Effect of Scaffold-delivery Growth Factors in Rotator Cuff Repair

 描述（由申请人提供）： 肩袖肌腱撕裂是一个常见的问题，往往需要手术修复。然而，修复的成功率参差不齐，许多患者由于愈合失败而经历肌腱再撕裂。肩袖修复失败后，盂肱关节可能发生退行性变化，导致进一步的疼痛和功能障碍。即使发生愈合，修复的肌腱也很少达到与损伤前状态相当的功能。有效的肌腱愈合在很大程度上受到其固有的不良细胞结构和血管化的抑制，阻止了足够的基质产生和营养输送。为了促进及时和稳健的愈合，已经利用组织工程技术，包括递送生长因子。转化生长因子β（TGF β）刺激肌腱细胞增殖和细胞外基质蛋白如胶原蛋白I和III的表达，其有助于肌腱机械强度的恢复。碱性成纤维细胞生长因子（bFGF）具有血管生成和促有丝分裂特性，促进组织重塑，并且已知在伤口愈合的初始阶段上调。这些生长因子在修复过程中发挥重要作用。然而，与生长因子递送有关的各种问题仅在愈合方面产生了适度的改善。为了解决这些问题，我们开发了一种纳米纤维生物材料支架和微球药物递送系统，可以进行微调，以在空间和时间上控制药物释放。这种方法，再加上我们完善的体内大鼠肩袖模型，使我们能够解决几个研究问题。本研究的总体目标是确定单个靶向肌腱修复相关生长因子的受控递送的作用和作用机制，以改善损伤后的组织特性和关节力学。我们的具体目标是：目标1：开发和表征包含微球的静电纺丝纳米纤维支架，该微球将递送TGF β和bFGF的持续释放曲线，目的2：通过一组集中的体内大鼠旋转器来确定生长因子的局部递送对肌腱愈合的影响。 袖带研究和相关的结果测量。这些分析将确定在受控系统中持续的生长因子递送对肌腱愈合的影响。研究结果将提供一个框架，开发一个优化的组织工程方法，以补充正常的愈合反应。最终，这将为医生提供更有效地治疗肌腱损伤患者的工具。肩袖撕裂是费城退伍军人事务医疗中心肩关节诊所最常见的诊断。在肩袖修复手术中通过纳米纤维支架持续局部递送生长因子的有益效果有可能对患有急性战斗相关损伤和慢性退行性疾病的退伍军人（无论年轻人还是老年人）的手术结果产生积极影响。

 DESCRIPTION (provided by applicant): Rotator cuff tendon tears are a common problem that often require surgical repair. However, the success of repair has been mixed, with many patients experiencing tendon re-tears due to failed healing. Following cuff repair failure, glenohumeral joint degenerative changes can ensue, resulting in further pain and dysfunction. Even when healing does occur, repaired tendon rarely achieves functionality equivalent to the pre-injured state. Effective tendon healing is largely inhibited by its inherently poor cellularity and vascularization, preventing adequate matrix production and nutrient delivery. To facilitate timely and robust healing, tissue engineering techniques have been utilized, including the delivery of growth factors. Transforming growth factor ß (TGFß) stimulates tendon cell proliferation and the expression of extracellular matrix proteins such as collagen I and III that contribute to the restoration of tendon mechanical strength. Basic fibroblast growth factor (bFGF) has both angiogenic and mitogenic properties, encourages tissue remodeling, and is known to be upregulated in the initial stages of wound healing. These growth factors both play important roles in the repair process. However, various issues with growth factor delivery have produced only modest improvements in healing. To address these issues, we developed a nanofibrous biomaterial scaffold and microsphere drug delivery system that can be fine-tuned to spatially and temporally control drug release. This approach, coupled with our well-established in vivo rat rotator cuff model, allows us to address several research questions. The overall objective of this study is to determine the role, and mechanisms of action, of controlled delivery of individual targeted tendon repair-related growth factors to improve tissue properties and joint mechanics after injury. Our specific aims are: Aim 1: To develop and characterize electrospun nanofibrous scaffolds incorporating microspheres that will deliver sustained release profiles for TGFßand bFGF and Aim 2: To determine effects of local delivery of a growth factor on tendon healing through a focused set of in vivo rat rotator cuff studies and associated outcome measures. These analyses will determine the effect of sustained growth factor delivery on tendon healing in a controlled system. Results will provide the framework to develop an optimized tissue engineering approach to supplement normal healing responses. Ultimately, this will provide physicians with tools to more effectively treat patients with tendon injuries. Rotator cuff tears are the most common diagnosis encountered in the shoulder clinic at the Philadelphia Veterans Affairs Medical Center. The beneficial effects of sustained local delivery of growth factors via a nanofibrous scaffold at the rotator cuff repair sie has the potential to positively affect surgical outcomes in veterans, both young and old, with acute combat related injuries and chronic degenerative conditions alike.