Mineralized collagen composite to accelerate craniofacial bone regeneration

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ABSTRACT Defects in craniofacial bones of the skull occur congenitally, after high-energy impacts, and during the course of treatment for stroke and cancer. Autologous bone or alloplastic implants are the current gold-standards for surgical reconstruction. However, limited quantities and time-intensive intraoperative fitting of autologous bone, the non-regenerative nature of alloplastic implants, and surgical challenges that stem from irregular defect margins and the quality of the surrounding bone all contribute to poor healing and high complication rates. A biomaterial that could be shaped precisely and quickly like an alloplastic implant but that works in a regenerative fashion like autologous bone would be transformative for craniofacial reconstruction. The objective of this proposal is to potentiate regeneration of the structure, composition, and mechanical properties of craniofacial bone using an innovative scaffold-mesh composite biomaterial. We have generated extensive proof-of-principle data for a surgically-practical composite biomaterial for craniofacial bone regeneration. Our core technology is a porous mineralized collagen scaffold to expand MSCs in vivo. We have identified microstructural features of this material to activate mechanotransduction and BMP receptor signaling to accelerate MSC osteogenicity and secretion of osteoprotegerin (OPG), a soluble glycoprotein and endogenous inhibitor of osteoclast activity. As a result, this material increases osteogenicity and transiently inhibits osteoclast activity to accelerate regenerative healing of craniofacial bone defects osteogenic supplements or exogenously-seeded stem cells. We have independently developed a millimeter-scale polymeric mesh that can be integrated into the scaffold, à la rebar in concrete, to form a modular composite that can be shaped intraoperatively to conformally fit irregular defects. Excitingly, prototype scaffold-mesh composites generated using a mesh printed from an advanced Hyperelastic Bone® material increases MSC OPG secretion. These findings suggest the exciting possibility to co-optimize scaffold microstructural properties as well as the composition and architecture of the integrated polymer mesh to both passively aid surgical-practicality and actively accelerate regenerative healing. Our central hypothesis is that a multi-scale scaffold-mesh composite will accelerate MSC recruitment and retention, increase osteogenesis while inhibiting osteoclast activity, and facilitate vascular remodeling to improve regeneration. To do this we will first define the contribution of scaffold anisotropy on the recruitment and activity of osteoprogenitors and endothelial cells (Aim 1). We will establish topology parameters of a scalable mesh to aid surgical practicality and regenerative potential (Aim 2). Lastly, we will demonstrate in vivo efficacy of a scaffold-mesh composite in a confined calvarial defect model (Aim 3). Our unified effort to develop craniofacial regenerative technologies will generate significant preclinical data to support an FDA IDE application essential for accelerating this technology towards clinical use as a material-only regenerative therapy for craniofacial bone injuries.