PRECLINICAL EVALUATION OF NANOPARTICULATE MINERALIZED COLLAGEN GLYCOSAMINOGLYCAN MATERIALS IN CALVARIAL REGENERATION

纳米颗粒矿化胶原蛋白糖胺聚糖材料在颅骨再生中的临床前评估

• 批准号: 9906198
• 负责人: Justine Chia Lee
• 金额: $ 37.49万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906198
• 关键词: Autologous; Biocompatible Materials; Biomechanics; Bone Regeneration; Calcium Channel; Calvaria; Cells; Cephalic; Cerebrum; Childhood; Clinical; Collagen; Complement; Consumption; Data; Defect; Development; Devices; Dimensions; Equilibrium; Extracellular Matrix; GAG Gene; Glycosaminoglycans; Goals; Growth Factor; Human; Infection; Inflammation; Instruction; Investigation; Ions; Knowledge; Malignant Neoplasms; Mechanics; Mediating; Mediator of activation protein; Mesenchymal Stem Cells; Methods; Minerals; Morbidity - disease rate; Natural regeneration; Neurologic; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Performance; Phosphorylation; Preparation; Process; Property; Receptor Signaling; Research; Safety; Secondary to; Signal Pathway; Signal Transduction; Site; Skeleton; Stroke; Supplementation; Techniques; Testing; Time; Tissues; Trauma; United States Food and Drug Administration; Vascularization; Work; base; biomechanical model; bone; bone healing; bone morphogenetic protein receptors; calcium phosphate; clinical material; clinical translation; clinically relevant; congenital anomaly; cost; cranium; cranium plastic repair; dosage; healing; implantation; in vivo; mineralization; nanoparticulate; osteogenic; preclinical evaluation; preclinical safety; psychologic; reconstruction; regenerative; regenerative therapy; sample fixation; scaffold; side effect; social; sodium phosphate; stem cells; symporter; technology development; vascular inflammation; voltage

PROJECT SUMMARY/ABSTRACT Defects of the cranial skeleton occur frequently in trauma, stroke, cancer, and congenital anomalies resulting in significant neurological, psychological, social, and vocational burdens. The limitations of current clinical options for cranial defect reconstruction, such as tissue availability and donor site morbidity in autologous bone and extrusion, infection, and cost in alloplastic materials, provide an impetus to develop methods that specifically target calvarial bone regeneration. Despite decades of research, contemporary regenerative strategies consisting of expanded stem cells and growth factor cocktails delivered by scaffolding materials have not attained clinical translation secondary to the drawbacks of surgical impracticality, cost, time consumption, and the untoward effects of supraphysiologic dosages of growth factors. With the increasing knowledge of the instructive capabilities of the extracellular matrix, we previously demonstrated the efficacy of an extracellular matrix-inspired material composed of nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) for regeneration of massive calvarial defects without ex vivo progenitor cell expansion or exogenous growth factor supplementation. We further showed that the mechanistic basis for MC-GAG induced osteogenic differentiation was due to an autogenous activation of the bone morphogenetic protein receptor (BMPR) signaling pathway. Our previous work established the concept of MC-GAG as a materials-only regenerative strategy. However, three questions require further investigation. First, what are the properties of MC-GAG that induce osteogenesis and can they be refined? Second, are there any untoward side effects with the usage of MC- GAG? Third, as cerebral protection is paramount in clinically relevant defects and regeneration offers no protection until healing is complete, would MC-GAG demonstrate the same amount of regeneration as a composite with a clinically available resorbable material for cerebral protection? In Aim 1, we will determine the contributions of calcium and phosphate-induced signaling and mechanical stiffness in MC-GAG-mediated osteogenesis in human mesenchymal stem cells. We hypothesize that calcium and phosphate ion signaling may be the primary triggers for osteogenic differentiation on MC-GAG, bridging the connection between the material, autogenous BMPR signaling, matrix mineralization, and bone healing. In Aim 2, we will evaluate a composite of MC-GAG with poly-D,L-lactide (PDLLA) mesh, a clinically available resorbable cranioplasty material, in a rabbit calvarial defect model for biomechanical properties, vascularity, inflammation, bone healing, and local and systemic safety. We hypothesize that MC-GAG/PDLLA composites would result in bone regeneration equivalent to MC-GAG alone and add the dimension of cerebral protection during regeneration. Our proposed studies are unified in the goal of calvarial regenerative technology development. The current proposal will allow us to understand mechanistic interactions between MC-GAG and progenitor cells to further refine the material and to generate preclinical safety and performance data for an IDE application to the FDA.

项目概要/摘要 颅骨缺陷经常发生在外伤、中风、癌症和先天性异常中，导致 严重的神经、心理、社会和职业负担。当前临床选择的局限性 用于颅骨缺损重建，例如自体骨和供体部位的组织可用性和发病率 异体材料的挤压、感染和成本，为开发专门的方法提供了动力 目标颅骨骨再生。尽管经过了数十年的研究，当代的再生策略 由支架材料输送的扩增干细胞和生长因子混合物组成的 由于手术不切实际、成本、时间消耗等缺点而获得临床转化 生长因子的超生理剂量的不良影响。随着人们认识的不断加深 细胞外基质的指导能力，我们之前证明了细胞外基质的功效 由纳米颗粒矿化胶原糖胺聚糖 (MC-GAG) 组成的基质启发材料 无需离体祖细胞扩增或外源生长因子即可再生大量颅骨缺损 补充。我们进一步表明 MC-GAG 诱导成骨分化的机制基础 是由于骨形态发生蛋白受体（BMPR）信号通路的自体激活所致。 我们之前的工作确立了 MC-GAG 作为纯材料再生策略的概念。然而， 三个问题需要进一步调查。首先，MC-GAG 具有哪些特性，可以诱导 成骨作用以及它们可以被细化吗？其次，使用MC-有任何不良副作用吗？ 插科打诨？第三，由于脑保护对于临床相关缺陷至关重要，而再生并不能提供任何帮助。 保护直至愈合完成，MC-GAG 是否会表现出与 与临床可用的可吸收材料复合用于脑保护？在目标 1 中，我们将确定 钙和磷酸盐诱导的信号传导和机械刚度在 MC-GAG 介导中的贡献 人类间充质干细胞的成骨作用。我们假设钙离子和磷酸根离子信号传导 可能是 MC-GAG 成骨分化的主要触发因素，在 材料、自体 BMPR 信号传导、基质矿化和骨愈合。在目标 2 中，我们将评估 MC-GAG 与聚 D,L-丙交酯 (PDLLA) 网片的复合材料，一种临床可用的可吸收颅骨成形术 材料，在兔颅骨缺损模型中用于生物力学特性、血管分布、炎症、骨骼 愈合以及局部和全身的安全性。我们假设 MC-GAG/PDLLA 复合材料会导致骨 再生效果相当于单独的 MC-GAG，并在再生过程中增加了脑保护作用。 我们提出的研究统一于颅骨再生技术发展的目标。目前的 该提案将使我们能够了解 MC-GAG 和祖细胞之间的机制相互作用，以进一步 精炼材料并生成向 FDA 提交 IDE 申请的临床前安全性和性能数据。