ABSTRACT Our research goal is the development of a bioactive, ?self-fitting? shape memory polymer (SMP) scaffold to repair confined cranial defects by associated bone marrow-derived mesenchymal stem cells (BMSCs). Autografts are associated with lengthy harvesting procedures, donor site morbidity as well as difficulties in shaping and positioning the graft into the defect. Tissue engineering is a promising alternative but requires a currently unmet need - a biomaterial scaffold which simultaneously provides: (1) the ability to conformally fit into an irregular defect to enhance osseointegration, (2) bioactivity, (3) osteoinductivity and (4) highly interconnected pores and controlled biodegradability necessary for cell migration, nutrient diffusion and neotissue accumulation while avoiding brittle mechanical properties. The significance and innovation of this approach is a new ?self-fitting?, polydopamine-coated SMP scaffold design that achieves all of these properties. Developed by the PI, the proposed hybrid SMP scaffolds are comprised of an organic segment [poly(?-caprolactone), PCL] and an inorganic silicon-containing segment [polydimethylsiloxane, PDMS or poly(silyl ether), PSE]. The scaffold design meets key functional requirements: (1) Osseo- integration: The SMP scaffold will be ?self-fitting? as a result of its shape memory behavior, enabling conformal fitting into an irregular defect by brief exposure to warm saline and locking of the new temporary shape upon cooling to body temperature. (2) Bioactivity and (3) Osteoinductivity: A nanothick, bioactive polydopamine coating will be applied to the SMP scaffold pore surfaces to support progenitor cell osteogenesis as well the formation of hydroxyapatite necessary for osseointegration. (4) Interconnected Pores, Controlled Biodegradability, and Robust Mechanical Properties: The SMP scaffold fabrication strategy enables high porosities and pore interconnectivity while avoiding brittle mechanical behavior. The rate of scaffold biodegradation will be controlled by inorganic segment type (i.e. PDMS or PSE) and molecular weight (Mn) (i.e. crosslink density). The healing potential of SMP scaffolds will be evaluated in a critical size-rat calvarial model using histological testing, micro-CT and biomechanical testing. The team is comprised of experts in all key areas of the proposed work. Prof. Melissa Grunlan (PI) will lead efforts to prepare polydopamine-coated SMP scaffolds and uncoated controls (Aims 1-3). Prof. Mariah Hahn (Co-I) will lead in vitro tissue engineering studies with rat- and human-BMSCs incorporated into the scaffolds (Aim 2). Prof. Brian Saunders (Co-I) will implant cell-laden scaffolds into rat calvarial defects (Aim 3). Prof. Michael Moreno will lead efforts to study biomechanical properties of scaffolds, native tissues and bone-graft constructs (Aims 1-3). Healing will be evaluated by histology/immunohistochemistry (Prof. Roy Pool and Saunders, Co-Is), micro-CT (Saunders) and biomechanical tests (Moreno). Input will be provided by two craniofacial plastic surgeons, Drs. Raymond Harshbarger and Kevin Hopkins (consultants).