Mineralized collagen composite to accelerate craniofacial bone regeneration

摘要 颅骨的颅面骨缺陷是先天性的，在高能量撞击后，以及在撞击过程中， 治疗中风和癌症自体骨或异体骨植入物是目前的黄金标准， 手术重建然而，自体骨的数量有限且术中拟合耗时， 异体移植物的非再生性，以及不规则缺损引起的外科挑战 边缘和周围骨的质量都导致愈合不良和高并发症发生率。一 这种生物材料可以像异体植入物一样精确而快速地成形，但在再生过程中起作用。 像自体骨这样的时尚将是颅面重建的变革。的目的 建议是加强颅面结构，成分和机械性能的再生， 骨使用创新的支架网状复合生物材料。我们已经产生了广泛的原理证明 用于颅面骨再生的外科实用复合生物材料的数据。我们的核心技术 多孔矿化胶原支架体内扩增MSCs。我们已经确定了这种微结构特征， 激活机械传导和BMP受体信号传导以加速MSC成骨性的材料， 骨保护素（OPG）的分泌，一种可溶性糖蛋白和破骨细胞活性的内源性抑制剂。作为 结果，这种材料增加成骨性并短暂抑制破骨细胞活性，以加速再生 颅面骨缺损的愈合，成骨补充剂或外源性接种的干细胞。我们有 独立开发了一种毫米级的聚合物网，可以集成到支架中， 具体地说，形成一个模块化的复合材料，可以在手术中成形，以适应不规则的缺陷。 令人兴奋的是，使用先进的超弹性打印机打印的网格生成的原型支架-网格复合材料 Bone®材料增加MSC OPG分泌。这些发现表明了共同优化 支架微观结构特性以及集成聚合物网片的组成和结构 以既被动地帮助医疗实用性又主动地加速再生愈合。我们的核心假设是 多尺度支架-网状复合物将加速MSC的募集和保留，增加骨生成， 同时抑制破骨细胞活性，促进血管重塑，改善再生。为此，我们将 首先确定支架各向异性对骨祖细胞的募集和活性的贡献， 内皮细胞（Aim 1）。我们将建立一个可扩展的网格拓扑参数，以帮助手术的实用性 和再生潜力（目标2）。最后，我们将证明支架-网状复合物在体内的疗效， 局限性颅骨缺损模型（目标3）。我们共同努力开发颅面再生技术 将产生重要的临床前数据，以支持FDA IDE申请，这对加速这一进程至关重要。 技术走向临床应用，作为颅面骨损伤的纯材料再生治疗。

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.