Reinforced adhesive complex coacervates and methods of making and using thereof

Abstract

Described herein is the synthesis of reinforced adhesive complex coacervates and their use thereof. The reinforced adhesive complex coacervates are composed of (a) at least one polycation, (b) at least one polyanion, and (c) a reinforcing component. The adhesive complex coacervates described herein can be subsequently cured to produce strong, cohesive adhesives. The reinforced adhesive complex coacervates have several desirable features when compared to conventional adhesives. The reinforced adhesive complex coacervates are effective in wet or underwater applications. The reinforced adhesive complex coacervates described herein, being phase separated from water, can be applied underwater without dissolving or dispersing into the water. The reinforced adhesive complex coacervates have numerous biological applications as bioadhesives and bioactive delivery devices. In particular, the reinforced adhesive complex coacervates described herein are particularly useful in underwater applications and situations where water is present such as, for example, wet tissues in physiological conditions.

1 . An adhesive complex coacervate comprising (a) at least one polycation, (b) at least one polyanion, and (c) a reinforcing agent. 
     
     
         2 . The adhesive complex coacervate of  claim 1 , wherein the polycation comprises a polyamino compound. 
     
     
         3 . The adhesive complex coacervate of  claim 1 , wherein the polycation comprises a biodegradable polyamine. 
     
     
         4 . The adhesive complex coacervate of  claim 3 , wherein the biodegradable polyamine comprises a polysaccharide, a protein, a recombinant protein, or a synthetic polyamine. 
     
     
         5 . The adhesive complex coacervate of  claim 3 , wherein the biodegradable polyamine comprises an amine-modified natural polymer. 
     
     
         6 . The adhesive complex coacervate of  claim 3 , wherein the biodegradable polyamine comprises a recombinant protein. 
     
     
         7 . The adhesive complex coacervate of  claim 3 , wherein the biodegradable polyamine comprises gelatin modified with ethylenediamine. 
     
     
         8 . The adhesive complex coacervate of  claim 1 , wherein the polycation comprises a polyacrylate comprising two or more pendant amino groups. 
     
     
         9 . The adhesive complex coacervate of  claim 4 , wherein the amino group comprises (1) an alkylamino group, or (2) a heteroaryl group, a guanidinyl group, or an aromatic group substituted with one or more amino groups. 
     
     
         10 . The adhesive complex coacervate of  claim 1 , wherein the polycation comprises a polymer comprising at least one fragment comprising the formula I 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 3  are, independently, hydrogen or an alkyl group, X is oxygen or NR S , where R 5  is hydrogen or an alkyl group, and m is from 1 to 10, or the pharmaceutically-acceptable salt thereof. 
     
     
         11 . The adhesive complex coacervate of  claim 10 , wherein R 1 , R 2 , and R 3  are methyl, X is O, and m is 3. 
     
     
         12 . The adhesive complex coacervate of  claim 2 , wherein the polyamino compound comprises from 10 to 90 mole % primary, secondary, or tertiary amino groups. 
     
     
         13 . The adhesive complex coacervate of  claim 1 , wherein the polycation comprises a cationic micelle or liposome. 
     
     
         14 . The adhesive complex coacervate of  claim 1 , wherein the polyanion comprises two or more sulfate, sulfonate, carboxylate, borate, boronate, phosphonate, or phosphate groups. 
     
     
         15 . The adhesive complex coacervate of  claim 1 , wherein the polyanion comprises a polyphosphate. 
     
     
         16 . The adhesive complex coacervate of  claim 15 , wherein the polyphosphate comprises a natural polymer or a synthetic polymer. 
     
     
         17 . The adhesive complex coacervate of  claim 15 , wherein the polyphosphate comprises a polyphosphoserine. 
     
     
         18 . The adhesive complex coacervate of  claim 15 , wherein the polyphosphate comprises a polyacrylate comprising one or more pendant phosphate groups. 
     
     
         19 . The adhesive complex coacervate of  claim 15 , wherein the polyphosphate further comprises one or more ortho-dihydroxy aromatic groups. 
     
     
         20 . The adhesive complex coacervate of  claim 15 , wherein the polyphosphate is the copolymerization product between (1) a phosphate acrylate and/or phosphate methacrylate and (2) a second acrylate and/or second methacrylate comprising a pendant dihydroxy aromatic group covalently bonded to the second acrylate or second methacrylate. 
     
     
         21 . The adhesive complex coacervate of  claim 15 , wherein the polyphosphate comprises from 5 to 90 mole % phosphate groups. 
     
     
         22 . The adhesive complex coacervate of  claim 1 , wherein the polyanion comprises a polymer comprising at least one fragment comprising the formula X 
       
         
           
           
               
               
           
         
       
       wherein R 4  is hydrogen or an alkyl group;
 n is from 1 to 10; 
 Y is oxygen, sulfur, or NR 30 , wherein R 30  is hydrogen, an alkyl group, or an aryl group; 
 Z is an anionic group or a group that can be converted to an anionic group, or the pharmaceutically-acceptable salt thereof. 
 
     
     
         23 . The adhesive complex coacervate of  claim 22 , wherein Z is sulfate, sulfonate, carboxylate, borate, boronate, a substituted or unsubstituted phosphate, or a phosphonate. 
     
     
         24 . The adhesive complex coacervate of  claim 1 , wherein the polyanion comprises a polymer comprising at least one fragment comprising the formula II 
       
         
           
           
               
               
           
         
       
       wherein R 4  is hydrogen or an alkyl group, and n is from 1 to 10, or the pharmaceutically-acceptable salt thereof. 
     
     
         25 . The adhesive complex coacervate of  claim 24 , wherein R 4  is methyl and n is 2. 
     
     
         26 . The adhesive complex coacervate of  claim 1 , wherein the polyanion comprises an anionic micelle or liposome. 
     
     
         27 . The adhesive complex coacervate of  claim 1 , wherein the polycation and/or polyanion comprises at least one crosslinkable group. 
     
     
         28 . The adhesive complex coacervate of  claim 27 , wherein the crosslinking group on the polycation comprises a nucleophilic group and the crosslinking group on the polyanion comprises an electrophilic group. 
     
     
         29 . The adhesive complex coacervate of  claim 27 , wherein the crosslinking group on the polycation and polyanion comprises an ortho-dihydroxy aromatic group capable of undergoing oxidative crosslinking with a nucleophilic group. 
     
     
         30 . The adhesive complex coacervate of  claim 27 , wherein the crosslinking group on the polyanion comprises an ortho-dihydroxy aromatic group and the polycation comprises a nucleophilic group capable of reacting with the crosslinking group to form a covalent bond. 
     
     
         31 . The adhesive complex coacervate of  claim 27 , wherein (1) the crosslinking group on the polyanion comprises an olefinic group and (2) the crosslinking group on the polycation comprises a nucleophilic group that reacts with the olefinic group to produce a new covalent bond. 
     
     
         32 . The adhesive complex coacervate of  claim 27 , wherein (1) the crosslinking group on the polycation comprises an olefinic group and (2) the crosslinking group on the polyanion comprises a nucleophilic group that reacts with the olefinic group to produce a new covalent bond. 
     
     
         33 . The adhesive complex coacervate of  claim 27 , wherein (1) the crosslinking group on the polyanion comprises an olefinic group; (2) the crosslinking group on the polycation comprises an olefinic group; and (3) a multivalent crosslinker comprising two or more nucleophilic groups that react with the olefinic groups on the polycation and polyanion to produce a new covalent bond. 
     
     
         34 . The adhesive complex coacervate of  claim 1 , wherein the reinforcing component comprises a polymerizable monomer, water-insoluble filler, a nanostructure, a micelle, or a liposome. 
     
     
         35 . The adhesive complex coacervate of  claim 1 , wherein the reinforcing component comprises a polymerizable monomer, and the monomer comprises a polymerizable olefinic monomer comprising at least one olefinic group. 
     
     
         36 . The adhesive complex coacervate of  claim 35 , wherein the monomer comprises two olefinic groups. 
     
     
         37 . The adhesive complex coacervate of  claim 35 , wherein the olefinic group comprises a pendant acrylate group, methacrylate group, acrylamide group, methacrylamides group, allyl, vinyl group, vinylester group, or styrenyl group. 
     
     
         38 . The adhesive complex coacervate of  claim 35 , wherein the monomer is a diacrylate compound or dimethacrylate compound. 
     
     
         39 . The adhesive complex coacervate of  claim 35 , wherein the monomer is polyethylene glycol diacrylate or polyethylene glycol dimethacrylate. 
     
     
         40 . The adhesive complex coacervate of  claim 35 , wherein the monomer produces a biodegradable interpenetrating network upon polymerization. 
     
     
         41 . The adhesive complex coacervate of  claim 1 , wherein the reinforcing component comprises a filler, and the filler comprises a metal oxide, a ceramic particle, or a water insoluble inorganic salt. 
     
     
         42 . The adhesive complex coacervate of  claim 41 , wherein the filler comprises nanosilica or microsilica. 
     
     
         43 . The adhesive complex coacervate of  claim 41 , wherein the filler comprises a calcium phosphate nano- or microparticle. 
     
     
         44 . The adhesive complex coacervate of  claim 41 , wherein the filler comprises comprises hydroxyapatite or substituted hydroxyapatite, alpha-tricalcium phosphate, beta-tricalcium phosphate, amorphous-tricalcium phosphate, or any combination thereof. 
     
     
         45 . The adhesive complex coacervate of  claim 41 , wherein the filler comprises one or more polymerizable olefinic groups capable of reacting with a crosslinkable group on the polycation, polyanion, and/or the polymerizable olefinic monomer. 
     
     
         46 . The adhesive complex coacervate of  claim 41 , wherein the filler comprises one or more nucleophilic groups capable of reacting with a crosslinkable group on the polycation and/or polyanion, and, when present, the polymerizable monomer. 
     
     
         47 . The adhesive complex coacervate of  claim 1 , wherein the reinforcing component comprises a nanostructure. 
     
     
         48 . The adhesive complex coacervate of  claim 1 , wherein the reinforcing component comprises a micelle or liposome. 
     
     
         49 . The adhesive complex coacervate of  claim 1 , wherein the coacervate further comprises an initiator and optionally a co-initiator. 
     
     
         50 . The adhesive complex coacervate of  claim 49 , wherein the initiator and optionally a co-initiator are covalently attached to the polycation and/or polyanion. 
     
     
         51 . The adhesive complex coacervate of  claim 49 , wherein the initiator comprises a photoinitiator, wherein the photoinitiator comprises a water-soluble initiator comprising riboflavin, eosin, eosin y, or rose Bengal. 
     
     
         52 . The adhesive complex coacervate of  claim 1 , wherein the coacervate further comprises at least one multivalent cation. 
     
     
         53 . The adhesive complex coacervate of  claim 52 , wherein the multivalent cation comprises one or more transition metal ions or rare earth metals. 
     
     
         54 . The adhesive complex coacervate of  claim 52 , wherein the multivalent cation comprises one or more divalent cations. 
     
     
         55 . The adhesive complex coacervate of  claim 52 , wherein the multivalent cation comprises Ca +2  and Mg +2 . 
     
     
         56 . The adhesive complex coacervate of  claim 1 , wherein the coacervate further comprises one or more bioactive agents encapsulated in the coacervate. 
     
     
         57 . The adhesive complex coacervate of  claim 56 , wherein the bioactive agent comprises an antibiotic, a pain reliever, an immune modulator, a growth factor, or any combination thereof. 
     
     
         58 . A cured adhesive complex coacervate produced by the process comprising curing the adhesive complex coacervate of  claim 1 . 
     
     
         59 . A cured adhesive complex coacervate produced by the process comprising
 (a) providing an adhesive complex coacervate comprising (1) at least one polycation, (2) at least one polyanion, and (3) a polymerizable monomer; and   (b) curing the adhesive complex coacervate to polymerize the polymerizable monomer and produce an interpenetrating network.   
     
     
         60 . The cured adhesive complex coacervate of  claim 59 , further comprising crosslinking the polycation and polyanion, wherein crosslinking step can be performed prior to step (b), after step (b), or simultaneously with step (b). 
     
     
         61 . The cured adhesive complex coacervate of  claim 60 , wherein the coacervate is contacted with an oxidant in order to facilitate the crosslinking between the polycation and polyanion. 
     
     
         62 . The cured adhesive complex coacervate of  claim 61 , wherein the oxidant comprises O 2 , NaIO 4 , a peroxide, a transition metal oxidant, or a stabilized oxidant. 
     
     
         63 . The cured adhesive complex coacervate of  claim 59 , wherein the polymerizable monomer is polymerized by exposing the monomer to light in the presence of a photoinitiator and optionally a co-initiator. 
     
     
         64 . The cured adhesive complex coacervate of  claim 59 , wherein the polymerizable monomer is polymerized with the initiator ammonium persulfate and the coinitiator N,N, N′,N′-tetramethylethylenediamine. 
     
     
         65 . The cured adhesive complex coacervate of  claim 59 , wherein the polycation and/or polyanion are covalently attached to the interpenetrating network after step (b). 
     
     
         66 . The cured adhesive complex coacervate of  claim 59 , wherein the coacervate further comprises a filler, wherein the filler is electrostatically bonded to the polycation, polyanion, interpenetrating network, or any combination thereof. 
     
     
         67 . The cured adhesive complex coacervate of  claim 59 , wherein the coacervate further comprises a filler, wherein the filler is covalently bonded to the polycation, polyanion, interpenetrating network, or any combination thereof after step (b). 
     
     
         68 . A kit comprising (1) a polycation, (2) a polyanion, (3) a reinforcing component, and (4) an initiator and optionally a co-initiator. 
     
     
         69 . A kit comprising (1) a mixture of polycation and a polyanion, (2) a reinforcing component, and (3) an initiator and optionally a co-initiator. 
     
     
         70 . A kit comprising (1) a dry polycation, (2) a dry polyanion, (3) a polymerizable monomer, and wherein a polymerization initiator and optional coinitiator are covalently attached to the polycation and/or polyanion. 
     
     
         71 . The kit of  claim 68 , wherein the polycation and polyanion are dry powders. 
     
     
         72 . The kit of  claim 68 , wherein the reinforcing component comprises a polymerizable monomer and a water-insoluble filler. 
     
     
         73 . The kit of  claim 70 , wherein the kit further comprises a water-insoluble filler. 
     
     
         74 . The kit of  claim 68 , wherein the kit further comprises an oxidant. 
     
     
         75 . A method for repairing a bone fracture in a subject, comprising (1) contacting the fractured bone with the adhesive complex coacervate of  claims 1  and (2) curing the adhesive complex coacervate. 
     
     
         76 . A method for adhering a substrate to a bone of a subject comprising (1) contacting the bone with the adhesive complex coacervate of  claim 1 ; (2) applying the substrate to the coated bone; and (3) curing the adhesive complex coacervate. 
     
     
         77 . A method for adhering a bone-tissue scaffold to a bone of a subject comprising (1) contacting the bone and tissue with the adhesive complex coacervate of  claim 1 ; (2) applying the bone-tissue scaffold to the bone and tissue; and (3) curing the adhesive complex coacervate. 
     
     
         78 . A method to bond a soft tissue scaffold to soft tissue or two soft tissue scaffolds or two soft tissues comprising (1) applying the adhesive complex coacervate of  claim 1  to the tissue scaffold and/or soft tissue; and (2) curing the adhesive complex coacervate. 
     
     
         79 . A method for treating an ocular wound comprising (1) applying to the wound the adhesive complex coacervate of  claims 1 ; and (2) curing the adhesive complex coacervate. 
     
     
         80 . The method of  claim 79 , wherein the wound comprises a corneal laceration, a schleral laceration, a surgical incision, a wound from glaucoma surgery, or a corneal transplant. 
     
     
         81 . The use of the adhesive complex coacervate of  claim 1  to seal the junction between skin and an inserted medical device. 
     
     
         82 . A method of closing or sealing a puncture in internal tissue or membrane comprising (1) adhering a patch to the puncture with the adhesive complex coacervate of  claims 1 ; and (2) curing the adhesive complex coacervate. 
     
     
         83 . A method for delivering one or more bioactive agents to a subject comprising administering the adhesive complex coacervate of  claim 1  to the subject, wherein the bioactive agent is encapsulated in the adhesive complex coacervate. 
     
     
         84 . The method of  claim 83 , wherein the bioactive agent comprises antibiotics, pain relievers, immune modulators, growth factors, enzyme inhibitors, hormones, mediators, messenger molecules, cell signaling molecules, receptor agonists, receptor antagonists, nucleic acids, bone morphogenetic proteins (BMPs), prostaglandins, or any combination thereof. 
     
     
         85 . A method for delivering one or more bioactive agents to a subject comprising administering the cured adhesive complex coacervate of  claim 58  to the subject, wherein the bioactive agent is encapsulated in the cured adhesive complex coacervate. 
     
     
         86 . A method for inhibiting blood flow in a blood vessel of a subject comprising (1) introducing the adhesive complex coacervate of  claim 1  into the vessel; and (2) curing the adhesive complex coacervate.