Microenvironments for Tendon Tissue Engineering

描述(由申请人提供)：肩袖(RC)关节损伤在美国每年有超过400万名医生就诊和30万例手术修复。然而，手术治疗的选择有限，而且往往无效，再撕裂率高达90%。这些失败的部分原因是损伤组织的愈合潜力有限，移植物材料稀缺，以及目前可用的生物肌腱移植物无法产生相关的力学性能。这一问题的一个潜在解决方案是使用组织工程移植物，这种移植物更接近于健康的天然肌腱的结构和功能。对于肌腱组织工程应用，具有模拟天然肌腱胶原纤维的形貌线索的定向纳米纤维支架已被证明促进肌腱特异性分化、细胞形态和基质组织。尽管这些纳米纤维支架已经显示出相当大的前景，但对这些支架内特定的微环境信号如何影响和指导肌腱组织形成的了解仍然有限，促进最佳细胞和基质组织形成和产生功能性肌腱组织所需的信号的精确组合也不是很清楚。本研究的目的是确定促进肌腱新生组织形成的特定支架微环境特征，并了解肌腱组织形成的细胞机制。我们假设，在纳米和微尺度水平上排列的支架结构线索通过促进定向细胞迁移和高细胞内张力来协同指导肌腱新组织的形成。在具体目标1中，我们将使用高度适应性的微光调制(μPP)模型系统来确定特定的微环境结构特征在促进肌腱新组织形成中的作用，该模型系统允许精确和独立地操纵微环境变量。在具体目标2中，将测量细胞迁移行为和分子水平的细胞内张力，以响应在μPP架构上的培养，并确定细胞迁移和张力与肌腱新组织形成的关系。这项研究将使我们能够识别和理解导致肌腱组织形成改善的参数，并将这些特征纳入生物材料支架设计。这一奖学金不仅将使我获得新的知识和工具，促进我作为矫形外科生物工程领域一名富有成效的独立科学家的职业生涯，同时还将为改善肌腱手术结果的目标贡献关键信息。

DESCRIPTION (provided by applicant): Injuries to the rotator cuff (RC) joint account for over 4 million physician visits and 300,000 surgical repairs in the U.S. annually. Surgical treatment options are limited and often ineffective, however, with re-tear rates as high as 90%. These failures are due in part to the limited healing potential of the injured tissue, a scarcity of graf material, and an inability of currently available biologic tendon grafts to develop relevant mechanical properties. A potential solution to this problem is the use of tissue-engineered grafts that more closely recapitulate the structure and function of healthy native tendon. For tendon tissue engineering applications, aligned nanofiber scaffolds with topographical cues that mimic the collagen fibers of native tendon have been shown to promote tendon-specific differentiation, cell morphologies, and matrix organization. Although these nanofibrous scaffolds have shown considerable promise, there remains a limited understanding of how specific microenvironmental cues within these scaffolds affect and direct tendon tissue formation, and the precise combination of cues necessary to promote optimal cell and matrix organization and generate functional tendon tissues is not well understood. The goal of this study is to identify specific scaffold microenvironmental features that promote tendon neo- tissue formation, and to understand cellular mechanisms that underlie tendon tissue formation. We hypothesize that aligned scaffold architectural cues at both nano- and micro-scale levels synergize to direct tendon neo-tissue formation by promoting directed cell migration and high intracellular tension. In Specific Aim 1, we will determine the role of specific microenvironmental architectural features in promoting tendon neo-tissue formation using a highly adaptable micro-photopatterning (μPP) model system that permits precise and independent manipulation of microenvironmental variables. In Specific Aim 2, will measure cell migration behaviors and molecular-level intracellular tension in response to culture on μPP architectures and determine how cell migration and tension relate to tendon neo-tissue formation. This study will allow us to identify and understand the parameters that lead to improved tendon tissue formation and incorporate these features into biomaterial scaffold designs. This fellowship will not only equip me with new knowledge and tools to facilitate my career as a productive independent scientist in the field of orthopaedic bioengineering, but also simultaneously contribute key information towards the goal of improving tendon surgical outcomes.