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(12) Patent Application Publication (10) Pub. No.: US 2015/0056411 A1 ZHANG Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0056411 A1 ZHANG Et Al US 2015.0056411A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0056411 A1 ZHANG et al. (43) Pub. Date: Feb. 26, 2015 (54) NON-FOULING, ANTI-MICROBIAL, (60) Provisional application No. 61/353,208, filed on Jun. ANT-THROMBOGENC GRAFT 9, 2010. COMPOSITIONS (71) Applicants: Zheng ZHANG, Cambridge, MA (US); Jun LI, Brookline, MA (US); Chad C. Publication Classification HUVAL, Somerville, MA (US); Michael A. BOUCHARD, Wyomissing, PA (US); (51) Int. Cl. Arthur J. COURY, Boston, MA (US); A6IL 3 L/10 (2006.01) Christopher R. LOOSE, Cambridge, A6IL 3L/I6 (2006.01) MA (US) (52) U.S. Cl. CPC ................. A61L 3 1/10 (2013.01); A61L 3 1/16 (72) Inventors: Zheng ZHANG, Cambridge, MA (US); (2013.01); A61 L 2300/404 (2013.01); A61 L Jun LI, Brookline, MA (US); Chad C. 2300/42 (2013.01); A61L 2300/606 (2013.01); HUVAL, Somerville, MA (US); Michael A61L 2420/02 (2013.01) A. BOUCHARD, Wyomissing, PA (US); USPC ............ 428/142; 427/2.1; 428/447; 428/336; Arthur J. COURY, Boston, MA (US); 428/429: 428/391; 428/425.5 Christopher R. LOOSE, Cambridge, MA (US) (21) Appl. No.: 14/533,908 (57) ABSTRACT (22) Filed: Nov. 5, 2014 The present invention generally relates to articles of manu Related U.S. Application Data facture. Such as medical devices, having a non-fouling Sur (63) Continuation of application No. 13/156,708, filed on face comprising a grafted polymer material. The Surface Jun. 9, 2011. resists the adhesion of biological material. US 2015/0056411 A1 Feb. 26, 2015 NON-FOULING, ANTI-MICROBIAL, to or from a polymeric primer which, in turn, coats at least a ANT-THROMBOGENC GRAFT portion of the medical device or other article of interest. COMPOSITIONS 0007 Advantageously, the non-fouling polymeric mate rial may be used to modify the Surface of a range of substrates, CROSS-REFERENCE TO RELATED including Such diverse materials as metals, metal oxides, APPLICATIONS polymers, tissues, and fibers. Further, the non-fouling poly 0001. This application claims priority to U.S. Patent meric material may possess a range of polymeric backbones Application Ser. No. 61/353,208, filed Jun. 9, 2010, the con and substituents while providing the articles with a highly tents of which are incorporated herein by reference in its efficient, biocompatible, and non-fouling modified Surface. entirety. Additionally, the non-fouling polymeric material retains its activity in the presence of blood proteins and/or in vivo due to FIELD OF THE INVENTION improved molecular structures. In another embodiment, bio active compositions are attached to the modified Surface. 0002 The present invention generally relates to articles of 0008 Briefly, therefore, the present invention is directed manufacture, such as medical devices, having a non-fouling to an article of manufacture comprising a polymer layer, a Surface comprising a grafted polymer material. The Surface Substrate, and a polymeric primer between the polymer layer resists the adhesion of biological material. and the Substrate. The polymeric primer has upper and lower Surfaces, the lower Surface covering at least a portion of the BACKGROUND OF THE INVENTION Substrate, and the upper Surface being bound to the polymer 0003. Many different materials have been investigated to layer. The polymeric primer upper Surface and the polymer resist non-specific protein adsorption. Chemistries utilized layer, in combination, constitute a modified Surface for the for this purpose include, but are not limited to: polyethers article, the modified Surface having a fibrinogen adsorption of (e.g., polyethylene glycol), polysaccharides such as dextran, less than about 125 ng/cm in a fibrinogen binding assay in hydrophilic polymers such as polyvinylpyrrolidone or which the modified surface is incubated for 60 minutes at 37° hydroxyethyl-methacrylate, heparin, intramolecular Zwitteri C. in a solution containing 70 g/ml fibrinogen derived from ons or mixed charge materials, and hydrogen bond accepting human plasma and 1.4 ug/ml I-125 radiolabeled fibrinogen. groups such as those described in U.S. Pat. No. 7.276,286. In one embodiment, the polymeric primer upper Surface and The ability of these materials in preventing protein adsorption the polymer layer, in combination, constitute a modified Sur varies greatly between the chemistries. Of these materials, face having a fibrinogen adsorption of less than about 90 only a few resist fouling to the degree required for short-term ng/cm in a fibrinogen binding assay in which the modified in vivo application. However, the few materials appropriate surface is incubated for 60 minutes at 37° C. in a solution for short-term application, when used for longer periods of containing 70 ug/mL fibrinogen derived from human plasma time in complex media or in vivo, exhibit significant fouling and 1.4 ug/mL I-125 radiolabeled fibrinogen. In another or other degradation, making them unsuitable for long-term embodiment, the polymeric primer upper Surface and the applications. Furthermore, Surfaces coated with materials polymer layer in combination, constitute a modified Surface that resist in Vivo degradation are often susceptible to a having a fibrinogen adsorption of less than about 75 ng/cm in noticeable decrease in fouling resistance over time. a fibrinogen binding assay in which the modified Surface is 0004 Biocompatible coatings, especially those applied to incubated for 60 minutes at 37° C. in 70 g/mL fibrinogen medical device Substrates, have been applied by dip coating derived from human plasma containing 1.4 ug/mL I-125 the Substrate in a single polymer Solution. For hydrophilic radiolabeled fibrinogen. In another embodiment, the poly polymers applied to hydrophobic Substrates, this approach meric primer upper Surface and the polymer layer, in combi presents many challenges as it can be difficult to form stable nation, constitute a modified surface having a fibrinogen coatings. In an attempt to improve stability, hydrophilic mate adsorption of less than about 50 ng/cm in a fibrinogen bind rials have been cross-linked or copolymerized with hydro ing assay in which the modified surface is incubated for 60 phobic groups. However, such approaches can have signifi minutes at 37°C. in a solution containing 70 ug/mL fibrino cant negative effects on the overall coating performance, gen derived from human plasma and 1.4 g/mL I-125 radio especially when resistance to protein adsorption is desired. labeled fibrinogen. 0009. The present invention is further directed to a process 0005 Conventional fouling resistant or non-fouling mate for the preparation of an article of manufacture. The process rials and Surface coatings are Susceptible to fouling over comprises coating at least a portion of a Substrate with a prolonged exposure to complex media or in vivo environ polymer primer to form a polymeric primer on the Substrate. ments. The materials used for many non-fouling and fouling The process further comprises forming a bonded polymer resistant coatings, or the tethers used to immobilize the coat layer on the polymeric primer, the polymeric primer being ings on a Substrate, have not, to date, possessed the stability between the polymer layer and the substrate. The polymeric required to coat the substrate for extended periods of time, for primer has upper and lower Surfaces, the lower Surface cov example, at least 7, 14, 30, 60,90, 120, 365, or 1000 days. ering at least a portion of the Substrate, and the upper Surface being covalently bound to the polymer layer. The polymeric SUMMARY OF THE INVENTION primer and the polymer layer, in combination, constitute a 0006 Among the various aspects of the present invention modified Surface having a fibrinogen adsorption of less than is the provision of medical devices and other articles of manu about 125 ng/cm in a fibrinogen binding assay in which the facture having a grafted non-fouling polymeric material with modified surface is incubated for 60 minutes at 37° C. in 70 sufficient stability to protect the substrate for extended peri ug/ml fibrinogen derived from human plasma containing 1.4 ods of time, for example, at least 7, 14, 30, 60.90, 120, 365, ug/ml I-125 radiolabeled fibrinogen. In one embodiment, the or 1000 days. The non-fouling polymeric material is grafted polymeric primer and the polymer layer, in combination, US 2015/0056411 A1 Feb. 26, 2015 constitute a modified surface having a fibrinogen adsorption 0018 Anionic Monomer, Anionic Monomeric Unit or of less than about 90 ng/cm in a fibrinogen binding assay in Anionic Repeat Unit: unless otherwise indicated, an "anionic which the modified surface is incubated for 60 minutes at 37° monomer.” "anionic monomeric unit' or “anionic repeat C. in a solution containing 70Lug/mL fibrinogen derived from unit is a monomer or monomeric unit bearing an anion or human plasma and 1.4 ug/mL I-125 radiolabeled fibrinogen. other anionic species, e.g., a group that is present in a nega In another embodiment, the polymeric primer and the poly tively charged State or in a non-charged State, but in the mer layer in combination, constitute a modified Surface hav non-charged state is capable of becoming negatively charged, ing a fibrinogen adsorption of less than about 75 ng/cm in a e.g., upon removal of an electrophile (e.g., a proton (H+), for fibrinogen binding assay in which the modified Surface is example in a pH dependent manner) or a protecting group incubated for 60 minutes at 37° C. in 70 g/mL fibrinogen derived from human plasma containing 1.4 ug/mL I-125 (e.g., a carboxylic acid ester), or the addition of a nucleophile. radiolabeled fibrinogen. In another embodiment, the poly In certain instances, the group is substantially negatively meric primer and the polymer layer, in combination, consti charged at an approximately physiological pH but undergoes tute a modified Surface having a fibrinogen adsorption of less protonation and becomes Substantially neutral at a weakly than about 50 ng/cm in a fibrinogen binding assay in which acidic pH.
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