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

描述(申请人提供)：在此评估纳米技术驱动的组织工程策略，以开发旨在软组织移植物生物固定的创新方法。具体地说，我们着重于肌腱到骨的整合在肩袖修复和增强方面的挑战。肩袖撕裂是最常见的肩部损伤，在美国每年进行超过7.5万例修复手术。我们的生物固定方法集中在肌腱和骨之间的解剖附着点的再生。鉴于天然植入部位固有的细胞类型、基质成分和矿物质含量的特征空间差异，预计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，我们开发了一种用于肌腱-骨整合的仿生纳米纤维基双相支架，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。该建议的目的是优化多细胞培养和仿生支架的设计参数，以实现界面再生和多组织形成。目的1将验证这样一种假设，即纳米纤维支架上的成纤维细胞和成骨细胞的反应将由纳米纤维的几何形状和矿物质含量决定。目的2将通过成纤维细胞和成骨细胞的共培养，在双相支架上形成不同但连续的非钙化和钙化组织区域，以及这些不同区域在体内的维持。作为肩袖修复的一部分，我们重建解剖纤维软骨界面的努力代表了一种创新的解决方案，以应对重大的临床挑战。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具有很高的原创性。预计拟议研究的成功完成将促进新一代一体化固定装置的开发，并展示纳米技术在设计可与人体无缝结合的复杂肌肉骨骼组织系统方面的潜力。生物固定的肩袖肌腱移植物到骨提出了重大的临床挑战。本项目致力于设计和优化一种仿生的纳米纤维支架，以促进袖带修复后肌腱与骨的整合，重点是通过多阶段支架设计和成纤维细胞-成骨细胞共培养对成纤维细胞和成骨细胞的分布和多组织形成进行空间控制。计划中的研究结果将对公共健康产生重大影响，因为全国和世界各地都进行了大量的肩袖修复手术。此外，该项目可以通过移植物之间以及与宿主环境的整合来形成复杂的组织系统，从而在将组织工程移植物转化为临床环境方面产生广泛的影响。

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.