Department of Biomedical Engineering, University of Delaware, Newark, Delaware, USA.
Department of Chemical and Biomolecular Engineering, University of Delaware, Newark, Delaware, USA.
Tissue Eng Part C Methods. 2020 Oct;26(10):506-518. doi: 10.1089/ten.TEC.2020.0199.
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 . 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 and 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 gel crosslinking. Ultimately, the and success criteria evaluated in this study were designed for preclinical research to rigorously test the potential to achieve successful tendon repair before testing and indicate the promise of multifunctional and synthetic hydrogels for continued translation. Impact statement Tendon healing results in a weak scar that forms due to poor cell-mediated repair of the injured tissue. Treatments that tailor the instructions experienced by cells during healing afford opportunities to regenerate the healthy tendon. Engineered cell-instructive cues, including the biomechanical, biochemical, and structural properties of the cell microenvironment, within multifunctional synthetic hydrogels are promising therapeutic strategies for tissue regeneration. In this article, the preclinical efficacy of multifunctional synthetic hydrogels for tendon repair is tested against rigorous and success criteria. This study indicates the promise for continued preclinical translation of synthetic hydrogels for tissue regeneration.
肌腱损伤很难愈合，部分原因是内在的肌腱愈合主要由疤痕组织形成，不能有效地再生健康肌腱的固有结构和功能。此外，许多现有的治疗策略也未能产生具有健康肌腱固有特性的再生肌腱。人们越来越感兴趣地使用细胞指令性策略来限制损伤后的内在纤维化反应，并提高肌腱的再生能力。我们已经建立了多功能的、具有细胞指令性的水凝胶来治疗受伤的肌腱，这种水凝胶可以对细胞微环境的生物力学、生物化学和结构特性进行可调节的控制。具体来说，我们将整合素结合域（RGDS）整合到多功能胶原模拟肽中，使干细胞在具有设计生物力学特性的合成水凝胶中能够进行细胞黏附和伸长，并使用针对肌腱愈合等力学要求高的环境的靶向成功标准来评估这些材料。和成功标准是基于对用于肌腱修复的水凝胶最常报道的结果测量的系统评价和生物材料测试的既定标准确定的。然后，我们通过验证实验表明，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 bolus 暴露（水凝胶成分）和三维包封（完整水凝胶）中均无细胞毒性；随着时间的推移，在肌腱缺损中形成、保留和可视化（2 周）；并且在水凝胶交联时为肌腱缺损提供机械支撑。最终，本研究中评估的和成功标准是为临床前研究设计的，以便在临床试验前严格测试成功修复肌腱的潜力，并表明多功能和合成水凝胶在继续转化方面的前景。
影响说明肌腱愈合会形成一个薄弱的疤痕，这是由于受伤组织的细胞介导修复不良造成的。针对细胞在愈合过程中所经历的指令进行调整的治疗方法为再生健康肌腱提供了机会。在多功能合成水凝胶中，细胞微环境的生物力学、生物化学和结构特性等工程化的细胞指令性线索是组织再生的很有前途的治疗策略。在本文中，针对严格的和成功标准，测试了多功能合成水凝胶修复肌腱的临床前疗效。这项研究表明，继续进行多功能合成水凝胶的临床前转化用于组织再生具有广阔的前景。
