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.

项目摘要 大约20％的人口中存在肩袖撕裂，并导致机械 肩袖肌肉的卸载。结果，肌肉经历萎缩，对 手术修复的临床结果。最近的工作显示肩袖肌肉减少 间充质衍生的干细胞（MSC）移植后变性。但是，基于MSC 肌肉骨骼疾病的疗法受到了亚障碍的困扰，部分原因是由于缺乏 有效的方法1）达到治疗数量的高度有效细胞，2）保留细胞 在受伤部位，一旦移植。因此，我们假设MSC的文化和注入 在旨在促进治疗效力的微颗粒载体上 再生分泌组）将导致肌肉受损的细胞保留更大，并改善 肌腱重新连接后肌肉再生。 该应用的目的是确定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）如何使用移植细胞 材料上的高健身最终会影响旋转器的再生水平 手术修复肌腱后的袖口肌肉。这个目标将通过 以下特定目的：1）评估改变生物材料的生化组成的影响 在扩张期间，人类MSC的代谢和复制性衰老的载体，2）评估效果 改变生物材料载体的生化组成，分泌促再生因素 由人类MSC和3）评估培养后MSC移植对载体的影响 由肌腱重新连接后大鼠肌上肌再生的目标1和2确定。 拟议的工作具有创新性，因为它专注于材料基材的设计，以设计 移植细胞的分泌组，以促进肩袖撕裂后的组织愈合，以及 为基材的影响提供了重要的早期代谢组学筛查技术 细胞治疗适应性的特性。这些研究的结果预计将具有重要的 积极影响，因为它们将导致肩袖的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基于细胞的疗法。