers (including woven clays and other particles, glass (e.g., glass beads, and poly and non-woven sponges and fabrics), marine and underwater mers (i.e., a second polymeric material having a chemical coatings (including coatings for ships, Submarines, marine composition that differs from the first material), among oth and hydrokinetic devices, aquariums, underwater infrastruc ers. Other additional additives include, but are not limited to, tures, sewage pipes, and aqueduct tubes), packaging materi dispersing agents, binders, cross-linking agents, stabilizing als (including packaging for foods, beverages, cosmetics, and agents, coloring agents, UV absorbent agents, charge adjust consumer products), desalination and water treatment sys ing agents, softening agents, anti-oxidants, pigments, flame tems (including condensers, spacers, pipelines, and mem retardants, scorch retarders, foaming agents, tackifiers, blow branes), separation membranes (including membranes for ing agents, lubricants, UV-stabilizers, impact modifiers, and macrofiltration, microfiltration, ultrafiltration, nanofiltration, the like. 25 and reversed osmosis filtration), lab appliances and consumer The substrate may be in the form of, or form part of gels, products including containers (e.g., petri dishes, cell culture liquids, films, particles (nanoparticles, microparticles, or mil dishes, flasks, beakers), Valves, needles, tapes, sealants, limeter diameter beads), fibers (wound dressings, bandages, pipes, and tubes, earrings, body rings, contact lenses, cook gauze, tape, pads, sponges, including Woven and non-woven ware, gears (external/internal, spur, helical, double helical, sponges and those designed specifically for dental or oph 30 bevel, hypoid, crown, worm, non-circular, etc.), turboma thalmic Surgeries), blood storage bags, Surgical, medical or chinery (turbines and compressors), pumps (direct lift, dis dental instruments, blood oxygenators, ventilators, pumps, placement, velocity, buoyancy, and gravity), propellers, drug delivery devices, tubing, wiring, electrodes, contracep blades, knives, windshields, and glassware. tive devices, feminine hygiene products, endoscopes, grafts In one embodiment, the Substrate is a vascularly inserted (including Small diameter-6 mm), Stents (including coro 35 catheter Such as a peripherally inserted central catheter nary, ureteral, renal, biliary, colorectal, esophageal, pulmo (PICC), central venous catheter (CVC), or hemodialysis cath nary, urethral, vascular, peripheral, neurovascular), Stent eter, venous valves, punctual plugs, and intra-ocular devices grafts (including abdominal, thoracic, neurovascular and and implants. In another embodiment, the Substrate is a vas peripheral vascular), pacemakers, implantable cardioverter cularly inserted catheter formed from a medical grade poly defibrillators, cardiac resynchronization therapy devices, car 40 urethane or CARBOTHANER) or formed from a material diovascular device leads, Ventricular assist devices and driv coated with a medical grade polyurethane or CARBOTH elines, heart valves, Vena cava filters, endovascular coils, ANE(R). In another embodiment, the substrate is a vascularly catheters (including central venous, peripheral central, mid inserted catheter formed from a medical grade polyurethane line, peripheral, tunneled, dialysis access, urinary, neurologi or CARBOTHANER) containing a radiopaque additive, such cal, peritoneal, intra-aortic balloon pump, angioplasty bal 45 as barium Sulfate or bismuth salts to aid in radiographic loon, diagnostic, interventional, drug delivery, etc.), catheter imaging, or formed from a material coated with a medical connectors and valves (including needleless connectors), grade polyurethane or CARBOTHANER) containing a radio intravenous delivery lines and manifolds, shunts (including paque additive, such as barium Sulfate or bismuth salts to aid cardiac, cerebral, lumbar-peritoneal, pulmonary, portosys in radiographic imaging. temic, portacaval, etc.), wound drains (internal or external 50 In another embodiment, the Substrate is a vascularly including ventricular, Ventriculoperitoneal, and lumboperito inserted catheter formed from a medical grade polyurethane neal), dialysis membranes, protein separation membranes, or Tecothane(R) or formed from a material coated with a medi infusion ports, cochlear implants, endotracheal tubes, tra cal grade polyurethane or Tecothane(R). In another embodi cheostomy tubes, ventilator breathing tubes and circuits, ment, the substrate is a vascularly inserted catheter formed guide wires, fluid collection bags, drug delivery bags and 55 from a medical grade polyurethane or Tecothane(R) containing tubing, implantable sensors (e.g., intravascular, transdermal, a radiopaque additive, such as barium sulfate orbismuth Salts intracranial, glucose sensors), diagnostic devices (e.g., to aid in radiographic imaging, or formed from a material microfluidic, microelectromechanical, and optical), oph coated with a medical grade polyurethane or Tecothane(R) thalmic devices including contact lenses, intraocular lenses containing a radiopaque additive, Such as barium sulfate or and phacoemulsification devices, orthopedic devices (includ 60 bismuth salts, to aid in radiographic imaging. In another ing hip implants, knee implants, shoulder implants, spinal embodiment, the substrate is a vascularly inserted catheter implants (including cervical plates Systems, pedicle screw formed from a medical grade polyurethane or Pellethane(R) or systems, interbody fusion devices, artificial disks, and other formed from a material coated with a medical grade polyure motion preservation devices), Screws, plates, rivets, rods, thane or Pellethane(R). In another embodiment, the substrate is intramedullary nails, bone cements, artificial tendons, and 65 a vascularly inserted catheter formed from a medical grade other prosthetics or fracture repair devices), dental implants, polyurethane or Pellethane(R) containing a radiopaque addi periodontal implants, breast implants, penile implants, max tive. Such as barium sulfate or bismuth salts, to aid in radio US 8,574,660 B2 29 30 graphic imaging, or formed from a material coated with a a polymer layer (e.g., a layer or oligomers or low (er) molecu medical grade polyurethane or PellethaneR containing a lar weight polymers), which generally contributes to Vertical radiopaque additive, such as barium Sulfate or bismuth salts, deviations of the surface from its ideal form (that is, a rougher to aid in radiographic imaging. or less Smooth Surface). Another example of a defect that may Medical device substrates are often composed of multiple be considered a chemical defect are process aids including different materials, each with its own surface properties. Even waxes and oils. devices composed primarily of a single polymer may be made In one embodiment, a surface treatment is applied resulting up of material blends and can include plasticizers, radio in a Substrate having a concentration of particles of the second opacity agents, and other additives all of which will affect phase visible through microscopy or SEM on the substrate Substrate Surface properties. 10 surface of about 50% less than the concentration of particles Surface Treatments of the second phase visible through microscopy or SEM on As noted above, various flaws can be present in the Surface the substrate surface of the unmodified substrate; more pref structure of biocompatible materials. The quality of the sur erably in this embodiment, a surface treatment is applied face of the substrate prior to surface modification can influ resulting in a Substrate having a concentration of particles of ence the quality of Subsequent Surface modifications 15 the second phase visible through microscopy or SEM on the described elsewhere herein, such as graft to and graft from substrate surface of about 70% less than the concentration of modifications. Substrate surface flaws may be the result of particles of the second phase visible through microscopy or low molecular weight species, such as additives and process SEM on the substrate surface of the unmodified substrate; still ing aids (e.g., waxes and oils), or physical characteristics, more preferably in this embodiment, a surface treatment is Such as Surface roughness (e.g., micro-roughness and macro applied resulting in a Substrate having a concentration of roughness), intentionally introduced to the Substrate Surface particles of the second phase visible through microscopy or or material, or may be unintentionally present as artifacts of SEM on the substrate surface of about 90% less than the the manufacturing process or Subsequent handling. For concentration of particles of the second phase visible through example, the Surface may be contaminated with various par microscopy or SEM on the substrate surface of the unmodi ticles, waxes, oils and other compositions that remain on the 25 fied substrate. surface of the substrate. In one embodiment, for example, the In one embodiment, a surface treatment is applied resulting low molecular weight species comprises a wax or a oil. In in a Substrate having a concentration of barium sulfate par another embodiment, for example, the low molecular weight ticles of the second phase visible through microscopy or SEM species comprises an additive. In another embodiment, for on the substrate surface of about 50% less than the concen example, the low molecular weight species comprises a low 30 tration of barium sulfate particles of the second phase visible molecular weight polymer. Surface improvements according through microscopy or SEM on the substrate surface of the to the methods described herein may involve heat treatment, unmodified substrate. In one embodiment, a surface treat polishing or solvent treatment techniques, and combinations ment is applied resulting in a Substrate having a concentration thereof, which serve to reduce the concentration of various ofbarium sulfate particles of the second phase visible through defects (or even remove them completely), resulting a rela 35 microscopy or SEM on the substrate surface of about 70% tively smooth substrate surface. Moreover, surface pre-treat less than the concentration of barium sulfate particles of the ments can assist in establishing a Substantially uniform second phase visible through microscopy or SEM on the chemical composition throughout the Surface; that is, the substrate surface of the unmodified substrate. In one embodi resulting treated substrate surface is relatively chemically ment, a Surface treatment is applied resulting in a substrate homogeneous or at least with reduced heterogeneity relative 40 having a concentration of barium sulfate particles of the sec to the surface prior to the treatment. ond phase visible through microscopy or SEM on the sub In general, Substrate surface flaws may be of a chemical strate surface of about 90% less than the concentration of and/or physical nature; that is, the Surface may include chemi barium sulfate particles of the second phase visible through cal defects (e.g., low molecular weight species), physical microscopy or SEM on the substrate surface of the unmodi defects (e.g., roughness), or both chemical and physical 45 fied substrate defects. Reducing Such flaws or defects can Substantially In one embodiment, a surface treatment is applied resulting improve performance of the resulting article. in a Substrate having a barium sulfate concentration in the Irrespective of the type of substrate (i.e., polymeric or near surface Zone of less than about 20% of bulk barium non-polymeric), the Substrate Surface may include any num sulfate wt.% concentration, as measured by SEM-EDS; more ber of physical defects in the form of Scratches, ridges, pin 50 preferably in this embodiment, the barium sulfate surface holes, Voids, waves, grooves, cracks, hills, pores, pillars, and concentration is less than about 10% of bulk barium sulfate the like, which contribute to an overall surface roughness. In wt.% concentration, as measured by SEM-EDS; still more addition to physical defects, the Substrate Surface may include preferably in this embodiment, the barium sulfate surface chemical defects, such as the presence of undesirable or concentration is less than about 5% of bulk barium sulfate extraneous Substances in or on the Surface of the Substrate. 55 wt.% concentration, as measured by SEM-EDS; still more One example of a defect that may be considered both a chemi preferably in this embodiment, the barium sulfate surface cal and a physical defect are particle(s) of barium sulfate concentration is less than about 1% of bulk barium sulfate (typically added to provide radio pacificity) that are only wt.% concentration, as measured by SEM-EDS. partially contained within the substrate. For example, sub Depending on the type of Substrate and/or the particular strates containing barium Sulfate typically have some barium 60 species, flaw, or other component that is wished to be sulfate particles that are partially contained within the sub removed from, or reduced on or in the Substrate, for example, strate and partially exposed; the exposed portions of Such the surface may be treated in a number of ways to affect the barium sulfate particles may extend from the surface of a desired Smoothing, homogenizing, and/or improved result. In Substrate to a height of as much as 1 micrometer (as measured one embodiment, for example, the Surface treatment may from the surface of the substrate). Some or all of the exposed 65 involve a heat treatment; that is, the Substrate, the underling or partially exposed barium Sulfate particles protruding from bulk, and/or particular portions thereof, may be heated for a a generally planar Surface of the Substrate may further include Sufficient time and temperature to conceal, reduce, or Sub US 8,574,660 B2 31 32 stantially or completely remove the presence of chemical employed. Representative mechanical Surface treatments for species, flaws, or other components. By way of example, use alone or in combination with another Surface treatment heating all or a portion of the Substrate Surface or bulk may include Sonication, vibration, Vortexing, shaking Solutions, push processing materials, Surface materials, artifacts, and Surface polishing, and microwave. other components towards a cooler region of the Substrate or 5 In one embodiment, the substrate is treated prior to or bulk, thus resulting in Smoother and/or more homogeneous during formation of the grafted polymer layer with a compo Surface. By way of further example, heating all or a portion of sition Such as an acid, base, chelator or reactant (or mixtures the Substrate may allow heterogeneous regions of stress in the thereof) that dissolves or chemically reacts with and reduces Substrate to relax producing a more uniform Substrate. In or Substantially or completely removes any compositions that another embodiment, the Surface treatment may involve treat 10 are included as chemical and/or physical defects. In one ing the Surface with one or more reactants (e.g., acids, bases, embodiment, the treatment comprises contacting the Sub Solvents, chelating agents, etc.) that are capable of Washing strate with a treatment solution. In some embodiments, the away or dissolving processing materials, artifacts, and other treatment solution comprises one or more of water, an acid, a components, thus resulting in Smoother and/or more homo base, a chelator, a Surfactant, or other reactant. In some geneous Surface. Combinations of various Surface treatments 15 embodiments, the acid, base, chelator or reactant (or mixture may also be employed, either serially or concurrently (e.g., a thereof) may dissolve or chemically react with additional or combination of a solvent treatment and a heat treatment). extraneous Substrate material (i.e., polymer) that contributes In accordance with one embodiment, therefore, the sub to the Surface roughness and/or heterogeneity of the Substrate. strate Surface is Subjected to a treatment stage (i.e., is pre For example, exposed portions of barium sulfate particles treated) prior to the formation of the grafted polymer layer on may be removed or their presence reduced, e.g., partially or the substrate. This surface pre-treatment serves to reduce the completely dissolved, using a mineral or organic acid and incidence (i.e., Surface density) or the severity (e.g., the size) optionally, a chelator. In one such exemplary embodiment, of chemical and/or physical defects, thus providing a Sub polyurethane comprising particles of barium Sulfate may be strate Surface that is at least Substantially improved, if not treated with an acid (e.g., 1N hydrochloric acid) or a base substantially free of defects, prior to formation of the grafted 25 (e.g., 1N sodium hydroxide) to at least partially remove polymer layer. exposed barium sulfate particles. Alternatively, a chelator In accordance with another particular embodiment, the solution such as 1 Nethylenedioxy-diethylene-dinitrilo-tet Surface pre-treatment stage and the formation of the grafted raacetic acid (EDTA) may be applied on the polyurethane. polymer layer occur in a single step. As noted above, in some Acid, base, and/or chelator treatment times may be in the embodiments the solvent(s) or other reactants employed as 30 range of 1 hour to 24 hours, or longer, more preferably about part of the Surface treatment (for example, to dissolve mate 2 hours. Without being bound by any particular theory, acid, rial from the surface) may have additional functionality in the base, and/or chelator treatment can reduce or remove the Surface modification process. For instance, in one embodi particles from the surface by increasing their solubility in the ment, the Surface treatment solvent also functions to intro Solution and/or by decreasing the particle's adherence to the duce a polymerization initiator into and/or onto the Substrate 35 Substrate. Representative acids include, for example, hydro Surface by physio-adsorption, allowing the Substrate to Swell chloric acid, Sulfuric acid, nitric acid, phosphoric acid, boric and ultimately imbibing initiator into the substrate. Option acid, hydrofluoric acid, hydrobromic acid, lactic acid, acetic ally, the Surface treatment/imbibing process may be accom acid, carbonic acid, formic acid, citric acid, oxalic acid, uric panied by mechanical agitation (e.g., Sonication) in order to acid, carboxylic acids, Sulfonic acids, Sulfamic acid, chlorous promote dissolution or removal of the Substrate Surface mate 40 acid, and the like. Representative bases include, for example, rial and/or to enhance the imbibing process. Sodium hydroxide, potassium hydroxide, ammonia Solution, The type and method of treatment may generally depend sodium chlorite, and the like. Representative chelators on the type of substrate surface. For non-polymeric substrate include, for example, water, carbohydrates, including Surfaces, for example, the non-polymeric Surface may be polysaccharides, organic acids with more than one coordina mechanically, chemically, thermally, or chemomechanically 45 tion group, lipids, steroids, amino acids and related com treated or polished to reduce Surface roughness and/or the pounds, peptides, phosphates, nucleotides, tetrapyrrols, fer incidence and/or severity of cracks, pinholes and other struc rioxamines, ionophores, such as gramicidin, monensin, tural defects in the substrate surface. This may involve expos Valinomycin, phenolics, 2,2'-bipyridyl, dimercaptopropanol, ing the Surface to a solvent or a chemically reactive species to ethylenediaminotetraacetic acid, EDTA, ethylenedioxy-di dissolve or chemically react with the material in the discon 50 ethylene-dinitrilo-tetraacetic acid, EGTA, ethylene glycol tinuous material phase. For example, the Substrate may be bis-(2-aminoethyl)-N.N.N',N'-tetraacetic acid, nitrilotriace Solvent polished by exposing the Substrate to a vapor of a tic acid, NTA, ortho-phenanthroline, salicylic acid, Solvent Such as chloroform, dioxane or tetrahydrofuran. triethanolamine, TEA, 5-sulfosalicylic acid, oxalic acid, cit Where the substrate surface is a polymeric substrate surface, ric acid, tartaric acid, ethylene glycol-bis(2-aminoethyl for instance, treatment may involve chemical or solvent treat 55 ether)-N.N.N',N'-tetraacetic acid, enterobactin, ethylenedi ment methods or a combination thereof. Additionally, or aminetetra(methylenephosphonic acid) and corresponding alternatively, the substrate surface treatment may involve heat salts, and the like. Certain preferred chelators are polyamino treatment. carboxylic acids, e.g., glycine, beta-alanine, iminodiacetic Methods of treatment of the substrate surface, therefore, acid (IDA), nitrilotriacetic acid (NTA), ethylenediaminetet may include both mechanical, chemical, and thermal treat 60 raacetic acid, (EDTA), diethylene triamine pentaacetic acid ment steps, including combinations of mechanical, chemical, (DTPA), 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tet and thermal treatments. For example, the Substrate Surface raacetic acid (BAPTA), 1,4,7,10-tetraazacyclododecane-1,4, may be treated using water, Solvents, Surfactant Solutions, or 7,10-tetraacetic acid (DOTA), and the like. other cleaning solutions orgases, or polished, or Subjected to In another embodiment, the substrate is treated prior to or aheat treatment, to reduce or even remove particles, waxes or 65 during formation of the grafted polymer layer with a compo other foreign compositions that may be on the Surface of the sition Such as a solvent that dissolves or chemically reacts Substrate. In some embodiments, a heat treatment may be with and removes or reduces any compositions that are US 8,574,660 B2 33 34 included as chemical and/or physical defects. In one embodi tative examples thereof may also be employed. More specific ment, the Substrate is treated with a treatment solution com examples of solvents include aromatic hydrocarbons, chlori prising a solvent. In some embodiments, a solvent or mixture nated hydrocarbons, ethers, aliphatic hydrocarbons, alcohols, of solvents may dissolve or chemically react with additional esters, ketones, amides, and mixtures thereof. Exemplary or extraneous Substrate material (i.e., polymer) that can con polar protic solvents include, but are not limited to, acetic tribute to the Surface roughness and/or non-homogeneity of acid, formic acid, n-butanol, ethanol, isopropanol, methanol, the substrate. Preferred solvents include acetone, ethanol, n-propanol, and water. In one embodiment, the Solvent is a isopropanol, heptane, and methanol. Mixtures of these sol polar protic solvent selected from methanol, ethanol, isopro vents (and those discussed elsewhere herein) with each other panol, and combinations thereof. Exemplary aprotic polar or with water may also be applied. Preferred temperatures for 10 Solvents include, but are not limited to, acetone, acetonitrile, the treatment may be at or above room temperature, for cyclohexanone, cyclopentanone, dichloromethane, diglycol example, 30° C., 40°C., 50° C., 60° C., or 80°C. Treatment methyl ether, dimethylacetamide, dimethylformamide, dim times may be in the range of 1 hour to 24 hours, or longer; ethyl sulfoxide, hexamethylphosphoramide (HMPA), meth more preferably about 2 hours. ylethylketone, N-methylpyrrolidone (NMP), sulfolane, and In another embodiment, the substrate is subjected to a heat 15 tetrahydrofuran (THF). In one embodiment, the solvent is an treatment. In general, the temperature of the heat treatment is aprotic polar solvent selected from acetone, acetonitrile, Sufficient to achieve the desired result (i.e., providing an cyclohexanone, cyclopentanone, dimethylacetamide, dim improved Substrate Surface) without negatively affecting ethylformamide, methylethylketone, and combinations (e.g., melting or disassociating) the Substrate or the underly thereof. Exemplary non-polar solvents include, but are not ing bulk. It will be understood that the desired temperature of limited to, benzene, carbon disulfide, carbon tetrachloride, the heat treatment will generally depend on the particular chloroform, cyclohexane, cyclopentane, diethyl ether, diiso polymeric material(s) employed in the Substrate and/or bulk. propylether, 1,4-dioxane, hexane, heptane, mineral oil, pen Preferably, the thermal treatment is carried out at a tempera tane, and toluene. In one embodiment, the solvent is a non ture below the softening point of the substrate material. Typi polar solvent selected from cyclohexane, diethyl ether, cally, heat treatment is carried out at a temperature of from 25 hexane, heptane, toluene, and combinations thereof. In a par 20° C. to 100° C. for a period of about 30 seconds to about 2 ticularly preferred embodiment, the solvent is selected from hours. In one embodiment, for example, the Surface treatment the group consisting of acetone, methanol, ethanol, isopro involves heating all or a portion of the Substrate surface at a panol, heptane, and combinations thereof. temperature of about 30° C., 40°C., 50° C., 60° C., 80°C., or As noted above, mixtures of one or more organic solvents 100° C. In another embodiment, the surface treatment 30 (i.e., a solvent system) may also be employed. For example, involves heating all or a portion of the Substrate surface at a the solvent may be a mixture of polar protic solvent and a temperature of from about 25°C. to about 60°C. In another polar aprotic solvent (e.g., methanol:dimethylacetamide), a embodiment, the Surface treatment involves heating all or a mixture of a polar protic solvent and a non-polar solvent (e.g., portion of the substrate surface to a temperature of from about ethanol: heptane), and/or a mixture of a polar aprotic solvent 30° C. to about 50° C. In another embodiment, the surface 35 and a non-polar solvent (e.g., acetonitrile:benzene). Mixtures treatment involves heating all or a portion of the substrate of one or more organic solvents and water may also be surface to a temperature of from about 40°C. to about 80°C. applied. Various devices and methods for Supplying the thermal Inorganic and/or aqueous solvents may also be employed energy involved in the heat treatment may be used, including in the treatment processes described herein. Exemplary aque conventional ovens, microwave ovens, convection ovens, 40 ous solvents include water, Saline, acids (e.g., 1N hydrochlo infrared heaters, induction-type heaters, water baths, and the ric acid), bases (e.g., 1N sodium hydroxide), and Surfactants like. (e.g., SDS, Tween(R), and the like). In one preferred embodiment, a treatment solution, Such as In another embodiment, treating the Substrate surface com a solvent or a solution comprising a solvent, is applied to prises contacting the Substrate surface with a solution con reduce process aids. The treatment Solution (e.g., solvent) 45 taining an acid, a base, or a chelating agent to reduce (or even may be applied such that it is stationary relative to the sub completely remove) the second material from the substrate strate. In these embodiments, the solvent is generally dis Surface. Exemplary acids for use in the treatment Solution posed atop or Surrounding the Substrate for a period of time. include, but are not limited to, hydrochloric acid, acetic acid, In other embodiments, at least one of the substrate and treat and citric acid. Exemplary bases for use in the treatment ment Solution moves relative to the another—as examples, 50 Solution include, but are not limited to, sodium hydroxide, the solution may be sprayed on to the substrate, or the sub potassium hydroxide, and the like. Exemplary chelating strate may be conveyed through a falling curtain of fluid or agents for use in the treatment Solution include, but are not conveyed through a pool or bath of treatment solution mate limited to, ethylenediamine tetra-acetic acid ("EDTA), rial. Treatment solution can also be flowed, bubbled, sprayed, diethylenetriaminepentaacetic acid (“DTPA), and nitrilotri spin cast, dipped, painted on, brushed on, immersed, and the 55 acetic acid (“NTA'). In one preferred embodiment, a combi like. Vapors of solvents may also be employed. Treatment nation of EDTA and potassium hydroxide. In another pre Solution(s) may be applied under ambient (e.g., static) con ferred embodiment, the treatment comprises contacting the ditions, but may also be applied under heating, cooling, Substrate Surface with a solution comprising a combination of increased or reduced pressure, agitation (e.g., vibration, Soni EDTA and sodium hydroxide. cation), increased or decreased humidity, and the like. Addi 60 Surfactants and solutions of Surfactants may be used in the tionally, or alternatively, the Substrate and treatment Solution treatment processes. Some preferred surfactants include can be subjected to a Soxhlet extraction (using, for example, anionic Surfactants, such as alkyl Sulfates: ammonium lauryl ethanol or isopropanol) for a period of time (e.g., 1-3 days). sulfate, sodium lauryl sulfate (SDS, sodium dodecyl sulfate, Solvents that may be used in the treatment processes another name for the compound); alkyl ether sulfates: sodium described herein include various kinds of organic solvents 65 laureth sulfate, also known as sodium lauryl ether sulfate Such as polar protic solvents, polar aprotic solvents and non (SLES), sodium myreth sulfate; sulfonates: for example polar solvents. Mixtures of two or more of these or represen docusates: dioctyl Sodium Sulfo Succinate; Sulfonate fluoro US 8,574,660 B2 35 36 surfactants: perfluorooctanesulfonate (PFOS), perfluorobu In certain preferred embodiments, the substrate and solvent tanesulfonate; alkyl benzene Sulfonates; phosphates: for are subjected to mechanical agitation during the treatment. example alkyl aryl ether phosphate, alkyl ether phosphate: For example, the substrate and solvent may be flowed, carboxylates: for example alkyl carboxylates: fatty acid salts bubbled, Swirled, mixed, shaken, or sonicated in order to (soaps): sodium Stearate; sodium lauroyl sarcosinate; car- 5 promote dissolution or removal of undesirable or less desir boxylate fluoroSurfactants: perfluorononanoate, perfluorooc able chemical species (e.g., processing aids such as waxes) tanoate (PFOA or PFO). present on the surface of or in the substrate. Optionally, but Some preferred surfactants also include cationic Surfac preferably, the Substrate and solvent are Sonicated during the tants, such as octenidine dihydrochloride; alkyltrimethylam treatment. Additionally or alternatively, the treatment step monium salts: cetyl trimethylammonium bromide (CTAB) 10 may involve the use of energy Such as shear or compression (as known as hexadecyl trimethylammonium bromide); cetyl forces, or the like, to reduce the concentration of chemical trimethylammonium chloride (CTAC); cetylpyridinium chlo species on the surface of or in the substrate. In one embodi ride (CPC); polyethoxylated tallow amine (POEA); benza ment, the Substrate can be suspended, immersed, or otherwise lkonium chloride (BAC); benzethonium chloride (BZT): contacted with a solvent and then Subjected to Sonication. The 5-bromo-5-nitro-1,3-dioxane; dimethyldioctadecylammo- 15 Substrate and solvent may be agitated for a time period effec nium chloride; and dioctadecyldimethylammonium bromide tive to reduce the concentration of chemical species on the (DODAB). Some preferred surfactants also include Zwitteri surface of or in the substrate to an acceptable level. The onic (amphoteric) surfactants: such as CHAPS (3-(3-Chola substrate may then be dried in alternative embodiments. midopropyl)dimethylammonio-1-propanesulfonate); coca Thus, for example, the substrate surface may be subjected midopropyl hydroxysultaine; amino acids; Imino acids: 20 to a one or more mechanical, chemical, thermal, chemome cocamidopropyl betaine; and lecithin. Some preferred Surfac chanical, chemothermal treatments, and combinations tants also include nonionic Surfactants such as fatty alcohols: thereof. Among other things, these treatments can assist cetyl alcohol, Stearyl alcohol, cetostearyl alcohol (consisting transmittance (imbibing) of molecules into a Substrate, predominantly of cetyl and Stearyl alcohols), oleyl alcohol; reduce the incidence and/or the severity of physical defects polyoxyethylene glycol alkyl ethers (Brij): CH (CH)10- 25 and chemical species, and/or selectively or non-selectively 16-(O—CH)1-25-OH: octaethylene glycol monododecyl remove molecules from the substrate or modified surface. For ether, pentaethylene glycol monododecyl ether, Polyoxypro instance, ultra-sonication between 40 and 50 Khz may be pylene glycol alkyl ethers: CH (CH)10-16-(O—CH)1- used to assist in permeation of initiators into Substrates. Ultra 25-OH: Glucoside alkyl ethers: CH (CH)10-16-(O-Glu Sonication in combination with specific solvents and varied coside)1-3-OH: Decyl glucoside, Lauryl glucoside, Octyl 30 thermal conditions, for instance, assists the imbibing process glucoside; Polyoxyethylene glycol octylphenol ethers: by maximizing penetration and distribution of molecular CH (CH)–(O CH)1-25-OH: Triton X-100; Poly entities while minimizing exposure for each individual oxyethylene glycol alkylphenol ethers: CoH (CH)— energy. Ultra-Sonication can also be used to reduce or Sub (O CH)1-25-OH: Nonoxynol-9; Glycerol alkyl esters: stantially or completely remove processing aids and may be Glyceryl laurate; Polyoxyethylene glycol sorbitan alkyl 35 applied in conjunction with solvent exposure and thermal esters: Polysorbates; Sorbitan alkyl esters: Spans; Cocamide conditioning. Ultra-Sonication baths and wands may be used MEA, cocamide DEA. Dodecyldimethylamine oxide; and for either of these applications. Preferred powers include 100 Block copolymers of polyethylene glycol and polypropylene to 600 watts. In one preferred embodiment, catheters are glycol: Poloxamers exposed to an alcohol while placed in a Sonication bath. This interaction between the substrate surface and the sol- 40 Temperature is controlled to less than 37°C. for varied speci vent advantageously reduces the concentration of chemical fied periods, depending, for example, on the ultrasonic bath species on the Surface of in the Substrate without significantly power, device loading, and transducer generating frequency, altering the bulk physical properties of the article. In general, to facilitate the imbibing process or chemical species the substrate may be treated with the solvent for a period of removal. Iflumens within devices are being treated, a solvent time to reduce at least some or substantially all of the unde- 45 may be drawn into the lumen before ultra-sonication is sirable chemical species at or near the Substrate surface. In applied to prevent air exposure to ultrasonic power in the certain embodiments, for example, the Substrate surface is imbibing and/or species removal process. Solvents may also treated for a period of time of at least about 1 hour. Typically, be periodically or continually drawn through the lumen dur however, greater treatment times will be employed. For ing ultra-Sonication processing, alone or in combination with example, in Some embodiments, the Substrate Surface is 50 thermal conditioning, for both imbibing and/or species treated for a period of time of at least about 2 hours; at least removal. about 4 hours; at least about 6 hours; at least about 8 hours; at It will be understood that the particular of surface least about 10 hours; at least about 12 hours; at least about 14 treatment(s) selected, and the corresponding parameters hours; at least about 16 hours; at least about 18 hours; at least thereof (e.g., the choice of Solvent, acid, base, or other reac about 20 hours; at least about 22 hours; or at least about 24 55 tant for the treatment (if any); the choice of polishing tech hours. By way of further example, in some embodiments; the nique; the temperature and duration of the treatment, and so substrate surface is treated for a period of time of about 2 on) will generally depend on the species being reduced or hours to about 4 hours; about 2 hours to about 8 hours; about substantially or completely removed from the substrate sur 2 hours to about 12 hours; about 2 hours to about 16 hours; face and the composition of the substrate and/or bulk. Pref about 2 hours to about 20 hours; or about 2 hours to about 24 60 erably, the Solvent or reactant and corresponding treatment hours. In one particular embodiment, the Substrate Surface is conditions will not substantially dissolve the substrate. Addi treated for a period of time of about 2 hours. In another tionally, the solvent or reactant is preferably substantially particular embodiment, the substrate surface is treated for a inert (i.e., will not react with) when interacting with the period of time of about 2 hours to about 24 hours. In such substrate. It is also preferred to select a solvent or reactant that embodiments, the treatment temperature may be in the range 65 will not substantially swell the substrate; for example, swell of 22 to 60° C., more preferably in the range of 22 to 37° C., ing of less than 25%, more preferably less than 10%, more with about 25°C. being preferred in certain embodiments. preferably less than 5%, and still more preferably less than US 8,574,660 B2 37 38 1%, is generally desired. The choice of solvent or reactant Advantageously, the Surface treatment processes described should also be capable of dissolving, solubilizing, or other herein do not substantially disturb or alter the various physi wise affecting the undesired, extraneous, or other compo cal properties of the bulk or the visual or surface characteris nents or materials at the surface of the substrate that contrib tics of the substrate. Physical properties may include, but are ute to the Surface roughness or heterogeneity. Solvents or 5 not limited to. Such geometrical characteristics such as size, reactants that can be relatively easily removed from the sub length, width, height, Volume, diameter, cross-sectional area, strate once the treatment is complete, e.g., by low boiling or thickness etc., mechanical characteristics Such as ductility, extraction, are also preferred. flexural modulus, flexural strength, shear strength, specific The particular solvent(s) or other reactants that are selected modulus, tensile strength, yield strength, elongation, and for use in the treatments described herein are preferably those 10 gauging, and other device characteristics Such as separation in which the process aids or other low molecular weight force (to pull components of the device apart), stress cracking species are soluble, but in which the substrate is not substan and liquid and air leakage resistance. Visual and Surface char tially soluble or insoluble. Preferably, process aids such as acteristics include color, marking clarity and legibility of amide wax will have solubility in the solvents chosen for 15 printed indicia. For many substrates such as medical devices treatment above. In some embodiments, for example, the for which geometrical and mechanical properties are impor processing aids will have a solubility of at least 0.5 wt.% in tant for device function, preferable combinations of solvent, the treatment solvent at the temperature applied. More pref time and temperature of treatment are used during the treat erably, the processing aids will have a solubility of at least 1 ment process to minimize changes to these geometrical and wt.%; at least 2.5 wt.%; or at least 5 wt.%. Further, the mechanical properties. Extruded materials such as catheters Substrate components that are not intended to be reduced or may be particularly sensitive to dimensional changes during removed. Such as large molecular weight polyurethane in a treatment processes due to stresses in the catheter from the catheter, have a solubility in the treatment solvent below 1 extrusion process. It is generally preferred, therefore, that, as wt.% at the temperature applied. More preferably, the sub a result of the solvent treatment process described herein, any strate components that are not intended to be removed. Such 25 one or more of the desired physical properties of the under as large molecular weight polyurethane in a catheter will have lying bulk substrate materials change by less than 50%: more a solubility of less than 0.5 wt.%; less than 0.2 wt.%; or less preferably less than 30%; still more preferably less than 20%: than 0.1 wt.%. By applying mechanical treatment, process still more preferably less than 10%; still more preferably less aids may be removed above their solubility limit in the treat than 5%; still more preferably less than 3%; still more pref ing solvent as they may come off the substrate in the form of 30 particles or non-dissolved materials. erably less than 2%; still more preferably less than 1%; still In one embodiment, the substrate surface is treated for a more preferably less than 0.5%; and still more preferably less time period of about 2 hours with a solvent selected from the than 0.25%. Among the various methods for measuring these group consisting of acetone, methanol, ethanol, isopropanol, physical properties include, but are not limited to, calibrated heptane, and combinations thereof. In another embodiment, 35 rulers (e.g., for dimensions such as length); non-contact mea the substrate surface is treated for a time period of about 2 Surement systems (e.g., for cross-sectional dimensions); hours with a solvent selected from the group consisting of Syringe pumps (e.g., for pumped flow rate-representative con acetone, methanol, ethanol, isopropanol, heptane, and com ditions 11.9 mL/min); and various ISO measurement stan binations thereof, wherein the substrate and solvent are sub dards including, for example: ISO 10555-3 (e.g., for gravity jected to Sonication during at least a portion (e.g., about 5 40 flow rate): ISO 10555-1 and ISO 10555-3 (e.g., for tensile minutes, about 15 minutes, about 30 minutes, about 1 hour, testing); ISO 594-1 and ISO 594-2 (e.g., for luer testing); and about 1 hour 15 minutes, about 1 hour 30 minutes, about 1 ISO 10555-1 (e.g., for catheter leakage). hour 45 minutes, or about 2 hours) of the surface treatment. In In one embodiment, for example, as a result of the Solvent Some of these embodiments, for example, a Surface treatment treatment, the length of the bulk substrate material is reduced is applied resulting in a Substrate having a process aid con 45 by less than 50%; more preferably less than 30%; more pref centration of less than about 0.1%: more preferably in this erably less than 20%; more preferably less than 10%: more embodiment, the process aid concentration is less than about preferably less than 3%; more preferably less than 2%: more 0.05%; still more preferably in this embodiment, the process preferably less than 1%; more preferably less than 0.5%; still aid concentration is less than about 0.01%. In some embodi more preferably less than 0.25%. ments described above, the process aid is a wax or oil, and the 50 In another embodiment, for example, as a result of the Substrate is a polyurethane. solvent treatment, the diameter of the bulk substrate material In some embodiments, the final concentration of the pro is reduced by less than 50%; more preferably less than 30%; cess aid in or on the Substrate is reduced in an article on which more preferably less than 20%; more preferably less than a non-fouling Surface is formed. In some of these embodi 10%: more preferably less than 3%; more preferably less than ments, for example, the Substrate has a process aid concen 55 2%: more preferably less than 1%; more preferably less than tration of less than about 0.1%, the treated surface and the 0.5%; still more preferably less than 0.25%. grafted polymer layer, in combination, constitute a low-foul In another embodiment, for example, as a result of the ing Surface having a fibrinogen adsorption of less than about solvent treatment, the ductility of the bulk substrate material 125 ng/cm in a fibrinogen binding assay in which the low is reduced by less than 50%; more preferably less than 30%; fouling surface is incubated for 60 minutes at 37° C. in a 60 more preferably less than 20%; more preferably less than composition containing 70 ug/mL fibrinogen derived from 10%: more preferably less than 3%; more preferably less than human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. 2%: more preferably less than 1%; more preferably less than More preferably in this embodiment, the process aid concen 0.5%; still more preferably less than 0.25%. tration is less than about 0.05%; still more preferably in this In another embodiment, for example, as a result of the embodiment, the process aid concentration is less than about 65 solvent treatment, the flexural modulus of the bulk substrate 0.01%. In some embodiments described above, the process material is reduced by less than 50%; more preferably less aid is a wax or an oil, and the Substrate is a polyurethane. than 30%; more preferably less than 20%; more preferably US 8,574,660 B2 39 40 less than 10%: more preferably less than 3%; more preferably and polyester Surfaces), and glass treatment with hydrogen less than 2%: more preferably less than 1%: more preferably fluoride. In one preferred embodiment, hydrochloric acid is less than 0.5%. particularly effective for the removal of barium sulfate par In another embodiment, for example, as a result of the ticles on the surface of polymers. Chelators may also be solvent treatment, the flexural strength of the bulk substrate employed to reduce or even completely remove Surface min material is reduced by less than 50%; more preferably less erals. By way of example, mineral deposit and Scale may be than 30%; more preferably less than 20%; more preferably partially or Substantially removed using ethylenediaminetet less than 10%: more preferably less than 3%; more preferably raacetic acid and bisphosphonates. less than 2%: more preferably less than 1%: more preferably Surface modified to mask defects, including: over-coating, less than 0.5%; still more preferably less than 0.25%. 10 In another embodiment, for example, as a result of the Solvent coating, grafted or adsorbed Surface modification, solvent treatment, the shear strength of the bulk substrate interpenetrating network modification, Surface active bulk material is reduced by less than 50%; more preferably less modification, polyelectrolyte multilayer films, metallization, than 30%; more preferably less than 20%; more preferably sprayed hydroxyapatite (for e.g., orthopedic applications). less than 10%: more preferably less than 3%; more preferably 15 Other exemplary treatments include: less than 2%: more preferably less than 1%: more preferably (1) coaxial compositions with homogeneous Surfaces, for less than 0.5%; still more preferably less than 0.25%. example, from the co-extrusion or co-injection of purified In another embodiment, for example, as a result of the polymer over polymers with additives, solvent treatment, the specific modulus of the bulk substrate (2) Surface crosslinking, for example using Surface material is reduced by less than 50%; more preferably less silanization for metals glass and Kevlar fibers; than 30%; more preferably less than 20%; more preferably (3) UV; less than 10%: more preferably less than 3%; more preferably (4) electrochemical methods including anodization and less than 2%: more preferably less than 1%: more preferably cathodization. For example, aluminum protect aluminium, less than 0.5%; still more preferably less than 0.25%. titanium, zinc, magnesium, niobium, and tantalum with anod In another embodiment, for example, as a result of the 25 ization; solvent treatment, the tensile strength of the bulk substrate (5) oxidation including high Voltage cornea treatment in material is reduced by less than 50%; more preferably less the presence of oxygen. Oxidation also including treatment of than 30%; more preferably less than 20%; more preferably the Substrate with oxidants, for example, hydrogen peroxide, less than 10%: more preferably less than 3%; more preferably chromic acid, nitrous acid, Sulfuric acid/hydrogen peroxide less than 2%: more preferably less than 1%: more preferably 30 Solution. For example, titanium treatment an oxidant. less than 0.5%; still more preferably less than 0.25%. (6) Aluminum treatment with sulfuric acid; In another embodiment, for example, as a result of the (7) Base treatments: solvent treatment, the yield strength of the bulk substrate (8) Flame treatment; and material is reduced by less than 50%; more preferably less (9) Sonication. than 30%; more preferably less than 20%; more preferably 35 After treatment, the substrate surface preferably has a R, less than 10%: more preferably less than 3%; more preferably Surface roughness that is less than the R. Surface roughness less than 2%: more preferably less than 1%: more preferably of the untreated substrate. By way of further example, in one less than 0.5%; still more preferably less than 0.25%. embodiment the treated Substrate Surface has a R, Surface In addition to the surface treatments described herein, a roughness that is no more than 90% of the R. Surface rough range of other, different Surface treatments may be employed 40 ness of the untreated substrate surface. By way of further in accordance with the processes disclosed herein. Electro example, in one embodiment the treated Substrate Surface has lytic process can be used to increase the thickness of the a R, surface roughness that is no more than 75% of the R. natural oxide layer on the surface of metals. Electrochemical Surface roughness of the untreated Substrate Surface. By way methods include, for example, anodization and cathodiza of further example, in one embodiment the treated substrate tion. For example, aluminium, titanium, zinc, magnesium, 45 Surface has a R, Surface roughness that is no more than 50% niobium, and tantalum treatment with anodization yields of the R. Surface roughness of the untreated Substrate Sur oxide layers. Electroplating with other metal(s) may also be face. performed. In one embodiment, for example, mechanical and In certain embodiments, the Substrate may contain a radio physical treatments include Sonication, Ion beam etching paque agent, such as BaSO orbismuth, to aid in radiographic (e.g., argon, Xenon), Plasma etching (e.g., nitrogen, argon, 50 imaging of the Substrate. In one embodiment the polymer is oxygen, water vapor), Corona discharge, UV irradiation, Tecoflex-93A, Carbothane 85A, Pellethane 2363, Tecothane Mechanical polishing, Solvent washing to Smooth polymer 97A, or PVC optionally containing 0 to 40% by weight Surfaces, Flame treatment, physical vapor deposition (e.g., BaSO4. In one embodiment, the Substrate comprises a poly Surface coating with diamond membrane). The Surface may mer that does not contain extrusion or release waxes, which additionally or alternatively be oxidized; for instance oxida 55 may be referred to as solvent grade. In a further embodiment, tion including high Voltage cornea treatment in the presence the Substrate is a solvent grade polyurethane. In one embodi of oxygen may be employed. Oxidation methods may also ment, the Substrate comprises a polyurethane that is Substan include treatment of the substrate with oxidants such as, for tially free of barium sulfate or other radiopaque crystals. In a example, hydrogen peroxide, chromic acid, nitrous acid, Sul further embodiment, the substrate is a solvent grade polyure furic acid/hydrogen peroxide Solution, and combinations 60 thane that is substantially free of radiopaque crystals. In a thereof. For example, in addition to removing organic con further embodiment, the polymeric substrate is a solvent tamination, titanium treatment with Sulfuric acid/hydrogen grade Carbothane. In a further embodiment, the polymeric peroxide is thought to result in an increased surface hydroxyl substrate is a solvent grade Tecoflex. Inafurther embodiment, function. the polymeric Substrate is a copolymer of silicone copolymer. Exemplary chemical polishing techniques include, chemi 65 In a further embodiment, the polymeric Substrate is a copoly cal vapor deposition (CVD), acid and base treatments (in mer of silicone and polyurethane. In a further embodiment, cluding, for example, Sodium hydroxide treatment of glass the polymeric substrate is Biomer. US 8,574,660 B2 41 42 The substrate can also include, but is not limited to, poly material is grafted from a polymeric primer layer, Such as a mers such as polystyrene and Substituted polystyrenes, poly polyurethane layer which overlies a polymeric bulk, Such as ethylene, polypropylene, poly(urethane)S. polyacrylates and polyurethane. polymethacrylates, polyacrylamides and polymethacryla In one embodiment, the non-fouling polymeric material mides, polyesters, polysiloxanes, polyethers, poly(orthoe that is grafted from the Substrate comprises a chain-growth ster), poly(carbonates), poly(hydroxyalkanoate)S. polyfluo polymer (that is, a polymer or polymer block formed by rocarbons, PEEK, Teflon, silicones, epoxy resins, addition polymerization), or a combination thereof. The KEVLARR, NOMEX(R), DACRONR), HYTRELR), chain-growth polymer may be, for example, an addition poly PEBAX(R), SURLYNR), nylon, polyalkenes, phenolic resins, mer derived from monomer(s) incorporating double or triple PTFE, natural and synthetic elastomers, adhesives and seal 10 bonds, e.g., an olefin. By way of further example, the chain ants, polyolefins, polysulfones, polyacrylonitrile, biopoly growth polymer may comprise an addition polymer derived merS Such as polysaccharides and natural latex copolymers from a cyclic monomer by means of a ring-opening polymer thereof, and combinations thereof. ization reaction. Thus, the polymer may be a chain-growth Regardless of the pre-treatment steps, or even whether homopolymer or copolymer. In a preferred embodiment, the pre-treatment steps are employed, the Surface of the Substrate 15 polymer is a chain growth addition homopolymer or a chain preferably has a R, surface roughness that is no more than growth addition copolymer comprising the residue of two or 200 nm. In one embodiment, for example, the surface of the OOOCS. Substrate has a R, Surface roughness of no more than 150 In accordance with one aspect of the present invention, it is nm; more preferably in this embodiment, the surface of the generally preferred that the non-fouling polymeric material Substrate has a R, Surface roughness of no more than 100 be prepared without inordinate use of a polyfunctional nm. In certain embodiments, the Surface is even Smoother. For crosslinking agent. For example, it is generally preferred that example, the Surface may have a R, Surface roughness of the non-fouling polymeric material contain less than 50 less than 50 nm. In some embodiments, the Surface may have mole % of the residue of a polyvalent crosslinker. In one such a R, Surface roughness of less than 20 nm. embodiment, the non-fouling polymeric material contains Additionally, or alternatively, and regardless of the pre 25 less than 25 mole% of the residue of a polyvalent crosslinker. treatment steps, or even whether pre-treatment steps are In one such embodiment, non-fouling polymeric material employed, the surface of the substrate to be subjected to containless than 10 mole% of a polyvalent crosslinker. In one further surface modifications has a surface defect density of Such embodiment, the non-fouling polymeric material con defects having a size greater than about 0.5 micrometers that tains less than 5 mole % of the residue of a polyvalent is less than 0.1 defects/um For example, the surface of the 30 crosslinker. In one Such embodiment, non-fouling polymeric substrate to be subjected to further surface modifications may material contain less than 3 mole % of a polyvalent have a surface defect density of defects having a size greater crosslinker. In one such embodiment, the non-fouling poly than about 0.5 micrometers that is less than 0.05 defects/um. meric material contains less than 0.1 mole'/6 of the residue of By way of further example, the surface of the substrate to be a polyvalent crosslinker. In one such embodiment, the non Subjected to further Surface modifications may have a Surface 35 fouling polymeric material contains no residue of a polyva defect density of defects having a size greater than about 0.5 lent crosslinker. micrometers that is less than 0.01 defects/um. By way of Through grafting, step-growth or chain-growth tech further example, the surface of the substrate to be subjected to niques, the non-fouling polymeric material may comprise any further surface modifications may have a surface defect den of a range of polymer types or combinations thereof. The sity of defects having a size greater than about 0.5 microme 40 polymer backbone may be neutral (e.g., polyalkylene or poly ters that is less than 0.002 defects/um. By way of further ether) or contain permanently charged moieties (e.g., cyclic example, the surface of the substrate to be subjected to further or acyclic quaternized nitrogen atoms), or even Zwitterionic Surface modifications may have a surface defect density of backbones (e.g., phosphorylcholine backbones). In one defects having a size greater than about 0.5 micrometers that embodiment, therefore, the non-fouling polymeric material is less than 0.001 defects/um. 45 comprises a polymer or copolymer selected from the group Surface Modifications consisting of polyamide, polyamine, polyanhydride, In accordance with the methods described herein, the polyazine, poly(carbonate), polyester, polyether, polyethere treated Substrate layers are subjected to Surface modification; therketone (PEEK), polyguanidine, polyimide, polyketal, that is, a graft polymeric material layer is formed on a treated poly(ketone), polyolefin, poly(orthoester), polyphosphazine, polymeric Substrate surface layer having the characteristics 50 polysaccharide, polysiloxane, polysulfone, polyurea, poly described above. urethane, halogenated polymer, silicone, hydrocarbon, ether In general, a non-fouling polymeric material is grafted ester, ether-amide or ionized polyethylene and combinations from or to a polymeric Substrate using, for example, conven thereof. tional grafting techniques. The polymer may also contain a wide range of pendant In one preferred embodiment, a graft-from approach is 55 (side-chain) groups, hydrophilic and hydrophobic, neutral, employed in which one or more polymerization initiators anionic, cationic, or mixed charged. For example, the pendant have been incorporated. groups may include neutral hydrophilic groups such as In one embodiment, a non-fouling polymeric material is hydroxy, oligo(ethylene glycol) and/or poly(ethylene glycol) grafted from a substrate that is a composite of two or more moieties, or it may include charged groups such as anionic materials, e.g., an underlying material Such as a metal, 60 moieties, cationic moieties, and Zwitterionic moieties. ceramic, glass, semi-metal, polymer or other material with a Zwitterionic Groups polymeric or other material coating thereon (e.g., a primer Zwitterions are molecules that carry formal positive and coat as previously described herein). For example, in one negative charges on non-adjacentatoms within the same mol embodiment, a non-fouling polymeric material is grafted ecule and molecules that may be ionized by addition or from a polymeric primer coat, such as a polyurethane layer 65 removal of an electrophile or a nucleophile, or by removal of which overlies a metal or ceramic bulk. By way of further a protecting group. Both natural and synthetic polymers, con example, in one embodiment the non-fouling polymeric taining Zwitterion functionality, have been shown to resist US 8,574,660 B2 43 44 protein adhesion. In one embodiment, the Zwitterionic mono mer contains a phosphorylcholine moiety, a carboxyammo Formula ZI-3 nium moiety, a Sulfoammonium moiety, derivatives thereof, T9 or combinations thereof. In one embodiment, the Zwitterionic TS Gl-T G. monomer contains a carboxyammonium moiety, a Sulfoam 1. N- N. monium moiety, derivatives thereof, or combinations thereof. T10 In one embodiment, the Zwitterionic monomer contains a sulfobetaine moiety or a carboxybetaine moiety. The Zwitte wherein rionic polymer may be formed by initiating polymerization T is a bond, hydrocarbylene, substituted hydrocarbylene, with radicals present in the polymeric Substrate, in the pres heterocyclo, or in combination with Tand T'and the nitro ence of one or more monomers, such as Sulfobetaine meth gen atom to which they are attached form a nitrogen-contain acrylate or carboxybetaine methacrylate monomers. ing heteroaromatic ring, Polysulfoammonium polymers such as polysulfobetaines, Tand T' are independently hydrogen, hydrocarbyl, sub polycarboxyammonium polymers such as polycarboxybe stituted hydrocarbyl or heterocyclo, or, T and T', in com 15 bination with T and the nitrogen atom to which they are taines and other natural and synthetic Zwitterion chemistries attached form a nitrogen-containing heteroaromatic ring, can be used to design non-fouling materials for the biomedi T'' is hydrocarbylene, substituted hydrocarbylene, ether, cal applications described herein. Some examples of natural or oxylated alkylene, Zwitterions chemistries that could be used for non-fouling Z is carboxylate, phosphate, phosphonic, phosphonate, Sulfate, Sulfinic, or Sulfonate, and materials include, but are not limited to, amino acids, pep * designates the point of covalent attachment, direct or tides, natural Small molecules including, but not limited to, indirect, of the Zwitterion of Formula ZI-3 to the poly N.N.N-trimethylglycine (glycine betaine), trimethylamine merbackbone. oxide (TMAO), dimethylsulfoniopropionate sarcosine, lyser In certain preferred embodiments in which the polymer 25 contains Zwitterionic pendant group corresponding to For gic acid and psilocybin. Additional synthetic Zwitterions that mula ZI-3, T, T, T', and T''' are selected from a more could be used to create non-fouling materials, include, but are narrow range of substituents, Z is carboxylate or sulfate, and not limited to, amino-carboxylic acids (carboxybetaines), the Zwitterion corresponds to Formula ZI-4: amino-Sulfonic acids (sulfo betaines), cocamidopropyl 30 betaine, quinonoid based Zwitterions, decaphenylferrocene, Formula ZI-4 and non-natural amino acids. Natural and synthetic polymers T13 2 5 G also include mixed charged structures with both positive 1. Tse G-T NA charged and negative charged moieties on the pendant 35 groups, in the main chains, or at the terminal groups. T14 Materials containing, or composed of these natural or synthetic Zwitterions, can be grafted from Surfaces, particu wherein * designates the point of covalent attachment, direct larly the surfaces of medical devices, in order to improve or indirect, of the Zwitterion of Formula ZI-4 to the polymer 40 backbone; T' is a bond or —(CH), with m being 1 to 3: biocompatibility, reduce thrombogenesis (Such as on the Sur T' and T'are independently hydrogen, alkyl, or substituted face of stents or venous valves), and reduce fouling by pro alkyl:T' is optionally substituted alkylene, phenylene, ether, teins or bacteria present in solution. This is particularly appli or oxylated alkylene; and Z is carboxylate or sulfate. For cable for Surfaces where non-specific binding of proteins in example, in this embodiment, T'and T''may independently Solution could negatively impact the desired or necessary 45 be hydrogen or lower alkyl, e.g., methyl, ethyl, or propyl. By mechanics of a device. way of further example, in this embodiment, T'and T''may In one embodiment, the non-fouling polymer contains independently be hydrogen or lower alkyl, e.g., methyl, ethyl, Zwitterionic pendant groups covalently attached, directly or or propyl. By way of further example, in this embodiment, indirectly to the polymer backbone. The Zwitterionic pendant T' may be —(CH), with n being 1-8. By way of further groups may have an overall net charge, for instance, by having 50 example, in this embodiment, T' may be -(CH2)2 or a divalent center of anionic charge and monovalent center of —(CH2) and T and T'' may be methyl. By way of cationic charge or vice versa, or by having two centers of further example, in this embodiment, T''may be—(CH) cationic charge and one centerofanionic charge or vice versa. or —(CH) , T and T'' may be hydrogen or alkyl. By Preferably, however, the Zwitterion has no overall net charge way of further example, in this embodiment, T' may be and most preferably has a center of monovalent cationic 55 —(CH) , T' and T'' may be methyl, T' may be charge and a center of monovalent anionic charge. Addition —(CH) — and Z may be carboxylate. By way of further ally, the center(s) of cationic charge are preferably perma example, in this embodiment, T' may be —(CH) , T' nent; that is, it is preferably a quaternary nitrogen, quaternary and T''may be methyl, T' may be —(CH), and Z' may phosphonium or tertiary Sulfonium group. Additionally, the be sulfate. center(s) of anionic charge are also permanent; that is, they 60 In certain preferred embodiments in which the polymer are completely ionized at physiological pH and are preferably contains Zwitterionic pendant group corresponding to For carboxylate, phosphate, phosphonic, phosphonate, Sulfate, mula ZI-3, T, Tand T'and the nitrogenatom to which they Sulfinic, or Sulfonate. are attached form a nitrogen-containing heteroaromatic ring. In another embodiment, the polymer contains Zwitterionic For example, T, Tand T'and the nitrogen atom to which pendant groups covalently attached, directly or indirectly, to 65 they are attached may form an optionally substituted hetero the polymer back bone, and the Zwitterion corresponds to cycle, containing a quaternary nitrogen atom. One Such Formula ZI-3: embodiment corresponds to Formula ZI-5: US 8,574,660 B2 45 46

Formula ZI-5 Formula ZI-1 Gl-T G. O IET21 N24 O GE) 1N -S2 -7 wherein * designates the point of covalent attachment, direct | or indirect, of the Zwitterion of Formula ZI-5 to the polymer O backbone; HET is a heterocycle containing a quaternary nitrogen atom, T is optionally substituted alkylene, phe wherein nylene, ether, or oxylated alkylene; and Z is carboxylate or 10 T' and T are independently oxygen, sulfur, NH or a bond, sulfate. For example, in this embodiment, T' may be T is hydrocarbylene, substituted hydrocarbylene, ether, or —(CH), with n being 1-8. By way of further example, in oxylated alkylene, this embodiment, T' may be —(CH), or—(CH), and Z' is a moiety comprising a quaternary nitrogen, phospho Z may be carboxylate or sulfate. By way of further example, nium or Sulfonium cationic group, and in this embodiment, T' may be —(CH2) and Z' may be 15 * designates the point of covalent attachment, direct or sulfate. By way of further example, in this embodiment, T' indirect, of the Zwitterion of Formula ZI-1 to the poly may be -(CH2) and Z' may be carboxylate. Exemplary merbackbone. Zwitterions corresponding to Formula ZI-5 include Zwitteri In certain preferred embodiments in which the polymer contains Zwitterionic pendant group corresponding to For ons corresponding to Formulae ZI-6A and ZI-6B: mula ZI-1, T and T are oxygen, Z' is quaternary nitrogen, and the Zwitterion corresponds to Formula ZI-2: Formula ZI-6A : 5 N 749 Formula ZI-2 Ye 25 Formula ZI-6B GE) 1 : N/St-GT5 NZ O 1 n

30 wherein * designates the point of covalent attachment of the wherein * designates the point of covalent attachment, direct Zwitterion of Formula ZI-2 to the polymer backbone, T is or indirect, of the Zwitterion of Formulae ZI-6A and ZI-6B to hydrocarbylene, substituted hydrocarbylene, or oxylated the polymer backbone; T' is optionally substituted alkylene, alkylene, and T, T and T are independently hydrogen, phenylene, ether, or oxylated alkylene; and Z' is carboxylate 35 hydrocarbyl, substituted hydrocarbyl or heterocyclo. For or sulfate. For example, in this embodiment, T' may be example, in this embodiment, T may be -(CH2), with n —(CH), with n being 1-8. By way of further example, in being 1-8. By way of further example, in this embodiment, this embodiment, T' may be -(CH2)2 or -(CH2) and T.T and T may independently be lower alkyl, e.g., methyl, Z may be carboxylate or sulfate. By way of further example, ethyl or propyl. By way of further example, in this embodi in this embodiment, T' may be —(CH2) and Z' may be 40 ment, T may be —(CH), with n being 1-3, and T.T and sulfate. By way of further example, in this embodiment, T' T may independently be lower alkyl, e.g., methyl, ethyl or may be —(CH) - and Z may be carboxylate. propyl. By way of further example, in this embodiment, T In one embodiment, the polymer contains Zwitterionic may be -(CH2), with n being 1-3, and one or more of T. pendant groups covalently attached, directly or indirectly, to 45 Tand T may be substituted hydrocarbyl such as oligomeric the polymer back bone, and the Zwitterion corresponds to phosphorylcholine (e.g., Formula 9). Formula ZI-7 Neutral Hydrophilic Pendant Groups In one embodiment, the polymer contains neutral hydro philic pendant groups covalently attached, directly or indi Formula ZI-7 rectly, to the polymer backbone. Exemplary neutral hydro 50 philic groups include hydroxy, thiol, oxylated alkyls (e.g., oligoethylene glycol, polyethylene glycol and/or polypropy lene glycol), ether, thioether, and the like. In one Such specific embodiment, the polymer contains pendant groups compris 55 ing alkoxylated moieties corresponding to Formula POA-1:

Formula POA-1 wherein T, Tand T are independently hydrogen, hydrocar R2 byl, substituted hydrocarbyl or heterocyclo: T' is a bond, : O hydrocarbylene, substituted hydrocarbylene, or heterocyclo, 60 R3 and * designates the point of covalent attachment, direct or indirect, of the Zwitterion of Formula ZI-7 to the polymer RI backbone. In one embodiment, the polymer contains Zwitterionic wherein a is 1-3, b is 1-8, each R' and R is independently pendant groups covalently attached, directly or indirectly, to 65 selected from the group consisting of hydrogen, halogen, and the polymer back bone, and the Zwitterion corresponds to optionally substituted lower alkyl, R is hydrocarbyl, substi Formula ZI-1: tuted hydrocarbyl or heterocyclo, and * designates the point US 8,574,660 B2 47 48 of attachment of the moieties corresponding to Formula corresponding to Formula ZI-1, ZI-2, ZI-3, ZI-4, ZI-5, ZI-6A, POA-1 to the remainder of the pendant group and the back ZI-6B, or ZI-7. By way of further example, the repeat unit of bone. By way of example, in one such embodiment, each R' Formula 2 may be a cationic repeat unit. By way of further and Rare hydrogen, n is 2 or 3. By way of further example, example, the repeat unit of Formula 2 may be an anionic in one such embodiment, each RandR is hydrogen, n is 2 or repeat unit. By way of further example, X may be hydrogen 3, and b is 3-5. By way of further example, in one such or methyl and X may be a pendant group comprising an embodiment, each RandR is hydrogen, n is 2 or 3, b is 3-5, oxylated alkylene moiety corresponding to Formula POA-1 and R is alkyl. In one embodiment, the repeat units are ora Zwitterionic moiety corresponding to Formula ZI-1, ZI-2, derived from macromonomers containing 2-20 alkylene ZI-3, ZI-4, ZI-5, ZI-6A, ZI-6B, or ZI-7. oxide units. 10 In one presently preferred embodiment, the non-fouling Repeat Units polymeric material comprises repeat units corresponding to In general, homopolymers or copolymers comprising Zwit Formula 2 wherein X* is acyl and the repeat units correspond terionic pendant groups, neutral hydrophilic pendant groups, to Formula 3: cationic pendant groups and/or anionic pendant groups may be prepared by polymerization of any of a wide range of 15 monomers. In one preferred embodiment, the non-fouling Formula 3 polymeric material is a homopolymer or copolymer compris ing repeat units derived from an olefinic monomer. Thus, for example, in one embodiment the non-fouling polymeric material comprises repeat units derived from an olefinic monomer and corresponding to Formula 1: wherein X comprises an oxylated alkylene moiety, a zwit Formula 1 25 terionic moiety, an anionic moiety, or a cationic moiety. For XI X3 example, X may be XX, NXX or SX', C-C wherein X* is a substituted hydrocarbylor heterocyclo moi ety comprising an oxylated alkylene moiety, a Zwitterionic X2 X4 moiety, an anionic moiety, or a cationic moiety, and X* is 30 hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocy wherein clo. For example, X may behydrogen or lower alkyl. By way X' and X’ are independently hydrogen, hydrocarbyl, sub of further example, X may be OX', or NHX". By stituted hydrocarbyl, heterocyclo, or substituted carbonyl, way of further example, X may be OX', or - NHX" provided, however, X" and X’ are not each selected from the wherein X comprises an oxylated alkylene moiety corre group consisting of aryl, heteroaryl, and heterosubstituted 35 sponding to Formula POA-1. By way of further example, X." carbonyl, may be —OX', or -NHX' wherein X comprises a zwit X is hydrogen, alkyl or substituted alkyl, and terionic moiety corresponding to Formula ZI-1, ZI-2, ZI-3, X is OX0, NXX2, N*X4x42x43, SX40 aryl, ZI-4, ZI-5, ZI-6A, ZI-6B, or ZI-7. By way of further example, heteroaryl or acyl, the repeat unit of Formula 3 may be a cationic repeat unit. By X" is hydrogen, hydrocarbyl, substituted hydrocarbyl, 40 way of further example, the repeat unit of Formula 3 may be heterocyclo or acyl, and an anionic repeat unit. By way of further example, X may be X', X and X’ are independently hydrogen, hydrocar hydrogen or methyl and X may comprise an oxylated alky byl, substituted hydrocarbyl or heterocyclo. lene moiety corresponding to Formula POA-1 or a Zwitteri In certain embodiments in which the non-fouling poly onic moiety corresponding to Formula ZI-1, ZI-2, ZI-3, ZI-4, meric material comprises repeat units corresponding to For 45 ZI-5, ZI-6A, ZI-6B, or ZI-7. In one particularly preferred mula 1, it is preferred that X of at least a fraction of the repeat embodiment, the polymer contains repeat units correspond units comprise alkoxylated moieties, Zwitterionic moieties, ing to Formula 3 and X* is —O(CH)N(CH)(CH), anionic moieties, or cationic moieties. In Such embodiments, SO, O(CH)N(CH)(CH),CO. NH(CH)N" for example, X' and X may be hydrogen, and the polymer (CH)(CH) CO, or NH(CH)N(CH)(CH),SO, 50 wherein n is 1-8. In one embodiment, the polymer contains comprises repeat units corresponding to Formula 2: repeat units corresponding to Formula 3 and X* is NH (CH), N(CH2)CH(CH2)SO, NH(CH), N(CH2), Formula 2 CH(CH2)CO. NH(CH),N'I(CH2)CH)(CH2), SOs, NH(CH.)N(CH2)CH,)(CH),CO. NH(CH),N- 55 cyclo-(CH2)CO, or NH(CH2).Ncyclo-(CH2), SOs, (Ncyclo is a heterocyclic structure or a heterocyclic derivative containing at least one nitrogen element), wherein m is 1-8; in is 0-5; and p is 1-8. In one embodiment, the polymer contains repeat units corresponding to Formula 3 and X is wherein X is hydrogen, alkyl or substituted alkyl, and X* is 60 O(CH2), N(CH2)CH(CH2)SO, O(OH), N(CH2), a pendant group comprising an oxylated alkylene moiety, a CH,(OH), CO., O(CH),N" (CH), CH,-(CH2)SO, Zwitterionic moiety, an anionic moiety, or a cationic moiety. O(CH2)N(CH2)CHI (CH2)CO, O(OH).Ncy For example, X may be hydrogen or lower alkyl. By way of clo-(CH) CO, or O(OH),Ncyclo-(CH.)SO, wherein further example, X may be a pendant group comprising an m is 1-8; n is 0-5; and p is 1-8. In one embodiment, the oxylated alkylene moiety corresponding to Formula POA-1. 65 polymer contains repeat units corresponding to Formula 3 By way of further example, the repeat unit of Formula 2 may and X* is O(CH), N-(CH)(CH)SO, O(CH)N" be Zwitterionic repeat unit comprising a Zwitterionic moiety (CH)(CH2)CO. —NH(CH)N(CH)(CH2)SO, US 8,574,660 B2 49 50 —NH(CH)N(CH)(CH),CO, NH(CH)N(CH), sum of a and c is at least 0.3 and b is at least 0.1. By way of (CH)SO, —NH(CH)N(CH)(CH), CO, —O(CH) further example, in one embodiment the Sum of a and c is at N(CH2CH)(CH)SO. —O(CH)N(CH2CH)(CH) least 0.4 and b is at least 0.1. By way of further example, in CO. —O(CH)N(CH2CH2CHCH) (CH)SO, one embodiment the sum of a and c is at least 0.5 and b is at –O(CH)N(CHCHCHCH)(CH) CO, or -NH 5 least 0.1. By way of further example, in one embodiment the (CH).Ncyclo-(CH2)SO. sum of a and c is at least 0.6 and b is at least 0.1. By way of In one preferred embodiment, the non-fouling polymeric further example, in one embodiment the Sum of a and c is at material is a Zwitterionic polymer or copolymer. For example, least 0.7 and b is at least 0.1. By way of further example, in the non-fouling polymeric material may comprise carboxy one embodiment the sum of a and c is at least 0.8 and b is at betaine repeat units and/or Sulfobetaine repeat units. Alterna 10 least 0.1. By way of further example, in one embodiment the tively, the non-fouling polymeric material may be a polyam sum of a and c is at least 0.9 and b is at least 0.1. By way of pholyte, containing anionic and cationic repeat units. further example, in one embodiment the Sum of a and c is at Optionally, the non-fouling polymer may contain poly(ethyl least 0.1 and d is at least 0.1. By way of further example, in ene oxide) repeat units and/or other neutral olefinic repeat one embodiment the sum of a and c is at least 0.2 and d is at units. Thus, for example, in one preferred embodiment, the 15 least 0.1. By way of further example, in one embodiment the non-fouling polymeric material is a Zwitterionic polymer or sum of a and c is at least 0.3 and d is at least 0.1. By way of copolymer comprising the repeat units of Formula 4: further example, in one embodiment the Sum of a and c is at least 0.4 and d is at least 0.1. By way of further example, in one embodiment the sum of a and c is at least 0.5 and d is at A B C D least 0.1. By way of further example, in one embodiment the X3 X3 X3 X3 sum of a and c is at least 0.6 and d is at least 0.1. By way of H H H H further example, in one embodiment the Sum of a and c is at C C C C least 0.7 and d is at least 0.1. By way of further example, in X4 d one embodiment the sum of a and c is at least 0.8 and d is at (O or KH) (O or KH) O O 25 least 0.1. By way of further example, in one embodiment the sum of a and c is at least 0.9 and d is at least 0.1. By way of further example, in one embodiment the Sum of a and c is at least 0.1, b is at least 0.1 and d is at least 0.1. By way of further -N- 30 example, in one embodiment the Sum of a and c is at least 0.2, . . b is at least 0.1 and d is at least 0.1. By way of further example, in one embodiment the sum of a and c is at least 0.3, b is at least 0.1 and d is at least 0.1. By way of further example, in O one embodiment the Sum of a and c is at least 0.4, b is at least O 35 0.1 and d is at least 0.1. By way of further example, in one embodiment the sum of a and c is at least 0.5, b is at least 0.1 a is 0-1 b is 0-1; c is 0-1; d is 0-1; m is 1-20; n and o are and d is at least 0.1. By way of further example, in one independently 0-11; p and q are independently 0-11: X is embodiment the sum of a and c is at least 0.6, b is at least 0.1, hydrogen, alkyl or substituted alkyl, X is —OX", and d is at least 0.1. By way of further example, in one - NX'X', SX', aryl, heteroaryl or acyl: X" is hydro 40 embodiment the sum of a and c is at least 0.7, b is at least 0.1 gen, hydrocarbyl, substituted hydrocarbyl, heterocyclo or and d is at least 0.1. By way of further example, in one acyl: X' and X’ are independently hydrogen, hydrocarbyl, embodiment the sum of a and c is at least 0.8, b is at least 0.1 substituted hydrocarbylor heterocyclo; and X is hydrogen, and d is at least 0.1. By way of further example, in one hydrocarbyl or substituted hydrocarbyl, provided the sum of embodiment the sum of a and c is at least 0.9, b is at least 0.1 a, b, c and d is greater than 0 and X of repeat unit D differs 45 and d is at least 0.1. In each of these exemplary embodiments, from the corresponding pendant group of repeat units A, B a may be 0, c may be 0, or a and c may each be greater than 0. and C. In one such embodiment, X is hydroxy-substituted In one preferred embodiment, the non-fouling polymeric alkyl Such as hydroxypropyl. material is a Zwitterionic polymer or copolymer comprising In one embodiment, it is preferred that the non-fouling the repeat units of Formula 4 m is 1-8; X is hydrogen, alkyl polymeric material is a Zwitterionic polymer comprising 50 or substituted alkyl, X is OX, NX'X', SX', aryl, repeat units corresponding to the A and/or the C repeat units. heteroaryl or acyl: X" is hydrogen, hydrocarbyl, substituted For example, in one embodiment the Sum of a and c is at least hydrocarbyl, heterocyclo or acyl: X' and X’ are indepen 0.1. By way of further example, in one embodiment the sum dently hydrogen, hydrocarbyl, substituted hydrocarbyl or ofa and c is at least 0.2. By way of further example, in one heterocyclo; and X is hydrogen, hydrocarbyl or substituted embodiment the sum of a and c is at least 0.3. By way of 55 hydrocarbyl, with the proviso that X of the D repeat differs further example, in one embodiment the Sum of a and c is at from the corresponding pendant groups of the A, B or C least 0.4. By way of further example, in one embodiment the repeat units and a, b, c, and d, in combination, are selected sum of a and c is at least 0.5. By way of further example, in from one of the sets of combinations appearing in Table I: one embodiment the sum of a and c is at least 0.6. By way of further example, in one embodiment the Sum of a and c is at 60 TABLE I least 0.7. By way of further example, in one embodiment the Combination 8. b C d sum of a and c is at least 0.8. By way of further example, in 1 0.1-1.0 O. 1-0.5 0.1-1.0 0.1-1.0 one embodiment the sum of a and c is at least 0.9. By way of 2a >O >0.1 O O further example, in one embodiment the Sum of a and c is at 2b >O O O >0.1 least 0.1 and b is at least 0.1. By way of further example, in 65 2c >O >0.1 O >0.1 one embodiment the Sum of a and c is at least 0.2 and b is at 3a >0.1 >0.1 O O least 0.1. By way of further example, in one embodiment the US 8,574,660 B2 51 TABLE I-continued TABLE I-continued

Combination 8. b C Combination 8. b C d

O 29b. >0.7 >0.1 >O >0.1 5 29c. >0.7 O >O >0.1

O In one embodiment, the non-fouling polymeric material is O a polyampholyte Zwitterionic polymer or copolymer com 10 prising repeat units corresponding to repeat unit D of Formula 4. That is, d is greater than 0 and a fraction of the repeat units O corresponding to repeat unit Dare anionic repeat units (X" for Such units is an anionic pendant group) and a fraction of the repeat units corresponding of Formula 4 are cationic repeat 15 units (X for such units is a cationic pendant group). For example, in one such embodiment, d is at least 0.1 and O approximately one-half the repeat units corresponding to repeat unit D are anionic repeat units (X for such units is an anionic pendant group) and approximately one-half of the O repeat units corresponding of Formula 4 are cationic repeat O units (X for such units is a cationic pendant group). By way of further example, in one such embodiment, d is at least 0.2 O and approximately one-half the repeat units corresponding to O repeat unit D are anionic repeat units (X for such units is an 25 anionic pendant group) and approximately one-half of the O repeat units corresponding of Formula 4 are cationic repeat units (X for such units is a cationic pendant group). By way O of further example, in one such embodiment, d is at least 0.3 and approximately one-half the repeat units corresponding to 30 repeat unit D are anionic repeat units (X for such units is an O anionic pendant group) and approximately one-half of the repeat units corresponding of Formula 4 are cationic repeat O units (X for such units is a cationic pendant group). By way of further example, in one such embodiment, d is at least 0.4 35 and approximately one-half the repeat units corresponding to O repeat unit D are anionic repeat units (X for such units is an anionic pendant group) and approximately one-half of the repeat units corresponding of Formula 4 are cationic repeat units (X for such units is a cationic pendant group). By way O 40 of further example, in one such embodiment, d is at least 0.5 and approximately one-half the repeat units corresponding to repeat unit D are anionic repeat units (X for such units is an b anionic pendant group) and approximately one-half of the O repeat units corresponding of Formula 4 are cationic repeat O 45 units (X for such units is a cationic pendant group). By way of further example, in one such embodiment, d is at least 0.6 O and approximately one-half the repeat units corresponding to O repeat unit D are anionic repeat units (X for such units is an anionic pendant group) and approximately one-half of the O 50 repeat units corresponding of Formula 4 are cationic repeat units (X for such units is a cationic pendant group). By way O of further example, in one such embodiment, d is at least 0.7 and approximately one-half the repeat units corresponding to repeat unit D are anionic repeat units (X for such units is an O 55 anionic pendant group) and approximately one-half of the repeat units corresponding of Formula 4 are cationic repeat O units (X for such units is a cationic pendant group). By way of further example, in one such embodiment, d is at least 0.8 O and approximately one-half the repeat units corresponding to 60 repeat unit D are anionic repeat units (X for such units is an anionic pendant group) and approximately one-half of the repeat units corresponding of Formula 4 are cationic repeat units (X for such units is a cationic pendant group). By way O of further example, in one such embodiment, d is at least 0.9 65 and approximately one-half the repeat units corresponding to repeat unit D are anionic repeat units (X for such units is an anionic pendant group) and approximately one-half of the US 8,574,660 B2 53 54 repeat units corresponding of Formula 4 are cationic repeat L' and L are independently hydrocarbylene, substituted units (X for such units is a cationic pendant group). By way hydrocarbylene, heterocyclo, amide, anhydride, ester, imide, of further example, in each of said examples in this paragraph, thioester, thioether, urethane, or urea; and the remaining repeat units may correspond to repeat unit A. X" is hydrogen, hydrocarbyl, substituted hydrocarbyl, By way of further example, in each of said examples in this heterocyclo or acyl, and paragraph, the remaining repeat units may correspond to X' and X’ are independently hydrogen, hydrocarbyl, repeat unit B. By way of further example, in each of said substituted hydrocarbyl or heterocyclo. examples in this paragraph, the remaining repeat units may In one embodiment, the non-fouling polymeric material correspond to repeat unit C. comprises repeat units corresponding to Formula 7 wherein More preferably, the non-fouling polymeric material is a 10 the heterocycle. HET corresponds to Formulae 10, 11 or 12: Zwitterionic polymer or copolymer comprising repeat units corresponding to repeat unit A and/or repeat unit C of For mula 4. Formula 10 In certain embodiments, the non-fouling polymeric mate --X rial is a homopolymer or copolymer comprising repeat units 15 corresponding to Formula 5. Formula 6, Formula 7. Formula 8, or Formula 9:

Formula 11 Formula 5 X3 X-C

X4 25 Formula 6 X7 Formula 12 le X6-N --X GE) X8 30 N Formula 7 / V --X-HET-- Formula 8 X10 X13 wherein X is hydrocarbylene, substituted hydrocarbylene, 35 heterocyclo, amide, anhydride, ester, imide, thioester, thioet X9 X12 her, urethane, or urea; X is hydrogen, alkyl or substituted XII X14 alkyl; and X is an anionic moiety. Formula 9 Suitable comonomers include, but are not limited to, acry lates, acrylamides, vinyl compounds, multifunctional mol fGE 40 ecules, such as di-, tri-, and tetraisocyanates, di-, tri-, and tetraols, di-, tri-, and tetraamines, and di-, tri-, and tetrathio -to--0-1l--1-O X8 cyanates; cyclic monomers, such as lactones and lactams, and G combination thereof. In the interests of brevity, exemplary methacrylate monomers are listed below (but it should be HET is part of a heterocyclic structure, 45 understood that analogous acrylate, acrylamide and meth X is hydrogen, alkyl or substituted alkyl, acrylamide monomers may be similarly listed and are simi X is OX', NX'X', SX', aryl, heteroaryl or larly included): acyl, Charged methacrylates or methacrylates with primary, sec ondary or tertiary amine groups, such as, 3-sulfopropyl X is ester, anhydride, imide, amide, ether, thioether, 50 methacrylate potassium salt, (2-dimethylamino)ethyl thioester, hydrocarbylene, substituted hydrocarbylene, het methacrylate) methyl chloride quaternary salt, 2 erocyclo, urethane, or urea; (methacryloyloxy)ethyltrimethyl-ammonium chloride, X is hydrocarbylene, substituted hydrocarbylene, hetero methacryloyl chloride, 3-(methacryloylamino)propyl cyclo, amide, anhydride, ester, imide, thioester, thioether, trimethylammonium chloride), 2-aminoethyl methacry urethane, or urea; 55 late hydrochloride, 2-(diethylamino)ethyl methacrylate, X is hydrogen, alkyl or substituted alkyl: 2-(dimethylamino)ethyl methacrylate, 2-(tert-buty X is an anionic moiety; lamino)ethyl methacrylate, and 2-(tert-butylamino X is hydrocarbylene, substituted hydrocarbylene, hetero ethyl methacrylate. cyclo, amide, anhydride, ester, imide, thioester, thioether, Alkyl methacrylates or other hydrophobic methacrylates, urethane, or urea; 60 Such as ethyl methacrylate, butyl methacrylate, hexyl X' is hydrogen, alkyl or substituted alkyl: methacrylate, 2-ethylhexyl methacrylate, methyl meth X' is a cationic moiety; acrylate, lauryl methacrylate, isobutyl methacrylate, X' is hydrocarbylene, substituted hydrocarbylene, hetero isodecyl methacrylate, phenyl methacrylate, decyl cyclo, amide, anhydride, ester, imide, thioester, thioether, methacrylate, 3,3,5-trimethylcyclohexyl methacrylate, urethane, or urea; 65 benzyl methacrylate, cyclohexyl methacrylate, Stearyl X' is hydrogen, alkyl or substituted alkyl: methacrylate, tert-butyl methacrylate, tridecyl meth X'' is an anionic moiety; acrylate, 2-naphthyl methacrylate, 2.2.3,3-tetrafluoro US 8,574,660 B2 55 56 propyl methacrylate, 1,1,1,3,3,3-hexafluoroisopropyl non-fouling performance because the charged groups are methacrylate, 2.2.2-trifluoroethyl methacrylate, 2.2.3,3, ionically solvated with water. The presence of commonly 3-pentafluoropropyl methacrylate, 2.2.3.4.4.4- used groups which can have permanent charges in the Zwit hexafluorobutyl methacrylate, 2.2.3.3.4.4.4-heptafluo terionic polymers can be detected by usingXPS to analyze the robutyl methacrylate, 2.2.3,3,4,4,5,5-octafluoropentyl elements present in the top approximately 1-50 nm of the methacrylate, 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooc Surface. One representative group commonly used in Zwitte tyl methacrylate, and 3.3.4.4.5,5,6,6,7,7,8,8,9,9,10,10. rions is nitrogen in quaternary amine groups. In Sulfobetaine, 10-heptadecafluorodecyl methacrylate. elemental signal of nitrogen may be approximately equiva Reactive or crosslinkable methacrylates, such as 2-(trim lent to a signal for sulfur. Further, techniques such as TOF ethylsilyloxy)ethyl methacrylate, 3-(trichlorosilyl)pro 10 SIMS may be used to identify Zwitterionic groups in the pyl methacrylate, 3-(trimethoxysilyl)propyl methacry grafted polymer layer. In some preferred embodiments, the late, 3-tris(trimethylsiloxy)silylpropyl methacrylate, grafted polymer layer contains XPS signals of nitrogen, and trimethylsilyl methacrylate, allyl methacrylate, vinyl optionally sulfur. methacrylate, 3-(acryloyloxy)-2-hydroxypropyl meth The polymeric surface modifications of the present inven acrylate, 3-(diethoxymethylsilyl)propyl methacrylate 15 tion may be formed by synthetic means including, but not 3-(dimethylchlorosilyl)propyl methacrylate 2-isocy limited to, free radical polymerization, ionic polymerization, anatoethyl methacrylate, glycidyl methacrylate, 2-hy atom transfer radical polymerization (ATRP), nitroxide droxyethyl methacrylate, 3-chloro-2-hydroxypropyl mediated polymerization (NMP), reversible addition-frag methacrylate, Hydroxybutyl methacrylate, glycol meth mentation polymerization (RAFT), ring opening metathesis acrylate, hydroxypropyl methacrylate, and 2-hydrox polymerization (ROMP), telluride mediated polymerization ypropyl 2-(methacryloyloxy)ethyl phthalate. (TERP) or acyclic diene metathesis polymerization (AD Other methacrylates, such as ethylene glycol methyl ether MET), and UV, thermal, or redox free radical initiated poly methacrylate, di(ethylene glycol) methyl ether meth merization. In a preferred embodiment, the polymer is acrylate, ethylene glycol phenyl ether methacrylate, formed using an oxidizing agent and a reducing agent, in 2-butoxyethyl methacrylate, 2-ethoxyethyl methacry 25 combination, i.e., a redox pair, as the polymerization initiator late, and ethylene glycol dicyclopentenyl ether meth in a redox free radical polymerization. acrylate. In some embodiments, it is preferable that initiators and Multifunctional monomers, such as di, tri, or tetraacrylates ligands often used in ATRP Such as bromine-containing ini and di, tri, or tetraacrylamides can be used to form highly tiators and ligands such as bipyridine are not used in the branched structures which can provide a higher concentration 30 process as they may be non-biocompatible at certain levels. In of non-fouling groups on the Surface. As previously noted, the further embodiments, it is preferred not to have a detectable non-fouling polymeric material may contain a non-Zwitteri level of bipyridine in the polymer modified article or in aque onic non-fouling material, alone or in combination with a ous or organic extractions of the polymer modified article. In Zwitterionic material. These non-fouling groups may have further embodiments, it is preferred not to have a detectable varying degrees of non-fouling performance in a range of 35 level of bromine in the polymer modified article or in aqueous environments. Suitable non-Zwitterionic materials include, or organic extractions of the polymer modified article. Bipy but are not limited to, polyethers, such as polyethylene glycol, ridine and bromine can be detected with one or a combination poly(ethylene oxide-co-propylene oxide) (PEO-PPO) block of HPLC, HPLC-MS, UV, ion chromatography, combustion copolymers, polysaccharides such as dextran, hydrophilic analysis, ICP-MS, EDS, and XPS analysis. polymers such as polyvinylpyrrolidone (PVP) and hydroxy 40 The general procedure described herein can be modified as ethyl-methacrylate (HEMA), acrylonitrile-acrylamide necessary to accommodate different Substrate materials, ini copolymers, heparin, heparin fragments, derivatized heparin tiators systems, and/or monomer compositions and to incor fragments, hyaluronic acid, mixed charge materials, and porate high concentrations of the initiator into and/or onto the materials containing hydrogen bond accepting groups. Such Substrate or undercoating layer. High initiator concentrations as those described in U.S. Pat. No. 7,276.286. Suitable poly 45 may result in highly densely coated Surfaces which improves mer structures included, but are not limited to, polymers or the non-fouling activity of the composition. For example, copolymers containing monomers of Formula I wherein ZI is highly densely coated Surfaces contain polymer chains that replaced by a non-Zwitterionic, non-fouling head group. reduce penetration of fouling molecules into the coating. In one embodiment, the non-fouling material is a polymer Without being bound to any particular theory it is presently containing repeat units derived from Sulfobetaine-containing 50 theorized that a reservoir of initiator incorporated in the sub and/or carboxybetaine-containing monomers. Examples of strate may enhance re-initiation and branching of non-fouling monomers include sulfobetaine methacrylate (SBMA), sul polymer from the surface and near the surface of the substrate. fobetaine acrylamide, Sulfobetaine methacrylamide, car This re-initiation, in turn, may increase the thickness of the boxybetaine methacrylate (CBMA), carboxybetaine acryla non-fouling polymer (in other words, the distance the non mide and carboxybetaine methacrylamide. Examples of Such 55 fouling polymer stretches above the substrate in a direction polymers include, but are not limited to, poly(carboxy betaine normal to the substrate surface) as well as the degree of methacrylate) (polyCBMA), poly(carboxybetaine acryla branching. mide), poly(carboxybetaine methacrylamide) poly(Sulfobe As described in greater detail elsewhere herein, incorpora taine methacrylate) (polySBMA), poly(sulfobetaine acryla tion of initiator into the substrate enables polymeric material mide), and poly(Sulfobetaine methacrylamide). In another 60 to be grafted from the surface and from within the near embodiment, the non-fouling material polymer is a polymer Surface Zone. In general, however, it is preferred that poly containing the residue of CBMA or SBMA and one or more meric material not extend too far into the Substrate; thus, in additional monomers. The additional monomers can be Zwit one embodiment polymeric material is present in the near terionic or non-Zwitterionic monomers. Surface Zone but not at greater depths, i.e., not in the bulk. The In some embodiments, it is preferred to have use Zwitteri 65 maximum depth to which near-Surface Zone extends, i.e., the onic polymers that possess permanently charged groups, distance of the lower boundary from the surface is, at least in which, without being bound by any theory, may improve part, a function of the initiator and the technique used to US 8,574,660 B2 57 58 incorporate initiator in the substrate. Typically, however, it is like. Representative chelators include, for example, water, generally preferred that the lower boundary not be greater carbohydrates, including polysaccharides, organic acids with than 20 micrometers from the surface. By way of example, more than one coordination group, lipids, steroids, amino the lower boundary may not be greater than 15 micrometers acids and related compounds, peptides, phosphates, nucle from the surface. By way of further example, the lower otides, tetrapyrrols, ferrioxamines, ionophores, such as boundary may not be greater than 10 micrometers from the gramicidin, monensin, Valinomycin, phenolics, 2,2'-bipy surface. Similarly, the minimum depth of the near-surface ridyl, dimercaptopropanol, ethylenediaminotetraacetic acid, Zone, i.e., the distance of the upper boundary from the Surface EDTA, ethylenedioxy-diethylene-dinitrilo-tetraacetic acid, is, at least in part, also a function of the initiator and the EGTA, ethylene glycol-bis-(2-aminoethyl)-N.N.N',N'-tet technique used to incorporate initiator in the Substrate. Typi 10 raacetic acid, nitrilotriacetic acid, NTA, ortho-phenanthro cally, however, the upper boundary will be at least 0.1 line, salicylic acid, triethanolamine, TEA, 5-sulfosalicylic micrometers from the Surface. By way of example, the upper acid, oxalic acid, citric acid, tartaric acid, ethylene glycol-bis boundary may be at least 0.2 micrometers from the surface. (2-aminoethylether)-N.N.N',N'-tetraacetic acid, enterobac By way of further example, the upper boundary may be at tin, ethylenediaminetetra (methylenephosphonic acid) and least 0.3 micrometers from the surface. 15 corresponding salts, and the like. Certain preferred chelators The quality of the surface modification formed in the poly are polyamino carboxylic acids, e.g., glycine, beta-alanine, merization process is, at least in part, influenced by the quality iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), ethyl of the surface of the substrate prior to polymerization. For enediaminetetraacetic acid, (EDTA), diethylene triamine example, prior to polymerization, the Surface may be con pentaacetic acid (DTPA), 1.2-bis(o-aminophenoxy)ethane taminated, intentionally or otherwise, with particles, waxes N.N.N',N'-tetraacetic acid (BAPTA), 1,4,7,10-tetraazacy and other compositions that may remain on the Surface of the clododecane-1,4,7,10-tetraacetic acid (DOTA), and the like. Substrate as an artifact of the manufacturing process, Subse Alternatively, or additionally, the substrate may be chemi quent handling of the Substrate, and/or as part of the intended cally, mechanically, thermally, or chemomechanically pol Substrate composition. The Substrate Surface may also ished prior to polymerization to reduce Surface roughness, include significant Surface roughness, physical defects Such 25 reduce the incidence and/or severity of cracks, pinholes and as Scratches, pinholes, or Voids, and chemical defects, such as other structural defects in the substrate surface. For example, particle(s) of radiopacifing agents (such as barium Sulfate, the substrate may be solvent polished by exposing the sub bismuth oxychloride, bismuth subcarbonate, bismuth triox strate to a vapor of a solvent Such as chloroform, dioxane or ide, lanthanum oxide, tantalum pentoxide, and metallic gold, tetrahydrofuran. After polishing the substrate surface prefer silver, platinum, palladium, tungsten, and tantalum) that are 30 ably has a global average R. Surface roughness that is less only partially contained within the substrate. For example, than the global average R. Surface roughness of the unpol substrates containing barium sulfate typically have some ished substrate. By way of further example, in one embodi barium sulfate particles that are partially contained within the ment the polished substrate surface has a global average R. Substrate and partially exposed; the exposed portions of Such surface roughness that is no more than 90% of the global barium sulfate particles may extend from the surface of a 35 average R. Surface roughness of the unpolished substrate Substrate to a height of as much as 1 micrometer (as measured surface. By way of further example, in one embodiment the from the surface of the substrate using SEM). polished Substrate Surface has a global average R. Surface In accordance with one embodiment, the Substrate Surface roughness that is no more than 75% of the global average R. is preferably pre-treated prior to polymerization as discussed Surface roughness of the unpolished Substrate Surface. By in detail above. For example, the substrate surface may be 40 way of further example, in one embodiment the polished treated using water, solvents, Surfactant solutions, enzymes, Substrate Surface has a global average R. Surface roughness or other cleaning solutions or gases to reduce or Substantially that is no more than 50% of the global average R. Surface or completely remove particles, waxes or other foreign com roughness of the unpolished substrate Surface. positions that may be on or near the Surface of the Substrate. Regardless of the pre-treatment steps, or even whether Alternatively, or additionally, the substrate surface may be 45 pre-treatment steps are employed, the Surface of the Substrate mechanically, chemically, thermally, or chemomechanically from which the non-fouling material is to be grafted has a treated to reduce the incidence and/or the severity of physical global average R. Surface roughness that is no more than and chemical defects. 200 nm. In one embodiment, for example, the surface of the In one embodiment, the substrate is treated prior to poly substrate from which the non-fouling material is to be grafted merization with a composition Such as an acid, base, chelator 50 has a global average R. Surface roughness of no more than or reactant that dissolves or chemically reacts with and 150 nmi; more preferably in this embodiment, the surface has reduces the concentration of any compositions that are a global average R. Surface roughness of no more than 100 included as chemical defects, or even swells the substrate nm. In certain embodiments, the Surface is even Smoother. For allowing the particles to be released from the substrate. For example, the surface may have a global average R. Surface example, exposed portions of barium Sulfate particles may be 55 roughness of less than 50 nm. In some embodiments, the partially or completely dissolved using a mineral or organic surface may have a global average R. Surface roughness of acid and optionally, a chelator. In one Such exemplary less than 20 nm. embodiment, polyurethane comprising particles of barium Additionally, or alternatively, and regardless of the pre sulfate may be treated with hydrochloric acid to at least par treatment steps, or even whether pre-treatment steps are tially remove exposed barium Sulfate particles. Representa 60 employed, the surface of the substrate from which the non tive acids include, for example, hydrochloric acid, Sulfuric fouling material is to be grafted has a visually observable acid, nitric acid, phosphoric acid, boric acid, hydrofluoric surface defect density (i.e., visually observable number over acid, hydrobromic acid, lactic acid, acetic acid, carbonic acid, a field size of 20x20 micrometers) of defects having a size formic acid, citric acid, oxalic acid, uric acid, carboxylic (i.e., alongest dimension) greater than about 0.5 micrometers acids, Sulfonic acids, chlorous acid, and the like. Represen 65 that is less than 0.1 defects/um. For example, the surface of tative bases include, for example, Sodium hydroxide, potas the substrate from which the non-fouling material is to be sium hydroxide, ammonia Solution, Sodium chlorite, and the grafted may have a surface defect density of defects having a US 8,574,660 B2 59 60 size greater than about 0.5 micrometers that is less than 0.05 rated) is not significantly Swelled by the polymerization mix defects/um. By way of further example, the surface of the ture (e.g., by the polymerization mixture solvent system, the substrate from which the non-fouling material is to be grafted polymerization monomers, or both) and the initiator(s) incor may have a Surface defect density of defects having a size porated into the substrate has/have limited solubility in the greater than about 0.5 micrometers that is less than 0.01 solvent system. As a result, the interface between substrate defects/um. By way of further example, the surface of the Surface and the polymerization mixture can have a relatively substrate from which the non-fouling material is to be grafted high local concentration of initiator(s) to initiate non-fouling may have a Surface defect density of defects having a size polymer growth from or near the Substrate surface and to greater than about 0.5 micrometers that is less than 0.002 (re)initiate polymer growth from the grafted non-fouling defects/um. By way of further example, the surface of the 10 polymer. Without being bound to any particular theory, it is substrate from which the non-fouling material is to be grafted presently believed that this approach leads to the grafting of a may have a Surface defect density of defects having a size relatively highly branched non-fouling polymer from the sub greater than about 0.5 micrometers that is less than 0.001 Strate. defects/um. In a preferred embodiment, the substrate polymer from The average thickness of a polymeric Surface modification 15 which the non-fouling polymer will be grafted will not swell or coating on a Substrate can be approximated using attenu more than 30% by volume at 25°C. under equilibrium con ated total reflectance (ATR) infrared spectrometry if the infra ditions in the polymerization mixture solvent system. In cer red spectra and refractive indices of the typical polymeric tain embodiments, the substrate polymer from which the Surface material and the typical Substrate material can be non-fouling polymer will be grafted will not swell more than determined independently and if the range of the modification 15% by volume at 25°C. under equilibrium conditions in the or coating thickness is between 10 nm and 5000 nm. A matrix polymerization mixture solvent system. In certain embodi of synthetic infrared absorbance spectra can be constructed ments, the Substrate polymer from which the non-fouling using the principal component spectra (those of the coating polymer will be grafted will not swell more than 5% by material and the substrate material) and Beer's law (A=cbC) volume at 25°C. under equilibrium conditions in the poly where b, the optical path length, is replaced by the exponen 25 merization mixture solvent system. In certain embodiments, tially decaying and wavelength dependent depth of penetra the substrate polymer from which the non-fouling polymer tion of the ATR evanescent wave. An empirically measured will be grafted will not swell or may even shrink at 25°C. sample is then compared across all the synthetic spectra in the under equilibrium conditions in the polymerization mixture matrix and the closest match, determined by the minimum Solvent system. As previously noted, the Substrate may be a n-dimensional cosine statistical distance, is the one of the 30 composite of materials. In Such instances, it is preferred that sample's polymeric Surface modification or coating thick the near-surface region of the substrate into which the poly SS. merization initiator is incorporated satisfy the swelling crite For example, the average thickness of a homopolymeric ria recited herein. For example, in those embodiments in SBMA (N-(3-sulfpropyl)-n-methacryloxyethyl-n, n-dim which the Substrate comprises a coating of a precoat material ethylammonium betaine) hydrogel Surface modification or 35 overlying a metal, ceramic, glass or semi-metallic material, it coating on a polyetherurethane plus 10% to 50% BaSO is preferred that the coating of the precoat material not swell Substrate can be approximated using attenuated total reflec more than 30% by volume at 25°C. under equilibrium con tance (ATR) infrared spectrometry if the range of the modi ditions in the polymerization mixture solvent system. fication or coating thickness is between 10 nm and 5000 nm The initiator(s) incorporated into the substrate preferably and the BaSO content of the substrate is constant to within 40 have limited solubility in the solvent system comprised by the +/-5%. The value of the absorbance of the vibrational SO polymerization mixture and include any of the initiators iden stretch at 1037.0 cm (point baseline corrected by subtract tified herein. In general, it is preferred that the incorporated ing the absorbance value at 994.7 cm) divided by the value initiator(s) have a 10 hour T1/2 decomposition temperature of of the absorbance of the urethane peak at 1309.5 cm (point 25-175° C. In one particular embodiment, the incorporated baseline corrected by subtracting the absorbance value at 45 initiator(s) have a 10 hour T1/2 decomposition temperature of 1340.0 cm) equals a value relative to the concentration of 70-130° C. Advantageously, having a 10 hour T1/2 decom SBMA present. position temperature of 70-130°C. tends to increase the den To induce Small polymerization initiator molecules to con sity of interfacial initiation events from the redox reaction and centrate at or near the Substrate Surface, where polymeriza effectively outcompete thermal initiation. tion is initiated and propagated, polymerization mixture sol 50 As described elsewhere herein, the initiator may comprise vent systems with Surface tensions of a magnitude differing a redox pair; in Such embodiments, at least one member of from the Surface energy of the Substrate and one or more such pair have such a limited solubility in the polymerization polymerization initiators having limited solubility in the mixture solvent system. In one embodiment, both members polymerization mixture solvent system are selected. The Sur of the redox pair have limited solubility in the polymerization faces of the substrate from which the non-fouling material is 55 mixture solvent system. In an alternative embodiment, one to be grafted surfaces may be hydrophobic or hydrophilic, member of the pair is soluble in the polymerization mixture and the polymerization mixture solvent system may be acque solvent system but the other has limited solubility in the ous, comprise polar organic solvents, aqueous mixtures of polymerization mixture solvent system. Without being bound polar organic Solvents, or aqueous mixtures of any organic to any particular theory, it is presently believed that when one compound designed to modify the Surface tension of aqueous 60 member of a redox pair is soluble in the polymerization solutions. Optionally, for hydrophobic substrates, hydropho mixture solvent system and the other has limited solubility in bic initiator(s) and hydrophilic solvent systems, e.g., aqueous the polymerization mixture solvent system, the two are phase media are selected. Preferably, if the substrate is hydrophilic, separated and initiation is enhanced at the interface of the two at least one hydrophilic initiator and a non-polar organic phases which tends to decrease solution polymerization and Solvent system is selected. 65 increase grafting at or near the Substrate surface. Thus, for Preferably, the substrate (or at least the portion of the example, either member of the redox pair may be hydropho Substrate into which the polymerization initiator is incorpo bic and either member of the pair may be hydrophilic, pro US 8,574,660 B2 61 62 vided at least one of the members has limited solubility in the dine, polyimide, polyketal, poly(ketone), polyolefin, poly polymerization mixture solvent system. In one preferred (orthoester), polyphosphazine, polysaccharide, polysiloxane, embodiment, a hydrophobic oxidizer is paired with a hydro polysulfone, polyurea, polyurethane, halogenated polymer, philic reducing agent. In another preferred embodiment, a silicone, aldehyde crosslinked resin, epoxy resin, phenolic hydrophilic oxidizer is paired with a hydrophobic reducing resin, latex, or a copolymer or blend thereof, and the pre agent. For example, in one embodiment, the redox pair com coated substrate is then imbibed as previously described. prises a peroxide and a reducing agent wherein the peroxide The quantity of initiator introduced to the substrate can be has limited solubility in the polymerization solvent system controlled by changing the concentration of the initiator in the and the reducing agent has high solubility in the polymeriza Solvent solution and/or by changing the amount of time the tion solvent system. By way of further example, in certain 10 Substrate is allowed to Soak in the initiator Solution during one embodiments, the peroxide has a log P partition coefficient initiator imbibing period or by repeating any number of ini greater than or equal to 3 for hydrophobic Substrates and tiator imbibing periods as required. Temperature is not nar phases and a log P partition coefficient less than 3 for hydro rowly critical, with temperatures in the range of room tem philic Substrates and phases. By way of further example, in perature to elevated temperatures being typical. When certain embodiments, the peroxide has a log P partition coef 15 utilizing multiple periods of initiator imbibing, the initiator ficient greater than or equal to 5 for hydrophobic substrates used in the Subsequent imbibing periods can be the same as, and phases and a log P partition coefficient less than 1 for different from, or a mixture with the initiator used in the hydrophilic substrates and phases. By way of further previous initiator imbibing period. In general, the Substrate is example, in certain embodiments, the peroxide has a log P immersed in the initiator-containing Solution for at least sev partition coefficient greater than or equal to 7 for hydrophobic eral seconds before polymerization is initiated. In some Substrates and phases and a log P partition coefficient less embodiments, the Substrate is immersed in the initiator-con than -1 for hydrophilic substrates and phases. By way of taining Solution for longer times. For example, the Substrate further example, in certain embodiments, the peroxide has a may be immersed in the initiator-containing Solution for at log Ppartition coefficient greater than or equal to 9 for hydro least several minutes. By way of further example, the sub phobic Substrates and phases and a log P partition coefficient 25 strate may be immersed in the initiator-containing Solution less than -3 for hydrophilic substrates and phases. for at least about 15 minutes before polymerization is initi In one embodiment, an initiator is incorporated into the ated. In some embodiments, the substrate will be immersed in Substrate by initially incorporating an initiator-precursor into the initiator-containing Solution for at least 1 hour at room the Substrate and activating the initiator-precursor to an ini temperature or elevated temperatures for initiators having a tiator. 30 10 hour T1/2 decomposition temperature of 70-130° C. In accordance with one aspect of the present invention, the before polymerization is initiated. In further embodiments, polymerization initiator(s) may be incorporated into and/or the substrate will be immersed in the initiator-containing onto the Substrate by various techniques. In one such method, solution for at least 2 hour before polymerization is initiated. the Substrate (including Substrates having precoat or under In yet further embodiments, the substrate will be immersed in coat as previously described) is imbibed with the polymer 35 the initiator-containing solution for at least 16 hour before ization initiator; that is, the polymerization initiator is polymerization is initiated. Depending upon the time, tem absorbed into the substrate. In one embodiment, the perature and concentration of initiator in the initiator-contain initiator(s), i.e., an initiator or a mixture of different initiators, ing Solution, a concentration gradient of initiator in the Sub is introduced into and/or onto the substrate's surface by strate may be established. In some embodiments, it may be physio-adsorption, wherein the initiator is dissolved in a sol 40 preferable to have a higher concentration of initiator in the vent or combination of solvents and the substrate (with or substrate nearer to the surface. As noted, the initiator may be without an undercoating layer) is submerged in the mixture presentina range of concentrations in the initiator-containing for a time and at a temperature to achieve Sufficient absorption Solution. For example, in some embodiments, the concentra by the substrate. The substrate is allowed to swell ultimately tion of the initiator will generally be at least 0.1% by weight. imbibing initiator into the Substrate. In general, the amount of 45 In Some embodiments, the concentration will be even greater, initiator incorporated into a substrate during the Soak will, at e.g., at least 0.5% by weight. In some embodiments, the least in part, be a function of the solubility of the initiator in concentration will be even greater, e.g., at least 1% by weight. the solvent system, solubility of the initiator in the substrate In Some embodiments, the concentration will be even greater, as well as the Soak time, temperature and concentration of the e.g., at least 10% by weight. In each of these embodiments, initiator in the Solution, as well as the chemical composition 50 the initiator is preferably one of the UV, thermal or redox of the substrate and the initiator. initiators described elsewhere herein. In a preferred embodiment, the surface of the substrate to The solvent used to imbibe the substrate with initiator may be imbibed with the polymerization initiator(s) comprises a have the capacity to swell the substrate (or at least the portion polymer, natural or synthetic. In an alternative embodiment, of the substrate to be imbibed with initiator) to various the substrate is an imbibable material selected from among 55 degrees. Typically, the imbibing solvent swells the substrate polymers, natural or synthetic, biological tissues, living or (or at least the portion of the substrate to be imbibed with dead, woven non-woven fibers, and combinations thereof. initiator) less than 900% by volume at room temperature and Certain (uncoated) Substrates such as a metal, ceramic, glass, ambient pressure. For example, in one Such embodiment, the and semi-metallic Substrates lack the capacity to absorb Suf imbibing solvent swells the substrate (or at least the portion of ficient initiator. In general, therefore, for these substrates it is 60 the substrate to be imbibed with initiator) less than 100% by preferred to precoat the Surface of the metal, ceramic, glass or volume. By way of further example, in one such embodiment, semi-metallic Substrate with an undercoating or precoating, the imbibing solvent swells the substrate (or at least the por from which the polymeric material may be grafted. For tion of the substrate to be imbibed with initiator) less than example, metal, ceramic, glass, and semi-metallic Substrates 100% by volume. By way of further example, in one such may be precoated with a polymer selected from polyamide, 65 embodiment, the imbibing solvent swells the substrate (or at polyamine, polyanhydride, polyazine, poly(carbonate), poly least the portion of the substrate to be imbibed with initiator) ester, polyether, polyetheretherketone (PEEK), polyguani less than 25% by volume. In a preferred embodiment, the US 8,574,660 B2 63 64 imbibed substrate is preferably washed using a solvent, contain any of the pendant groups corresponding to Formulae optionally with a solvent that swells that substrate, and ZI-1 to ZI-7. By way of further example, upon polymerization optionally dried. In other embodiments, the substrate is the monomers may provide the polymer with repeat units washed with solvents, which may be the same or different corresponding to any of Formula 1-12. In a preferred embodi from the imbibing solvents, or the substrate may not be ment, the monomers are miscible with the polymerization washed. For example, the wash solvent may swell the sub mixture solvent system. strate, shrink the substrate, or neither. In one embodiment, the In processes for modification of the surface of a hydropho substrate is dried, partially dried or not dried. Optionally, bic substrate, a hydrophilic solvent system preferably is there may be a solvent exchange. employed. Aqueous solutions preferably are used as the Sol In an alternative method, the initiator(s) is/are incorporated 10 vent system, optionally containing ions or buffers, such as into the substrate by co-deposition of the initiator(s) as a Sodium, ammonium, potassium, chloride, phosphate, or component of a coating, i.e., a precoating or undercoating as acetate. In processes for modifying hydrophilic Substrates, a described herein, on the surface of the substrate. For example, hydrophobic solvent system preferably is used. In such pro a thin film of polymer and initiator are deposited onto the cesses, the preferred media is an organic solvent, typically a Substrate by dipping the Substrate in a solution of initiator(s) 15 non-polar organic solvent, or a mixture thereof. Exemplary and polymer. Alternatively, a precoat layer of a flowable organic solvents include one or more of toluene, hexane, mixture of the initiator(s) and a second material Such as a cyclohexane, benzene, Xylene, tetrahydrofuran, and aliphatic polymeric material are deposited onto the surface of the sub alcohols. In a preferred embodiment, the solvent system does strate. The precoating may thus be applied to any of the not swell the substrate (or at least that portion of the substrate Substrates described herein, including metals, ceramics, from which the polymer will be grafted) by more than 25% by glasses, polymers, biological tissues, living or dead, woven Volume. For example, in one Such embodiment, the Solvent and non-woven fibers, semi-metals such as silicon. For system does not swell the substrate (or at least that portion of example, the metal, ceramic, glass, polymer, biological tis the substrate from which the polymer will be grafted) by more Sue, fiber, or semi-metal may be precoated with a polymerand than 10% by volume. In a preferred embodiment, the solvent initiator mixture wherein the polymer is selected from polya 25 system does not swell the substrate (or at least that portion of mide, polyamine, polyanhydride, polyazine, poly(carbon the substrate from which the polymer will be grafted) by more ate), polyester, polyether, polyetheretherketone (PEEK), than 5% by volume. In one embodiment, the solvent system polyguanidine, polyimide, polyketal, poly(ketone), polyole may even shrink the substrate (or at least that portion of the fin, poly(orthoester), polyphosphazine, polysaccharide, pol substrate from which the polymer will be grafted). ysiloxane, polysulfone, polyurea, polyurethane, halogenated 30 In one particularly preferred embodiment, the non-fouling polymer, silicone, aldehyde crosslinked resin, epoxy resin, polymeric materials are grafted from the Substrate by chain phenolic resin, latex, or a copolymer or blend thereof. growth addition polymerization. The polymerization condi In some embodiments, one or more solvents or other reac tions described herein are generally mild compared to other tants used in a surface treatment to dissolve or clean up methods of polymerization and thus do not significantly alter processing materials, Surface materials, artifacts, and other 35 the mechanical properties, flexibility, or dimensional proper components as described above, may also introduce a poly ties of the underlying substrate. In one preferred embodiment, merization initiator to the substrate. Thus, the surface treat for example, polymerization is carried out at a temperature ment/imbibing process may optionally be accompanied by not in excess of 60°C. The polymerization may be carried out mechanical agitation (e.g., Sonication) and/or elevated tem over a relatively wide pH range, e.g., about 0-10. In one peratures, for example, to promote dissolution or removal of 40 embodiment, the polymerization reaction is carried out at a the low molecular weight species (e.g., Substrate Surface pH of about 2-8. For example, when DCP and ferrous glu materials or processing materials) and other flaws (e.g., Sur conate are used as redox pair, the polymerization reaction face roughness) and/or to enhance the imbibing process. may be carried out at a pH of about 6-8. By way of further In one embodiment, the amount of initiator co-deposited example, when benzoyl peroxide and ferrous gluconate are with the polymer is relatively great. In certain embodiments, 45 used as redox pair, the polymerization reaction may be carried for example, the weight ratio of initiator to polymer co-de out at a pH of about 4-6. By way of further example, when posited will be at least 1:1000, respectively. In some embodi TBEC and ferrous gluconate are used as redox pair, the poly ments, the weight ratio of initiator to polymer co-deposited merization reaction may be carried out at a pH of about 5-7. will be even greater, e.g., at least 1:100, 1:10, 1:1, 10:1, 100:1, Examples of radical polymerization processes include, but or 1000:1 respectively. Typically, the ratio of initiator to poly 50 are not limited to, UV, thermal, and redox initiated processes. mer will be in the range of about 1:1 to about 20:1. In addition, In particular embodiments, the polymer is grafted from the the co-deposited layers (i.e., the layers containing co-depos Substrate, by first incorporating one or more initiators, such as ited initiator and polymer) will have a thickness of at least 100 an ultraviolet (UV), thermal, or redox initiator into the sub nm. For example, in one embodiment, the co-deposited layer strate and initiating polymerization of one or more monomers will have a thickness of about 100 nm to about 500 microme 55 from the surface. Preferably, the initiator is incorporated into ters. In each of these embodiments, the initiator is preferably the substrate by imbibing the substrate with initiator or coat one of the UV, thermal or redox initiators described elsewhere ing the Substrate with a layer, e.g., an undercoating layer herein. (sometimes referred to herein as the co-deposited layer), Monomers can be selected such that their reactivity ratios comprising the initiator. The polymerization is typically ini give alternating copolymers, periodic copolymers with a pre 60 tiated by exposing the initiator-imbibed substrate with a solu specified ratio of each monomer, random copolymers, block tion or Suspension of the monomer or monomers to be poly copolymers or homopolymers. Inclusion of more than two merized. The quantity of polymer introduced to the substrate reactive groups on each monomer unit allows for the forma can be controlled by changing the concentration of the poly tion of star polymers, dendrimers, regularly branched poly mer in the Solvent Solution, Surface tension of the polymer mers, randomly branched polymers, and brush polymers. In 65 Solution, polymerization temperature, pH of the polymer general, the monomer may be selected from any of the mono Solution, polymerization solution agitation or flow condi mers disclosed herein. Thus, for example, the monomers may tions, by changing the amount of time the Substrate is allowed US 8,574,660 B2 65 66 to be in the polymer Solution during one polymerization polyethylene glycol (<2000 MI) is incorporated into the period, and/or by repeating any number of polymerization grafted polymer in a post-polymerization aqueous wash periods as required. When utilizing multiple polymerization period. periods, the polymer(s) used in the Subsequent polymeriza i. UV Initiators tion periods can be the same as, different from, or a mixture In one embodiment, the initiator is an ultraviolet (UV) with the polymer(s) used in the previous polymerization initiator. The substrate and initiator are typically placed into period. an aqueous, degassed, Solution containing a Zwitterionic Chain transfer agents can be added to the monomer Solu monomer and exposed to UV light, initiating the radical poly tion to mediate the graft from radical polymerization reaction merization. In one exemplary embodiment, the UV light has kinetics. Chain transfer agents include, but are not limited to, 10 a peak wavelength of 365 nm, generated by a 100 WUV. molecules containing halocarbons, thiols, dithiocarbamates, Examples of UV radical initiators include, but are not trithiocarbonates, dithioesters, Xanthates, primary or second limited to. 1-Hydroxycyclohexyl phenyl ketone, 2.2-Di ary alcohols. Examples of chain transfer agents are bromot ethoxyacetophenone, 2-Benzyl-2-(dimethylamino)-4'-mor richloromethane, 4-methylbenzenethiol, benzyl alcohol, pholinobutyrophenone, 2-Hydroxy-2-methylpropiophe methanol, ethanol, ethyleneglycol, glycerol, and isopropanol. 15 none, 2-Hydroxy-4-(2-hydroxyethoxy)-2- In one embodiment the radical polymerization graftings are methylpropiophenone, 2-Methyl-4-(methylthio)-2- mediated using 2.2.6,6-tetramethylpiperidinie-1-oxyl morpholinopropiophenone, 3'-Hydroxyacetophenone, (TEMPO). In one embodiment the radical polymerization 4'-Ethoxyacetophenone, 4-Hydroxyacetophenone, 4'-Phe graftings are mediated using reversible addition fragmenta noxyacetophenone, 4'-tert-Butyl-2',6'-dimethylacetophe tion transfer (RAFT) agents. Examples of RAFT agents none, Diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide/2- include 2-(Dodecylthiocarbonothioylthio)-2-methylpropi hydroxy-2-methylpropiophenone, 2,2-Dimethoxy-2- onic acid, 2-Cyano-2-propylbenzodithioate, 2-Cyano-2-pro phenylacetophenone, 4,4'-Dimethoxybenzoin, 4,4'- pyl dodecyl trithiocarbonate, 4-Cyano-4-(phenylcarbono Dimethylbenzil, Benzoin ethyl ether, Benzoin isobutyl ether, thioylthio)pentanoic acid, 4-Cyano-4- Benzoin methyl ether, Benzoin, 2-Methylbenzophenone, 3,4- (dodecylsulfanylthiocarbonyl)sulfanylpentanoic acid, Bis 25 Dimethylbenzophenone, 3-Hydroxybenzophenone, 3-Meth (dodecylsulfanylthiocarbonyl)disulfide, Bis(thiobenzoyl) ylbenzophenone, 4,4'-Bis(diethylamino)benzophenone, 4,4'- disulfide, Cyanomethyl dodecyl trithiocarbonate, Dihydroxybenzophenone, 4,4'-Bis2-(1-propenyl)phenoxy Cyanomethyl methyl(phenyl)carbamodithioate, and their benzophenone, 4-(Diethylamino)benzophenone, analogues and derivatives 4-Benzoylbiphenyl, 4-Hydroxybenzophenone, 4-Methyl Oxygen can act as an inhibitor in free radical polymeriza 30 benzophenone, Benzophenone-3,3',4,4-tetracarboxylic tion as it can react quickly with the free radicals generated by dianhydride, BenZophenone, Methyl benzoylformate, the initiator to form stable radical species, which in turn can Michler's ketone, Sulfoniums, iodiums, 2-(4-Methoxy react with other radical species to form unreactive species styryl)-4,6-bis(trichloromethyl)-1,3,5-triazine, Diphenyli which terminate the polymerization. Therefore, creating an odonium p-toluenesulfonate, N-Hydroxy-5-norbornene-2,3- oxygen-free environment by degassing with nitrogen or 35 dicarboximide perfluoro-1-butanesulfonate, argon or vacuum is typically used to remove oxygen before N-Hydroxynaphthalimide triflate, 2-tert-Butylan and during polymerization. However, for certain embodi thraquinone, 9,10-Phenanthrenequinone, Anthraquinone-2- ments, it would preferable not to require Such degassing steps Sulfonic acid sodium salt monohydrate, Camphorquinone, in commercial production. In one preferred embodiment, the Diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide, 10-Me polymerization method is other than ATRP, which typically 40 thylphenothiazine, thioxanthones, and IRGRCURE 2959. requires stringent control of oxygen levels that may be diffi ii. Thermal Initiators cult to achieve during manufacturing. In another embodiment a heat activated (thermal) initiator Alternatively, oxygen in the system can be minimized by is used, in place of the UV initiator described above, and the filling the reactor with the reaction mixtures thus physically graft from polymerization is initiated by heating the aqueous displacing the oxygen in the reactor. In another embodiment, 45 monomer Solution temperature to a desired temperature and reagents which scavenge oxygen can be added to the reaction holding the temperature constant until the desired degree of mixture. Suitable oxygen-Scavenging reagents include, but polymerization is achieved. are not limited to, Sodium (meta) periodate, riboflavin, and Suitable thermal initiators include, but are not limited to, ascorbic acid. These agents may improve the efficacy of the tert-Amyl peroxybenzoate, 4.4-Azobis(4-cyanovaleric acid), resulting polymer if the polymerization does not employ an 50 2,2'-AZobis(2-carboxyethyl)-2-methylpropionamidine. inert atmosphere. 2,2'-Azobis(4-methoxy-2,3-dimethylvaleronitrile), 1,1'- In addition to monomer and a solvent system, the polymer Azobis(cyclohexanecarbonitrile), 2,2'-Azobisisobutyroni ization mixture may optionally containa free radical inhibitor trile (AIBN), Benzoyl peroxide, 2.2-Bis(tert-butylperoxy) to encourage surface grafting. Without being bound to any butane, 1,1-Bis(tert-butylperoxy)cyclohexane, 2.5-Bis(tert particular theory, it is presently believed that the addition of a 55 butylperoxy)-2,5-dimethylhexane, 2.5-Bis(tert free radical inhibitor, including, hydroquinone, hydro Butylperoxy)-2,5-dimethyl-3-hexyne, Bis(1-(tert quinone monomethyl ether, phenothiazine, 3.7-bis(dimethy butylperoxy)-1-methylethyl)benzene, 1,1-Bis(tert lamino)phenazathionium chloride, triethylene diamine, t-bu butylperoxy)-3,3,5-trimethylcyclohexane, tert-Butyl tylcatechol, butylated hydroxytoluene, and 4-t-butylphenol hydroperoxide, tert-Butyl peracetate, tert-Butyl peroxide, to the grafting Solution decreases solution polymerization, 60 tert-Butyl peroxybenzoate, tert-Butylperoxy isopropyl car thereby allowing more monomer to be available for grafting bonate, Cumene hydroperoxide, Cyclohexanone peroxide, at or near the Substrate surface/polymerization mixture inter Dicumyl peroxide, Lauroyl peroxide, 2.4-Pentanedione per face. oxide, Peracetic acid, Potassium persulfate. Plasticizers can be incorporated into the grafted polymer at The temperature to which the solution is heated is depen any time during and/or Subsequent to Surface polymerization. 65 dent, among other things, on the monomer and/or the initiator, In the preferred embodiment, a hydrophilic plasticizer (such and/or the substrate. Examples of thermal radical initiators as citrated esters, ethylene glycol, propylene glycol, and/or include, but are not limited to, azo-compounds such as azo US 8,574,660 B2 67 68 bisisobutyronitrile (AIBN) and 1,1'-Azobis(cyclohexanecar Exemplary hydroperoxides include cumene hydroperoxide bonitrile) (ABCN). Preferable grafting temperatures are near and t-butyl hydroperoxide. Exemplary ketone peroxides the 10 hour T1/2 of the initiator selected. The graft from include methyl ethyl ketone peroxide mixture and 2.4-pen radical polymerization reaction can be thermally quenched tanedione peroxide. Exemplary peroxydicarbonates include by heating beyond the initiators half life. di(n-propyl)peroxydicarbonate, di(sec-butyl)peroxydicar iii. Redox Initiators In another embodiment, a redox initiator system is used to bonate, and di(2-ethylhexyl)peroxydicarbonate. Exemplary initiate polymerization from the surface of the substrate. The peroxyesters include 3-hydroxy-1,1-dimethylbutyl peroxy redox initiator System typically includes a pair of initiators: neodecanoate alpha-cumyl peroxyneodecanoate, t-amyl per an oxidant and a reducing agent. The redox chemistry oxyneodecanoate, t-butyl peroxyneodecanoate, t-amyl per described herein can be modified to prepare non-fouling 10 oxypivalate, t-butyl peroxypivalate, 2,5-di(2-ethyl polymeric materials, for example, Such as Zwitterionic poly hexanoylperoxy)-2,5-dimethylhexane, t-amyl peroxy-2- meric materials. Redox initiation is regarded as a one-elec ethyl hexanoate, t-butyl peroxy-2-ethyl hexanoate, t-amyl tron transfer reaction to effectively generate free radicals peroxyacetate, t-butyl peroxyacetate, t-butyl peroxyacetate, under mild conditions. Suitable oxidants include, but are not t-butyl peroxybenzoate, OO-(t-amyl) O-(2-ethylhexyl) limited to, peroxide, hydroperoxide, persulfates, peroxycar 15 bonates, peroxydisulfates, peroxydiphosphate, permangan monoperoxycarbonate, OO-(t-butyl)-O-isopropyl monoper ate, salts of metals such as Mn(III), Ce(IV), V(V), Co(III), oxycarbonate, OO-(t-butyl)-O-(2-ethylhexyl)monoperoxy Cr(VI) and Fe(III). carbonate, polyether poly-t-butylperoxy carbonate, and Suitable reducing agents include, but are not limited to, t-butyl peroxy-3.5.5-trimethylhexanoate. metal salts such as Fe(II), Cr(II), V(II), Ti(III), Cu(II), and Any of the aforementioned peroxides such as benzoyl per Ag(I) salts, and oxyacids of Sulfur, hydroxyacids, alcohols, oxide, lauroyl peroxide, hydrogen peroxide, or dicumyl per thiols, ketones, aldehydes, amine, and amides. For example, oxide are imbibed into the polymer such as polyurethane by in some embodiments, the reducing agent is an iron(II) salt, dipping the polymer into a peroxide Solution in an organic Such as iron(II) L-ascorbate, ferrous Sulfate, iron(II) acetate, solvent for a predetermined period of time and dried. The iron(II) acetylacetonate, iron(II) ethylenediammonium Sul 25 peroxide containing polymer is put into a solution of mono fate, iron(II) gluconate, iron(II) lactate, iron(II) oxalate, or mer. The redox polymerization is initiated by the addition of iron(II) sulfate. a reducing agent, for example salts of Fe(II), such as Fe(II) Polymerization can be initiated by radicals formed directly chloride, Fe(II) sulfate, ammonium Fe(II) sulfate, or Fe(II) from the redox reaction and/or by macroradicals formed by gluconate, at room temperature or elevated temperature, to the abstraction of a hydrogenatom from the substrate by the 30 the monomer Solution. transient radicals formed during the redox reaction. For modifying the Surface of an article and/or Surface graft In one embodiment, the substrate is coated with a under polymerization, it has been found particularly useful to use coating coating and the non-fouling material is grafted from hydrophobic-hydrophilic redox initiator pairs. For example, the undercoating layer by redox polymerization. The under in one embodiment the hydrophobic member of a hydropho coating coating contains oxidants or reducing agents. In a 35 bic-hydrophilic redox initiator pair is incorporated into a preferred embodiment, the undercoating layer contains one hydrophobic substrate as previously described. The substrate or more reducing agents, such as acids, alcohol, thiols, Surface is then treated with an aqueous polymerization mix ketones, aldehydes, amines and amides. An oxidant is used to ture containing monomers, typically hydrophilic monomers, react with one or more functional groups of the undercoating and the hydrophilic member of the redox pair. This method layer to form radicals which initiate the graft from polymer 40 offers particular advantages when polymers are being grafted ization. from components having exposed external and internal Sur In a particular embodiment, the undercoating layer is a faces to be modified (such as catheters) and any Substrate that copolymer with pendant groups of aliphatic chains contain cannot readily be exposed to light. Additionally, such a sys ing silanol and/or hydroxyl groups. Such materials can be tem tends to minimize the extent of non graft polymerization used to form a undercoating layer on polymeric Substrates, 45 in the bulk polymerization mixture away from the polymer Such as polyurethane (PU). An oxidant, such as a salt of ization mixture/substrate Surface interface. Ce(IV), reacts with the hydroxyl group under mild conditions In a preferred embodiment, the hydrophilic-hydrophobic to form hydroxyl radicals in the undercoating layer to grow redox pair is a hydrophobic oxidizing agent/hydrophilic the Zwitterionic polymers. reducing agent pair wherein (i) the hydrophobic oxidizing In still another embodiment, a pair of peroxides and metal 50 agent is tert-amyl peroxybenzoate, O.O-t-Butyl-O-(2-ethyl salts (such as Fe(II) as used in the Fenton Reaction) is used in hexyl)mono-peroxycarbonate, benzoyl peroxide, 2.2-bis the redox polymerization to graft Zwitterionic polymers from (tert-butylperoxy)butane, 1,1-bis(tert-butylperoxy)cyclohex polymers such as polyurethane. Peroxides for use in the redox ane, 2.5-bis(tert-butylperoxy)-2,5-dimethylhexane, 2.5-Bis polymerization include diacyl peroxides, dialkyl peroxides, (tert-Butylperoxy)-2,5-dimethyl-3-hexyne, bis(1-(tert diperoxyketals, hydroperoxides, ketone peroxides, peroxydi 55 butylperoxy)-1-methylethyl)benzene, 1,1-bis(tert carbonates, and peroxyesters. Exemplary diacyl peroxides butylperoxy)-3,3,5-trimethylcyclohexane, tert-butyl include decanoyl peroxide, lauroyl peroxide. Succinic acid hydroperoxide, tert-butyl peracetate, tert-butyl peroxide, tert peroxide, and benzoyl peroxide. Exemplary dialkyl peroX butyl peroxybenzoate, tert-butylperoxy isopropyl carbonate, ides include dicumyl peroxide, 2,5-di(t-butylperoxy)-2,5- cumene hydroperoxide, cyclohexanone peroxide, dicumyl dimethylhexane, t-butyl cumyl peroxide, a.a'-bis(t-butylper 60 peroxide, lauroyl peroxide, 2.4-pentanedione peroxide, 4.4- oxy)diisopropylbenzene mixture of isomers, di(t-amyl) aZobis(4-cyanovaleric acid), or 1, 1'-Azobis(cyclohexanecar peroxide, di(t-butyl) peroxide and 2,5-di(t-butylperoxy)-2,5- bonitrile), 2,2'-Azobisisobutyronitrile (AIBN) and (ii) the dimethyl-3-hexyne. Exemplary diperoxyketals include 1,1- hydrophilic reducing agent is Fe", Cr", V", Ti", Co.", di(t-butylperoxy)-3,3,5-trimethylcyclohexane, 1,1-di(t-bu Cu", oran amine; transition metalion complexes, e.g., copper tylperoxy)cyclohexane, 1,1-di(t-amylperoxy)cyclohexane, 65 (II) acetylacetonate, HSO, SO, SO, or SOs’. Exem n-butyl 4,4-di(t-butylperoxy)Valerate, ethyl 3,3-di-(t-amylp plary combinations include any of the aforementioned per eroxy)butanoate and ethyl 3,3-di-(t-butylperoxy)butyrate. oxides and Fe". In some preferred embodiments, benzoyl US 8,574,660 B2 69 70 peroxide, dicumyl peroxide, or O,O-t-Butyl-O-(2-ethyl In contrast, redox chemistries generally do not require a hexyl) mono-peroxycarbonate are used in combination with direct line of sight to a light Source to initiate polymerization Fe2+. since polymerization is not initiated photolytically and there In an alternative embodiment, the hydrophilic-hydropho fore may be advantageous for coating Substrates that have one bic redox pair is a hydrophilic oxidizing agent/hydrophobic or more surfaces that are difficult to expose to the UV source, reducing agent pair wherein (i) the hydrophilic oxidizing Such as catheter lumens. Further, redox polymerization typi agent is peracetic acid, a persulfate Such as potassium persul cally can be done at low temperatures, for example less than fate, Fe", CIO, H.O., Ce", V", Cr', or Mn, or their 60° C., less than 55° C., less than 50° C., less than 45° C., less combinations; and (ii) the hydrophobic reducing agent is an than 40°C., less than 35°C., or less than 30° C. alcohol, carboxylic acid, amine, or a boronalkyl or their com 10 The graft from polymerization can propagate through a binations. cationic or anionic reaction, where the Substrate Surface acts as the cation oranion initiator or a cationic oranionic initiator Other suitable redox systems include (1) organic-inorganic is immobilized on the Substrate and the monomer contains a redox pairs, such as oxidation of an alcohol by Ce", V", reactive olefin. Examples of anionic polymerization are Cr'", Mn"; (2) monomers which can act as a component of 15 anionic ring opening, as in the case of synthesizing polyca the redox pair, such as thiosulfate plus acrylamide, thiosulfate prolactone or polycaprolactam, where the polymerization plus methacrylic acid, and N,N-dimethylaniline plus methyl proceeds through a lactone or lactam moiety in a ring struc methacrylate, and (3) boronalkyl-oxygen systems. ture containing a pendant Zwitterion group. Alternatively, an iv. Exemplary Initiators organic ring containing one or more units of unsaturation and Exemplary initiators include, but are not limited to, diacyl a pendant Zwitterionic group are polymerized. In one embodi peroxides Such as benzoyl peroxide, dichlorobenzoyl peroX ment a pendant olefin is included in the monomer unit and is ide, dilauroyl peroxide, didecanoyl peroxide, diacetyl peroX used for crosslinking, Such as in ring opening metathesis ide Succinic acid peroxide, disuccinic peroxide and di(3.5.5- polymerization (ROMP). trimethylhexanoyl) peroxide. In a preferred embodiment, the Bioactive Agents diacyl peroxide is an aromatic diacyl peroxide, Such as ben 25 Therapeutics, diagnostic, and/or prophylactic agents can Zoyl peroxide. be immobilized on or otherwise incorporated into an article of Other exemplary initiators include, but are not limited to, the present invention. When optionally included, such bioac peroxydicarbonates such as diethyl peroxydicarbonate, di-n- tive agents may be leachable or non-leachable. For example, butyl peroxydicarbonate, diisobutyl peroxydicarbonate, di-4- the bioactive agent may be dissolved or otherwise contained tert-butylcyclohexyl peroxydicarbonate, di-sec-butyl per 30 within the Substrate, or covalently or non-covalently associ oxydicarbonate, di-2-ethylhexyl peroxydicarbonate, di-n- ated with the grafted polymer layer, and leached or otherwise propyl peroxydicarbonate and diisopropyl disassociated with the article in a controlled or uncontrolled peroxydicarbonate; peroxyesters, such as t-butyl perneode manner (e.g., by leaching). These agents can interact pas canoate, t-butyl and t-amyl peroxy 2-ethylhexanoate, and sively or actively with the Surrounding in Vivo environment. t-butyl peroxybenzoate; monoperoxycarbonates based on 35 The agents can also be used to alter the Surrounding in vivo t-butyl and t-amyl monoperoxy 2-ethylhexylcarbonates; per chemistry or environment. Two or more agents can be immo Sulfates, such as potassium persulfate, ammonium persulfate, bilized to a substrate surface, wherein the activity of the two and sodium persulfate; cumene hydroxide, tert-butyl hydro agents is greater than either of the agents alone. A substance, peroxide, di(tert-amyl) peroxide, tert-butyl peroxide, 2.5-Bis material or agent that is not considered active, can become (tert-butylperoxy)-2,5-dimethylhexane, 1,1-Bis(tert-butylp 40 active if an active agent is immobilized on the Substance, eroxy)-3,3,5-trimethylcyclohexane: 1,1-Bis(tert material or agent. Active agents include, but are not limited to amylperoxy)cyclohexane, 1,1-Bis(tert-butylperoxy)-3,3,5- inorganic compounds, organometallic compounds, organic trimethylcyclohexane, 1,1-Bis(tert-butylperoxy) compounds or any synthetic or natural, chemical or biological cyclohexane, 2.2-Bis(tert-butylperoxy)butane, 2,4- compounds of known or unknown therapeutic effect. Pentanedione peroxide, 2.5-Bis(tert-butylperoxy)-2,5- 45 In general, a bioactive agent can be immobilized covalently dimethylhexane, 2,5-Di(tert-butylperoxy)-2,5-dimethyl-3- or non-covalently directly on the Substrate, on the undercoat hexyne, 2-Butanone peroxide, cumene hydroperoxide, ing layer, on the grafted polymer layer, or combinations di-tert-amyl peroxide, dicumyl peroxide, lauroyl peroxide, thereof. In one embodiment, the bioactive agent is immobi tert-butyl peracetate, tert-butyl peroxide, tert-butyl peroxy lized covalently by reacting one or more functional groups on benzoate, tert-butylperoxy 2-ethylhexyl carbonate, tert-Bu 50 the active agent with one or more functional groups on the tylperoxy isopropyl carbonate, 4-nitro-benzenecarboper Substrate, undercoating layer, and/or grafted polymer layer. oXoic acid t-butyl ester, cyclohexanone peroxide, Covalent bonds can beformed by a variety of reaction mecha (methylperoxy) (diphenyl)methylbenzene, bis(t-butylcy nisms including, but not limited to, Substitution, addition, and clohexyl)peroxydicarbonate, and 2,4,6-triphenylphenoxyl condensation reactions. dimer. 55 Typically, the bioactive agent will typically be immobi For Substrates requiring coating on both internal and exter lized on the grafted polymer layer after the grafted polymer nal Surfaces, additional considerations are required for initi layer has been grown from the Surface. In an alternative ating polymerization. Thermal initiators can be used; how embodiment, the bioactive agent can be co-immobilized with ever, the elevated temperature typically required can the grafted polymer layer in a side by side structure. In the adversely affect the substrate material. UV based approaches 60 graft from methods, a tether can be grown from the Surface must be designed such that they can penetrate through the and the active agent immobilized on the tether. Alternatively, material or can be applied intralumenally, for instance from a the active agent can be immobilized directly on the surface fiber optic source threaded into the lumen. This may be without the use of a tether. achieved by selecting a photoactive initiator which is labile at Cell adhesion agents can be immobilized to the composi a UV wavelength not absorbed by the substrate polymer. 65 tions described herein. The efficacy of a cell adhesion agent in Generally, lower wavelength UV irradiation is less absorbed binding cells in complex environments may be enhanced by and penetrates more readily than higher wavelength UV. reducing non-specific protein adsorption on the Surface from US 8,574,660 B2 71 72 which they are presented, given that cell attachment may be a tor binders, transglutimase, reversible NO binders, polyl competitive process with other protein adsorption. Further, ysine, Sulphonated polymers, thrombin inhibitors including there may an advantage to resisting attachment of any cells hirudin, urokinase, and streptokinase. other than those specifically targeted by the cell adhesion Device-centered infection remains a large problem. Non agent to prevent competitive blocking of the Surface. fouling materials, such as Zwitterions materials, can by them Examples of desirable cell attachment agents include, but selves diminish microbial adhesion and retard biofilm devel are not limited to, integrin binders. Exemplary integrin bind opment. Prevention of microbial adhesion and biofilm can be ers include, but are not limited to, RGD peptides, along with further enhanced on non-fouling Surfaces, such as Zwitteri a number of variants that include RGD motifs, YIGSR pep onic Surfaces, by presentation of antimicrobials including, tides, fibronectin, laminin or other proteins or peptides. 10 but not limited to, membrane-targeting antimicrobial agents, Longer variants of these peptide may have more specific antimicrobial peptides and Small molecule antimicrobial target cell binding. Further, the ability to present locally dense agents. Generally, antimicrobial peptides are cationic mol concentrations of cell attachment agents may increase the ecules with spatially separated hydrophobic and charged effectiveness of cell attachment by creating multimeric inter regions. Exemplary antimicrobial peptides include linear actions. Other cell adhesion agents include, but are not lim 15 peptides that form an O-helical structure in membranes or ited, to REDV peptides. Tailored integrin binders can be used peptides that form B-sheet structures, optionally stabilized for a variety of applications including osteointegration. with disulfide bridges in membranes. Representative antimi Cell adhesion agents that bind specific immune cells may crobial peptides include, but are not limited to, cathelicidins, also benefit from attachment to Zwitterions. Adhesion of defensins, dermcidin, and more specifically magainin 2, pro immune cells to the biomaterial surface activates these cells tegrin, protegrin-1, melittin, LL-37, dermaseptin 01. and prefaces their phenotypic response, Such as the transition cecropin, caerin, ovispirin, cecropin A melittin hybrid, and of monocytes to macrophages that can result, in Some cases, alamethicin, or hybrids or analogues of other AmPs. Natu in the fusion into undesirable foreign body giant cells. The rally occurring antimicrobial peptides include peptides from inherent resistivity to random protein fouling that Zwitterions Vertebrates and non-vertebrates, including plants, humans, possess provides a unique platform to couple biomolecules 25 fungi, microbes, and insects. that act as specific ligands for immune cells including neu Antimicrobial peptides can be made from naturally occur trophils, monocytes, helper T-cells, killer T-cells, suppressor ring amino acids, non-naturally occurring amino acids (e.g., T-cells, B-cells and dendritic cells. Selection of appropriate synthetic or semisynthetic amino acids and peptidomimet ligands may prime these cells for beneficial instead of detri ics), or combinations thereof. Antimicrobial peptides which mental functions. These ligands include peptides or proteins 30 retain their activity when immobilized on a Surface are gen that specifically bind immune cell receptors such as integrins, erally referred to as membrane-targeting antimicrobial selectins, complement, or Fc gamma. When bound to these agents. Antimicrobial peptides can be immobilized on the cell-associated proteins, such ligands may stimulate intracel non-fouling grafted polymer layer, the Substrate, the under lular signaling pathways that lead to responses including coating or combinations thereof by reacting a functional cytoskeletal rearrangements, production and secretion of 35 group on the peptide with a functional group on the non molecules including chemokines, cytokines and other fouling grafted polymer layer, the Substrate, and/or the primer chemoattractants, and induction of apoptosis. Desirable coat. For example, the peptide can be designed to have a behaviors that could be tailored by presentation of biomol cysteine residue which can be used to immobilize the peptide ecules via Zwitterionic tethers may include prevention/reduc on a Surface by reacting the thiol group of the cysteine residue tion in the secretion of proinflammatory cytokines, enhance 40 with a thiol-reactive group on the Surface. ment of phagocytosis, and modulation of the release of Tethering of these agents via non-fouling materials, such as soluble factors that influence tissue-device integration. Zwitterions, should provide stable, long-term activity. Addi Osteointegration may also be promoted or induced by fac tionally, immobilization of enzymes that degrade bacterial tors which would benefit from the non-fouling properties and attachment and biofilm proteins, such as glycosylases, lyases, stable presentation of non-fouling materials, such as Zwitte 45 and serine-proteases, or those that degrade microbial com rions. Osteointegration promoting agents include, but are not munication signal molecules, such as N-acyl-homoserine lac limited to, bone-morphogenic proteins, such as BMP2 and tone acylases, could provide improved efficacy in prevention shortened analogues thereof. Non-fouling Surfaces, such as of initial microbial adhesion events and subsequent biofilm Zwitterionic Surfaces, may enhance the activity of agents formation. designed to promote desired cell regrowth over a surface. 50 A broad range of antimicrobial or antiseptic agents may be Reducing attachment of neutrophils and macrophages may incorporated in the Substrate or the non-fouling polymer to inhibit the foreign body response and enable desired cell enhance antimicrobial activity at the surface or be released to attachment and growth process to be favored. provide antimicrobial activity in the environment Surround Presentation of antithrombotic agents may also be more ing the article. Suitable agents include silver metals, silver effective when tethered to grafted polymers, such as Zwitte 55 salts such as silver Sulfadiazine, silver oxide, silver carbonate, rionic materials, relative to other tethers. The process of silver acetate, silveralginate, silver azide, silver citrate, silver thrombosis involves both surface and bulk pathways. Zwitte lactate, silver nitrate, silver sulfate, silver chloride, silver rions have shown an ability to reduce platelet attachment and thiocyanate, silver-sodium-hydrogen-Zirconium phosphate, activation, reducing one pathway. Combining an active anti silver Sulfadiazine, silver cyclohexanediacetic acid and disil thrombotic that assists in the reduction of platelet activation 60 ver 2,5-dichloro-3,6-dihydroxy-2,5-cyclohexadiene-1,4-di or directly targets additional pathways for thrombosis with a one, among others, a bismuth Salt Such as bismuth nitrate, Zwitterionic tether could enhance the antithrombotic effect bismuth citrate or bismuth Salicylate among others, a Zinc compared to either a non-platelet adherent Surface or the salt, a cerium salt, triclosan, combinations of chlorhexidine antithrombotic agent alone. Suitable antithrombotic agents free base and chlorhexidine acetate, benzalkonium chloride, include, but are not limited to, thrombomodulin, heparin, 65 citrate, povidoneiodine, parachlorometaxylene, gramicidin, heparin fragments, derivatized heparin fragments, hyaluronic polymixin, norfloxacin, tobramycin, Sulfamylon, polyhex acid, reversible albumin binders, tissue plasminogen activa amethylene biguanide, alexidine, iodine, rifampicin, micona US 8,574,660 B2 73 74 Zole, bacitracin, and minocycline, ciprofloxacin, clindamy morphone, methadone, morphine, oxycodone, cin, erythromycin, gentamycin, tetracycline and Vancomycin. papavereturn, pentazocine, pethidine, phenopefidine, Biguanide compounds which may be used according to the codeine dihydrocodeine) Non-selective COX inhibitors invention include poly (hexamethylene biguanide) hydro Such as Salicylic acid derivatives, aspirin, Sodium sali chloride and chlorhexidine compounds. Chlorhexidine is the cylate, choline magnesium trisalicylate, Salsalate, term denoting the chemical compound 1.6 bis(N5-p-chlo diflunisal, SulfaSalazine and olSalazine). Para-ami rophenyl-N1-biguanido)hexane). Chlorhexidine compounds nophenol derivatives Such as acetaminophen. Indole and include chlorhexidine free base (“CHX”) as well as chlo indene acetic acids such as indomethacin and Sulindac. rhexidine salts, such as chlorhexidine diphosphanilate, chlo Heteroaryl acetic acids such as tolmetin, dicofenac and rhexidine digluconate (“CHG'), chlorhexidine diacetate 10 ketorolac. Arylpropionic acids such as ibuprofen, (“CHA), chlorhexidine dihydrochloride, chlorhexidine naproxen, flurbiprofen, ketoprofen, fenoprofen and dichloride, chlorhexidine dihydroiodide, chlorhexidine Oxaprozin. Anthranilic acids (fenamates) Such as mefe diperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate, namic acid and meloxicam. Enolic acids such as the chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexi oxicams (piroXicam, meloxicam). Alkanones Such as dine di-acid phosphate, chlorhexidine difluorophosphate, 15 nabumetone. Selective COX-2 Inhibitors (such as dia chlorhexidine diformate, chlorhexidine dipropionate, chlo ryl-substituted furanones such as rofecoxib; diaryl-sub rhexidine di-iodobutyrate, chlorhexidine di-n-Valerate, chlo stituted pyrazoles Such as celecoxib; indole acetic acids rhexidine dicaproate, chlorhexidine malonate, chlorhexidine Such as etodolac and Sulfonanilides such as nimeSulide); Succinate, chlorhexidine malate, chlorhexidine tartrate, chlo Anti-inflammatory steroids (such as cortisone, hydrocorti rhexidine dimonoglycolate, chlorhexidine mono-diglycolate, Sone, prednisone, dexamethasone, methylprednisolone, chlorhexidine dilactate, chlorhexidine di-O-hydroxyisobu triamcinolone, beclomethasone, flunisolide, fluticasone tyrate, chlorhexidine diglucoheptonate, chlorhexidine proprionate, triamcinolone acetonide, budesonide, lot di-isothionate, chlorhexidine dibenzoate, chlorhexidine erednol etabonate, mometasone, aclometasone, des dicinnamate, chlorhexidine dimandelate, chlorhexidine di onide, hydrocortisone, betamethasone, clocortolone, isophthalate, chlorhexidine di-2-hydroxy-napthoate, and 25 desoximetaSone, fluocinolone, flurandrenolide, chlorhexidine embonate. mometasone, prednicarbate; amcinonide, desoximeta Bismuth salts which may be used according to the inven Sone, diflorasone, fluocinolone, fluocinonide, halcinon tion include bismuth nitrate, bismuth citrate, bismuth salicy ide, clobetasol, augmented betamethasone, diflorasone, late, bismuth borate, bismuth mandelate, bismuth palmitate, halobetasol, prednisone, dexamethasone and methyl bismuth benzoate, and bismuth sulfadiazine. 30 prednisolone and their derivatives); Cerium salts which may be used according to the invention Antiulcer drugs (such as ecabet sodium, enprostil, include cerium nitrate and other cerium salts having a water Sulpiride, cetraxate hydrochloride, gefarnate, irsoglad solubility similar to cerium nitrate. ine maleate, cimetidine, ranitidine hydrochloride, famo The term silver-containing compound, as used herein, tidine, nizatidine and roXatidine acetate hydrochloride); refers to a compound comprising silver, either in the form of 35 Coronary vasodilators (such as nifedipine, isosorbide dini a silver atom or a silver ion unlinked or linked to another trate, diltiazem hydrochloride, trapidil, dipyridamole, molecule via a covalent or noncovalent (e.g., ionic) linkage, dilaZep hydrochloride, Verapamil, nicardipine, nicar including but not limited to covalent compounds such as dipine hydrochloride and Verapamil hydrochloride); silver sulfadiazine (AgSD) and silver salts such as silver Peripheral vasodilators (such as ifenprodil tartrate, oxide ("AgO), silver carbonate (AgCO), silver deoxy 40 cinepacide maleate, ciclandelate, cynnaridine and pen cholate, silver salicylate, silver iodide, silver nitrate toxyphylin); ('AgNO), silver paraminobenzoate, silver paraminosalicy Antibiotics (such as amplicillin, amoxicillin, cefalexin, late, silver acetylsalicylate, silver ethylenediaminetetraacetic cephalexin, cefoxytin and cephalothin, erythromycm acid ('Ag EDTA), silver picrate, silver protein, silver citrate, ethyl Succinate, vacampicillin hydrochloride, minocy silver lactate and silver laurate. 45 cline hydrochloride, chloramphenicol, tetracycline, Zinc salts which may be used according to the invention erythromycin, ceftazidime, cefuroxime Sodium, include Zinc acetate and other Zinc salts having a water Solu aspoxicillin chloramphenicol, clindamycin, erythromy bility similar to Zinc acetate. cin, erythromycin ethyl carbonate, erythromycin esto The classes of bioactive agents identified above may be late, erythromycin glucepate, erythromycin ethylsucci incorporated in the Substrate or the non-fouling polymer to 50 nate, erythromycin lactobionate, roXithromycin, enhance antimicrobial activity at the surface or be released to lincomycin, natamycin, nitrofurantoin, spectinomycin, provide antimicrobial activity in the environment Surround Vancomycin, aztreonarn, colistin IV, metronidazole, ing the article. timidazole, fusidic acid, trimethoprim, and 2-thiopyri Additional groups/classes of bioactive agents may be dine N-oxide); incorporated in the Substrate or the non-fouling polymer to 55 Synthetic antimicrobials (such as nalidixic acid, piromidic enhance antimicrobial activity at the surface or be released to acid, pipemidic acid trihydrate, enoxacin, cinoxacin, of provide antimicrobial activity in the environment Surround loxacin, norfloxacin, ciprofloxacin hydrochloride and ing the article and include the following groups/classes: Sulfamethoxazole-trimethoprim); Antipyretics, analgesics and antiphlogistics (Such as Antiviral agents (such as acyclovir, ganciclovir, acyclovir indometacin, acetylsalicylic acid, diclofenac sodium, 60 prodrugs, famcyclovir, Zidovudine, didanosine, stavu ketoprofen, ibuprofen, mefenamic acid, aZulene, phen dine, lamivudine, Zalcitabine, Saquinavir, indinavir, acetin, isopropyl antipyrine, acetaminophen, benzadac, ritonavir, n-docosanol, tromantadine and idoxuridine); phenylbutaZone, flufenamic acid, acetylsalicylic acid Anticonvulsants (such as propantheline bromide, atropine (aspirin), paracetamol, phenaZone, Sodium salicylate, Sulfate, oxitropium bromide, timepidium bromide, Sco Salicylamide, Sazapyrine, and etodolac) Opioid analge 65 polamine butylbromide, troSpium chloride, butropium sics (such as buprenorphine, dextromoramide, dextro bromide, N-methylscopolaminemethylsulfate and propoxyphene, fentanyl, alfentanil, Sufentanil, hydro methyloctatropine bromide); US 8,574,660 B2 75 76 Antitussives (such as tipepedine hibenzate, methylephe Antiepileptics (such as phenyloin, Sodium valproate, met drine hydrochloride, codeine phosphate, tranilast, dex albital and carbamazepine); tromethorphan hydrobromide, dimemorfan phosphate, Antihistamines (such as chlorpheniramine maleate, clem clobutinol hydrochloride, fominoben hydrochloride, astine fumarate, meduitazine, alimemazine tartrate, benproperine phosphate, eprazinone hydrochloride, cyproheptadine hydrochloride and bepotastin besilate); clofedanol hydrochloride, ephedrine hydrochloride, Antiemitics (such as difenidol hydrochloride, metoclopra noscapine, pentoxyverine citrate, oxeladin citrate and mide, domperidone and betahistine mesilate and trime isoaminyl citrate); butine maleate); Expectorants (such as bromhexine hydrochloride, car Depressors (such as dimethylaminoethyl reserpilinate bocysteine, ethylcysteine hydrochloride and methylcys 10 dihydrochloride, rescinnamine, methyldopa, prazocin teine hydrochloride); hydrochloride, bunazosin hydrochloride, clonidine Bronchodilators (such as theophylline, aminophylline, hydrochloride, budralazine, urapidil and N-6-2-(5- Sodium cromoglicate, procaterol hydrochloride, trime bromo-2-pyrimidinyl)oxyethoxy-5-(4-methylphe toquinol hydrochloride, diprophilline, salbutamol Sul nyl)-4-pyrimidinyl)-4-(2-hydroxy-1,1-dimethyl-ethyl) fate, clorprenaline hydrochloride, formoterol fumarate, 15 benzenesulfonamide Sodium); ocriprenaline sulfate, pilbuterol hydrochloride, hexo Hyperlipidemia agents (such as pravastatin Sodium and prenaline sulfate, bitolterol mesilate, clenbuterol hydro fluvastatin Sodium); chloride, terbutaline sulfate, malbuterol hydrochloride, Sympathetic nervous stimulants (such as dihydroergota fenoterol hydrobromide and methoxyphenamine hydro mine mesilate and isoproterenol hydrochloride, etile chloride), (13) cardiotonics (such as dopamine hydro frine hydrochloride); chloride, dobutamine hydrochloride, docarpamine, Oral diabetes therapeutic drugs (such as glibenclamide, denopamine, caffeine, digoxin, digitoxin and ubide tolbutamide and glimidine sodium); carenone); Oral carcinostatics (Such as malimastat); Diuretics (such as furosemide, acetazolamide, triclorme Alkaloid narcotics (such as morphine, codeine and thiazide, methylclothiazide, hydrochlorothiazide, 25 cocaine); hydroflumethiazide, ethiazide, cyclopenthiazide, Vitamins (such as vitamin B1, vitamin B2, vitamin B6, spironolactone, triamterene, florothiazide, piretanide, vitamin B12, vitamin C and folic acid); mefruside, etacrynic acid, azosemide and clofenamide) Thamuria therapeutic drugs (such as flavoxate hydrochlo Muscle relaxants (such as chlorphenesin carbamate, tolp ride, oxybutynin hydrochloride and terolidine hydro erisone hydrochloride, eperisone hydrochloride, tizani 30 chloride); dine hydrochloride, mefenicine, chlorZoxaZone, phen Angiotensin converting enzyme inhibitors (such as imi probamate, methocarbamol, chlormezazone, pridinol dapril hydrochloride, enalapril maleate, alacepril and mesilate, afloqualone, baclofen and dantrolene Sodium); delapril hydrochloride); Cerebral metabolism ameliorants (such as nicergoline, Non-steroidal anti-inflammatory agents (including their meclofenoxate hydrochloride and taltirelin); 35 racemic mixtures or individual enantiomers where Minor tranquilizers (such as oxazolam, diazepam, clotiaz applicable) (such as ibuprofen, flurbiprofen, ketoprofen, epam, medazepam, temazepam, fludiazepam, mep aclofenac, diclofenac, aloxiprin, aproxen, aspirin, robamate, nitrazepam and chlordiazepoxide); diflunisal, fenoprofen, indomethacin, mefenamic acid, Major tranquilizers (such as Sulpiride, clocapramine naproxen, phenylbutaZone, piroxicam, salicylamide, hydrochloride, Zotepine, chlorpromazine and haloperi 40 Salicylic acid, Sulindac, desoxysulindac, tenoxicam, tra dol); madol, ketoralac, flufenisal, Salsalate, triethanolamine Beta-blockers (such as bisoprolol fumarate, pindolol, pro Salicylate, aminopyrine, antipyrine, oxyphenbutaZone, pranolol hydrochloride, carteolol hydrochloride, meto apaZone, cintaZone, flufenamic acid, clonixerl, clonixin, prolol tartrate, labetanol hydrochloride, acebutolol meclofenamic acid, flunixin, coichicine, demecolcine, hydrochloride, bufetolol hydrochloride, alprenolol 45 allopurinol, oxypurinol, benzydamine hydrochloride, hydrochloride, arotinolol hydrochloride, oxprenolol dimefadane, indoxole, intrazole, mimbane hydrochlo hydrochloride, nadolol, bucumorolhydrochloride, inde ride, paranylene hydrochloride, tetrydamine, benzin nolol hydrochloride, timolol maleate, befunolol hydro dopyrine hydrochloride, fluprofen, ibufenac, naproXol, chloride and bupranolol hydrochloride); fenbufen, cinchophen, diflumidone sodium, fenamole, Antiarrthymics (such as procainamide hydrochloride, 50 flutiazin, metazamide, letimide hydrochloride, nexeri diso-pyramide, ajmaline, quinidine Sulfate, aprindine dine hydrochloride, octaZamide, molinazole, neocin hydrochloride, propafenone hydrochloride, mexiletine chophen, nimazole, proxazole citrate, tesicam, tesimide, hydrochloride and azmilide hydrochloride); tolimetin, and triflumidate); Athrifuges (such as allopurinol, probenicid, colchicine, Antineoplastic/antiangiogenic (Such as acivicin, aclarubi Sulfinpyrazone, benzbromarone and bucolome); 55 cin, acodazole, acronycine, adoZelesin, alanosine, Anticoagulants/Antiplatelets (such as heparin, chondroi aldesleukin, allopurinol sodium, altretamine, aminoglu ten sulfate ticlopidine hydrochloride, dicumarol, potas tethimide, amonafide, ampligen, amsacrine, androgens, sium warfarin, and (2R,3R)-3-acetoxy-5-2-(dimethy anguidine, aphidicolin glycinate, asaley, asparaginase, lamino)ethyl-2,3-dihydro-8-methyl-2-(4- 5-azacitidine, azathioprine, Bacillus calmette-guerin methylphenyl)-1,5-benzothiazepin-4 (5H)-onemaleate); 60 (BCG), Baker's Antifol (soluble), beta-2'-deox Thrombolytics (such as stretokinase, urokinase and tissue ythioguanosine, bisantrene hcl, bleomycin Sulfate, plasminogin activators, methyl (2E.3Z)-3-benzylidene busulfan, buthionine sulfoximine, BWA 773U82, BW 4-(3,5-dimethoxy-C.-methylbenzyliden-e)-N-(4-meth 502U83.HCl, BW 7U85 mesylate, ceracemide, carbe ylpiperazin-1-yl)-Succinamate hydrochloride); timer, carboplatin, carmustine, chlorambucil, chloroqui Liver disease drugs (such as (+)r-5-hydroxymethyl-t-7-(3, 65 noxaline-Sulfonamide, chlorozotocin, chromomycin 4-dimethoxyphenyl)-4-oxo-4,5,6,7-tetrahydro-obenzo A3, cisplatin, cladribine, corticosteroids, Corynebacte bifuran-c-6-carboxylactone); rium parvum, CPT-11, crisinatol, cyclocytidine, cyclo US 8,574,660 B2 77 78 phosphamide, cytarabine, cytemberna, dabis maleate, sulphated and sulponated polymers such as PC-515 (car dacarbazine, dactinomycin, daunorubicin HCl, deazau rageenan), Pro-2000, and Dextrin 2 Sulphate); ridine, dexraZOxane, dianhydrogalactitol, diaziquone, Antiretroviral agents (e.g., PMPA gel) that prevent retro dibromodulcitol, didemnin B, diethyldithiocarbamate, viruses from replicating in the cells; diglycoaldehyde, dihydro-5-azacytidine, doxorubicin, Agents which change the condition of the tissue to make it echinomycin, edatrexate, edelfosine, eflornithine, hostile to the pathogen (Such as Substances which alter Elliott's Solution, elsamitrucin, epirubicin, esorubicin, mucosal pH (e.g., Buffer Gel and Acid form): estramustine phosphate, estrogens, etanidazole, ethio Agents that treat or prevent an allergic or immune response fos, etoposide, fadrazole, faZarabine, fenretinide, and/or cellular proliferation (Such as various cytokine 10 inhibitors such as humanized anti-cytokine antibodies, filgrastim, finasteride, flavone acetic acid, floXuridine, anti-cytokine receptor antibodies, recombinant antago fludarabine phosphate, 5-fluorouracil, Fluosol R, fluta nists, or Soluble receptors; various leucotriene modifiers mide, gallium nitrate, gemcitabine, goserelin acetate, Such as Zafirlukast, montelukast and Zileuton; immuno hepsulfam, hexamethylene bisacetamide, homohar globulin E (IgE) inhibitors such as Omalizumab (an ringtonine, hydrazine Sulfate, 4-hydroxyandrostenedi 15 anti-IgE monoclonal antibody) and secretory leukocyte one, hydrozyurea, idarubicin HCl, ifosfamide, inter protease inhibitor) and SYK Kinase inhibitors); feron alfa, interferon beta, interferon gamma, Agents that prevent restenosis (such as paclitaxel, siroli interleukin-1 alpha and beta, interleukin-3, interleukin mus, everolimus, Vincristine, biolimus, mycophenolic 4, interleukin-6.4-ipomeanol, iproplatin, isotretinoin, acid, ABT-578, cervistatin, simvastatin, methylpred leucovorin calcium, leuprolide acetate, levamisole, lipo nisolone, dexamethasone, actinomycin-D, angiopeptin, Somal daunorubicin, liposome encapsulated doxorubi L-arginine, estradiol, 17-B-estradiol, tranilast, methotr cin, lomustine, lonidamine, maytansine, mechlore exate, batimistat, halofuginone, BCP-671, QP-2, lant thamine hydrochloride, melphalan, menogaril, runculin D. cytochalasin A, nitric oxide, and analogues merbarone, 6-mercaptopurine, mesna, methanol extrac and derivatives); tion residue of Bacillus calmette-guerin, methotrexate, 25 Growth factors and inflammatory cytokines involved in N-methylformamide, mifepristone, mitoguaZone, mito angiogenesis, fibroblast migration, fibroblast prolifera mycin-C, mitotane, mitoxantrone hydrochloride, mono tion, ECM synthesis and tissue remodeling, such as epi cyte/macrophage colony-stimulating factor, nabilone, dermal growth factor (EGF) family, transforming nafoxidine, neocarzinostatin, octreotide acetate, orma growth factor-O. (TGF-C), transforming growth factor-B platin, oxaliplatin, paclitaxel, pala, pentostatin, pipera 30 (TGF-9-1, TGF-9-2, TGF-9-3, platelet-derived growth Zinedione, pipobroman, pirarubicin, piritrexim, piroX factor (PDGF), fibroblast growth factor (acidic—aFGF: antrone hydrochloride, PIXY-321, plicamycin, porfimer and basic bFGF), fibroblast stimulating factor-1, Sodium, prednimustine, procarbazine, progestins, pyra activins, vascular endothelial growth factor (including Zoflurin, razoxane, SargramoStim, semustine, spiroger VEGF-2, VEGF-3, VEGF-A, VEGF-B, VEGF-C, pla manium, Spiromustine, Streptonigrin, Streptozocin, 35 cental growth factor—PIGF), angiopoietins, insulin Sulofenur, Suramin Sodium, tamoxifen, taxotere, tegafur, like growth factors (IGF), hepatocyte growth factor teniposide, terephthalamidine, teroxirone, thioguanine, (HGF), connective tissue growth factor (CTGF), thiotepa, thymidine injection, tiazofurin, topotecan, myeloid colony-stimulating factors (CSFs), monocyte toremifene, tretinoin, trifluoperazine hydrochloride, tri chemotactic protein, granulocyte-macrophage colony fluridine, trimetrexate, tumor necrosis factor, uracil 40 stimulating factors (GM-CSF), granulocyte colony mustard, vinblastine Sulfate, Vincristine Sulfate, Vin stimulating factor (G-CSF), macrophage colony-stimu desine, vinorelbine, Vinzolidine, Yoshi 864, Zorubicin, lating factor (M-CSF), erythropoietin, interleukins and mixtures thereof); (particularly IL-1, IL-8, and IL-6), tumor necrosis fac Immunosuppressant agents (such as cyclosporine A, tor-O. (TNF9), nerve growth factor (NGF), interferon-C. mycophenolic acid, tacrolimus, rapamycin, rapamycin 45 interferon-B, histamine, endothelin-1, angiotensin II, analogues, azathioprine, recombinant or monoclonal growth hormone (GH), and synthetic peptides, ana antibodies to interleukins, T-cells, B-cells and/or their logues orderivatives of these factors are also suitable for receptors); release from specific implants and devices to be Vasodilators (such as cyclandelate, isoxSuprine, papaver described later. Other examples include CTGF (connec ine, dipyrimadole, isosorbide dinitrate, phentolamine, 50 tive tissue growth factor); inflammatory microcrystals nicotinyl alcohol, co-dergocrine, nicotinic acid, glycerl (e.g., crystalline minerals such as crystalline silicates); trinitrate, pentaerythritol tetranitrate and xanthinol): bromocriptine, methylsergide, methotrexate, chitosan, Antiproliferative agents (such as paclitaxel, actinomycin N-carboxybutyl chitosan, carbon tetrachloride, thioac D., rapamycin, tacrolimus, everolimus, dexamethasone etamide, fibrosin, ethanol, bleomycin, naturally occur and rapamycin analogues); 55 ring or synthetic peptides containing the Arg-Gly-Asp Local anaesthetics (such as benzocaine, bupivacaine, ame (RGD) sequence, generally at one or both termini (see thocaine, lignocaine, lidocaine, cocaine, cinchocaine, e.g., U.S. Pat. No. 5,997.895), and tissue adhesives, such dibucaine, mepivacaine, prilocalne, etidocaine, Veratri as cyanoacrylate and crosslinked poly(ethylene glycol)- dine (specific c-fiber blocker) and procaine); methylated collagen compositions, such as described Antifungals (such as amorolfine, isoconazole, clotrima 60 below. Other examples of fibrosis-inducing agents Zole, econazole, miconazole, nystatin, terbinafine, include bone morphogenic proteins (e.g., BMP-2, BMP bifonazole, amphotericin, griseo fulvin, ketoconazole, 3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), fluconazole and flucytosine, salicylic acid, fezatione, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, ticlatone, tolnaftate, triacetin, Zinc, pyrithione and BMP-14, BMP-15, and BMP-16. Of these, BMP-2, Sodium pyrithione); 65 BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7 are of Agents/chemicals that block microbial attachment to target particular utility. Bone morphogenic proteins are cells and/or inhibits entry of infectious pathogens (e.g., described, for example, in U.S. Pat. Nos. 4,877,864; US 8,574,660 B2 79 80 5,013,649; 5,661,007: 5,688,678; 6,177,406; 6,432,919; hormone; luteinizing hormone; LHRH; GHRH, tissue and 6,534,268 and Wozney, J. M., et al. (1988) Science: plasminogen activators; macrophage activator; chori 242(4885); 1528 1534: onic gonadotropin; heparin; atrial natriuretic peptide; Other representative fibrosis-inducing agents include com hemoglobin, retroviral vectors; relaxin; cyclosporin; ponents of extracellular matrix (e.g., fibronectin, fibrin, 5 Oxytocin, and peptide or polypeptide vaccines. Cell fibrinogen, collagen (e.g., bovine collagen), fibrillar and response modifiers. (Cell response modifiers include non-fibrillar collagen, adhesive glycoproteins, pro chemotactic factors such as platelet-derived growth fac teoglycans (e.g., heparin Sulfate, chondroitin Sulfate, tor (PDGF), pigmented epithelium-derived factor dermatan Sulfate), hyaluronan, secreted protein acidic (PEDF), neutrophil-activating protein, monocyte and rich in cysteine (SPARC), thrombospondins, tena 10 chemoattractant protein, macrophage-inflammatory cin, and cell adhesion molecules (including integrins, protein, SIS (small inducible secreted) proteins, platelet vitronectin, fibronectin, laminin, hyaluronic acid, elas factor, platelet basic protein, melanoma growth stimu tin, bitronectin), proteins found in basement mem lating activity, epidermal growth factor, transforming branes, and fibrosin) and inhibitors of matrix metallo growth factor (alpha), fibroblast growth factor, platelet proteinases, such as TIMPs (tissue inhibitors of matrix 15 derived endothelial cell growth factor, insulin-like metalloproteinases) and synthetic TIMPs, e.g., mari growth factor, nerve growth factor, Vascular endothelial mistat, batimistat, doxycycline, tetracycline, minocy growth factor, bone morphogenic proteins, and bone cline, TROCADE, Ro-1130830, CGS 27023A, and growth/cartilage-inducing factor (alpha and beta). Other BMS-275291; cell response modifiers (such as the interleukins, inter Anti-thrombotic and/or antiplatelet agents (include hep leukin inhibitors or interleukin receptors, including arin, heparin fragments, organic salts of heparin, heparin interleukin 1 through interleukin 10; interferons, includ complexes (e.g., benzalkonium heparinate, tridodecy ing alpha, beta and gamma; hematopoietic factors, lammonium heparinate, heparin-tridodecylmethylam including erythropoietin, granulocyte colony stimulat monium chloride, heparin-benzalkonium chloride, hep ing factor, macrophage colony stimulating factor and arin-steralkonium chloride, heparin-poly-N-vinyl 25 granulocyte-macrophage colony stimulating factor; pyrrolidone, heparin-lecithin, heparin tumor necrosis factors, including alpha and beta; trans didodecyldimethylammonium bromide, heparin forming growth factors (beta), including beta-1, beta-2, pyridinium chloride, and heparin-synthetic glycolipid beta-3, inhibin, and activin) Therapeutic enzymes (Such complex), dextran, Sulfonated carbohydrates such as as proteases, phospholipases, lipases, glycosidases, cho dextran Sulphate, coumadin, coumarin, heparinoid, dan 30 lesterol esterases, and nucleases) Peptide-nucleic acid aparoid, argatroban chitosan Sulfate, chondroitin Sul (PNA) conjugate, polysaccharide-peptide conjugates fate, danaparoid, lepirudin, hirudin, AMP adenosine, such as glyosylated polypeptides; glycoproteins), a poly 2-chloroadenosine, aspirin, phenylbutaZone, (ethyleneglycol)-polypeptide conjugate (PEG-ylated indomethacin, meclofenamate, hydrochloroquine, dipy polypeptides), or polymer pharmaceuticals; ridamole, iloprost, Streptokinase, and factor Xa inhibi 35 Antibodies and antibody fragments (such as, but are not tors, such as DX9065a, magnesium, and tissue plasmi limited to, therapeutic antibodies include trastuzumab, nogen activator. In one aspect, the anti-thrombotic agent alemtuzumab, gemtuzumab, rituximab, ibritumomab, is a modified heparin compound, Such as a hydrophobi to situmomab, edrecolomab, cetuximab, bevacizumab, cally modified heparin or modified hirudin compound RanibiZumab, Satumomab, pertuZumab, and dacli (e.g., Stearylkonium heparin, benzalkonium heparin, 40 Zumab); cetylkonium heparin, or traodecylmethyl ammonium Therapuetic enzymes (such as recombinant human tissue heparin). Further examples of anti-thrombotic agents plasminogen activator (alteplase), RNaseA, RNaselJ. include plasminogen, lys-plasminogen, alpha-2-anti chondroitinase, pegaspargase, arginine deaminase, plasmin, urokinase, ticlopidine, clopidogrel, glycopro Vibriolysin, sarcosidase, N-acetylgalactosamine-4-sul tein IIb/IIIa inhibitors such as abcixamab, eptifibatide, 45 fatase, glucocerebrocidase, C.-galactosidase, and and tirogiban. Other agents capable of affecting the rate laronidase); of clotting include glycosaminoglycans, danaparoid, Enzyme inhibitors (such as edrophonium chloride, N-me 4-hydroxycourmarin, warfarin Sodium, dicumarol, thylphysostigmine, neostigmine bromide, physostig phenprocoumon, indan-1,3-dione, acenocoumarol, mine Sulfate, tacrine HCL, tacrine, 1-hydroxy maleate, anisindione, and rodenticides including bromadiolone, 50 iodotubercidin, p-bromotetramisole, 10-(C-diethylami brodifacoum, diphenadione, chlorophacinone, and pid nopropionyl)-phenothiazine hydrochloride, calmidazo none); lium chloride, hemicholinium-3,3,5-dinitrocatechol, Polypeptide drugs (such as but are not limited to, insulin; diacylglycerol kinase inhibitor I, diacylglycerol kinase growth factors, such as epidermal growth factor (EGF), inhibitor II, 3-phenylpropargylaminie, N-monomethyl insulin-like growth factor (IGF), transforming growth 55 L-arginine acetate, carbidopa, 3-hydroxybenzylhydra factor (TGF), nerve growth factor (NGF), platelet-de zine HCl, hydralazine HCl, clorgyline HCl, deprenyl rived growth factor (PDGF), bone morphogenic protein HCl L(-), deprenyl HCl D(+), hydroxylamine HCl, (BMP), fibroblast growth factor and the like; somatosta iproniazid phosphate, 6-MeO-tetrahydro-9H-pyrido-in tin: Somatotropin; somatropin; Somatrem, calcitonin; dole, nialamide, pargyline HCl, quinacrine HCl, semi parathyroid hormone; colony Stimulating factors (CSF); 60 carbazide HCl, tranylcypromine HCl, N,N-diethylami clotting factors; tumor necrosis factors; interferons; noethyl-2,2-di-phenylvalerate hydrochloride, interleukins; gastrointestinal peptides, such as vasoac 3-isobutyl-1-methylxanthne, papaverine HC1, tive intestinal peptide (VIP), cholecytokinin (CCK), indomethacind, 2-cyclooctyl-2-hydroxyethylamine gastrin, secretin, and the like; erythropoietins; growth hydrochloride, 2,3-dichloro-O-methylbenzylamine hormone and GRF; vasopressins; octreotide; pancreatic 65 (DCMB), 8,9-dichloro-2,3,4,5-tetrahydro-1H-2-benza enzymes; dismutases Such as Superoxide dismutase; thy Zepine hydrochloride, p-aminoglutethimide, p-amino rotropin releasing hormone (TRH); thyroid stimulating glutethimide tartrate R(+), p-aminoglutethimide tartrate US 8,574,660 B2 81 82 S(-), 3-iodotyrosine, alpha-methyltyrosine L(-), alpha dine hydrochloride, octaZamide, molinazole, neocin methyltyrosine D(-), cetazolamide, dichlorphenamide, chophen, nimazole, proxazole citrate, tesicam, tesimide, 6-hydroxy-2-benzothiazolesulfonamide, and allopu tolimetin, and triflumidate). rinol); Formulations of the above antimicrobial or antiseptic Steroids (such as glucocorticoids, estrogens and andro 5 agents may be enhanced by altering the solubility or physical gens. By way of example, steroids can include dexam characteristics of the agent if salts or crystals are used, for ethasone, dexamethasone acetate, dexamethasone instance by using nanoparticles or other formulations with Sodium phosphate, cortisone, cortisone acetate, hydro reduced size or enhanced surface area per mass. cortisone, hydrocortisone acetate, hydrocortisone cypi Non-fouling Surfaces, such as Zwitterionic Surfaces, may onate, hydrocortisone sodium phosphate, hydrocorti 10 also present a particularly attractive surface for immobiliza tion of biomolecules, such as antibodies, for use as biosen Sone sodium Succinate, prednisone, prednisolone, sors. Immobilized antibodies on non-fouling Surface Sur prednisolone acetate, prednisolone sodium phosphate, faces, such as Zwitterionic Surfaces, have been demonstrated prednisolone tebutate, prednisolone pivalate, triamcino to retain both antibody activity and antigen specificity in lone, triamcinolone acetonide, triamcinolone hexac 15 whole blood. “Smart” implanted medical devices that detect etonide, triamcinolone diacetate, methylprednisolone, undesirable activation of specific immune pathways. Such as methylprednisolone acetate, methylprednisolone proinflammatory cytokines, or the presence of a possible Sodium Succinate, flunsolide, beclomethasone dipropi infectious agent, perhaps through detection of a secreted onate, betamethasone sodium phosphate, betametha microbial toxin, could be designed, for example, by utilizing Sone, Vetamethasone disodium phosphate, Vetametha specific antibodies or biomolecules tailored to monitor these Sone sodium phosphate, betamethasone acetate, threats. Appropriate therapeutic strategies could then be betamethasone disodium phosphate, chloroprednisone employed before an unfavorable outcome, such as infection, acetate, corticosterone, desoxycorticosterone, desoxy arises. The stability of the Zwitterionic molecule in vivo pro corticosterone acetate, desoxycorticosterone pivalate, vides a unique advantage in this type of scenario due to its desoximethasone, estradiol, fluorocortisone, fluorocor 25 longevity. tisone acetate, dichlorisone acetate, fluorohydrocorti Methods of Use Sone, fluorometholone, fluprednisolone, parametha The materials described above may be in the form of a SOne, paramethasone acetate, androsterone, medical device or other article to which the non-fouling mate fluoxymesterone, aldosterone, methandrostenolone, rial is grafted. Suitable devices include, but are not limited to, methylandrostenediol, methyl testosterone, nore 30 Surgical, medical or dental instruments, ophthalmic devices, wound treatments (bandages, Sutures, cell scaffolds, bone thandrolone, testosterone, testosterone enanthate, test cements, particles), appliances, implants, scaffolding, Sutur osterone propionate, equilenin, equilin, estradiol ben ing material, Valves, pacemaker, stents, catheters, rods, Zoate, estradiol dipropionate, estriol, estrone, estrone implants, fracture fixation devices, pumps, tubing, wiring, benzoate, acetoxypregnenolone, anagestone acetate, 35 electrodes, contraceptive devices, feminine hygiene prod chlormadinone acetate, fluorogestone acetate, ucts, endoscopes, wound dressings and other devices, which hydroxymethylprogesterone, hydroxymethylprogester come into contact with tissue, especially human tissue. one acetate, hydroxyprogesterone, hydroxyprogester In one embodiment, the non-fouling materials are grafted O acetate, hydroxyprogesterone caproate, directly from a fibrous material, incorporated into a fibrous melengestrol acetate, normethisterone, pregnenolone, 40 material or grafted indirectly from a fibrous material (e.g., progesterone, ethynyl estradiol, mestranol, dimethister coated on a different Surface coating). These include wound one, ethisterone, ethynodiol diacetate, norethindrone, dressings, bandages, gauze, tape, pads, Sponges, including norethindrone acetate, norethisterone, fluocinolone woven and non-woven sponges and those designed specifi acetonide, flurandrenolone, hydrocortisone sodium Suc cally for dental or ophthalmic surgeries (See, e.g., U.S. Pat. cinate, methylprednisolone sodium Succinate, predniso 45 Nos. 4,098,728; 4,211,227; 4,636,208; 5,180,375; and 6,711, lone phosphate Sodium, triamcinolone acetonide, 879), paper or polymeric materials used as Surgical drapes, hydroxydione sodium, Spironolactone, Oxandrolone, disposable diapers, tapes, bandages, feminine products, oxymetholone, prometholone, testosterone cypionate, Sutures, and other fibrous materials. testosteronephenylacetate, estradiol cypionate, and nor Fibrous materials are also useful in cell culture and tissue ethynodrel, analogs thereof, or combinations thereof); 50 engineering devices. Bacterial and fungal contamination is a Non-steroidal anti-inflammatory agents (including their major problem in eukaryotic cell culture and this provides a racemic mixtures or individual enantiomers where safe and effective way to minimize or eliminate contamina applicable) (such as ibuprofen, flurbiprofen, ketoprofen, tion of the cultures, aclofenac, diclofenac, aloxiprin, aproxen, aspirin, The non-fouling agents are also readily bound to particles, diflunisal, fenoprofen, indomethacin, mefenamic acid, 55 including nanoparticles, microparticles, millimeter beads, or naproxen, phenylbutaZone, piroxicam, salicylamide, formed into micelles, that have uses in a variety of applica Salicylic acid, Sulindac, desoxysulindac, tenoxicam, tra tions including cell culture, as mentioned above, and drug madol, ketoralac, flufenisal, Salsalate, triethanolamine delivery. Non-fouling, biocompatible, polymeric micelles Salicylate, aminopyrine, antipyrine, oxyphenbutaZone, would prevent protein denaturation preventing activation of apaZone, cintaZone, flufenamic acid, clonixerl, clonixin, 60 the immune response allowing for a more stealthy delivery of meclofenamic acid, flunixin, coichicine, demecolcine, the desired therapeutic. allopurinol, oxypurinol, benzydamine hydrochloride, The non-fouling material can also be applied directly to, or dimefadane, indoxole, intrazole, mimbane hydrochlo incorporated in, polymeric, metallic, or ceramic Substrates. ride, paranylene hydrochloride, tetrydamine, benzin Suitable devices include, but are not limited to surgical, medi dopyrine hydrochloride, fluprofen, ibufenac, naproXol, 65 cal or dental instruments, blood oxygenators, pumps, tubing, fenbufen, cinchophen, diflumidone sodium, fenamole, wiring, electrodes, contraceptive devices, feminine hygiene flutiazin, metazamide, letimide hydrochloride, nexeri products, endoscopes, grafts, stents, pacemakers, implant US 8,574,660 B2 83 84 able cardioverter-defibrillators, cardiac resynchronization fied surface exhibits a fibrinogen adsorption of less than 90 therapy devices, Ventricular assist devices, heart valves, cath ng/cm in such an assay. By way of further example, in one eters (including vascular, urinary, neurological, peritoneal, such embodiment, the modified surface exhibits a fibrinogen interventional, etc.), shunts, wound drains, dialysis mem adsorption of less than 70 ng/cm in such an assay. By way of branes, infusion ports, cochlear implants, endotracheal tubes, further example, in one Such embodiment, the modified Sur guide wires, fluid collection bags, sensors, wound treatments face exhibits a fibrinogen adsorption of less than 50 ng/cm in (dressings, bandages, Sutures, cell scaffolds, bone cements, Such an assay. By way of further example, in one Such particles), ophthalmic devices including contact lenses, embodiment, the modified surface exhibits a fibrinogen orthopedic devices (hip implants, knee implants, spinal adsorption of less than 30 ng/cm in such an assay. By way of implants, screws, plates, rivets, rods, intramedullary nails, 10 further example, in one Such embodiment, the modified Sur bone cements, artificial tendons, and other prosthetics or frac face exhibits a fibrinogen adsorption of less than 20 ng/cm in ture repair devices), dental implants, breast implants, penile Such an assay. By way of further example, in one Such implants, maxillofacial implants, cosmetic implants, valves, embodiment, the modified surface exhibits a fibrinogen appliances, scaffolding, Suturing material, needles, hernia adsorption of less than 15 ng/cm in such an assay. By way of repair meshes, tension-free vaginal tape and vaginal slings, 15 further example, in one Such embodiment, the modified Sur tissue regeneration or cell culture devices, or other medical face exhibits a fibrinogen adsorption of less than 12 ng/cm in devices used within or in contact with the body or any portion Such an assay. By way of further example, the treated Surface of any of these. Preferably, the non-fouling coating herein and the grafted polymer layer, in combination, constituting a does not significantly adversely affect the desired physical low-fouling Surface, exhibits a fibrinogen adsorption of less properties of the device including, but not limited to, flexibil than 10 ng/cm in such an assay. By way of further example, ity, durability, kink resistance, abrasion resistance, thermal the treated Surface and the grafted polymer layer, in combi and electrical conductivity, tensile strength, hardness, and nation, constituting a low-fouling Surface, exhibits a fibrino burst pressure. gen adsorption of less than 8 ng/cm in such an assay. More In one embodiment, the Substrate is a vascularly inserted preferably, the treated surface and the grafted polymer layer, catheter Such as a peripherally inserted central catheter 25 in combination, constituting a low-fouling Surface, exhibits a (PICC), central venous catheter (CVC) or hemodialysis cath fibrinogen adsorption of less than 6 ng/cm in such an assay. eter, venous valves, punctual plugs, and intra-ocular devices Still more preferably, the treated surface and the grafted poly and implants. merlayer, in combination, constituting a low-fouling Surface, In another embodiment, the Substrate is a vascularly exhibits a fibrinogen adsorption of less than 4 ng/cm in such inserted catheter formed from a medical grade polyurethane 30 an assay. Still more preferably, the treated surface and the or CARBOTHANER) or formed from a material coated with grafted polymer layer, in combination, constituting a low a medical grade polyurethane or polycarbothane. fouling surface, exhibits a fibrinogen adsorption of less than 2 In one specific embodiment, the catheter comprises an ng/cm in such an assay. In certain embodiments, the treated elongated catheter body containing multiple lumens. For Surface and the grafted polymer layer exhibits a fibrinogen example, the catheter may be a double-lumen or a triple 35 adsorption of less than 1 ng/cm in such an assay; for lumen catheter. The lumens may be coaxial or side-by-side. In example, in one embodiment, the grafted polymer layer one exemplary embodiment, the catheter body has two side exhibits a fibrinogen adsorption of less than 0.5 ng/cm in by-side lumens, each having a “D” shape and the catheter such an assay, and more preferably less than 0.25 ng/cm in body has a length that is greater than 5 cm; typically the Such an assay. In one embodiment, the grafted polymer in catheter body of such catheters have a length of at least 11 cm. 40 each of the foregoing examples recited in this paragraph is a In one particularly preferred embodiment, the catheter body Zwitterionic polymer. In one embodiment, the grafted poly is a medical-grade polycarbonate-based aliphatic and aro mer in each of the foregoing examples recited in this para matic polyurethane. graph is a polymer containing Sulfobetaine or carboxybetaine The non-fouling materials can also be added to paints and repeat units. In one embodiment, the grafted polymer in each other coatings and filters to prevent mildew, bacterial con 45 of the foregoing examples recited in this paragraph is a Zwit tamination, and in other applications where it is desirable to terionic polymer and the Zwitterionic polymer is grafted from prevent fouling, Such as marine applications (ship hull coat a polyurethane polymer. In one embodiment, the grafted ings), contact lenses, dental implants, coatings for in vivo polymer in each of the foregoing examples recited in this sensors, devices for separations, such as membranes for paragraph is a polymer containing Sulfobetaine or carboxy microbial Suspension, biomolecule separation, protein frac 50 betaine repeat units and the polymer containing Sulfobetaine tionation, cell separation, waste water treatment, bioreactors, or carboxybetaine repeat units is grafted from a polyurethane and food processing. polymer. In one embodiment, the treated surface exhibits a Other applications include the treatment of fibers, particu fibrinogen adsorption of <125 ng/cm, <90 ng/cm, <70 lates and films for applications in textiles, additives, electric/ ng/cm, <50 ng/cm, <30 ng/cm, <20 ng/cm, <15 ng/cm, optical appliances, carbon nanotubes, packaging materials 55 <12 ng/cm, <10 ng/cm, <8 ng/cm, <6 ng/cm, <4 ng/cm, and colorants/inks. <2 ng/cm, <1 ng/cm, <0.5 ng/cm, or <0.25 ng/cm. Independent of any theory, articles of the present invention Preferred embodiments also show reduction in thrombus. having a treated Surface and a grafted polymer layer exhibit For example, thrombus reduction of treated and modified low fibrinogen adsorption in a fibrinogen adsorption assay. In Substrates can be assessed relative to unmodified Substrates general, the treated Surface and the grafted polymer layer, in 60 that are otherwise Substantially identical by exposing them to combination, constituting a modified Surface, exhibits a freshly harvested bovine blood, heparinized, with radiola fibrinogen adsorption of less than 125 ng/cm in a fibrinogen beled platelets, in a flow loop for 2 hours. As an assessment of adsorption assay in which samples are incubated for 60 min anti-thrombogenic performance, samples are placed in an utes at 37°C. in 70 ug/mL fibrinogen derived from human ex-vivo flow loop model of thrombosis. Anti-thrombogenic plasma, and the amount of adsorbed fibrinogen is determined 65 activity can be evaluated using ex-vivo flow loop model of using a standard protocol, preferably by using radiolabled thrombosis. Briefly, up to 10 liters of fresh blood are collected fibrinogen. For example, in one Such embodiment, the modi from a single animal. This blood is heparinized to prevent US 8,574,660 B2 85 86 coagulation, filtered to remove particulates, and autologous Preferred embodiments show antibiofilm activity of at least radio-labeled platelets are added. Within eight hours after 0.5 log, 1 log, 1.5 log, 2 log, 2.5 log, 3 log, or 4 log. More blood harvesting, coated and uncoated articles are placed in a preferred embodiments have antibiofilm activity after flow loop circuit, which pumps blood from a bath over the extended exposures to PBS, serum, or plasma products. In article and thenbackinto the bath. A second internal flow loop one preferred embodiment, antibiofilm activity of 1 log is circuit can be established for Substrate containing a lumen by achieved after 30 days storage in PBS at 37° C. In a further connecting the two ports of the Substrate through a 2nd peri preferred embodiment, antibiofilm activity of 1 log is staltic pump. The size of tubing into which the article is achieved after 90 days storage in PBS at 37°C. In one pre placed and speed of the bloodflow may be adjusted based on ferred embodiment, antibiofilm activity of 2 log is achieved the size of the article being tested. Preferably, when the 10 after 30 days storage in PBS at 37° C. In a further preferred articles are 14-15.5 French dialysis catheters, they are placed embodiment, antibiofilm activity of 2 log is achieved after 90 in a flow loop circuit with tubing diameter of approximately days storage in PBS at 37°C. In one preferred embodiment, 12.5-25.4 mm inner diameter. Blood is pumped in the outer antibiofilm activity of 1 log is achieved after 30 days storage circuit at a rate of approximately 2.5 L/min, while blood in the 15 in citrated human plasma at 37° C. In a further preferred inner circuit is pumped at a rate of approximately ~200-400 embodiment, antibiofilm activity of 1 log is achieved after 90 mL/min. When the articles are 5 French PICC catheter shafts, days storage in citrated human plasma at 37°C. In one pre they are placed in a flow loop circuit of approximately 6.4 mm ferred embodiment, antibiofilm activity of 2 log is achieved inner diameter and blood flow rate is approximately 200 after 30 days storage in citrated human plasma at 37°C. In a mL/min. The lumens may be locked with a solution, for further preferred embodiment, antibiofilm activity of 2 log is example saline, during evaluation. Alternatively, the distal tip achieved after 90 days storage in citrated human plasma at may be sealed, for example with epoxy, during evaluation. 37° C. Optionally, but preferably, articles may be stored in When the articles are 10 French rods, they are placed in a flow solutions that contain PBS, citrated human plasma, fetal loop circuit of approximately 6.4 mm inner diameter and bovine serum, or adult human serum, for a period of 14, 30, blood flow rate is approximately 200 mL/min. After 60-120 25 60, or 90 days prior to assessment of anti-thrombogenic per minutes, the articles are removed, inspected visually for formance. thrombus formation, and adhered platelets are quantified Preferred embodiments show resistance to protein adsorp using a Gamma counter. For samples not containing alumen, tion after extended exposure to PBS, which may indicate only an outer circuit may be used to measure thrombus on the hydrolytic stability. In some embodiments, the treated surface outside of the device. Optionally, each of the ends of the 30 and the grafted polymer layer, in combination, constituting a articles may be trimmed up to 2 cm after blood exposure but low-fouling Surface, exhibits a fibrinogen adsorption of less before measuring adhered platelets to eliminate end effects. than 50 ng/cm in a fibrinogen adsorption assay in which Optionally, but preferably, articles may be stored in solutions samples are incubated for 60 minutes at 37°C. in 70 ug/mL that contain PBS, citrated human plasma, fetal bovine serum, fibrinogen derived from human plasma after 30 days expo or adult human serum, for a period of 14, 30, 60, or 90 days 35 sure to PBS at 37° C. In some embodiments, the treated prior to assessment of anti-thrombogenic performance. Surface and the grafted polymer layer, in combination, exhib Preferred embodiments show at least an 80% reduction its a fibrinogen adsorption of less than 20 ng/cm in a fibrino relative to untreated and unmodified substrate in adsorbed gen adsorption assay in which samples are incubated for 60 platelets and substantial visual reduction of thrombus. minutes at 37°C. in 70 ug/mL fibrinogen derived from human Embodiments show a visual reduction of thrombus relative to 40 plasma after 30 days exposure to PBS at 37° C. In some untreated and unmodified substrate. Preferred embodiments embodiments, the treated Surface and the grafted polymer show at least a 90% reduction in adsorbed platelets. Preferred layer, in combination, exhibits a fibrinogen adsorption of less embodiments show at least a 98% reduction in adsorbed than 10 ng/cm in a fibrinogen adsorption assay in which platelets. Alternatively, in a preferred embodiment, the samples are incubated for 60 minutes at 37°C. in 70 ug/mL thrombogenecity is reduced relative to the untreated and 45 fibrinogen derived from human plasma after 30 days expo unmodified substrate, after exposure to a 47% (w/v) sodium Sure to PBS at 37° C. Preferred embodiments show resistance citrate solution in DI water for greater than 3 days. Embodi to protein adsorption after extended exposure to PBS, which ments show a visual reduction of thrombus relative to may indicate hydrolytic stability. In some embodiments, the untreated and unmodified substrate. Preferred embodiments treated Surface and the grafted polymer layer, in combination, show at least an 80% reduction relative to untreated and 50 exhibits a fibrinogen adsorption of less than 30 ng/cm in a unmodified substrate in adsorbed platelets and substantial fibrinogen adsorption assay in which samples are incubated visual reduction of thrombus. Preferred embodiments show at for 60 minutes at 37°C. in 70 ug/mL fibrinogen derived from least a 90% reduction in adsorbed platelets. Preferred human plasma after 90 days exposure to PBS at 37° C. In embodiments show at least a 98% reduction in adsorbed Some embodiments, the treated Surface and the grafted poly platelets. Alternatively, the thrombogenecity of preferred 55 merlayer, in combination, exhibits a fibrinogen adsorption of embodiments are reduced relative to the untreated and less than 20 ng/cm in a fibrinogen adsorption assay in which unmodified Substrate after exposure to animal serum and/or samples are incubated for 60 minutes at 37°C. in 70 ug/mL plasma. For example, the thrombogenecity of preferred fibrinogen derived from human plasma after 90 days expo embodiments are reduced after 60 day exposure to citrated sure to PBS at 37° C. In some embodiments, the treated human plasma at 37° C. Embodiments show a visual reduc 60 Surface and the grafted polymer layer, in combination, exhib tion of thrombus relative to untreated and unmodified sub its a fibrinogen adsorption of less than 10 ng/cm in a fibrino strate. Preferred embodiments show at least an 80% reduction gen adsorption assay in which samples are incubated for 60 relative to untreated and unmodified substrate in adsorbed minutes at 37°C. in 70 ug/mL fibrinogen derived from human platelets and substantial visual reduction of thrombus. Pre plasma after 90 days exposure to PBS at 37° C. ferred embodiments show at least a 90% reduction in 65 Having described the invention in detail, it will be apparent adsorbed platelets. Preferred embodiments show at least a that modifications and variations are possible without depart 98% reduction in adsorbed platelets. ing from the scope of the invention defined in the appended US 8,574,660 B2 87 88 claims. Furthermore, it should be appreciated that all of the pellethane. The surface wax of pellethane single lumen examples in the present disclosure are provided as non-lim tubing was approximated by analysis of IR spectra. iting examples. Approximation of amide waxes using FTIR. The infrared spectrum of a primary amide exhibits a sharp C NH vibra EXAMPLES tion peak at 1636 cm. The region of 1620 cm to 1680cm is free of peaks for most polyurethanes, barium Sulfate, and The following non-limiting examples are provided to fur betaine homopolymer. Water exhibits a very broad peak cen ther illustrate the present invention. It should be appreciated tered 1640 cm. Because the water peak at 1640 cm' is very by those of skill in the art that the techniques disclosed in the broad, monitoring for the presence of a distinct, sharp peak examples that follow represent approaches the inventors have centered at 1636 cm' is indicative of the presence of a pri found function well in the practice of the invention, and thus 10 mary amide in a matrix of polyurethane, barium sulfate, can be considered to constitute examples of modes for its betaine homopolymer, and water. The assumption is made practice. However, those of skill in the art should, in light of that the presence a primary amide is most likely a wax, Such the present disclosure, appreciate that many changes can be as FINAWAX-OPA, used as an extrusion lubricant in the made in the specific embodiments that are disclosed and still manufacture of the polyurethane and not some other primary obtain a like or similar result without departing from the spirit 15 amide contaminant. A two-point baseline correction is per and scope of the invention. formed by monitoring the non-ATR-corrected absorbance values at 1625.3 cm, 1658.1 cm, and 1635.9 cm. The Example 1 corrected absorbance value of the primary amide C NH vibrational peak is found by Subtracting the mean absorbance Stress Reduction and Lower Surface Roughness values of 1625.3 cm and 1658.1 cm from the absorbance value at 1635.9 cm. Using Beer's law, A=eIDC, with molar High residual levels of stress in a polymer Surface can absorptivity (e)and pathlength (b) held constant, a correlation cause diffusion of species to relieve the stress, resulting in a between concentration of amide wax present can be con rough Surface with undulations. Additionally, high stress lev structed using Successive dry-dilutions of a primary amide els can cause micro-cracking and other Surface defects. A 25 wax Such as ethylene bis-Stearamide in dehydrated potassium thermal annealing step (raising local temperatures up to the bromide salt on the same ATR (attenuated total reflectance) glass transition temperature) can relieve these stresses and IRE (internal reflection element). Correlation for A=eIDC result in a Smoother, more uniform surface. Surface point using the method described here with 95% pure ethylene defects can also cause rough features in a Surface and are bis-Stearamide in spectroscopy grade KBr on a Thermo associated with high localized stresses and their resulting Nicolet iZ10 FTIR spectrometer with a 45° incident angle, strains. By providing sufficient localized energy during 30 single bounce, diamond IRE SMART iTR ATR accessory annealing, defects can be annealed out relieving the stress and yields Abs=3700*Cethylenebis-stearamidewith Cethyl accompanying plastic strain. The annealing can be focused on enebis-Stearamide in units of uMol. The approximate amount the entire body of the article, thus relieving stresses through of surface wax (average of four spectra) after different washes out the bulk as well as at the surface. Conversely, the anneal is summarized in the table below. Surface wax increases after ing can be localized to the surface without affecting the bulk 35 heating at 80 deg C. in an oven, and the amount of wax can be mechanical and physical properties of the article. reduced by ethanol washes or Sonicating in ethanol. Additionally, the nature of a substrate materials surface can influence the growth and uniformity of a grown coating, for example by the fraction of crystalline domains compared to amorphous domains. The existence of defects in the Sub 40 Pellethane single lumen tubing, Inside Surface strate surface also influence the growth and uniformity of a Surface Untreated 80 C. oven 80 C. 80 C. 80 C. Surface coating that is covalently bonded to the Substrate. Pre- for 4h oven for oven for oven for treat- 4h then 4h then 4h then Control of the surface stress can hence be used to modify the ment washed EtOH washed coating density and nature, by reducing the amount of crys 2 hr with Sonica- overnight tallinity and the number of defects, or, on the other hand, by 45 EtOH tion with EtOH increasing the density of defects and crystalline domains. Surface 17.8 0.4 66.5 - 23.6 46.016.4 0.00.0 33.726.9 Wax Example 2 Content (10-6 M) Pellethane single lumen tubing, Outside Surface Thermal Reflow and Roughness 50 Surface Untreated 80 C. oven 80 C. 80 C. 80 C. Pre- for 4h oven for oven for oven for A surface that is rough can be smoothed by thermally treat- 4h then 4h then 4h then re-flowing the Surface material. In this case, the material is ment washed EtOH washed heated above its Tg and Surface energy considerations will 2 hr with Sonica- overnight cause the material to attempt to achieve a smoother Surface. 55 EtOH tion with EtOH Surface 3.45.9 129.3 48.5 42.0 - 52.7 O.O. O.O 1.5 3.0 By applying the heat in a rapid and controlled manner, for Wax example by using a laser or a radiant furnace through which Content the article is rapidly moved, the bulk properties of the material (10-6 M) can be unaffected. 60 Example 3 Example 4 Removal of Surface Wax by Washing with an Modification of Surfaces that Exhibit Different Organic Solvent Amounts of Surface Wax 65 Pellethane single lumen tubing was heated at 80 deg C. in The washed catheters (A: 613.7+1.8 mm body length, and an oven for 4 hours in order to drive amide wax to the surface B and C, 562.2+0.9 mm body length) were imbibed with US 8,574 660 B2 89 90 O.O-t-Butyl-O-(2-ethylhexyl)mono-peroxycarbonate Example 6 (“TBEC’) and modified with SBMA monomer and Fe(II) reaction solution and washed with PBS and deionized water. Effects of Imbibing and Grafting Conditions on Thickness of the SBMA modification, and wax content as Mark Retention approximated from IRare summarized in the table below. The 5 thickness of the SBMA modification decreases with the ini Visual examination of black marks on Tecothane 97 A-30% tial presence of Surface wax. BaSO 5FR double D lumen tubing after exposure to imbib

Pellethane single lumen tubing, inside Surface

Surface Pre- Untreated 80 C. Owen 80 C. Owen 80 C. Owen 80 C. Owen treatinent for 4h for 4h then for 4h then for 4h then washed EtOH washed 2hr with Sonication overnight EtOH with EtOH Surface Wax 17.8 O.4 66.5 - 23.6 46.O. 16.4 O.O.O.O 33.78 - 26.9 content (10-6 M) Surface Wax O4 O.7 58.0 - 13.5 42.3 26.5 O.O.O.O 29.7 27.8 content post imbibe (10-6 M) Surface Wax 9.53.1 103.8 - 20.2 85.8 15.O 1.0 + 1.4 28.5 - 10.8 content post modification (10-6 M) Modification 871.034.8 118.5 - 86.2 2S2O 63.9 579.892.2. 6913 98.3 Thickness ill ill ill ill ill Pellethane single lumen tubing, outside surface

Pre- Control 80 C. Owen 80 C. Owen 80 C. Owen 80 C. Owen treatinent for 4h for 4h then for 4h then for 4h then washed EtOH washed 2hr with Sonication overnight EtOH With EtOH Wax content 3.45.9 129.3 485 42.O 52.7 O.O.O.O 1.5 - 3.0 (10-6 M) Wax content O.O.O.O 146.33 6.7 17.3 24.8 O.O.O.O post-imbibe (10-6 M) Wax content O.O.O.O 90.8 - 18.3 31.5 - 21.8 OS 1.0 post modification (10-6 M) Modification 1577.0453.4 163.3 - 65.0 596.3261.3 1065.8124.0 9 62.O. 1491 thickness ill ill ill ill ill

Example 5 ing isopropanol/initiator Solutions and ensuing SBMA/iron 45 (II) gluconate solutions revealed all marks were retained. Changes in Tubing Length Post Modification Example 7 The final length of Tecothane 97A-30% BaSO 5FR double D lumen tubing after exposure to imibibing solvent? 50 Bulk Physical Properties Comparison initiator solutions and ensuing redox SBMA solutions reveals varying changes in tubing length. Catheters (A: 613.7+1.8 mm body length, and B and C, 562.2+0.9 mm body length) were imbibed with O.O-t-Butyl 55 O-(2-ethylhexyl) mono-peroxycarbonate (“TBEC’) and modified with SBMA monomer and Fe(II) reaction solution Reduc and washed with PBS and deionized water. Bulk physical % Sonica- Redox Redox tion in properties were measured for the corresponding starting TBEC Solvent tion Temp Time Temp Time Length unmodified catheter and the modified catheters using stan 60 dard methods from the International Organization for Stan 1 EtOH No RT 120 60 4 3.3% dardization (ISO) and equipment for their evaluation that include, dimensions (length): calibrated ruler, dimensions 1 EtOH No RT 60 37 16 3.1% (cross-sectional): noncontact measurement system; Pumped 1 IPA Yes RT 120 37 16 1.6% flow rate: Syringe pump set to 11.9 mL/min: Tensile testing: 5 IPA Yes RT 120 37 4 1.0% 65 ISO 10555-1, ISO 10555-3. The percent changes relative to unmodified starting control are Summarized in the table below. US 8,574,660 B2 91 92 4. The process of claim 1 wherein the solvent system com prises a polar protic solvent, a polar aprotic solvent, a non Attribute Percent Change polar solvent, or a combination thereof. Catheter body length -1.93 5. The process of claim 1 wherein the solvent system com Extension line length -0.518 prises a polar protic solvent selected from methanol, ethanol, Outer diameter (body), at juncture hub O.OO isopropanol, and combinations thereof. Outer diameter (body), at distal tip 1.15 Roundness (body), at distal tip -33.3 6. The process of claim 1 wherein the solvent system com Cross-sectional area 5.5 prises an aprotic polar solvent selected from acetone, aceto Lumen width -0.84 nitrile, cyclohexanone, cyclopentanone, dimethylacetamide, Lumen height O.OO 10 dimethylformamide, methylethylketone, and combinations Wall thickness O.OO thereof. Septum width O.OO Flow rate, pumped O.OO 7. The process of claim 1 wherein the solvent system com Tensile strength, catheter body 2.59 prises a non-polar solvent selected from cyclohexane, diethyl Elongation, catheter body 0.855 ether, hexane, heptane, toluene, and combinations thereof. Tensile strength, extension line 1122 15 Tensile strength, catheter body- 5.52 8. The process of claim 1 wherein the solvent system com juncture hub joint prises (i) a polar protic solvent and a polar aprotic solvent; (ii) a polar protic solvent and a non-polar solvent; or (iii) a polar aprotic solvent and a non-polar solvent. 9. The process of claim 1 wherein the solvent system is Example 8 selected from the group consisting of acetone, methanol, ethanol, isopropanol, heptane, and combinations thereof. Protein Resistance—Catheter Walls 10. The process of claim 1 wherein the substrate and sol vent are subjected to mechanical agitation during the treat Catheters (613.7+1.8 mm body length) were imbibed with O.O-t-Butyl-O-(2-ethylhexyl) mono-peroxycarbonate ment. 25 11. The process of claim 10 wherein the substrate and (“TBEC’) with sonication and modified with SBMA mono Solvent are subjected to Sonication during the treatment. mer and Fe(II) reaction solution. The modified samples were 12. The process of claim 1 wherein the substrate is sub washed and dried. Protein resistance of the outside portion of jected to a heat treatment. the shaft of the samples was determined using the radiolabel 13. The process of claim 1 wherein the treatment comprises ing method and the results appear in the following table 30 contacting the Substrate Surface with a surfactant. 14. The process of claim 1 wherein the treatment does not alter any one or more of the bulk physical properties of the Estimated article selected from the group consisting of length, width, Modification height, volume, diameter ductility, flexural modulus, flexural Thickness 35 strength, shear strength, specific modulus, tensile strength, Sample by IR % Reduction Std Dev Fg (ngi cm2) and yield strength. A. 1654 299 87% 2% (n = 4) 47 15. The process of claim 1 wherein the low-fouling surface (n = 6) has a fibrinogen adsorption of less than 70 ng/cm. B 1630 - 201 90% 2% (n = 4) 37 16. The process of claim 1 wherein the low-fouling surface (n = 5) 40 has a fibrinogen adsorption of less than 50 ng/cm. 17. The process of claim 1 wherein the low-fouling surface has a fibrinogen adsorption of less than 30 ng/cm. What is claimed is: 18. The process of claim 1 wherein the low-fouling surface 1. A process for preparing a vascularly inserted catheter has an antibiofilm activity of 1 log after 30 days storage in having a low-fouling Surface on a Substrate, the Substrate 45 PBS at 37° C. having a Surface comprising a polyurethane material, the 19. The process of claim 1 wherein the low-fouling surface process comprising has an antibiofilm activity of 2 log after 30 days storage in (a) treating the Substrate surface to improve Surface char PBS at 37° C. acteristics without significantly altering the bulk physi 20. The process of claim 1 wherein the low-fouling surface cal properties of the article, said treatment comprising 50 has an antibiofilm activity of 2 log after 90 days storage in contacting the Substrate Surface with a solvent system to PBS at 37° C. Swell the substrate and remove wax or oil from the 21. The process of claim 1 wherein the substrate of the Substrate Surface, and vascularly inserted catheter is marked with a printed visual (b) forming a grafted polymer layer on the treated Substrate indicia before the substrate surface is treated to improve sur Surface, the treated Surface and the grafted polymer 55 face characteristics without significantly altering the bulk layer, in combination, constituting a low-fouling Surface physical properties of the vascularly inserted catheter. having a fibrinogen adsorption of less than about 125 22. The process of claim 21 wherein the vascularly inserted ng/cm in a fibrinogen binding assay in which the low catheter is a peripherally inserted central catheter, central fouling surface is incubated for 60 minutes at 37°C. in a venous catheter or hemodialysis catheter. composition containing 70 g/mL fibrinogen derived 60 23. The process of claim 22 wherein the solvent system from human plasma and 1.4 g/mL I-125 radiolabeled comprises a polar protic solvent. fibrinogen. 24. The process of claim 23 wherein the polar protic sol 2. The process of claim 1 wherein the treatment includes vent comprises methanol, ethanol, isopropanol or a combina reducing the Surface roughness. tion thereof. 3. The process of claim 1 wherein the treatment includes 65 25. The process of claim 1 wherein the vascularly inserted removing or reducing the presence of low molecular weight catheter is a peripherally inserted central catheter, central species on the Surface of or in the Substrate. venous catheter or hemodialysis catheter. US 8,574,660 B2 93 94 26. The process of claim 1 wherein the process further comprises imbibing a polymerization initiator into the Sub strate and the contacting and imbibing steps are carried out simultaneously. 27. The process of claim 1 wherein the vascularly inserted catheter has a physical characteristic selected from length, diameter, ductility, flexural modulus, flexural strength, shear strength, specific modulus, tensile strength, and yield strength and the step of treating the Substrate surface to improve surface characteristics causes such physical charac 10 teristic to change by less than 50%. 28. The process of claim 27 wherein the physical charac teristic is length.