Tissue Engineered Tendon Complex for Rotator Cuff Repair and Regeneration

项目总结/摘要 肩袖撕裂是一种常见的致残性肌肉骨骼损伤，且代价高昂。手术修复是常见的 治疗，但复发性撕裂发生在20至90%的患者，特别是在那些大或大量的眼泪。 使用生物材料加固进行肩袖修复，包括机械加固以增加修复 强度和生物愈合，加速组织再生，可减少术后并发症。 然而，目前用于增强的移植物材料远不能令人满意。组织工程提供 然而，产生功能性组织替代物的潜力，设计合适的支架， 具有天然的肌腱机械性能，并为细胞接种、生长和 分化，特别是肌腱起点再生，已被证明具有挑战性。在本申请中，我们 提出了一种新的组织工程方法，使用切片肌腱纤维软骨骨复合材料（TFBC）作为 骨髓源性干细胞（BMSC）用于肩袖修复增强的支架。我们的初步 研究表明，这种TFBC可以机械地增强肩袖修复。TFBC可以重振 通过接种BMSC，其在机械负荷下在天然肌腱环境中表达腱生成。我们 最近的体内数据表明，我们的工程TFBC生物增强肩袖修复 在我们的新开发的实验中，术后6周后，与单独修复或TFBC支架相比， 模拟人肩功能和活动的犬非负重肩模型。基于我们 初步研究，目前建议的总体目标是开发和测试一个功能 用于肩袖撕裂治疗的工程复合组织（TFBC）。我们的基本假设是 工程TFBC作为一种增强生物材料，将改善肩关节术后的功能结局， 与临床使用的生物材料（GraftJacket）相比，袖带修复。我们还假设TFBC将 有助于重建肌腱附着点，这在目前的再生中是一个巨大的挑战。 方法，因为TFBC含有天然纤维软骨区。为了验证我们的假设，以下两个 提出了具体目标。具体目标1是测试TFBC机械增强性能， TFBC在体外模型中用于肩袖修复。具体目标2是测试工程化TFBC生物 增强和附着点再生在犬体内模型与长期随访。我们期待两个 本研究的重要结果是：1）TFBC增强了转子的力学性能 肩袖修复，2）工程化TFBC有效减少肩袖修复失败，改善肩袖 修复愈合，并重建迄今为止尚未成功再生的肌腱附着点。如果我们的 假设得到支持，我们将开发出一种新型，有效和临床适用的生物材料， 提高肩袖修复的质量，这对肩袖撕裂领域有重大影响， 具有挑战性的临床和研究问题。

PROJECT SUMMARY/ABSTRACT Rotator cuff tears are common, disabling, and are costly musculoskeletal injuries. Surgical repair is a common treatment, but recurrent tears occur in 20 to 90% of patients, especially in those with large or massive tears. Rotator cuff repair with biomaterial augmentations, including mechanical augmentation to increase the repair strength and biological healing to accelerate tissue regeneration, may reduce postoperative complications. However, the current graft materials used for augmentation are far from satisfactory. Tissue engineering offers the potential to generate functional tissue replacement, however, designing an appropriate scaffold that can has native tendon mechanical properties and provide an optimal environment for cell seeding, growth, and differentiation, especially for tendon enthesis regeneration, has proven challenging. In this application, we propose a novel tissue engineering approach using a sliced tendon fibrocartilage bone composite (TFBC) as a scaffold to seed bone marrow-derived stem cells (BMSC) for rotator cuff repair augmentation. Our preliminary studies indicated that this TFBC can mechanically enhance the rotator cuff repair. The TFBC can be revitalized by seeding BMSCs, which express tenogenesis in native tendon environment under mechanical loading. Our recent in vivo data demonstrated that our engineered TFBC biologically augmented the rotator cuff repair better when compared to repair or TFBC scaffold alone after six weeks post-surgery in our newly developed canine non-weight bearing shoulder model which mimics human shoulder function and activities. Based on our preliminary studies, the overall goal of the current proposal is to develop and test a functional engineered composite tissue (TFBC) for rotator tear treatment. Our underlying hypothesis is that our engineered TFBC, as an augmentation biomaterial, will improve functional outcomes following rotator cuff repairs compared to the clinically used biomaterial (GraftJacket). We also postulate that TFBC will help to rebuild the tendon enthesis, which has been a great challenge to regenerate in the current approaches, as the TFBC contains a native fibrocartilage zone. To test our hypothesis, the following two specific aims are proposed. Specific Aim 1 is to test the TFBC mechanical augmentation properties when the TFBC is used for rotator cuff repair in an in vitro model. Specific Aim 2 is to test engineered TFBC biological augmentation and enthesis regeneration in a canine in vivo model with a long-term followup. We expect two important outcomes from this investigation: 1) The TFBC strengthens the mechanical properties of the rotator cuff repair, and 2) the engineered TFBC effectively reduce the rotator repair failure, improve the rotator cuff repair healing, and rebuild a tendon enthesis which has not been successfully regenerate to date. If our hypothesis is supported, we would have developed a novel, effective, and clinically-applicable biomaterial to improve the quality of rotator cuff repairs, which has a significant impact on the field of rotator cuff tear, a challenging clinical and research issue.