Biphasic Nanofiber-based Scaffold for Tendon-to-Bone Integration

描述（由申请人提供）：本文评价了纳米技术驱动的组织工程策略，以开发旨在生物固定软组织移植物的创新方法。具体来说，我们专注于肩袖修复和增强的肌腱-骨整合的挑战。肩袖撕裂是最常见的肩关节损伤，在美国每年进行超过75，000例修复手术。我们的生物学固定方法的中心是肌腱和骨之间解剖附着部位的再生。鉴于天然插入部位固有的细胞类型、基质组成和矿物质含量的特征性空间变化，预期界面再生将需要多种细胞类型和能够支持多组织形成的分层支架。因此，我们开发了一种仿生的，基于纳米纤维的双相支架用于肌腱-骨整合，每个阶段都设计用于形成天然插入部位的非矿化和矿化区域。该提案的目的是优化多细胞培养和仿生支架设计参数，以实现界面再生和多组织形成。目的1将测试的假设，即成纤维细胞和成骨细胞的纳米纤维为基础的支架上的反应将由纳米几何形状和矿物质含量。目标2将集中于通过成纤维细胞和成骨细胞的共培养在双相支架上形成非钙化和钙化组织区域的不同但连续的区域，以及这些不同区域在体内的维持。我们努力再生解剖纤维软骨界面作为肩袖修复的一部分，代表了一个重大临床挑战的创新解决方案。此外，本文提出的基于纳米纤维的多相支架设计和共培养方法是高度原创的。预计拟议研究的成功完成将促进新一代一体化固定器械的开发，并展示纳米技术在工程复杂肌肉骨骼组织系统中的潜力，这些系统可以与身体无缝整合。肩袖肌腱移植物与骨的生物学固定是一个重大的临床挑战。该项目的重点是设计和优化仿生纳米纤维支架，用于促进肌腱-骨整合后修复，重点是通过多阶段支架设计和成纤维细胞-成骨细胞共培养来控制成纤维细胞和成骨细胞的空间分布和多组织形成。由于在国内和世界范围内进行了大量肩袖修复手术，计划研究的结果将对公共卫生产生重大影响。此外，该项目可以通过移植物相互整合以及与宿主环境整合来形成复杂的组织系统，从而在组织工程移植物向临床环境的转化中产生广泛的影响。

DESCRIPTION (provided by applicant): Nanotechnology-driven tissue engineering strategies are evaluated here for the development of innovative methods aimed at the biological fixation of soft tissue grafts. Specifically, we focus on the challenge of tendon-to-bone integration for Rotator Cuff repair and augmentation. Rotator cuff tear is the most common shoulder injury, with over 75,000 repair procedures performed annually in the US. Our approach to biological fixation centers on the regeneration of the anatomic insertion site between tendon and bone. Given the characteristic spatial variation in cell type, matrix composition and mineral content inherent at the native insertion site, it is expected that interface regeneration will require multiple cell types and a stratified scaffold capable of supporting multi-tissue formation. We have therefore developed a biomimetic, nanofiber-based biphasic scaffold for tendon-bone integration, with each of the phases designed for the formation of the non-mineralized and mineralized regions of the native insertion site. The objective of this proposal is to optimize multi-cell culture and biomimetic scaffold design parameters for interface regeneration and multi-tissue formation. Aim 1 will test the hypothesis that fibroblast and osteoblast response on the nanofiber-based scaffold will be governed by nanofiber geometry and mineral content. Aim 2 will focus on the formation of distinct yet continuous regions of non-calcified and calcified tissue regions on the biphasic scaffold through co-culture of fibroblasts and osteoblasts, as well as the maintenance of these distinct regions in vivo. Our effort to regenerate the anatomic fibrocartilage interface as part of rotator cuff repair represents an innovative solution to a significant clinical challenge. Moreover, the nanofiber-based multiphasic scaffold design and co-culture methods proposed here are highly original. It is anticipated that the successful completion of the proposed studies will facilitate the development of a new generation of integrative fixation devices, as well as demonstrating the potential of nanotechnology for engineering complex musculoskeletal tissue systems that can integrate seamlessly with the body. Biological fixation of the Rotator Cuff tendon grafts to bone poses a significant clinical challenge. This project focuses on the design and optimization of a biomimetic, nanofiber-based scaffold for promoting tendon-to-bone integration post cuff repair, focusing on exercising spatial control of fibroblasts and osteoblasts distribution and multi-tissue formation through multi-phased scaffold design and fibroblast-osteoblast co-culture. Findings from the planned studies will have a significant impact in public health due to the large number of Rotator Cuff repair procedures performed nationally and worldwide. In addition, this project can have broad impact in the translation of tissue engineered grafts to the clinical setting, by enabling the formation of complex tissue systems through graft integration with each other as well as with the host environment.