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Metzmacher, Iris (2005): Enzymatic Degradation and Drug Release Behavior of Dense Collagen Implants. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Dense collagen implants were developed which can be easily manufactured by extrusion at room temperature without the need of organic solvents. The physicochemical properties (matrix surface pattern, apparent matrix density, melting temperatures and swelling behavior) of the collagen materials and matrices were investigated. Furthermore, the diffusion coefficients of water inside the collagen devices (5.76*E-02cm²/h) and of various FITC dextrans in solution (e.g. FITC dextran 70: 2.4*E-03cm²/h) were determined by PFG-NMR and FCS, respectively. The developed collagen devices were used to investigate the enzymatic collagen matrix degradation and the release of higher molecular weight drugs, e.g. proteins. Several processes, i.e. diffusion, swelling and erosion, contribute to the overall release profile from collagen devices. Since it was desired to obtain a delivery system which controls release mainly by erosion, insoluble collagen type I materials were used to enhance the resistance against enzymatic attack. Besides this, collagen was physically or chemically cross-linked in some experiments to further restrict collagen digestion and drug delivery. It was shown that model compounds like BSA or FITC dextran 20, 70 and 150, respectively, could be incorporated and that their delivery could be controlled by the used collagen matrix material, e.g. animal source or cross-linking degree, the matrix dimensions (length or diameter of the extrudates), the molecular weight of the incorporated model compound and the drug load. The in vitro release of FITC dextrans and BSA was investigated and delivery of 80% model drug was in the range between 7h and 5d. Comparsion of the in vitro and the in vivo release (monitored in adult domestic pigs) of BSA was made by ESR. Similar results were obtained and it was shown that the mechanism of release changed from mainly diffusion towards erosion control by increasing the degree of matrix cross-linking. The degradation of insoluble collagen type I by bacterial collagenase was studied in detail to gain further insights into the enzymatic hydrolysis of collagen. In contrast to a simple Michaelis-Menten kinetic, adsorption of collagenase onto the substrate surface plays an important role. Based on the obtained in vitro results a mathematical model was developed to describe drug release from collagen matrices undergoing enzymatic degradation. Equations for the collagen degradation and the drug release were implemented, adsorption and diffusion phenomena were incorporated and a mixture of experimentally determined and fitted parameters was used to feed the model. Good correlation between experimental and simulated data was found. Histological evaluations demonstrated that the developed minirods showed good biocompatibility, with only minor inflammation reactions and normal tissue remodeling. This emphasized the assumption that collagen extrudates could be used in vivo without surgical removal after drug depletion.