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

基本信息

批准号：
9884753
负责人：
KRISTI S. ANSETH
金额：
$ 56.08万
依托单位：
UNIVERSITY OF COLORADO
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：
2019-03-05 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884753
关键词：
Address Attention Biocompatible Materials Bone Marrow Bone Regeneration Calvaria Cell Communication Cell Count Cell Survival Cell Therapy 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 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 mechanotransduction microCT osteogenic osteoporotic bone regenerative repaired scaffold self-renewal socioeconomics stem cell proliferation stem cell therapy stem cells

项目摘要

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.

项目概要颅面骨缺损的修复是一个具有重大社会经济影响的重要临床问题。外伤或患病通常需要手术修复，但 5-10% 的骨折无法愈合，失败率可能很高当患者的骨质量受损（例如骨质疏松）时，基于干细胞的疗法会更高。作为改善复杂颅面缺损愈合的方法，受到越来越多的关注。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，而且 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着重要作用。 MSC 体外扩增至治疗相关数量会降低其再生能力，然后直接单独注射间充质干细胞通常会导致低存活率，本研究解决了这一重要的临床问题。通过基于创新材料的策略，即用于 MSC 的可调谐微凝胶支架的合成和组装使用高效的“点击”化学并开发光响应材料，我们陷入了困境。支架可以调整为：i) 延长 MSC 在体外扩增过程中的自我更新和再生能力 ii) 促进所输送的间充质干细胞的存活和再生功能，这将改善健康和具体来说，我们建议：目标 1. 开发用于 MSC 扩增和定量的水凝胶培养系统。机械信号和传递历史对 MSC 增殖、多能性、分泌特性的影响表观遗传景观；目标 2. 将水凝胶材料加工成用于 MSC 输送的模块化微凝胶单元并定制它们促进 MSC 存活、保留和再生潜力的特性；以及目标 3. 测试 MSC 扩增的影响如果成功，该项目将在体内条件和模块化微凝胶递送系统中影响间充质干细胞存活和骨再生。通过为扩展和特定地点提供强大的新平台，将对公共卫生产生重要影响鉴于该方法的多功能性，可应用于多种细胞递送系统，结果将产生更广泛的影响，超越骨再生的范畴。