Spatiotemporal control of tendon healing through modular, injectable hydrogel composites

通过模块化、可注射水凝胶复合材料对肌腱愈合的时空控制

• 批准号: 10605456
• 负责人: Robert Nathan Kent
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605456
• 关键词: 3-Dimensional; Ablation; Actins; Adult; Affinity; Automobile Driving; Biocompatible Materials; Biological; Cell Differentiation process; Cell Lineage; Cells; Chronic; Cicatrix; Collagen; Connective Tissue; Cues; Data; Deposition; Dextrans; Engineering; Extracellular Matrix; Fiber; Fibrillar Collagen; Fibroblasts; Functional Regeneration; Future; Gel; Goals; Growth Factor; Heparin; Hydrogels; Implant; In Vitro; Infiltration; Injectable; Injury; Integrins; Invaded; Kinetics; Magnetism; Mechanics; Mediating; Methods; Modeling; Mohawk; Mus; Myofibroblast; Natural regeneration; Neonatal; Outcome; Pain; Phase; Population; Process; Production; Proteolysis; Regenerative capacity; Risk; Route; Site; Smooth Muscle; Structure; Surface; System; Technology; Tendon Injuries; Tendon structure; Testing; Therapeutic; Tissues; Work; achilles tendon; cell motility; chemokine; chronic pain; combinatorial; crosslink; decorin; density; design; divinyl sulfone; healing; hydrogel scaffold; improved; injured; mechanical properties; mimetics; morphogens; neonatal injury; neonatal mice; novel; permissiveness; platelet-derived growth factor BB; programs; recruit; regenerative; release factor; repaired; response; response to injury; scaffold; scleraxis; soft tissue; spatiotemporal; stem cells; therapeutic target; tissue regeneration; transcription factor; transforming growth factor beta3; wound; wound healing

PROJECT SUMMARY Biomaterials-based approaches have potential for treating tendon injury, the chronic sequelae of which include pain, diminished function, and heightened risk of reinjury due to aberrant scar formation. Unfortunately, the undefined origin and function of numerous cellular players involved in the tendon injury response have made it difficult to identify biological mechanisms of these poor outcomes. As a result, therapeutic targets for biomaterials-mediated tendon repair approaches have not been established. Recently, it has been shown that neonatal mice fully regenerate completely transected tendons. Key differences in their injury response compared to that of adults suggest that recruitment of progenitor cells and their subsequent tenogenic differentiation can lead to regenerative healing. Thus, the long-term goal of the proposed work is to develop a biomaterial therapy capable of coordinating multiple, distinct phases of tendon healing. Toward this end, we aim to design a synthetic, hydrogel-based composite scaffold that integrates physical (mechanical and topographical) and soluble cues to 1) recruit specific progenitor cell populations to the injury site and 2) direct tenogenic progenitor cell differentiation and de novo matrix synthesis of the appropriate composition and organization following tendon injury. Our central hypothesis is that spatiotemporal presentation of combinatorial microenvironmental cues can control the abundance and identity of reparative cells entering the injury site and promote their differentiation and matrix remodeling activity, both of which will improve the adult tendon healing response. Our preliminary data establishes a material that is permissive to tendon progenitor cell (TPC) migration and tenogenic differentiation; moreover, we have established a tunable soluble factor release system enabling gradual release of chemotactic cues and cell-triggered release of differentiation factors. We have already found that physical and microgel- delivered soluble cues synergistically enhance TPC recruitment into these composite hydrogels. Therefore, in Aim 1, we will optimize microenvironmental cues for driving robust tenogenic differentiation in vitro. In Aim 2, this dextran vinyl sulfone-based material system will be tested in a murine Achilles tendon injury model to study the effects of these cues on recruitment of TPCs to the wound site, subsequent tenogenesis, and matrix deposition/organization. The extent of tenogenic differentiation will be quantified through the expression of a panel of tenogenic factors, deposition of organized de novo matrix supporting tenogenesis, and functional analysis of regenerated tendons. This work will establish a novel, injectable, modular hydrogel scaffold capable of driving a robust tendon healing response in adult mice. Moreover, this work will provide a deeper understanding of the microenvironmental cues regulating tenogenesis, information critical to the advancement of biomaterial therapeutics geared toward connective tissue regeneration.

项目摘要 基于生物材料的方法具有治疗肌腱损伤的潜力，其慢性后遗症包括 疼痛、功能减退和由于异常瘢痕形成而增加的再损伤风险。可惜 许多参与肌腱损伤反应的细胞的起源和功能尚未明确， 很难确定这些不良结果的生物学机制。因此， 生物材料介导的肌腱修复方法尚未建立。最近的研究表明， 新生小鼠完全再生完全横断的肌腱。他们的伤害反应的关键差异比较 提示祖细胞的募集及其随后的肌腱分化可以 导致再生愈合。因此，所提出的工作的长期目标是开发生物材料治疗 能够协调肌腱愈合的多个不同阶段。为此，我们的目标是设计一种合成的， 基于水凝胶的复合支架，其整合了物理（机械和形貌）和可溶性线索， 1)将特定的祖细胞群募集到损伤部位，和2）直接肌腱生成祖细胞分化 以及肌腱损伤后适当组成和组织的从头基质合成。我们的中央 假设是组合微环境线索的时空呈现可以控制 进入损伤部位的修复细胞的丰度和身份，并促进其分化和基质 重塑活动，这两者都将改善成人肌腱愈合反应。我们的初步数据 建立允许肌腱祖细胞（TPC）迁移和肌腱形成分化的材料; 此外，我们还建立了一个可调的可溶性因子释放系统， 提示和细胞触发的分化因子释放。我们已经发现物理和微凝胶- 递送的可溶性提示物协同增强TPC向这些复合水凝胶中的募集。因此在 目的1，我们将优化微环境的线索，在体外驱动强大的tenogenic分化。在Aim 2中， 将在鼠跟腱损伤模型中测试葡聚糖乙烯砜基材料系统，以研究 这些线索对TPC向伤口部位的募集、随后的腱生成和基质的影响 沉积/组织。肌腱分化的程度将通过表达一种 一组腱形成因子，支持腱形成的组织化从头基质沉积，以及功能性 分析再生肌腱。这项工作将建立一种新型的，可注射的，模块化的水凝胶支架， 在成年小鼠中驱动强大的肌腱愈合反应。此外，这项工作将提供一个更深入的 了解微环境的线索调节tenogenesis，信息的进展至关重要 生物材料治疗学的发展方向是结缔组织再生