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In Vivo Model of Human Enthesis Regeneration

人体附着点再生的体内模型

基本信息

批准号：
10652314
负责人：
Rowena McBeath
金额：
$ 23.05万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652314
关键词：
3-Dimensional Acute Pain Adopted Affect Aging Algorithms American Animal Model Automobile Driving Biochemical Biological Assay Bioreactors Cell Aging Cell Density Cells Cellular biology Chronic Clinical Trials Data Defect Degenerative Disorder Development Elderly Engineering Engraftment Exhibits Failure Fibrocartilages Funding Goals Growth Factor Guanosine Triphosphate Phosphohydrolases Harvest Healthcare Histopathology Human Human Activities Hypoxia Injections Injury Left Maintenance Mechanics Methods Modeling Molecular Nanofiber Scaffold Natural History Natural regeneration New Zealand Operative Surgical Procedures Oryctolagus cuniculus Outcome Oxygen Pain Pattern Phenotype Physical therapy Physiological Quantitative Reverse Transcriptase PCR Role Spectroscopy, Fourier Transform Infrared Stains Steroids Stretching Techniques Tendinopathy Tendon Injuries Tendon structure Testing Time Tissue Engineering Tissues Translating Western Blotting achilles tendon age related aged aging population bone clinical translation cost disability functional restoration healing human model in vivo in vivo Model innovation interdisciplinary approach kinematics loss of function mechanical force mineralization molecular marker normoxia novel older patient patient population repaired replacement tissue research clinical testing scaffold tissue degeneration

项目摘要

Tendinopathies are ubiquitous and age-related. The natural history of tendinosis includes age-related tissue degeneration of the tendon mid-substance, or of the enthesis – the tendon-bone interface – often resulting in acute pain, loss of function and chronic disability. The primary reason for poor outcomes after surgical repair is failure of the endogenous cells to recreate fibrocartilage at the tendon-bone interface. Our prior studies of aged and young human tendon have revealed tenocytes develop a fibrochondrocyte and mineralized fibrochondrocyte phenotype depending on relative intracellular levels of Rac1 and RhoA GTPase activity, which are determined by the cell microenvironment. We have characterized this effect of RhoA/Rac1 GTPase activity on the human tenocyte phenotype, and have discovered an essential role of combined Rac1 in-activity and RhoA over-activity in development of the fibrochondrocyte phenotype. The goal of this proposal is to create a fibrocartilage construct fit for eventual clinical translation. First we will create a human tenocyte-engrafted electrospun nanofiber scaffold and culture it under conditions of hypoxia or normoxia, under tension or compression in a bioreactor. Biochemical, immunohistochemical and kinematic assays will be used to evaluate time and oxygen-dependent changes in human tenocyte phenotype on the scaffolds, via expression of selected markers, assessment of tissue organization and mechanical strength. Human tenocytes will then be treated with RhoA/Rac1 agents to produce Rac-1 in-activity and RhoA over- activity and cultured as above. The final objective of this proposal is to create an in vivo rabbit model for enthesis regeneration. First we will perform proof-of-concept studies: enthesis defects will be created in the Achilles tendon of rabbits and observed for healing at week 6 and 12 after defect creation, harvested and analyzed as above. Using the same enthesis defect model, tenocyte-engrafted scaffolds with stable Rac1 in-activity and RhoA over-activity will then be used to repair the enthesis defects, harvested at week 6 and 12, and analyzed as described above to evaluate maintenance of the enthesis phenotype as well as construct integrity during physiologic loading in vivo. Our aging patient population is in dire need of an innovative, consistent therapy for tendinosis. Our proposed interdisciplinary approach using cell biology, biochemical, tissue engineering and translational techniques will create a novel enthesis construct, fit to undergo clinical testing, with the goal of decreasing pain and restoring function in the elderly.

肌腱病是普遍存在的，与年龄有关。肌腱病的自然病程包括与年龄相关的组织肌腱中间物质或附着点（肌腱-骨界面）的退化通常导致急性疼痛、功能丧失和慢性残疾。手术修复后结果不佳的主要原因是内源性细胞在腱-骨界面处重建纤维软骨的失败。我们之前的研究老年人和年轻人的肌腱已经揭示了肌腱细胞发育成纤维软骨细胞和矿化纤维软骨细胞表型取决于Rac 1和RhoA GT酶活性的相对细胞内水平，这取决于细胞微环境。我们已经表征了RhoA/Rac 1 GTdR的这种作用，活性的人肌腱细胞表型，并发现了一个重要的作用，结合Rac 1的活性和RhoA在纤维软骨细胞表型发育中的过度活性。该提案的目标是创建适合最终临床转化的纤维软骨结构。首先我们将制造人腱细胞嫁接的电纺支架并在缺氧条件下培养，或常氧，在张力或压缩下在生物反应器中。生化、免疫组织化学和运动学试验将用于评估在人肌腱细胞表型中的时间和氧依赖性变化，支架，通过表达选定的标志物，评估组织组织和机械强度。然后将人腱细胞用RhoA/Rac 1试剂处理以产生Rac-1失活和RhoA过度表达。活性和培养如上。本建议的最终目的是建立一个在体内兔模型的附着点再生。首先我们将进行概念验证研究：将在家兔跟腱中创建附着点缺损，在缺损形成后第6周和第12周观察愈合情况，如上所述采集和分析。使用相同的附着点缺陷模型，具有稳定的Rac 1失活和RhoA过度活性的肌腱细胞移植支架然后用于修复附着点缺陷，在第6周和第12周收获，并如上所述进行分析评价生理负荷期间附着点表型的维持以及结构完整性， vivo. 我们的老龄化患者群体迫切需要一种创新的、一致的肌腱病治疗方法。我们提出的利用细胞生物学、生物化学、组织工程和转化技术的跨学科方法将创造一种新的附着点结构，适合进行临床试验，目的是减少疼痛和恢复在老年人中发挥作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Zone 1 Flexor Tendon Repairs: Laceration and Avulsion Injuries.

1 区屈肌腱修复：撕裂伤和撕脱伤。

DOI：
10.1016/j.hcl.2023.01.001
发表时间：
2023
期刊：
Hand clinics
影响因子：
1.1
作者：
Patel,SaralJ;Miller,AndrewJ;Osterman,ALee;McBeath,Rowena
通讯作者：
McBeath,Rowena

Role of Preoperative Nerve Conduction Studies for Penetrating Hand Injuries Involving the Median Palmar Cutaneous Nerve.

DOI：
10.5435/jaaosglobal-d-23-00110
发表时间：
2023-10-01
期刊：
Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews
影响因子：
0
作者：
Patel S;Hutchinson D;Arango SD;Miller AJ;McBeath R
通讯作者：
McBeath R

Principles of Tendon Structure, Healing, and the Microenvironment.

肌腱结构、愈合和微环境的原理。