In Vivo Remodeling of Settable, Cell-Degradable, and Application-Specific Poly(thioketal urethane) Tissue Engineering Composite Bone Grafts with Bone-Like Strength

Abstract

Bone grafts are scaffold constructs required for the treatment of bone diseases and fracture when a defect is above a critical size to heal naturally. Bone tissue engineering approaches aim to recapitulate the physical, chemical, and mechanical properties of the host tissue in a bone graft that resorbs at a rate that complements osteogenesis. The Guelcher Lab has previously demonstrated lysine-based polyurethane bone grafts promote osteogenesis and support remodeling in vivo. However, these undergo autocatalytic hydrolytic degradation in which acidic breakdown products accelerate resorption and the degradation rate in vivo is unpredictable. The central goal of this dissertation was to develop a lysine-based poly(thioketal urethane) (PTKUR) that degrades in the presence of reactive oxygen species produced by the cells involved in bone healing. A novel, low molecular weight thioketal diol was used to synthesize a PTKUR that degraded selectively in oxidative conditions. PTKUR/ceramic composites were moldable by hand and set to strengths exceeding those of trabecular bone in situ within clinically relevant working times. Histological evidence of osteoclast-mediated resorption of the composites was observed at 6 and 12 weeks in a rabbit femoral condyle plug defect. By modifying the formulation and fabrication procedures of the PTKUR, up to 70 wt% autograft (AG) was incorporated for a compression resistant PTKUR autograft extender that expands the utility of the gold standard. The PTKUR AG extender supported cellular infiltration and remodeling in two rigorous in vivo models and the extender maintained implanted AG in the defect up to 12 weeks post-implantation. Finally, the addition of a nanocrystalline hydroxyapatite (nHA) to the PTKUR microstructure was hypothesized to allow for the addition of porosity without sacrificing material mechanics. Sucrose leaching induced porosity to accelerate cellular infiltration and peripheral remodeling. nHA-PTKUR hybrid polymers degraded selectively in oxidative environments and demonstrated mechanical properties exceeding those of trabecular bone after leaching up to 45 wt% sucrose. nHA-PTKUR composites containing a range of sucrose:ceramic filler component ratios were implanted in rabbit femoral condyle plug defects to explore the addition of slowly-degrading, mechanically robust, osteoconductive ceramic particles and porosity on remodeling in vivo. These materials demonstrated a unique combination of endochondral and intramembranous bone formation as early as four months. Together, this work addresses the limitations of currently available synthetic bone grafts from biomaterial, biological, and mechanical perspectives. The conclusions drawn culminate in a cell-degradable biomaterial that balances osteoconductivity and osteoinductivity with biomaterial properties for optimal bone graft remodeling for given implantation site demands.