Biomaterials to enhance the efficacy of MSCs for rotator cuff repair

项目总结 肩袖撕裂在大约20%的人群中存在，并导致机械性 肩袖肌肉的卸载。结果，肌肉会萎缩，这会对身体产生负面影响。 手术修复的临床结果。最近的研究显示肩袖肌肉减少。 间充质干细胞(MSCs)移植后的变性。但是，基于MSC的 肌肉骨骼疾病的治疗一直受到疗效不佳的困扰，部分原因是缺乏 有效的方法1)获得治疗相关数量的高潜能细胞，2)保留细胞 在移植后的损伤部位。因此，我们假设MSCs的培养和注射 设计用于促进治疗效果的微粒载体(延缓衰老和促进 再生分泌体)将导致更大的细胞保留在受损的肌肉，并改善 肌腱再附着后冈上肌再生。 本申请目的是确定1)生物材料载体之间的关系 种子间充质干细胞的特性、细胞代谢和治疗适合性，以及2)如何将细胞与 对提高局部固位力的材料的高适应性最终影响旋转体的再生水平 肌腱撕裂手术修复后的袖带肌肉。这一目标将通过 具体目标如下：1)评价改变生物材料生化成分的效果 载体对人骨髓间充质干细胞扩增过程中代谢和复制衰老的影响 改变生物材料载体的生化成分对促再生因子分泌的影响 3)培养后移植MSCs对载体的影响 根据AIMS 1和2确定的对大鼠冈上肌腱再附着后再生的影响。 这项拟议的工作具有创新性，因为它专注于材料衬底的设计，以设计 移植细胞的分泌体，以促进肩袖撕裂后的组织愈合 提供了一种重要的基于早期代谢组学的底物影响的筛选技术 细胞治疗适合性的特性。这些研究的结果预计将具有重要的 积极影响，因为它们将为肩袖带来更有效的再生医学疗法 泪水，并可能进一步导致更有效的基于细胞的疗法，以治疗各种疾病。

PROJECT SUMMARY Rotator cuff tears are present in approximately 20% of the population and result in mechanical unloading of the rotator cuff muscle. As a result, the muscle undergoes atrophy, which negatively impacts clinical outcomes of surgical repair. Recent work has shown reduction in rotator cuff muscle degeneration after transplantation of mesenchymal-derived stem cells (MSCs). However, MSC-based therapies for musculoskeletal diseases have been plagued by sub-optimal efficacy, due, in part, to lack of effective methods to 1) reach therapeutically relevant numbers of highly potent cells, and 2) retain cells at the site of injury once transplanted. Therefore, we hypothesize that that culture and injection of MSCs on microparticle carriers designed to promote therapeutic potency (reduced senescence and a pro- regenerative secretome) will result in greater cellular retention in the damaged muscle, and improved supraspinatus muscle regeneration after tendon reattachment. The objective of this application is to determine 1) the relationship between biomaterial carrier properties, cell metabolism, and therapeutic fitness of seeded MSCs, and 2) how transplanting cells with high fitness on materials to improve local retention ultimately affects the level of regeneration of rotator cuff muscle after surgical repair of the torn tendon. This objective will be approached through the following specific aims: 1) Evaluate the effects of altering the biochemical composition of the biomaterial carrier on metabolism and replicative senescence of human MSCs during expansion, 2) Evaluate effects of altering the biochemical composition of the biomaterial carrier on secretion of pro-regenerative factors by human MSCs, and 3) Evaluate the effects of transplantation of MSCs after culture on carriers determined from Aims 1&2 on regeneration in the rat supraspinatus muscle after tendon reattachment. The proposed work is innovative because it focuses on design of material substrates to engineer the secretome of transplanted cells in order to promote tissue healing after rotator cuff tear, as well as provides an important early metabolomics-based screening technique for the effects of substrate properties on cellular therapeutic fitness. Results from these studies are expected to have an important positive impact because they will lead to more efficacious regenerative medicine therapies for rotator cuff tears, and may further lead to more effective cell-based therapies for a wide variety of diseases.