Osteoclast modulatory biomaterials for skull regeneration

用于颅骨再生的破骨细胞调节生物材料

• 批准号: 10220944
• 负责人: Justine Chia Lee
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220944
• 关键词: Affect; Autologous; Biocompatible Materials; Biological; Biomechanics; Bone Regeneration; Bone Transplantation; Calvaria; Cell Communication; Cells; Cephalic; Clinical; Collagen; Consumption; Data; Defect; Development; Extracellular Matrix; GAG Gene; Glycosaminoglycans; Goals; Growth Factor; Human; In Vitro; Infection; Inflammation; Instruction; Knowledge; Malignant Neoplasms; Mediator of activation protein; Methods; Minerals; Morbidity - disease rate; Natural regeneration; Neurologic; Operative Surgical Procedures; Oryctolagus cuniculus; Osteoclasts; Osteogenesis; Performance; Property; Research; Safety; Secondary to; Site; Skeleton; Stroke; Supplementation; System; Time; Tissues; Trauma; Tumor necrosis factor receptor 11b; Vascularization; base; bone; bone healing; clinical material; clinical translation; congenital anomaly; cost; cranium; cranium plastic repair; experimental study; improved; in vivo; inhibitor/antagonist; mineralization; nanoparticulate; osteoclastogenesis; osteogenic; osteoprogenitor cell; paracrine; pre-clinical; preclinical efficacy; psychologic; reconstruction; regenerative; regenerative approach; regenerative therapy; scaffold; social; stem cell growth; stem cells; technology development

PROJECT SUMMARY/ABSTRACT Skull defects occur secondary to trauma, stroke, cancer, and congenital anomalies resulting in significant neurological, psychological, social, and vocational burdens. Current clinical options for cranioplasty, or calvarial reconstruction, are limited by availability and morbidity in autologous bone grafts and complications and cost in alloplastic materials. Such drawbacks provide an opportunity 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 due to surgical impracticality, cost, time consumption, and safety concerns. The increasing knowledge of instructive capabilities of the extracellular matrix (ECM) in cell fate determination has provided an alternative paradigm for regeneration. We demonstrated that an ECM-inspired material composed of nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) regenerates up to 60% the mineralization and biomechanical properties of native calvarium without ex vivo progenitor cell loading or exogenous growth factor supplementation. Simultaneously, MC-GAG inhibits osteoclast activation and resorption without affecting the paracrine osteoinductive properties offered by osteoclasts via direct material to cell interactions as well as indirectly by inducing osteoprogenitors to secrete osteoprotegerin (OPG), an endogenous inhibitor for osteoclast activation. With the addition of exogenous OPG, this uncoupling of osteogenesis from osteoclastogenesis is augmented. In combination, these data provided a proof of principle that a composite material of MC-GAG and OPG (MCGO) delivered in a temporospatially-limited manner may be a potential material for calvarial regeneration. In order to develop the MCGO material for clinical translation, three questions must be answered: 1. What are the mechanisms activated in osteoclasts by direct interactions with MC-GAG? 2. As the resorptive abilities of osteoclasts are necessary for remodeling and maturation of bone, how long should OPG exist in the system? 3. Should OPG be eluted or anchored to the material? To answer these questions, we have developed two MCGO materials via non-covalent and covalent incorporation of OPG resulting in a high concentration, fast release and a low concentration, extended release MCGO material, respectively. In Aim 1, we will elucidate the anti-osteoclastogenic mechanisms induced by MC-GAG and MCGO materials. We hypothesize that MC-GAG and the two MCGO materials will differentially affect hOC activation and resorption. In Aim 2, we will evaluate the two MCGO materials compared to MC-GAG in rabbit calvarial regeneration to generate preclinical efficacy, safety, and performance data for MCGO materials compared to MC-GAG. Our proposed studies are unified in the goal of calvarial regenerative technology development. At the conclusion of the proposed studies, we expect to have amassed significant preclinical data to support an IDE application for MCGO materials to the FDA.

项目摘要/摘要 颅骨缺陷是继发于创伤，中风，癌症和先天异常的继发性，导致显着 神经，心理，社会和职业负担。当前的颅骨成形术或钙颅骨术的临床选择 重建，受自体骨移植物的可用性和发病率的限制，并发症和成本 同种塑料材料。此类缺点为开发专门针对的方法提供了机会 颅骨再生。尽管进行了数十年的研究，但当代的再生策略包括 脚手架材料提供的扩大干细胞和生长因子鸡尾酒尚未获得临床 由于手术不切实际，成本，时间消耗和安全问题而引起的翻译。增加 细胞命运确定中细胞外基质（ECM）的指导能力的了解已提供了 再生的替代范式。我们证明了由ECM启发的材料由 纳米式矿化胶原蛋白糖胺聚糖（MC-GAG）可再生高达60％的矿化 没有体内祖细胞载荷或外源生长的天然钙的生物力学特性 补充因子。同时，MC-GAG抑制破骨细胞的激活和吸收而不影响 破骨细胞通过直接材料与细胞相互作用以及 间接诱导骨基因生成剂分泌骨蛋白蛋白蛋白蛋白（OPG），一种内源性抑制剂 破骨细胞激活。通过添加外源性OPG，这种对成骨的解偶联 破骨细胞生成被增强。结合起来，这些数据提供了合成的原理证明 以暂时限制的方式传递的MC-GAG和OPG（MCGO）的材料可能是一种潜力 钙化再生的材料。为了开发用于临床翻译的MCGO材料，三个 必须回答问题：1。通过直接互动与破骨细胞中激活的机制是什么 MC-GAG？ 2。由于破骨细胞的吸收能力对于骨骼的重塑和成熟是必要的 系统中应该存在多长时间的OPG？ 3。应该将OPG洗脱或锚定在材料上吗？回答 这些问题，我们通过OPG的非共价和共价结合开发了两种MCGO材料 导致高浓度，快速释放和低浓度，扩展释放MCGO材料， 分别。在AIM 1中，我们将阐明由MC-GAG和 MCGO材料。我们假设MC-GAG和两种MCGO材料会差异地影响HOC 激活和吸收。在AIM 2中，我们将评估两种MCGO材料与兔子中的MC-GAG相比 MCGO材料的钙典礼再生以产生临床前功效，安全性和性能数据 与MC-GAG相比。我们提出的研究是统一的，以钙化再生技术的目标 发展。在拟议的研究结束时，我们预计会积累重要的临床前 数据支持MCGO材料向FDA的IDE应用程序。