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: 10451692
• 负责人: Justine Chia Lee
• 金额: $ 36.86万
• 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/10451692
• 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; 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.

项目总结/文摘