Covalent Binding of Protamine by Glutaraldehyde to Bioprosthetic Tissue: Characterization and Anticalcification Effect

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Abstract
Calcification is the principal cause of the clinical failure of bioprosthetic heart valves (BHV). The hypothesis of this work was that an impaired balance between positively and negatively charged amino acids, due to the reaction with Lys and Hyl tissue-collagen residues, expose affinity sites to Ca++. We further hypothesized that regardless of the cause(s) of BHV calcification, positive charge modification of the tissue will prevent their propensity to calcify. Modification of BHV tissue was obtained by covalently binding protamine sulfate, a polybasic peptide, via glutaraldehyde. The modification procedure resulted in stable, covalent links of approximately 5.3% w/w protamine with undiminished anticalcification properties, even after long storage. Significant prevention of calcification was exhibited by the p-bound tissue in comparison to BHV tissue, 66.0 and 106.5 micrograms/mg calcium, respectively, after 30 days of subdermal implants in rats. The results support our hypotheses, and orthotopical heart valve replacements are required in order to completely evaluate the treatment efficacy and biocompatibility.