Non-fouling, anti-microbial, anti-thrombogenic graft compositions

Abstract

The present invention generally relates to articles of manufacture, such as medical devices, having a non-fouling surface comprising a grafted polymer material. The surface resists the adhesion of biological material.

1 . A process for the preparation of article of manufacture, the process comprising (1) depositing a polymeric primer on the substrate, the polymeric primer having a thickness of at least 50 nm, and (2) grafting a polymer from or to the polymeric primer, the polymeric primer being between the grafted polymer and the substrate and having upper and lower surfaces, the lower surface covering at least a portion of the substrate, and the upper surface being covalently bound to the grafted polymer, the polymeric primer and the grafted polymer, in combination, constituting a modified surface having a fibrinogen adsorption of less than about 125 ng/cm 2  in a fibrinogen binding assay in which the modified surface is incubated for 60 minutes at 37° C. in a composition containing 70 μg/ml fibrinogen derived from human plasma and 1.4 μg/ml I-125 radiolabeled fibrinogen, provided the article is other than a polyurethane rod. 
     
     
         2 . The process of  claim 1  wherein the polymeric primer is deposited on the substrate by grafting a presynthesized polymer to the substrate. 
     
     
         3 . The process of  claim 1  wherein the deposited polymeric primer has a thickness of at least about 100 nm. 
     
     
         4 . The process of  claim 1  wherein the polymeric primer contains at least 5 nanomolar equivalents/cm 2  of a functional group that is chemically reactive with a functionality of the grafted polymer or of a moiety from which it is derived. 
     
     
         5 . The process of  claim 1  wherein the difference between the static contact angle of the polymeric primer, prior to the attachment of the grafted polymer, and the modified surface is at least 10 degrees. 
     
     
         6 . An article of manufacture comprising a grafted polymer, a substrate, and a polymeric primer between the grafted polymer and the substrate, the polymeric primer having upper and lower surfaces, the lower surface covering at least a portion of the substrate, and the upper surface being bound to the grafted polymer, the polymeric primer upper surface and the grafted polymer, in combination, constituting a modified surface having a fibrinogen adsorption of less than about 125 ng/cm 2  in a fibrinogen binding assay in which the modified surface is incubated for 60 minutes at 37° C. in a composition containing 70 μg/ml fibrinogen derived from human plasma and 1.4 μg/ml I-125 radiolabeled fibrinogen, provided the article is other than a polyurethane rod. 
     
     
         7 . The article of  claim 6  wherein the polymeric primer has a thickness of at least about 100 nm. 
     
     
         8 . The article of  claim 6  wherein the modified surface has a static contact angle of less than 35 degrees. 
     
     
         9 . The article of  claim 6  wherein the grafted polymer and the polymeric primer, in combination, have a global average dry thickness of at least 100 nm. 
     
     
         10 . The article of  claim 6  wherein the grafted polymer and the polymeric primer, in combination, have a global average dry thickness of at least 500 nm. 
     
     
         11 . The article of  claim 6  wherein the polymeric primer contains at least 5 nanomolar equivalents/cm 2  of a functional group that is chemically reactive with a functionality of the grafted polymer or of a moiety from which it is derived. 
     
     
         12 . The article of  claim 6  wherein the polymeric primer comprises a reactive group selected from the group consisting of alkyne, amine (primary, secondary or tertiary), anhydride, azide, carboxyl, epoxy (e.g., glycidyl), halogen, hydroxyl, isocyanate, peroxide, silanol, thiol, and photo-initiator groups, and combinations thereof. 
     
     
         13 . The article of  claim 6  wherein the grafted polymer comprises zwitterionic moieties. 
     
     
         14 . The article of  claim 6  wherein the grafted polymer comprises carboxybetaine moieties or sulfobetaine moieties. 
     
     
         15 . The article of  claim 6  wherein the substrate comprises a metal, ceramic, glass, polymer, biological tissue, woven fiber, non-woven fiber, semi-metal, or a combination thereof. 
     
     
         16 . The article of  claim 6  wherein the substrate comprises polyurethane. 
     
     
         17 . The article of  claim 6  wherein the standard deviation of the global average dry thickness wherein the standard deviation of the global average dry thickness does not exceed 100% of the global average dry thickness of the grafted polymer layer. 
     
     
         18 . The article of  claim 6  wherein the difference between the global average dry thickness of the combination as determined by scanning electron microscopy (SEM) and the average humidified thickness of the combination as determined by environmental scanning electron microscopy (ESEM) is less than 50% of the global average dry thickness. 
     
     
         19 . The article of  claim 6  wherein the grafted polymer and the polymeric primer, in combination, have a global average dry thickness that is at least equal to the global average R rms  surface roughness of the substrate surface. 
     
     
         20 . The article of  claim 6  wherein the grafted polymer comprises repeat units corresponding to Formula 1 
       
         
           
           
               
               
           
         
         wherein 
         X 1  and X 2  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, or substituted carbonyl, provided, however, X 1  and X 2  are not each selected from the group consisting of aryl, heteroaryl, and heterosubstituted carbonyl, 
         X 3  is hydrogen, alkyl or substituted alkyl, X 4  is —OX 40 , —NX 41 X 42 , —N + X 41 X 42 X 43 , —SX 40 , aryl, heteroaryl or acyl, 
         X 40  is hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo or acyl, and 
         X 41 , X 42  and X 43 , are independently hydrogen, hydrocaryl, substituted hydrocarbyl or heterocyclo 
       
     
     
         22 . The article of  claim 6  wherein the grafted polymer comprises repeat units corresponding to Formula 2: 
       
         
           
           
               
               
           
         
         wherein 
         X 3  is hydrogen, alkyl or substituted alkyl, and 
         X 4  is a pendant group comprising an oxylated alkylene moiety, a zwitterionic moiety, an anionic moiety, or a cationic moiety. 
       
     
     
         23 . The article of  claim 6  wherein the grafted polymer comprises repeat units corresponding to Formula 3: 
       
         
           
           
               
               
           
         
         wherein X 44  comprises an oxylated alkylene moiety, a zwitterionic moiety, an anionic moiety, or a cationic moiety. 
       
     
     
         24 . The article of  claim 23  wherein X 44  is —OX 45 , —NHX 45 , or —SX 45 , and X 45  is a substituted hydrocarbyl or heterocyclo moiety comprising an oxylated alkylene moiety, a zwitterionic moiety, an anionic moiety, or a cationic moiety. 
     
     
         25 . The article of  claim 23  wherein X 44  is —OX 45  or —NHX 45 , and X 45  comprises an oxylated alkylene moiety corresponding to Formula POA-1 or a zwitterionic moiety corresponding to Formula ZI-1, ZI-2, ZI-3, ZI-4, ZI-5, ZI-6A, ZI-6B, or ZI-7. 
     
     
         26 . The article of  claim 23  wherein the grafted polymer contains repeat units corresponding to Formula 3 and X 44  is —NH(CH 2 ) m N(CH 2 ) n CH 3 (CH 2 ) p SO 3 , —NH(CH 2 ) m N(CH 2 ) n CH 3 (CH 2 ) p CO 2 , —NH(CH 2 ) m N + [(CH 2 ) n CH 3 ] 2 (CH 2 ) p SO 3 , —NH(CH 2 )N + [(CH 2 ) p CH 3 ] 2  (CH 2 ) p CO 2 , —NH(CH 2 ) m Ncyclo-(CH 2 ) p CO 2 , or —NH(CH 2 ) m Ncyclo-(CH 2 ) p SO 3 , Ncyclo- is a heterocyclic structure or a heterocyclic derivative containing at least one nitrogen atom, m is 1-8; n is 0-5; and p is 1-8. 
     
     
         27 . A process for the preparation of article of manufacture, the process comprising (1) depositing a polymeric primer on a substrate, the polymeric primer having a thickness of at least 50 nm comprising and containing at least 5 nanomolar equivalent/cm 2  of a functional group, and (2) grafting a polymer from the deposited polymeric primer, the deposited polymeric primer being between the grafted polymer and the substrate and having upper and lower surfaces, the lower surface covering at least a portion of the substrate, and the upper surface being bound to the functional group, the polymeric primer and the grafted polymer, in combination, constituting a modified surface having a fibrinogen adsorption of less than about 75 ng/cm 2  in a fibrinogen binding assay in which the modified surface is incubated for 60 minutes at 37° C. in 70 μg/ml fibrinogen derived from human plasma containing 1.4 μg/ml I-125 radiolabeled fibrinogen. 
     
     
         28 . The process of  claim 27  wherein the polymer is grafted by exposing the function group to a free radical initiator and a monomer or monomer mixture, the upper surface of the polymeric primer being attached to the grafted polymer through the functional group. 
     
     
         29 . The process of  claim 27  wherein the functional group is selected from the group consisting of glycidyl, isocyanate, amine, benzophenone, bromoisobutyryl, hydroxy, carboxylate and combinations thereof. 
     
     
         30 . The process of  claim 27  wherein the free radical initiator is selected from UV, thermal, and redox initiators.