Project Summary/Abstract: Biodegradable Matrices for Bone Healing More than 6.5 million orthopaedic procedures require the use of grafts to repair bone defects every year in the US alone. Repair of large bone defects is a challenging problem in reconstructive surgery. Several bone graft options including autografts, allografts, and biodegradable porous scaffolds have been routinely used in the clinics with limited success. For example, tissue ingrowth is limited to the surface in bone tissue engineering scaffolds (BTE) because of poor access to cells and nutrients within scaffolds. The porosity that is necessary to support tissue ingrowth in BTE scaffolds results in sub-optimal mechanical properties of these materials for orthopedic applications. Therefore, there is a need to develop BTE scaffolds which will fulfill the requirements of both porosity necessary for tissue ingrowth and vascularization, and optimal mechanical properties necessary for load bearing. In addition, osteoconductive, osteoinductive, and osteointegrative properties will improve the success of bone graft materials. Our ongoing studies and publications have demonstrated the feasibility of developing mechanically strong non-porous composite scaffolds from materials with differential degradation profiles that result in the progressive formation of interconnected pores within the composite material allowing tissue ingrowth over a period of time (1, 2). Likewise, using spirally structured scaffolds we have shown that geometry can be designed to promote cell proliferation, infiltration, and homogenous mineralized matrix deposition throughout the scaffold architecture (3-6). These mechanically stable initially non-porous scaffolds were able to support bone ingrowth due to evolving porous architecture via matrix degradation in rat calvarial defects and rabbit segmental bone defects without inclusion of growth factors and cells. Based on these findings we hypothesize that by altering scaffold composition and geometry we will be able to create BTE scaffolds with programmable mechanical strength and porous structure to better serve the bone healing requirements at load bearing sites. The research project will have the four following phases: Aim 1: To optimize material composition and geometry to achieve necessary mechanical stability and progressive degradation for load-bearing bone-healing applications. Aim 2: To understand the effect of scaffold degradation on human bone marrow derived mesenchymal stem cell (MSCs) adhesion, infiltration, proliferation, differentiation, and mineralized matrix production. Aim 3: To assess in vivo biocompatibility and dynamic pore formation within the scaffolds. Aim 4: To evaluate the bone healing ability of scaffolds with different geometry and mechanical strength in a critical size segmental defect in the rabbit ulna.