US 2011 O305909A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0305909 A1 Weaver et al. (43) Pub. Date: Dec. 15, 2011

(54) ARTICLES HAVING NON-FOULING Publication Classification SURFACES AND PROCESSES FOR PREPARING THE SAME WITHOUT (51) Int. Cl. ALTERING BULK PHYSICAL PROPERTIES B32B 27/00 (2006.01) B32B 27/240 (2006.01) (76) Inventors: Douglas J.K. Weaver, Cambridge, BOSD 3/02 (2006.01) MA (US); Jun Li, Cambridge, MA BOSD 3/12 (2006.01) (US); Zheng Zhang, Cambridge, BOSD 3/00 (2006.01) MA (US); Abby N. Deleault, Cambridge, MA (US); Eric W. (52) U.S. Cl...... 428/423.1; 427/560; 427/322: Marchese, Cambridge, MA (US); 427/316; 428/411.1 Phu C. Nguyen, Cambridge, MA (US); Chad C. Huval, Cambridge, MA (US); Michael A. Bouchard, (57) ABSTRACT Cambridge, MA (US); Arthur J. Coury, Cambridge, MA (US); Processes are described herein for preparing medical devices Christopher R. Loose, Cambridge, and other articles having a low-fouling Surface on a substrate comprising a polymeric Surface. The polymeric Surface mate MA (US) rial may possess a range of polymeric backbones and Sub (21) Appl. No.: 13/156,904 stituents while providing the articles with a highly efficient, biocompatible, and non-fouling Surface. The processes (22) Filed: Jun. 9, 2011 involve treating the substrate to reduce the concentration of chemical species on the surface of or in the substrate without Related U.S. Application Data altering the bulk physical properties of the device or article, (60) Provisional application No. 61/353,200, filed on Jun. and thereafter forming a grafted polymer layer on the treated 9, 2010. Substrate Surface. US 2011/0305909 A1 Dec. 15, 2011

ARTICLES HAVING NON-FOULING Surface. This may include, for example, the employment of SURFACES AND PROCESSES FOR polymeric Substrate Surfaces that are resistant to biomaterials. PREPARING THE SAME WITHOUT 0007 Although advances have been made in biomolecule ALTERING BULK PHYSICAL PROPERTIES resistant polymer coatings generally, various flaws can be present in the Surface structure of biocompatible materials, FIELD OF THE INVENTION both globally and at particular locations and regions of the Surface (whether a non-polymeric Substrate Surface, a poly 0001. The present invention generally relates to articles of meric Substrate or polymer Substrate coating). Such flaws manufacture, such as medical devices, having a non-fouling may be the result of improper handling or artifacts of the Surface comprising a grafted polymer layer. The Surface manufacturing or polymerization process, or may be present resists the adhesion of biological material. The present inven on a Substrate surface prior to polymer growth and/or depo tion also relates to processes for preparing Such articles. sition. Regardless of their source, such flaws can Substantially limit the effectiveness of conventional polymer coatings and BACKGROUND OF THE INVENTION polymeric Substrate Surfaces. For instance, increased or 0002 Many different materials have been investigated to decreased protein adsorption may result from changes in one resist non-specific protein adsorption. Chemistries utilized or more of the specific chemical, morphological, and physical for this purpose include, but are not limited to: polyethers properties of the Substrate or Substrate coating. In general, the (e.g., polyethylene glycol), polysaccharides such as dextran, present invention is directed to processes for preparing hydrophilic polymers such as polyvinylpyrrolidone or articles having improved surfaces that will serve as Substrates hydroxyethyl-methacrylate, heparin, intramolecular Zwitteri for non-fouling grafted polymer layers. ons or mixed charge materials, and hydrogen bond accepting groups such as those described in U.S. Pat. No. 7.276,286. SUMMARY OF THE INVENTION The ability of these materials in preventing protein adsorption 0008 Among the various aspects of the present invention varies greatly between the chemistries. Of these materials, is the provision of medical devices and other articles having a only a few resist fouling to the degree required for short-term low-fouling Surface on a Substrate comprising a polymeric in vivo application. However, the few materials appropriate Surface. The polymeric Surface material may possess a range for short-term application, when used for longer periods of of polymeric backbones and substituents while providing the time in complex media or in vivo, exhibit significant fouling articles with a highly efficient, biocompatible, and non-foul or other degradation, making them unsuitable for long-term ing Surface. applications. Furthermore, Surfaces coated with materials 0009 Among the various aspects of the present invention that resist in Vivo degradation are often susceptible to a may be noted the provision of processes for preparing an noticeable decrease in fouling resistance over time. article having a low-fouling Surface on a Substrate comprising 0003 WO 2007/02493 describes grafting sulfobetaine a polymeric Surface. Also noted are the provision of articles, and carboxybetaine from self-assembled monolayers on gold Such as medical devices, having a non-fouling Surface com Substrates or from silyl groups on glass Substrates using atom prising a grafted polymeric material. transfer radical polymerization (ATRP). Gold and glass are 0010. One aspect of the present invention is directed to a not appropriate substrates for many medical devices used in process for preparing an article having a low-fouling Surface vivo. Self-assembled monolayers, such as thiol-based mono on a Substrate, the Substrate having a surface comprising a layers, may be unstable since the thiol group is not stably polymeric material. The process comprises (a) treating the bound to the substrate. Substrate surface to improve Surface characteristics without 0004 U.S. Pat. No. 6,358,557 to Wang et al. describes the significantly altering the bulk physical properties of the graft polymerization of Substrate Surfaces, but not with a high article and (b) forming a grafted polymer layer on the treated density of a highly non-fouling polymeric material. Athermal substrate surface. In accordance with this embodiment, the initiator is used to initiate polymerization, typically at tem treated Surface and the grafted polymer layer, in combination, peratures greater than 85°C. Such temperatures are generally constitute a low-fouling Surface having a fibrinogen adsorp not suitable for many medical devices. Such as thin-walled tion of less than about 125 ng/cm in a fibrinogen binding polyurethane catheters. Further, the “salt out' method assay in which the low-fouling surface is incubated for 60 described is generally not suitable for grafting polymers such minutes at 37° C. in a composition containing 70 ug/mL as Zwitterionic polymers. fibrinogen derived from human plasma and 1.4 ug/mL I-125 0005. Jian et al., Colloids and Surfaces B: Biointerfaces radiolabeled fibrinogen. In one embodiment, the treated Sur 28, 1-9 (2003) describes the surface modification of seg face and the grafted polymer layer, in combination, constitute mented poly(ether urethane) by grafting sulfobetaine Zwitte a low-fouling Surface having a fibrinogen adsorption of less rionic monomer, but not with a high density of non-fouling than about 90 ng/cm in a fibrinogen binding assay in which material. The resulting materials are not sufficiently non the modified surface is incubated for 60 minutes at 37°C. in fouling to be useful in medical device applications. a solution containing 70 ug/mL fibrinogen derived from 0006 Resistance of protein fouling in biocompatible solid human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. Surfaces can play an important role in a range oftechnological In another embodiment, the treated surface and the grafted disciplines, including biotechnology, medicine, food pro polymer layer, in combination, constitute a modified Surface cessing, and pharmaceutical applications, to name a few. It is having a fibrinogen adsorption of less than about 70 ng/cm in well known, for example, that protein adsorption and bacte a fibrinogen binding assay in which the modified Surface is rial adhesion and colonization can result in infection and incubated for 60 minutes at 37°C. in a solution containing 70 Subsequent failure of implanted medical devices. Incidences ug/mL fibrinogen derived from human plasma and 1.4 ug/mL of protein adsorption and fouling can be minimized by chang I-125 radiolabeled fibrinogen. In another embodiment, the ing the physical and/or chemical properties of the biomaterial treated Surface and the grafted polymer layer, in combination, US 2011/0305909 A1 Dec. 15, 2011 constitute a modified surface having a fibrinogen adsorption amido.” for example, refers to a group of the formula of less than about 50 ng/cm in a fibrinogen binding assay in - CONR'R'', wherein R' and Rare each hydrogen. which the modified surface is incubated for 60 minutes at 37° 0020 Anionic Monomer, Anionic Monomeric Unit or C. in a solution containing 70Lug/mL fibrinogen derived from Anionic Repeat human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. 0011. Another aspect of the present invention is directed to 0021 Unit: unless otherwise indicated, an “anionic mono an article of manufacture comprising a polymeric Substrate mer.” "anionic monomeric unit' or “anionic repeat unit is a having a Surface and a grafted polymeric Surface on the Sub monomer or monomeric unit bearing an anion or other strate surface, the Substrate having a process aid concentra anionic species, e.g., a group that is present in a negatively tion of less than about 0.1%, wherein the treated surface and charged State or in a non-charged state, but in the non-charged the grafted polymer layer, in combination, constitute a low state is capable of becoming negatively charged, e.g., upon fouling Surface having a fibrinogen adsorption of less than removal of an electrophile (e.g., a proton (H+), for example in about 125 ng/cm in a fibrinogen binding assay in which the a pH dependent manner) or a protecting group (e.g., a car low-fouling surface is incubated for 60 minutes at 37°C. in a boxylic acid ester), or the addition of a nucleophile. In certain composition containing 70 ug/mL fibrinogen derived from instances, the group is Substantially negatively charged at an human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. approximately physiological pH but undergoes protonation In each of the foregoing aspects and embodiments of the and becomes substantially neutral at a weakly acidic pH. The invention, preferably the article (i) is other than a non-luminal non-limiting examples of Such groups include carboxyl polyurethane rod and (ii) has a length greater than 5 centime groups, barbituric acid and derivatives thereof, Xanthine and ters when the article is a double lumen catheter. derivatives thereof, boronic acids, phosphinic acids, phos 0012. Other objects and features will be in part apparent phonic acids, sulfinic acids, Sulfonic acids, phosphates, and and in part pointed out hereinafter. Sulfonamides. 0022 Anionic species or Anionic moiety: unless other ABBREVIATIONS AND DEFINITIONS wise indicated, an “Anionic species' or an “Anionic moiety’ 0013 The following definitions and methods are provided is a group, residue or molecule that is present in a negatively to better define the present invention and to guide those of charged or non-charged state, but in the non-charged state is ordinary skill in the art in the practice of the present invention. capable of becoming negatively charged, e.g., upon removal Unless otherwise noted, terms are to be understood according of an electrophile (e.g., a proton (H+), for example in a pH to conventional usage by those of ordinary skill in the relevant dependent manner) or other protecting group (e.g., a carboxy art. lic acid ester), or the addition of a nucleophile. In certain 0014 When introducing elements of the present invention instances, the group, residue or molecule is Substantially or the preferred embodiment(s) thereof, the articles “a” “an.” negatively charged at an approximately physiological pH but “the' and “said are intended to mean that there are one or undergoes protonation and becomes Substantially neutral at a more of the elements. The terms “comprising.” “including weakly acidic pH. and “having are intended to be inclusive and mean that there 0023 Antibiofilm activity: unless otherwise indicated, may be additional elements other than the listed elements. 'antibiofilm activity” may be quantified, for example, using a 00.15 Aliphatic: unless otherwise indicated, “aliphatic' or standard continuous flow assay. In one such assay, Samples “aliphatic group” means an optionally Substituted, non-aro may be pre-incubated with 50% fetal bovine serum for 18-20 matic hydrocarbon moiety. The moiety may be, for example, hours at 120 RPM at 37° C. Following preincubation, samples linear, branched, or cyclic (e.g., mono or polycyclic Such as are then exposed to a subculture of bacteria via a modified fused, bridging, or spiro-fused polycyclic), or a combination CDC (mCDC) to make a bacterial suspension of 10°Cfu/mL thereof. Unless otherwise specified, aliphatic groups contain in 1xRBS. The reactor is run in batch mode for 2 hours at 37° 1-20 carbon atoms. C. with agitation. Thereafter, the samples are transferred to a 0016 Alkyl: unless otherwise indicated, the alkyl groups fresh reactor a suitable growth media for where flow of the described herein are preferably lower alkyl containing from sterile media (8 mL/min) runs 20-23 hours with agitation. In one to eight carbon atoms in the principal chain and up to 20 one preferred embodiment, the bacterial strain is Staphylo carbon atoms. They may be linear, branched or cyclic and coccus epidermidis (S. epidermidis, ATCC 35984), and the include methyl, ethyl, propyl, butyl, hexyl and the like. growth media used is 1:10 Tryptic soy broth (TSB)+0.25 wt 0017 Amino: unless otherwise indicated, the term % glucose. In an alternate preferred embodiment, the bacte “amino” as used herein alone or as part of another group rial strain is Escherichia coli (E. coli, ATCC 25922) and the denotes the moiety —NR'R' wherein R', and Rare inde growth media is M63 media supplemented with 1 mM pendently hydrogen, hydrocarbyl, substituted hydrocarbyl or MgSO, 0.2% glucose, and 0.5% casamino acids. After incu heterocyclo. bation, the samples are rinsed five times in 100 mL of 1xPBS 0.018 Ammonium: unless otherwise indicated, the term to remove bacteria not tightly attached. Then, accumulated “ammonium' as used herein alone or as part of another group bacteria on materials are macroscopically rated for biofilm denotes the moiety - N'R'R'R' wherein R', Rand Rare Surface coverage and are removed by Sonication in a new independently hydrogen, hydrocarbyl, Substituted hydrocar solution of PBS and the total number of bacterial cells quan byl or heterocyclo. tified through dilution plating. Preferably at least a 1, 2, 3 or 0.019 Amide or Amido: unless otherwise indicated, the 4 log reduction in bacterial count is found on the article with “amide' or "amido’ moieties representagroup of the formula the non-fouling polymer layer relative to a reference Sub —CONR'R' wherein R' and Rare as defined in connection strate, that is, the same or an otherwise functionally equiva with the term “amino.” “Substituted amide.” for example, lent Substrate lacking the non-fouling polymer layer. An refers to a group of the formula—CONR'R' wherein at least article that has a 1 log reduction in adhered bacteria relative to one of R' and R are other than hydrogen. “Unsubstituted a reference substrate is said to have antibiofilm activity of 1 US 2011/0305909 A1 Dec. 15, 2011

log. An article that has a 2 log reduction in adhered bacteria phenyl, substituted biphenyl or substituted naphthyl. Phenyl relative to a reference substrate is said to have antibiofilm and substituted phenyl are the more preferred aryl. activity of 2 log, and so forth. 0028. Attached: unless otherwise indicated, two moieties 0024. Antimicrobial: unless otherwise indicated, “antimi or compounds are “attached