The cross-linking and structure modification of the collagen matrix in the design of cardiovascular prosthesis

Glutaraldehyde cross-linking of native or reconstituted collagen fibrils and tissues rich in collagen significantly reduces biodegradation. Other aldehydes are less efficient than glutaraldehyde in generating chemically, biologically, and thermally stable cross-links. Implants of collagenous materials cross-linked with glutaraldehyde are subject long-term to calcification, biodegradation, and low-grade immune reactions. We have attempted to overcome these problems by enhancing cross-linking through (a) bridging of activated carboxyl groups with diamines and (b) using glutaraldehyde to cross-link the epsilon-NH2 groups in collagen and the unreacted amines introduced by aliphatic dismines. This cross-linking reduces tissue degradation and nearly eliminates humoral antibody induction. Covalent binding of diphosphonates, specifically 3-amino-1-hydroxypopane-1, 1-diphosphonic acid (3-APD), and to a lesser extent chondroitin sulfate to collagen or to the cross-ling-enhanced collagen network reduces its potential for calcification. Platelet aggregation also is reduced by glutaraldehyde cross-linking and nearly eliminated by the covalent binding of chondroitin sulfate to collagen. The cytotoxicity of residual glutaraldehyde can be minimized by chemical neutralization and thorough rough rinsing.