Process for providing antimicrobial surfaces

Abstract

Processes for providing durable antimicrobial surfaces are disclosed that comprise treating a polymer substrate surface with formaldehyde followed by treatment with an antimicrobial peptide. Further embodiments include articles, including medical devices, characterized by a durable antimicrobial surface provided by the processes of the invention.

1 . A process for providing a durable antimicrobial surface on a polymer substrate comprising:
 a) treating a polymer substrate with a first fluid comprising formaldehyde and a co-reactant selected from the group: acid, anhydride, reactive halide, or mixtures thereof; wherein the formaldehyde and co-reactant are present in amounts effective to provide a polymer substrate with a chemically modified surface; and   b) treating the chemically modified surface of step (a) with an antimicrobial fluid comprising an effective amount of an antimicrobial peptide sufficient to provide a durable antimicrobial surface.   
     
     
         2 . A process for providing a durable antimicrobial surface on a polymer substrate comprising:
 a) (1) treating a polymer substrate with a first alternative fluid comprising formaldehyde and a hydroxymethylation catalyst wherein the formaldehyde and hydroxymethylation catalyst are present in an amount effective to provide a polymer substrate with a hydroxymethyl surface;
 (2) treating the hydroxymethyl surface with a second alternative fluid comprising a reactant selected from the group: acid, anhydride, reactive halide, and mixtures thereof, in an amount effective to provide a polymer substrate with a chemically modified surface; and 
   b) treating the chemically modified surface of step (a) (2), with an antimicrobial fluid comprising an effective amount of an antimicrobial peptide sufficient to provide a durable antimicrobial surface.   
     
     
         3 . The process of  claims 1  or  2 , wherein the antimicrobial fluid further comprises an effective amount of base catalyst. 
     
     
         4 . The process of  claims 1  or  2  wherein the antimicrobial fluid further comprises a base catalyst selected from the group: potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, trimethylamine, triethylamine, tripropylamine, diisopropylethylamine and tributyl amine. 
     
     
         5 . The process of  claims 1  or  2 , wherein the polymer substrate of step (a) is comprised of one or more homopolymers, copolymers, block copolymers or graft polymers selected from the group: polyamide, polyurethane, and polyurea. 
     
     
         6 . The process of  claims 1  or  2 , wherein the polymer substrate of step (a) is a thermoplastic polyurethane elastomer. 
     
     
         7 . The process of  claims 1  or  2 , wherein said antimicrobial peptide is characterized by a weight average molecular weight of about 1000 to about 60,000 Daltons. 
     
     
         8 . The process of  claims 1  or  2 , wherein said antimicrobial peptide is one or more linear cationic peptide(s). 
     
     
         9 . The process of  claims 1  or  2 , wherein the durable antimicrobial surface is provided on a medical device. 
     
     
         10 . The process of  claims 1  or  2 , wherein said formaldehyde is selected from the group: aqueous formaldehyde, paraformaldehyde and trioxane. 
     
     
         11 . The process of  claim 1  wherein the co-reactant of step (a) is selected from the group: trimethylsilylchloride, trimethylsilylbromide, and hydrogen chloride. 
     
     
         12 . The process of  claim 2  wherein the reactant of step (a) (2) is selected from the group: trimethylsilylchloride, trimethylsilylbromide, and hydrogen chloride. 
     
     
         13 . The process of  claim 1 , wherein said first fluid consists essentially of paraformaldehyde and trimethylsilylchloride. 
     
     
         14 . The process of  claims 1  or  2 , wherein treating the chemically modified surface with said antimicrobial fluid is performed at a reaction temperature of about 4° C. to about 100° C., for a reaction time of about 0.1 to about 10 hours. 
     
     
         15 . The process of  claim 2 , wherein said hydroxymethylation catalyst is selected from the group: hydrogen chloride, sulfuric acid, glacial acetic acid formic acid, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. 
     
     
         16 . The process of  claims 1  or  2 , wherein the antimicrobial peptide is characterized by a weight average molecular weight of about 1,000 to about 60,000 Daltons and contains a net positive charge of greater than 1 at physiological pH. 
     
     
         17 . The process of  claims 1  or  2 , wherein the antimicrobial peptide is selected from the group consisting of linear cationic α-helical peptides of 8 to 40 amino acid residues. 
     
     
         18 . The process of  claims 1  or  2 , wherein the antimicrobial peptide is selected from the group: 
       
         
           
                 
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                     
                 
                 
                 
                 
               
                     
                   PKGLKKLLKGLKKLLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 2) 
                     
                 
                 
                 
                 
               
                     
                   KGLKKLLKGLKKLLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 3) 
                     
                 
                 
                 
                 
               
                     
                   KGLKKLLKLLKKLLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 4) 
                     
                 
                 
                 
                 
               
                     
                   LKKLLKLLKKLLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 5) 
                     
                 
                 
                 
                 
               
                     
                   LKKLLKLLKKLL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 6) 
                     
                 
                 
                 
                 
               
                     
                   VAKKLAKLAKKLAKLAL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 7) 
                     
                 
                 
                 
                 
               
                     
                   FAKLLAKALKKLL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 8) 
                     
                 
                 
                 
                 
               
                     
                   KGLKKGLKLLKKLLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 9) 
                     
                 
                 
                 
                 
               
                     
                   KGLKKLLKLGKKLLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 10) 
                     
                 
                 
                 
                 
               
                     
                   KGLKKLGKLLKKLLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 11) 
                     
                 
                 
                 
                 
               
                     
                   KGLKKLLKLLKKGLKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 12) 
                     
                 
                 
                 
                 
               
                     
                   KGLKKLLKLLKKLGKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 13) 
                     
                 
                 
                 
                 
               
                     
                   FALALKALKKLKKALKKAL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 14) 
                     
                 
                 
                 
                 
               
                     
                   FAKKLAKLAKKLAKLAL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 15) 
                     
                 
                 
                 
                 
               
                     
                   FAKLLAKLAKKLL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 16) 
                     
                 
                 
                 
                 
               
                     
                   FAKKLAKLALKLAKL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 17) 
                     
                 
                 
                 
                 
               
                     
                   FAKKLAKKLL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 18) 
                     
                 
                 
                 
                 
               
                     
                   FAKLLAKLAKKVL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 19) 
                     
                 
                 
                 
                 
               
                     
                   KYKKALKKLAKLL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 20) 
                     
                 
                 
                 
                 
               
                     
                   FALLKALLKKAL 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 21) 
                     
                 
                 
                 
                 
               
                     
                   KRLFKKLKFSLRKY 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 22) 
                     
                 
                 
                 
                 
               
                     
                   KRLFKKLLFSLRKY 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 23) 
                     
                 
                 
                 
                 
               
                     
                   LLLFLLKKRKKRKY 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 24) 
                     
                 
                 
                 
                 
               
                     
                   KWKLFKKIEKVGQNIRDGIIKAGPAVAWGQATQIAK 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 25) 
                     
                 
                 
                 
                 
               
                     
                   GIGKFLHSAKKFGKAFVGEIMNS 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 26) 
                     
                 
                 
                 
                 
               
                     
                   GIGKFLKKAKKFGKAFVKILKK 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 27) 
                     
                 
                 
                 
                 
               
                     
                   RLCRIVVIRVCR 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 28) 
                     
                 
                 
                 
                 
               
                     
                   ILPWKWPWWPWRR 
                     
                 
                     
                     
                 
                 
                 
                 
               
                     
                   (SEQ ID NO: 29) 
                     
                 
                 
                 
                 
               
                     
                   DSHAKRHHGYKRKFHEKHHSHRGY. 
                     
                 
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
     
     
         19 . The process of  claims 1  or  2 , wherein the polymer substrate is a nonwoven fabric. 
     
     
         20 . The process of  claims 1  or  2 , wherein the polymer substrate is a fiber. 
     
     
         21 . The process of  claims 1  or  2 , wherein the polymer substrate is a film. 
     
     
         22 . The process of  claim 1  or  2 , wherein the polymer substrate is selected from the group: catheters, pacemaker leads, vascular grafts, blood tubing, balloons, shunts, cardiac-assist devices, and urological implants; and barrier materials selected from the group: wound dressings, surgical gowns, gloves, aprons, and drapes. 
     
     
         23 . An article selected from the group consisting of a non-woven fabric, fiber, film, catheters, pacemaker leads, vascular grafts, blood tubing, balloons, shunts, cardiac-assist devices, and urological implants; and barrier materials selected from the group: wound dressings, surgical gowns, gloves, aprons, and drapes, characterized by a durable antimicrobial surface provided by the process of  claims 1  or  2 . 
     
     
         24 . A medical device characterized by a durable antimicrobial polymeric surface provided by the process of  claims 1  or  2 . 
     
     
         25 . The process of  claims 1  or  2 , further comprising washing said durable antimicrobial surface with one or more wash solvents to remove excess antimicrobial peptide, base if used, and any byproducts; to provide a durable antimicrobial surface substantially free of non-bonded contaminants.