Microenvironments for Tendon Tissue Engineering

描述（由申请人提供）：在美国，每年有超过400万的医生就诊和30万的手术修复肌腱套（RC）关节损伤。手术治疗的选择是有限的，但往往无效，再撕裂率高达90%。这些失败的部分原因是受伤组织的愈合潜力有限，移植物材料的稀缺，以及目前可用的生物肌腱移植物无法发展相关的机械性能。一个潜在的解决方案是使用组织工程移植物，更接近地再现健康天然肌腱的结构和功能。在肌腱组织工程应用中，排列纳米纤维支架具有模拟天然肌腱胶原纤维的地形线索，已被证明可以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，但对于这些支架内的特定微环境线索如何影响和指导肌腱组织的形成，以及促进最佳细胞和基质组织并产生功能性肌腱组织所需的线索的精确组合，人们的理解仍然有限。本研究的目的是确定促进肌腱新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观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，我们将使用高适应性微光模式（μPP）模型系统确定特定微环境建筑特征在促进肌腱新组织形成中的作用，该模型系统允许对微环境变量进行精确和独立的操作。在特异性目标2，将测量细胞迁移行为和分子水平的细胞内张力，以响应μPP结构的培养，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中。这项研究不仅将为我提供新的知识和工具，以促进我在骨科生物工程领域成为一名富有成效的独立科学家，同时也将为改善肌腱手术结果的目标提供关键信息。

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.