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

基本信息

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
项目类别：
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

项目摘要

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。