Biomimetic approaches for enthesis tissue engineering

摘要 肩袖撕裂很普遍，尤其是在老年人群中，通常需要手术修复 恢复肩部功能。不幸的是，成功的修复仍然是一项重大的临床挑战，术后并发症较多。 手术失败率。这些失败的根源是修复的肌腱到骨骼界面愈合不良， 不再生原生肌腱附着体结构。具体地说，健康的肌腱吻合 由在成分(例如，矿物质含量)和细胞表型上具有空间层次的过渡组织组成 (例如，腱细胞、软骨细胞和成骨细胞)，这为转移提供了强大和坚韧的附着性 从肌腱到骨骼的肌肉负荷。解决肌腱到骨移植术后改善预后的关键临床需求 修复，这个项目汇集了一个多学科的研究团队来开发、验证和翻译一本小说 一类用于促进愈合的仿生支架。该团队由汤莫普洛斯博士(MPI)领导，他是一位 肌腱到骨骼的发育、病理和修复)来自哥伦比亚大学骨科和生物医学工程 大学和生物医学工程的夏博士(MPI，材料科学和纳米技术专家) 佐治亚理工学院。自然肌腱-骨连接的主要成分和结构特征将是 在目标1中直接制造或由在目标2中提供适当线索的干细胞产生。第一 (非蜂窝)方法具有高吞吐量和现成可用性的优势，而第二种(蜂窝)方法 该方法的优点是具有响应性的细胞外基质生成组件。漏斗形 微通道将被激光打孔穿过支架的深度，以鼓励细胞迁移和细胞外 基质沉积，从而缓解了人们对插入的支架将成为愈合之间的障碍的担忧 肌腱和骨头。这两个设计将独立制造并在体外进行评估，然后进行测试 在临床相关的肩袖损伤和修复的动物模型中，目的3.降低旋转体的失败率 袖带手术修复将对大量患者产生重大影响。拟议的临床相关 翻译研究有可能直接影响肩袖损伤的治疗。此外， 该结果将广泛适用于其他位置的结缔组织到骨的修复(例如，前交叉韧带重建， 半月板修复)。

ABSTRACT Rotator cuff tears are prevalent, particularly in the elderly population, and typically require surgical repair to regain shoulder function. Unfortunately, successful repair remains a major clinical challenge, with high post- operative failure rates. At the root of these failures is poor healing at the repaired tendon-to-bone interface, which does not regenerate the native tendon enthesis attachment structures. Specifically, the healthy tendon enthesis consists of a transitional tissue with spatial gradations in composition (e.g., mineral content) and cell phenotype (e.g., tenocytes, chondrocytes, and osteoblasts), which provides a strong and tough attachment to transfer muscle load from tendon to bone. To address the critical clinical need to improve outcomes after tendon-to-bone repair, this project brings together a multidisciplinary research team to develop, validate, and translate a novel class of biomimetic scaffolds for enhancing healing. The team is led by Dr. Thomopoulos (MPI, an expert in tendon-to-bone development, pathology, and repair) from Orthopedics and Biomedical Engineering at Columbia University and Dr. Xia (MPI, an expert in materials science and nanotechnology) from Biomedical Engineering at Georgia Tech. Key compositional and structural features of the natural tendon-to-bone attachment will be directly fabricated in Aim 1 or generated by stem cells provided with the appropriate cues in Aim 2. The first (acellular) approach has the benefit of high throughput and off-the-shelf availability whereas the second (cellular) approach has the advantage of a responsive extracellular matrix generating component. Funnel-shaped microchannels will be laser drilled through the depth of the scaffolds to encourage cell migration and extracellular matrix deposition, and thus alleviate the concern that the interposed scaffold will be a barrier to healing between the tendon and bone. These two designs will be independently fabricated and evaluated in vitro and then tested in a clinically relevant animal model of rotator cuff injury and repair in Aim 3. Reducing the failure rates of rotator cuff surgical repairs will have a major impact on a large population of patients. The proposed clinically relevant translational studies have the potential to directly impact the treatment of rotator cuff injuries. Furthermore, the results will be broadly applicable to connective tissue-to-bone repair in other locations (e.g., ACL reconstruction, meniscal repair).