Tendon injuries are difficult to heal, in part, because intrinsic tendon healing, which is dominated by scar tissue formation, does not effectively regenerate the native structure and function of healthy tendon. Further, many current treatment strategies also fall short of producing regenerated tendon with the native properties of healthy tendon. There is increasing interest in the use of cell-instructive strategies to limit the intrinsic fibrotic response following injury and improve the regenerative capacity of tendon in vivo. We have established multifunctional, cell-instructive hydrogels for treating injured tendon that afford tunable control over the biomechanical, biochemical, and structural properties of the cell microenvironment. Specifically, we incorporated integrin-binding domains (RGDS) and assembled multifunctional collagen mimetic peptides that enable cell adhesion and elongation of stem cells within synthetic hydrogels of designed biomechanical properties and evaluated these materials using targeted success criteria developed for testing in mechanically demanding environments such as tendon healing. The in vitro and in situ success criteria were determined based on systematic reviews of the most commonly reported outcome measures of hydrogels for tendon repair and established standards for testing of biomaterials. We then showed, using validation experiments, that multifunctional and synthetic hydrogels meet these criteria. Specifically, these hydrogels have mechanical properties comparable to developing tendon; are noncytotoxic both in two-dimensional bolus exposure (hydrogel components) and three-dimensional encapsulation (full hydrogel); are formed, retained, and visualized within tendon defects over time (2-weeks); and provide mechanical support to tendon defects at the time of in situ gel crosslinking. Ultimately, the in vitro and in situ success criteria evaluated in this study were designed for preclinical research to rigorously test the potential to achieve successful tendon repair before in vivo testing and indicate the promise of multifunctional and synthetic hydrogels for continued translation.

中文翻译：

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用于肌腱再生的多功能水凝胶的成功标准和临床前测试

肌腱损伤难以愈合，部分原因在于以疤痕组织形成为主的内在肌腱愈合不能有效地再生健康肌腱的天然结构和功能。此外，许多当前的治疗策略也未能产生具有健康肌腱的天然特性的再生肌腱。人们越来越关注使用细胞指导策略来限制损伤后的内在纤维化反应并提高体内肌腱的再生能力. 我们已经建立了用于治疗损伤肌腱的多功能、细胞指导性水凝胶，可以对细胞微环境的生物力学、生化和结构特性进行可调控制。具体来说，我们整合了整合素结合域 (RGDS) 并组装了多功能胶原蛋白模拟肽，这些肽使干细胞能够在具有设计生物力学特性的合成水凝胶中进行细胞粘附和伸长，并使用为在机械要求苛刻的环境中进行测试而开发的目标成功标准评估这些材料，例如肌腱愈合。体外和原位_成功标准是根据对最常报告的用于肌腱修复的水凝胶结果测量的系统评价和既定的生物材料测试标准确定的。然后，我们使用验证实验证明多功能和合成水凝胶符合这些标准。具体来说，这些水凝胶具有与发育中的肌腱相当的机械性能；在二维推注（水凝胶成分）和三维封装（全水凝胶）中均无细胞毒性；随着时间的推移（2 周）在肌腱缺损内形成、保留和可视化；并在原位凝胶交联时为肌腱缺陷提供机械支撑。最终，体外和原位本研究中评估的成功标准旨在用于临床前研究，以在体内测试之前严格测试成功进行肌腱修复的潜力，并表明多功能和合成水凝胶用于持续转化的前景。