Enzymatic Degradation and Drug Release Behavior of Dense Collagen Implants

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.