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 由于异常形成疤痕，疼痛，功能减弱以及重新枪击的风险增加。不幸的是， 参与肌腱损伤反应的众多细胞玩家的不确定的起源和功能使它成为现实 难以识别这些不良结果的生物学机制。结果，治疗目标 尚未确定生物材料介导的肌腱修复方法。最近，已经表明 新生小鼠完全再生完全转换的肌腱。与他们的受伤反应相比 成年人表明，祖细胞及其随后的终结分化可以 导致再生治疗。因此，拟议工作的长期目标是开发生物材料疗法 能够协调肌腱愈合的多个不同的阶段。为此，我们旨在设计一个合成， 基于水凝胶的复合支架，将物理（机械和地形）和可溶性提示整合到 1）招募特定的祖细胞群体到损伤部位和2）直接终止祖细胞分化 和肌腱损伤后适当组成和组织的从头矩阵合成。我们的中心 假设是组合微环境提示的时空表现可以控制 进入伤害部位并促进其分化和矩阵的修复细胞的丰度和身份 重塑活性，两者都将改善成年肌腱愈合反应。我们的初步数据 建立一种允许肌腱祖细胞（TPC）迁移和终止分化的材料； 此外，我们已经建立了一个可调的可溶性因子释放系统，从而逐渐释放了趋化性 线索和细胞触发的分化因子的释放。我们已经发现物理和微凝胶 - 传递的可溶性线索协同增强了TPC募集到这些复合水凝胶中。因此，在 AIM 1，我们将优化微环境线索，以在体外驱动稳健的终止分化。在AIM 2中，这个 葡聚糖乙烯基磺极的材料系统将在鼠腱损伤模型中进行测试，以研究 这些线索对TPC募集到伤口部位的影响，随后的肾脏和矩阵 沉积/组织。通过表达A的表达，将量化延期分化的程度 延期因子的小组，有组织的从头基质的沉积支持肾和功能 再生肌腱的分析。这项工作将建立一个可注射的，可注射的模块化水凝胶支架 在成年小鼠中驱动强大的肌腱愈合反应。此外，这项工作将提供更深的 了解调节肾脏的微环境提示，对进步至关重要的信息 用于结缔组织再生的生物材料疗法。