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: 10584600
• 负责人: KRISTI S. ANSETH
• 金额: $ 53.4万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584600
• 关键词: Address; Attention; Biocompatible Materials; Bone Marrow; Bone Regeneration; Calvaria; Cell Communication; Cell Count; Cell Separation; Cells; Chemistry; Clinical; Clinical Trials; Coculture Techniques; 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; Gel; Goals; Histologic; Homeostasis; Hour; Human; Hydrogels; Image; Implant; In Situ; In Vitro; Inflammatory; Inflammatory Response; Injections; Luciferases; Macrophage; Measures; Mechanics; Mesenchymal Stem Cells; Methods; Modeling; Monitor; Musculoskeletal; Operative Surgical Procedures; Osteogenesis; Osteoporosis; Osteoporotic; Outcome; Ovariectomy; Patients; Peptides; Phenotype; Play; Porosity; Process; Proliferating; 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; bone; bone healing; bone quality; cell motility; clinically relevant; congenital anomaly; craniofacial; craniofacial bone; craniofacial complex; craniofacial repair; cytokine; economic impact; healing; improved; in vivo; in vivo evaluation; in vivo imaging system; in vivo regeneration; innovation; 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 population; 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.

项目总结 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。那就是骨头 创伤或疾病通常需要手术修复，但5%-10%的骨折无法愈合，失败率可能 当患者的骨骼质量受损(例如，骨质疏松)时，这一比例甚至更高。在这些情况下，基于干细胞的疗法 作为一种促进复杂颅面缺损愈合的方法，已受到越来越多的关注。建议数 研究集中在间充质干细胞(MSC)疗法上，因为它们在临床试验中广泛使用，以及 骨髓间充质干细胞在肌肉骨骼组织动态平衡和骨质疏松症的病理生理学中的重要作用。但是，在 骨髓间充质干细胞体外扩增到治疗相关的数量会降低其再生能力，然后直接 单独注射间充质干细胞往往会导致低存活率。拟议的研究解决了这一重要的临床问题。 通过一种创新的基于材料的策略，即合成和组装用于MSC的可调微凝胶支架 扩展和交付。通过使用高效的“点击”化学方法和开发光响应材料，我们假设 这种支架可以调整为：i)在体外扩增过程中延长MSCs的自我更新和再生能力 和ii)促进移植的间充质干细胞的存活和再生功能，这将促进健康和 骨质疏松的骨头。具体地说，我们提出：目标1.建立MSC扩增和量化的水凝胶培养体系 机械线索和传代历史对骨髓间充质干细胞增殖、多能性、分泌特性和 表观遗传景观；目标2.将水凝胶材料加工成模块化微凝胶单元，用于MSC输送并定制其 促进MSC存活、保留和再生能力的特性；以及目标3.测试MSC扩增的影响 体内MSC存活和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 将通过为扩展和特定地点提供强大的新平台，对公众健康产生重要影响 骨髓间充质干细胞的交付。考虑到该方法的多功能性，可以应用于许多细胞递送系统，结果 将具有更广泛的影响，可以延伸到骨骼再生之外。

项目成果

Photo-click living strategy for controlled, reversible exchange of biochemical ligands.

• DOI: 10.1002/adma.201304847
• 发表时间: 2014-04-23
• 期刊: Advanced materials (Deerfield Beach, Fla.)
• 作者: Gandavarapu NR;Azagarsamy MA;Anseth KS
• 通讯作者: Anseth KS

Covalently tethered transforming growth factor beta in PEG hydrogels promotes chondrogenic differentiation of encapsulated human mesenchymal stem cells.

• DOI: 10.1007/s13346-012-0090-2
• 发表时间: 2012-10
• 期刊: DRUG DELIVERY AND TRANSLATIONAL RESEARCH
• 影响因子: 5.4
• 作者: McCall, Joshua D.;Luoma, Jacob E.;Anseth, Kristi S.
• 通讯作者: Anseth, Kristi S.

Hydrogels with Reversible Mechanics to Probe Dynamic Cell Microenvironments.

• DOI: 10.1002/anie.201705684
• 发表时间: 2017-09-25
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Rosales AM;Vega SL;DelRio FW;Burdick JA;Anseth KS
• 通讯作者: Anseth KS

Extracellular matrix protein adsorption to phosphate-functionalized gels from serum promotes osteogenic differentiation of human mesenchymal stem cells.

• DOI: 10.1016/j.actbio.2012.09.007
• 发表时间: 2013-01
• 期刊: ACTA BIOMATERIALIA
• 影响因子: 9.7
• 作者: Gandavarapu, Navakanth R.;Mariner, Peter D.;Schwartz, Michael P.;Anseth, Kristi S.
• 通讯作者: Anseth, Kristi S.

Affinity peptides protect transforming growth factor beta during encapsulation in poly(ethylene glycol) hydrogels.

• DOI: 10.1021/bm101379v
• 发表时间: 2011-04-11
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: McCall JD;Lin CC;Anseth KS
• 通讯作者: Anseth KS