Biomaterials to enhance the efficacy of MSCs for rotator cuff repair

生物材料可增强 MSC 修复肩袖的功效

• 批准号: 10295835
• 负责人: Athanasios Mantalaris
• 金额: $ 38.57万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295835
• 关键词: 21 year old; Address; Affect; Aftercare; Atrophic; Biochemical; Biocompatible Materials; Biological Assay; Cell Aging; Cell Surface Receptors; Cell Therapy; Cell Transplantation; Cells; Cellular Metabolic Process; Clinical; Disease; Early identification; Elderly; Engineering; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gene Expression; General Population; Glycosaminoglycans; Goals; Heterogeneity; Histology; Human; Hydrogels; In Situ; In Vitro; Injections; Injury; Integrins; Isometric Exercise; Laboratories; Lead; Ligands; Measures; Mechanics; Mesenchymal; Metabolic; Metabolism; Methodology; Methods; Mission; Modeling; Modulus; Muscle; Muscle function; Musculoskeletal Diseases; Myoblasts; N-Cadherin; Natural regeneration; Operative Surgical Procedures; Outcome; Outcome Measure; Pathway Analysis; Patient-Focused Outcomes; Phase; Population; Production; Property; Public Health; Rattus; Regenerative Medicine; Research; Role; Rotator Cuff; Site; Stains; Stromal Cells; Styrenes; Techniques; Tendon structure; Testing; Therapeutic; Time; Tissues; Transplantation; United States National Institutes of Health; Work; angiogenesis; appropriate dose; base; beta-Galactosidase; design; experimental study; fitness; healing; immunoregulation; improved; in vitro Assay; in vivo; innovation; macrophage; metabolomics; migration; monocyte; muscle degeneration; muscle regeneration; recruit; regenerative; repaired; response; rotator cuff injury; rotator cuff tear; screening; senescence; shoulder injury; stem cell expansion; stem cell therapy; stem cells; supraspinatus muscle; surgery outcome; tissue culture; tissue regeneration; tool

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.

项目概要 大约 20% 的人口存在肩袖撕裂，并导致机械性损伤 肩袖肌肉的卸载。结果，肌肉萎缩，从而产生负面影响 手术修复的临床结果。最近的研究表明肩袖肌肉减少 间充质干细胞（MSC）移植后的退化。然而，基于MSC的 肌肉骨骼疾病的治疗一直受到疗效欠佳的困扰，部分原因是缺乏 有效的方法：1) 达到治疗相关数量的高效细胞，2) 保留细胞 移植后在受伤部位。因此，我们假设 MSC 的培养和注射 旨在提高治疗效力（减少衰老和促进治疗）的微粒载体 再生分泌组）将导致受损肌肉中更大的细胞保留，并改善 肌腱复位后冈上肌再生。 本应用的目的是确定 1) 生物材料载体之间的关系 种子 MSC 的特性、细胞代谢和治疗适应性，以及 2) 如何移植细胞 材料的高适应性以提高局部保持力最终影响旋转体的再生水平 撕裂肌腱手术修复后的袖口肌肉。这一目标将通过 以下具体目标： 1) 评估改变生物材料生化成分的影响 载体对人间充质干细胞扩增过程中代谢和复制衰老的影响，2）评估效果 改变生物材料载体的生化组成对促再生因子分泌的影响 3）评估培养后的MSC移植到载体上的效果 根据目标 1 和 2 确定肌腱重新附着后大鼠冈上肌的再生情况。 拟议的工作具有创新性，因为它侧重于材料基板的设计来设计 移植细胞的分泌蛋白组，以促进肩袖撕裂后的组织愈合，以及 为底物的影响提供了一种重要的基于代谢组学的早期筛选技术 细胞治疗适应性的特性。这些研究的结果预计将具有重要意义 积极影响，因为它们将为肩袖带来更有效的再生医学疗法 眼泪，并可能进一步导致针对多种疾病的更有效的细胞疗法。