Synthesis and Characterization of Cell-Responsive Biodegradable Polyureas for Ligament Tissue Engineering
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The anterior cruciate ligament (ACL) is the most frequently ruptured ligament, accounting for an estimated 200,000 injuries and approximately 100,000 reconstructive surgeries each year in the United States. Due to the poor regenerative potential of the ACL and limitations of current ACL reconstruction techniques, development of a tissue engineered graft could have a significant clinical impact. Despite the robust and versatile properties of synthetic scaffolds, current iterations still have high failure rates due to degradation, wear, or fatigue. Polyurethanes utilizing ester-based soft segments were recently investigated as potential ligament grafts due to their established biocompatibility, excellent mechanical properties, and exceptionally tunable structure. However, non-specific hydrolytic degradation makes it difficult to match tissue regeneration, resulting in premature graft failure or stress shielding of the neotissue. In contrast, a biomaterial that features system-responsive degradation would integrate with native ligament remodeling and thus provide effective load transfer. It is well established that a graded load transfer from the graft to the neotissue during remodeling is necessary for proper organization of connective tissues which is strongly correlated to the resulting mechanical properties. In this study, synthetic routes were first developed to create a linear polyurea elastomer system with appropriate chemistry to readily incorporate a biodegradable peptide diamine. Polyureas were selected due to their tunable segmental chemistry, high elasticity and fatigue strength, and mild reaction conditions that permits incorporation of biological molecules at ambient conditions. Collagen-mimetic soft segments were first created by conjugating an enzyme-labile peptide diamine and commercially available polyether diamines. Candidate prepolymers were then chain extended with hexamethylene diisocyanate and mixed diamines. Particular focus was given to identifying compositions that permitted high molecular weight generation without gelation. By varying soft segment chemistry, soft segment molecular weight, and the hard-to-soft segment ratio, a library of polyureas was developed. This library was then used to elucidate key structure-property relationships necessary to tune mechanical properties and degradation rates of candidate polyureas. Finally, the enzyme-mediated degradation of candidate polyureas with variable peptide concentrations was investigated. In summary, synthesis of a novel biomaterial that combines the strength and tunability of synthetic elastomers with cell-responsive degradation will assist in the development of an improved tissue engineered graft for ACL reconstruction.
