Stratified and mechanically-tough biomaterial implant to improve tendon-to-bone enthesis regeneration

摘要 肩袖撕裂是常见的，最常见的是纤维软骨内的部分宽度损伤。 连接肌腱和骨骼的界面。肌腱与骨的外科再附着术形成了狭窄的 纤维血管瘢痕而不是再生形成了连续的纤维软骨端部。由此产生的尖锐边界 肌腱和骨骼的机械不匹配导致应变集中和高再失败率 在菊花处。本提案的目的是指导结构、组合物、 以及使用一种创新的生物材料疗法对受损的肌腱到骨端部的机械性能的影响。 在手术修复过程中，在损伤部位局部植入MSCs是一种有吸引力的加速嵌合的选择 再生。然而，必须开发一种生物材料载体来提高生物活性MSCs的保留率 并提供优化的微环境，在空间上调节MSC的分化和 纤维软骨重塑。我们已经为一种创新的生物材料生成了严格的原理验证数据 包含多孔矿化(骨)和各向异性(肌腱)支架隔间，与连续的 明胶水凝胶界面。这种水凝胶界面抑制了通常形成的应变浓度的形成 在载荷作用下机械性能不匹配的生物材料之间。水凝胶界面还提供 为促进MSC纤维软骨分化和基质重塑提供局部形态构型的仓库。 为了达到我们的目标，我们将首先演示一种机械优化的水凝胶插入增加 生物材料的韧性和局部促进纤维软骨分化。随后，我们将建立一个 纤维软骨优化的生物分子构图策略加速牙本质特异性MSC分化和 基质重塑。我们将最终评估大鼠肩袖吻合口的功能再生 优化的生物材料--MSC构建。我们将使用体外循环应变生物反应器研究来优化MSC- 生物材料相互作用以及严格的在体大鼠肩袖损伤模型，以基准质量和 通过细胞、组织形态和机械测量来研究末端再生的动力学。这个项目 解决知识中的关键差距，并将验证创新的生物材料范例以加速 肌肉骨骼末端再生。

ABSTRACT Rotator cuff tears are common and occur most commonly as partial-width injuries within the fibrocartilage interface (enthesis) linking tendon to bone. Surgical reattachment of tendon to bone forms a narrow fibrovascular scar rather than regenerates a continuous fibrocartilage enthesis. The resultant sharp boundary between mechanically mismatched tendon and bone leads to strain concentrations and high rates of re-failure at the enthesis. The objective of this proposal is to guide functional regeneration of the structure, composition, and mechanical performance of the injured tendon-to-bone enthesis using an innovative biomaterial therapy. Local implantation of MSCs at the injury site during surgical repair is an attractive option to accelerate enthesis regeneration. However it is essential to develop a biomaterial carrier to improve retention of bioactive MSCs at the injury site and to provide an optimized microenvironment to spatially-regulate MSC differentiation and fibrocartilage remodeling. We have generated rigorous proof-of-principle data for an innovative biomaterial that contains porous mineralized (bone) and anisotropic (tendon) scaffold compartments linked with a continuous gelatin hydrogel interface. This hydrogel interface inhibits formation of strain concentrations that typically form between biomaterials with mismatched mechanical properties under load. The hydrogel interface also provides a depot to locally pattern morphogens to accelerate MSC fibrocartilage differentiation and matrix remodeling. To address our objective we will first demonstrate a mechanically-optimized hydrogel insertion increases biomaterial toughness and locally promotes fibrocartilage differentiation. We will subsequently establish a fibrocartilage-optimized biomolecule patterning strategy to accelerate enthesis-specific MSC differentiation and matrix remodeling. We will ultimately evaluate functional regeneration of the rat rotator cuff enthesis using an optimized biomaterial-MSC construct. We will use in vitro cyclic strain bioreactor studies to optimize MSC- biomaterial interactions as well as a rigorous in vivo rat rotator cuff injury model to benchmark the quality and kinetics of enthesis regeneration via cellular, tissue morphology, and mechanical metrics. This project addresses critical gaps in knowledge and will validate an innovative biomaterial paradigm to accelerate musculoskeletal enthesis regeneration.