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

基本信息

批准号：
10614475
负责人：
Justine Chia Lee
金额：
$ 36.95万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614475
关键词：
Autologous Biocompatible Materials Biomechanics Blood Vessels Bone Regeneration Calcium Calcium Channel Calvaria Cells Cephalic Cerebrum Childhood Clinical Collagen Complement Consumption Data Defect Development Devices Dimensions Equilibrium Extracellular Matrix Glycosaminoglycans Goals Growth Factor Human Infection Inflammation Investigation Ions Knowledge Malignant Neoplasms Mechanics Mediating Mediator 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 Induction Signal Pathway Signal Transduction Site Skeleton Stroke Supplementation Techniques Testing Time Tissues Trauma United States Food and Drug Administration Vascularization Vocation Work biomechanical model bone bone healing bone morphogenetic protein receptors clinical material clinical translation clinically relevant congenital anomaly cost cranium cranium plastic repair dosage healing implantation in vivo inorganic phosphate mineralization nanocomposite nanoparticulate osteogenic preclinical evaluation preclinical safety psychologic reconstruction regenerative regenerative approach regenerative therapy sample fixation scaffold side effect social sodium phosphate stem cell expansion stem cells symporter technology development voltage

项目摘要

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.

项目摘要/摘要颅骨骨骼的缺陷经常出现在创伤，中风，癌症和先天异常中，导致重要的神经，心理，社会和职业负担。当前临床选择的局限性用于颅骨缺陷重建，例如自体骨的组织可用性和供体部位发病率同种塑料材料中的挤出，感染和成本，为开发特定的方法提供了动力靶性颅骨再生。尽管进行了数十年的研究，当代的再生策略由脚手架材料传递的膨胀干细胞和生长因子鸡尾酒组成的尚未获得了手术不切实际，成本，时间消耗和生长因子上刻度生理学剂量的不良影响。随着对细胞外基质的启发性能力，我们先前证明了细胞外的功效由基质启发的材料组成的材料由纳米式矿化胶原蛋白糖胺聚糖（MC-GAG）组成没有体内祖细胞膨胀或外源生长因子的大规模颅骨缺陷的再生补充。我们进一步表明，MC-GAG的机械基础诱导成骨分化是由于骨形态发生蛋白受体（BMPR）信号通路的自体激活。我们以前的工作将MC-GAG的概念确立为仅材料再生策略。然而，三个问题需要进一步调查。首先，诱导MC-GAG的特性是什么成骨，可以改进吗？其次，使用MC-是否有任何不良副作用插科打诨？第三，因为脑部保护至关重要，而再生则没有在愈合完成之前的保护，MC-GAG会证明与一个相同的再生复合材料，具有临床上可用的可吸收材料以用于脑保护？在AIM 1中，我们将确定 MC-GAG介导的钙和磷酸盐诱导的信号传导和机械刚度的贡献人间充质干细胞中的成骨。我们假设钙和磷酸离子信号传导可能是MC-GAG上成骨分化的主要触发因素，桥接了材料，自体BMPR信号传导，基质矿化和骨愈合。在AIM 2中，我们将评估用聚-D，L-乳酸（PDLLA）网格的MC-GAG复合材料，这是一种临床可吸收的颅骨成形术材料，在生物力学特性，血管，炎症，骨骼中的兔校友缺陷模型中治愈，以及本地和系统的安全。我们假设MC-GAG/PDLLA复合材料会导致骨骼再生相当于单独使用MC-GAG，并在再生过程中添加大脑保护的维度。我们提出的研究是统一的，以钙化再生技术开发的目标。电流提案将使我们能够理解MC-GAG和祖细胞之间的机械相互作用，以进一步完善材料并生成临床前的安全性和性能数据，以将IDE应用于FDA。