In vivo Stability of Poly(ethylene glycol)-Collagen Composites

Collagen materials were crosslinked by two different difunctional poly ethylene glycols (PEGs) for a variety of applications. Crosslinking was mediated by carbamation of primary amines on collagen with N-hydroxysuccinimide ester end-groups on the PEG crosslinkers. One crosslinker, disuccinimidyl glutarate PEG (di-SG-PEG), contained internal ester linkages which were capable of hydrolyzing and hence produced degradable networks. The other crosslinker, disuccinimidyl propionate PEG (di-SE-PEG), contained hydrolytically stable internal ether linkages and hence produced a more durable network. In vitro experiments verified that di-SE-PEG networks were more hydrolytically stable. In vivo experiments (rat subcutaneous model) revealed similar degradation rates for both networks indicating that other degradation mechanisms (probably enzymatic) also influence degradation in vivo . Histologic analysis revealed a mild inflammatory response to the implants accompanied by fibroblast ingrowth. A second in vivo study (bovine collagen hypersensitized guinea pigs), examined the immunogenicity of di-SG-PEG crosslinked materials and revealed that the PEG crosslinked implants showed lower antibody titers compared to non PEG-crosslinked controls. Another in vivo study compared the osteoconductive properties of di-SG-PEG crosslinked fibrillar collagen with uncrosslinked fibrillar collagen in a rat parietal defect model. Both of the collagen implant materials displayed elevated levels of new bone formation relative the non implanted sites with the PEG crosslinked implant displaying a slightly higher density of new bone forming cells. In an ophthalmic application, methylated collagen was crosslinked by either di-SG- PEG or di-SE-PEG crosslinkers to form clear lenticules. In de-epithelialized primate corneas, di-SG-PEG and crosslinked implants resorbed within 3 months whereas the di-SE-PEG crosslinked lenticules exhibited enhanced stability.