Clickable Microgel Scaffolds for MSC Expansion and Delivery

用于 MSC 扩展和交付的可点击微凝胶支架

• 批准号: 10356090
• 负责人: KRISTI S. ANSETH
• 金额: $ 58.35万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-05 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356090
• 关键词: Address; Attention; Biocompatible Materials; Bone Marrow; Bone Regeneration; Calvaria; Cell Communication; Cell Count; Cells; Chemistry; Clinical; Clinical Trials; Complex; Confocal Microscopy; Craniofacial Abnormalities; Cues; Defect; Disease; Dose; Engineering; Engraftment; Enzyme-Linked Immunosorbent Assay; Epigenetic Process; Exposure to; Failure; Fibroblast Growth Factor; Formulation; Fracture; Functional disorder; Goals; Histologic; Homeostasis; Hour; Human; Hydrogels; Image; Implant; In Situ; In Vitro; Inflammatory; Inflammatory Response; Injections; Lead; Luciferases; Measures; Mechanics; Mesenchymal Stem Cells; Methods; Modeling; Monitor; Musculoskeletal; Operative Surgical Procedures; Osteogenesis; Osteoporosis; Osteoporotic; Outcome; Ovariectomy; Patients; Peptides; Phenotype; Play; Population; Porosity; Process; Property; Public Health; Rattus; Recording of previous events; Regenerative capacity; Research; Role; Signal Transduction; Site; Structure; System; TNF gene; Testing; Therapeutic; Time; Tissues; Transplantation; Traumatic injury; base; bone; bone healing; bone quality; cell motility; clinically relevant; congenital anomaly; craniofacial; craniofacial bone; craniofacial complex; craniofacial repair; cytokine; healing; improved; in vivo; in vivo evaluation; in vivo imaging system; in vivo regeneration; innovation; macrophage; mechanical signal; mechanotransduction; microCT; osteogenic; osteoporotic bone; regeneration function; regeneration potential; regenerative; repaired; reparative capacity; scaffold; self-renewal; socioeconomics; stem cell delivery; stem cell expansion; stem cell proliferation; stem cell survival; stem cell therapy; stem cells

PROJECT SUMMARY Repair of craniofacial bone defects is an important clinical problem with significant socioeconomic impact. Bone that is traumatically injured or diseased often requires surgical repair, but 5-10% of bone fractures fail to heal and failure rates can be even higher when the patient's bone quality is compromised (e.g., osteoporotic). In these cases, stem cell-based therapies have received increasing attention as a method to improve the healing of complex craniofacial defects. The proposed research focuses on mesenchymal stem cell (MSC) therapies because of their extensive use in clinical trials, as well as the major role that MSCs play in musculoskeletal tissue homeostasis and the pathophysiology of osteoporosis. However, in vitro expansion of MSCs to therapeutically relevant numbers reduces their regenerative capacity, and afterwards, direct injection of MSCs alone often leads to low survival. The proposed research addresses this important clinical problem through an innovative materials-based strategy, namely the synthesis and assembly of tunable microgel scaffolds for MSC expansion and delivery. Using efficient “click” chemistries and by developing photoresponsive materials, we hypothesize that scaffolds can be tuned to: i) prolong the self-renewing and regenerative capacity of MSCs during in vitro expansion and ii) promote the survival and regenerative functions of delivered MSCs that will improve healing of both healthy and osteoporotic bone. Specifically, we propose to: Aim 1. Develop a hydrogel culture system for MSC expansion and quantify the effects of mechanical cues and passaging history on MSC proliferation, multipotency, secretory properties, and epigenetic landscape; Aim 2. Process the hydrogel materials into modular microgel units for MSC delivery and tailor their properties to promote MSC survival, retention and regenerative potential; and Aim 3. Test the influence of MSC expansion conditions and modular microgel delivery systems on MSC survival and bone regeneration in vivo. If successful, this project will have an important impact on public health by providing a powerful new platform for the expansion and site specific delivery of MSCs. Given the versatility of the approach, which can be applied to numerous cell delivery systems, the results will have broader implications that can extend beyond bone regeneration.

项目摘要 修复颅面骨缺损是一个重要的临床问题，具有重大的社会经济影响。骨骼 创伤性受伤或疾病经常需要手术修复，但是5-10％的骨折无法治愈，失败率可以 当患者的骨骼质量受到损害（例如骨质疏松质）时，要更高。在这些情况下，基于干细胞的疗法 作为改善复杂颅面缺陷愈合的方法，人们受到了越来越多的关注。提议 研究重点是间充质干细胞（MSC）疗法，因为它们在临床试验中广泛使用，以及 MSC在肌肉骨骼组织稳态和骨质疏松症的病理生理学中发挥的主要作用。但是，在 MSC在治疗相关数字上的体外扩展降低了其再生能力，然后直接直接 仅注射MSC通常会导致生存率较低。拟议的研究解决了这个重要的临床问题 通过基于创新材料的策略，即MSC的可调微凝胶支架的合成和组装 扩展和交付。使用有效的“点击”化学物质并开发光退增长材料，我们假设 可以将脚手架调整为：i）在体外扩张期间延长MSC的自我更新和再生能力 ii）促进交付的MSC的生存和再生功能，这些功能将改善健康和健康的愈合 骨质疏松骨。具体而言，我们建议：目标1。开发用于MSC扩展的水凝胶培养系统并进行量化 机械提示和通过历史对MSC增殖，多统计，秘密特性和 表观遗传景观；目标2。将水凝胶材料处理到模块化微凝胶单元中以进行MSC交付并量身定制 促进MSC生存，保留和再生潜力的特性；和目标3。测试MSC扩展的影响 MSC存活和体内骨再生的条件和模块化微凝胶输送系统。如果成功，这个项目 通过为扩展和特定网站提供强大的新平台，将对公共卫生产生重要影响 交付MSC。考虑到该方法的多功能性，可以应用于众多单元输送系统，结果 将具有更广泛的含义，可以超越骨再生。