Design of Osteoinductive Bone Substitutes for Skeletal Site-Specific Healing

Abstract

Over 1.6 million bone grafting procedures are performed annually in the United States as a result of underlying illness or trauma. Bone grafts are required when a defect is critical sized or is unable to spontaneously heal on its own. Osteoinductive bone grafts and substitutes are used to enhance bone formation through the recruitment and differentiation of mesenchymal stem cells down an osteogenic pathway. In this work, osteoinductive polyurethane composites were evaluated in vitro and in vivo to evaluate the mechanisms of cellular differentiation, bone formation, and remodeling. Poly (thioketal urethane) (PTKUR) and poly (ester urethane) (PEUR) autograft extenders were evaluated in a rabbit radius model. PTKUR extenders were slower to degrade than PEUR extenders, but comparable bone formation was observed within both groups. However, reduced osteoinductivity of polymer-embedded autograft was observed thus prompting the transition to an alternative osteoinductive component. Nanocrystalline hydroxyapatite (nHA) was selected due to its ability to be homogenously dispersed within polymer and extensive research demonstrating its osteoinductivity. In vitro studies demonstrated that polymer dispersed nHA promoted mineralization and subsequent osteoblast differentiation in a dose-dependent manner through phosphate transporter-1 and downstream p42/44 MAPK signaling. In vivo results showed that nHA-PTKUR scaffolds promoted both intramembranous and endochondral ossification dependent on material formulation and anatomic sites. The results of these studies demonstrated how material formulation altered cellular behavior, osteogenesis, and bone and graft remodeling. Moving forward, more tailored approaches for bone regeneration based on natural healing response for specific skeletal sites and applications must be adopted in the graft design process.