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: 10664867
• 负责人: Justine Chia Lee
• 金额: $ 36.97万
• 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/10664867
• 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; Glycosaminoglycans; Goals; Growth Factor; Human; In Vitro; Infection; Inflammation; Knowledge; Malignant Neoplasms; Mediator; Methods; 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; Vocation; bone; bone healing; clinical material; clinical translation; congenital anomaly; cost; cranium; cranium plastic repair; experimental study; fabrication; improved; in vivo; inhibitor; mineralization; nanocomposite; nanoparticulate; osteoclastogenesis; osteogenic; osteoprogenitor cell; paracrine; pre-clinical; preclinical efficacy; psychologic; reconstruction; regenerative; regenerative approach; regenerative therapy; scaffold; social; stem cell expansion; 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.

项目概要/摘要 颅骨缺陷继发于外伤、中风、癌症和先天性异常，导致严重后果 神经、心理、社会和职业负担。当前颅骨成形术或颅骨成形术的临床选择 重建受到自体骨移植的可用性和发病率以及并发症和成本的限制 异质材料。这些缺点为开发专门针对的方法提供了机会 颅骨骨再生。尽管经过了数十年的研究，当代的再生策略包括 通过支架材料输送的扩增干细胞和生长因子混合物尚未达到临床 由于手术不切实际、成本、时间消耗和安全问题而需要翻译。不断增加的 细胞外基质（ECM）在细胞命运决定中的指导能力的知识提供了 再生的替代范例。我们证明了一种受 ECM 启发的材料由 纳米颗粒矿化胶原糖胺聚糖 (MC-GAG) 可再生高达 60% 的矿化 没有离体祖细胞负载或外源生长的天然颅骨的生物力学特性和生物力学特性 因子补充。同时，MC-GAG 抑制破骨细胞活化和吸收，而不影响 破骨细胞通过材料与细胞的直接相互作用提供的旁分泌骨诱导特性以及 间接通过诱导骨祖细胞分泌骨保护素（OPG），一种内源性抑制剂 破骨细胞激活。添加外源性 OPG 后，骨生成与 破骨细胞生成增强。结合起来，这些数据提供了复合材料的原理证明 以时空有限方式传递的 MC-GAG 和 OPG (MCGO) 材料可能是一种潜在的 颅骨再生材料。为了开发用于临床转化的 MCGO 材料，三个 必须回答的问题： 1. 破骨细胞通过与破骨细胞直接相互作用激活的机制是什么？ MC-GAG？ 2. 由于破骨细胞的吸收能力是骨骼重塑和成熟所必需的， OPG 应该在系统中存在多长时间？ 3. OPG 应该洗脱还是固定在材料上？来回答 针对这些问题，我们通过非共价和共价结合 OPG 开发了两种 MCGO 材料 产生高浓度、快速释放和低浓度、缓释的 MCGO 材料， 分别。在目标 1 中，我们将阐明 MC-GAG 诱导的抗破骨细胞生成机制， MCGO 材料。我们假设 MC-GAG 和两种 MCGO 材料会对 hOC 产生不同的影响 激活和吸收。在目标 2 中，我们将在兔子中评估两种 MCGO 材料与 MC-GAG 的比较 颅骨再生生成 MCGO 材料的临床前功效、安全性和性能数据 与 MC-GAG 相比。我们提出的研究统一于颅骨再生技术的目标 发展。在拟议研究结束时，我们预计将积累重要的临床前研究成果 数据支持向 FDA 提交 MCGO 材料的 IDE 申请。

项目成果

Facial Suture Pathology in Syndromic Craniosynostosis: Human and Animal Studies.

颅缝早闭症的面部缝合病理学：人类和动物研究。

• 发表时间: 2021-11-01
• 影响因子: 1.5
• 作者: Wang, Maxwell M;Haveles, Christos S;Zukotynski, Brian K;Reid, Russell R;Lee, Justine C
• 通讯作者: Lee, Justine C

COVID-19 Pandemic Associated With Increased Self-reported Depressive Symptoms in Patients With Congenital Craniofacial Diagnoses.

COVID-19 大流行与先天性颅面诊断患者自我报告的抑郁症状增加相关。

• 发表时间: 2023-08
• 作者: Huang, Kelly X;Oberoi, Michelle K;Caprini, Rachel M;Hu, Vivian J;Malapati, Sri Harshini;Mirzaie, Sarah;Bedar, Meiwand;Patel, Harsh;Lee, Justine C
• 通讯作者: Lee, Justine C

Convergence of Calcium Channel Regulation and Mechanotransduction in Skeletal Regenerative Biomaterial Design.

骨骼再生生物材料设计中钙通道调节和力传导的融合。

• 发表时间: 2023-10
• 影响因子: 10
• 作者: LaGuardia, Jonnby S;Shariati, Kaavian;Bedar, Meiwand;Ren, Xiaoyan;Moghadam, Shahrzad;Huang, Kelly X;Chen, Wei;Kang, Youngnam;Yamaguchi, Dean T;Lee, Justine C
• 通讯作者: Lee, Justine C

Meta-Analysis and Meta-Regression of Complications and Failures of Autologous Heterotopic Cranial Bone versus Alloplastic Cranioplasties.

自体异位颅骨与异体颅骨成形术并发症和失败的荟萃分析和荟萃回归。

• 发表时间: 2023-09-26
• 影响因子: 3.6
• 作者: Oberoi, Michelle K;Mirzaie, Sarah;Huang, Kelly X;Caprini, Rachel M;Hu, Vivian J;Dejam, Dillon;Ge, Shaokui;Cronin, Brendan J;Pfaff, Miles J;Lee, Justine C
• 通讯作者: Lee, Justine C

β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner.

β-连环蛋白以硬度依赖性方式限制再生材料的成骨。

• 发表时间: 2021-12
• 影响因子: 10
• 作者: Zhou, Qi;Ren, Xiaoyan;Oberoi, Michelle K;Bedar, Meiwand;Caprini, Rachel M;Dewey, Marley J;Kolliopoulos, Vasiliki;Yamaguchi, Dean T;Harley, Brendan A C;Lee, Justine C
• 通讯作者: Lee, Justine C