Mineralized collagen composite to accelerate craniofacial bone regeneration

矿化胶原复合物加速颅面骨再生

• 批准号: 10400873
• 负责人: Brendan A. Harley
• 金额: $ 44.61万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-03 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400873
• 关键词: Address; Affect; Anisotropy; Architecture; Autologous; Biocompatible Materials; Biological Process; Biophysics; Blood Vessels; Bone Injury; Bone Marrow; Bone Regeneration; Calvaria; Clinical; Collagen; Complex; Complication; Congenital Abnormality; Data; Defect; Deposition; Dose; Endothelial Cells; Failure; Family; Glycoproteins; Gold; Histologic; Implant; In Vitro; Malignant Neoplasms; Mechanics; Mesenchymal Stem Cells; Methods; Minerals; Modeling; Natural regeneration; Nature; Operative Surgical Procedures; Oryctolagus cuniculus; Osteoclasts; Osteogenesis; Performance; Phenotype; Polymers; Population; Process; Production; Property; Receptor Signaling; Recruitment Activity; Research; Signal Transduction; Structure; Technology; Time; Tissue Engineering; Trauma; Tumor necrosis factor receptor 11b; Vascular remodeling; Work; bone; bone morphogenetic protein receptors; collagen scaffold; cost; craniofacial; craniofacial bone; cranium; defined contribution; design; healing; improved; in vivo; in vivo regeneration; inhibitor; innovation; mechanical properties; mechanotransduction; millimeter; morphogens; osteogenic; osteoprogenitor cell; pre-clinical; prototype; reconstruction; recruit; regeneration potential; regenerative; regenerative therapy; repaired; sample fixation; scaffold; stem; stem cell expansion; stem cells; stroke therapy

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.

抽象的 颅骨的颅面骨缺陷是先天性的、高能量冲击后以及在生长过程中发生的。 自体骨或异体植入物是目前治疗中风和癌症的黄金标准。 然而，自体骨的手术重建数量有限且耗时。 同种异体植入物的非再生性质以及不规则缺损引起的手术挑战 边缘和周围骨骼的质量都会导致愈合不良和并发症发生率高。 生物材料可以像异体植入物一样精确快速地成型，但可以再生 像自体骨这样的时尚将为颅面重建带来变革。 建议是增强颅面结构、成分和机械性能的再生 我们已经进行了广泛的原理验证。 用于颅面骨再生的手术实用复合生物材料的数据。 用于在体内扩增 MSC 的多孔矿化胶原支架我们已经确定了其微观结构特征。 激活机械转导和 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。 结果，这种材料增加了成骨性并暂时抑制破骨细胞活性以加速再生 修复颅面骨缺损我们有成骨补充剂或外源种子干细胞。 独立开发了毫米级聚合物网，可以集成到脚手架中，就像钢筋一样 在混凝土中，形成模块化复合材料，可以在术中成形以保形地适应不规则缺陷。 令人兴奋的是，使用先进的超弹性材料打印的网格生成了原型支架网格复合材料 Bone® 材料可增加 MSC OPG 分泌。这些发现表明了共同优化的令人兴奋的可能性。 支架微观结构特性以及集成聚合物网的组成和结构 既被动地帮助手术实用性，又主动地加速再生愈合。 多尺度支架网复合材料将加速 MSC 的招募和保留，增加成骨 同时抑制破骨细胞活性，并促进血管重塑以改善再生。 首先定义支架各向异性对骨祖细胞的募集和活性的贡献， 我们将建立可扩展网格的拓扑参数以帮助手术实用性。 最后，我们将证明支架-网状复合材料的体内功效。 有限的颅骨缺损模型（目标 3）。 将生成重要的临床前数据来支持 FDA IDE 应用程序，这对于加速这一过程至关重要 技术作为一种纯材料再生疗法用于临床颅面骨损伤。