Collagen macromolecular drug delivery systems

Controlled release systems have been successfully applied for the delivery of low molecular weight compounds. The application of these systems to high molecular weight compounds has been more difficult due to their molecular size and the problems associated with diffusion of macromolecules through membranes. The objective of this dissertation was to examine collagen for use as a macromolecular drug delivery system by determining the mechanism of release through a matrix. Collagen membranes varying in porosity, crosslinking density, structure and crosslinker were fabricated. Collagen characterized by infrared spectroscopy and solution viscosity was determined to be pure and native. The collagen membranes were determined to possess native vs. non-native quaternary structure and porous vs. dense aggregate membranes by electron microscopy. Permeation studies determined that the proteins diffused by a pore mechanism, a consequence of the linear relationship between diffusion coefficients and the protein radius or membrane hydration. The diffusion coefficients were higher for membranes with porous fibril structure, low crosslinking density, membranes crosslinked with a hydrophilic crosslinker (polyglycerol polyglycidyl ether) and non-native quaternary structure. Collagen monolithic devices containing a model macromolecule (inulin) were fabricated. In vitro release rates were found to be linear with respect to t1/2 and were affected by crossl inking density, crosslinker and structure. The biodegradation of the collagen matrix was also examined. Proteolytic enzymes did not degrade the collagen devices, whereas, the degradation rate with collagenase was dependent on collagen structure, crosslinker, crosslinking density and enzyme concentration. in vivo biocompatibility, degradation and -inulin release rates were evaluated subcutaneously in rats. Three weeks implantation of the collagen discs did not induce severe cellular responses. Dacron® induced a stronger fibroblast response but fewer inflammatory cells as compared to the collagen discs. No significant degradation of the collagen discs occurred within three weeks, in vivo release of 14C-inulin from collagen monolithic devices was diffusion controlled. This dissertation demonstrated the feasibility of obtaining macromolecular release from collagen matrices. Important parameters regulating the release include porosity, structure, hydrophilicity of crosslinker and crosslinking density. The benefits of using collagen as a controlled release matrix include its biocompatibil ity and in vivo degradation.