A Developmentally-Based Tissue Engineering Approach to Improve Tendon Repair

一种基于发育的组织工程方法来改善肌腱修复

基本信息

批准号：
7753953
负责人：
DAVID L BUTLER
金额：
$ 65.38万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-10 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7753953
关键词：
Accounting Activities of Daily Living Acute Adult Affect Affinity Allografting Animal Model Attenuated Autologous Autologous Transplantation BMP2 gene Behavior Binding Biological Biology Biomechanics Biomedical Engineering Bone Marrow Candidate Disease Gene Cell Density Cells Chemical Stimulation Chemicals Chronic Clinical Complex Cues Data Data Set Defect Development Developmental Biology Diagnostic Environment Evaluation Face Failure Fatigue Fibroblast Growth Factor Fibroblast Growth Factor Receptors Figs - dietary Gene Expression Gene Proteins Generations Genes Genetic Genetic Models Genomics Goals Grant Growth and Development function Healed Homologous Gene Implant In Vitro Individual Industry Infection Inferior Injury Institution Joints Knowledge Lead Left Length Ligaments Ligands Limb Development Limb structure Maps Measures Mechanical Stimulation Mechanics Medical center Mesenchymal Stem Cells Methodology Modeling Monitor Morbidity - disease rate Mus Musculoskeletal National Institute of Arthritis and Musculoskeletal and Skin Diseases Operative Surgical Procedures Oryctolagus cuniculus Outcome Pathway interactions Patients Pattern Pediatric Hospitals Postoperative Pain Process Property Protein Isoforms Proteins Quality of life Rattus Recovery Regulation Research Research Personnel Risk Rotator Cuff Rupture Scientist Secondary pain Sheep Signal Pathway Signal Transduction Site Source Specificity Speed Stimulus Surface Tenascin Tendon Injuries Tendon structure Testing Text Time Tissue Engineering Tissues Transgenes Transgenic Mice Transgenic Organisms Translating United States National Institutes of Health Universities Workplace Wound Healing Writing aggrecan base bone bone morphogenetic protein 2 bone morphogenetic protein 4 candidate marker design design and construction experience fibroblast growth factor receptor 2c gene discovery healing improved improved functioning in vitro testing in vivo industry partner injured innovation ligament injury mRNA Expression meetings musculoskeletal injury programs protein expression public health relevance receptor repaired research study response scaffold scleraxis soft tissue spatiotemporal stem cell differentiation success thrombospondin 4 tool transcription factor wound

项目摘要

DESCRIPTION (provided by applicant): This Bioengineering Research Partnership (BRP) application, from PI's in the Department of Biomedical Engineering at the University of Cincinnati and the Division of Developmental Biology at Cincinnati Children's Hospital Medical Center, is written in response to NIH PAR-07-352 and NIAMS NOT-AR-002. The University of Cincinnati is serving as the lead institution. The purpose of the proposed research is use a Multi-Functional Tissue Engineering Strategy to stimulate repair of the entire tendon midsubstance and insertion using genetic patterns of normal development. The goal of the program is to identify genes normally expressed in a developing tendon, which will be used as a diagnostic tool for tissue engineered construct (TEC) maturation in culture, and the signaling pathways that control cellular activity so as to direct tendon TEC maturation in culture. In each case, we will correlate the degree of TEC maturation with its biomechanical properties, and its ability to effect tendon repair. This will generate more functional tissue engineering strategies and design criteria to speed musculoskeletal repair. Our short- to intermediate-term goals are: 1) Identify spatial and temporal patterns of expression of FGF and BMP signaling ligands, receptors, and targets downstream during normal murine patellar tendon development. Contrast these patterns with those expressed during adult PT healing. 2) Determine the extent to which in vitro mechanical stimulation of TECs affects FGF and BMP signaling and resulting construct biomechanics. Compare these patterns to those expressed during normal tendon development and during natural adult healing. 3) Determine if modulating expression of candidate markers within murine, rabbit and sheep TECs in culture can control in vitro biomechanics and biology and, furthermore, whether implanting corresponding rabbit TECs improves tendon repair in the rabbit model. We already have a large dataset on the ability of bone marrow-derived cellular constructs to repair damaged tendons in the rabbit. We will correlate TEC behavior between species in order to rapidly identify desirable candidates to bring forward for rabbit tendon surgery. By the end of 5 years, we will have generated a spatiotemporal map of gene expression during normal tendon development, the signaling pathways involved in tendon development, and the degree to which this information can be used to improve TEC maturation in culture and tendon repair for extension to the sheep model. Three key advisory groups (Research Steering Committee, Industry Partners and Clinician-Scientists) will regularly participate in monitoring progress and identifying translational aspects of the research. PUBLIC HEALTH RELEVANCE: This BRP application will use a Multi-Functional Tissue Engineering Strategy to better repair tendon injuries. Tendon and ligament injuries represent almost 45% of all musculoskeletal injuries and dramatically affect quality of life in both recreational and workplace settings. We seek to identify genes expressed during tendon development, and to use these data to control the generation of "tissue engineered constructs," made in culture, with the goal of using these to repair damaged tendons in small and large animal models and in the longer term, to accelerate repair of tendon injuries in patients.

描述（由申请人提供）：辛辛那提大学生物医学工程系的PI研究和辛辛那提儿童医院医疗中心的发育生物学科的这种生物工程研究合作伙伴关系（BRP）申请，是针对NIH PAR-07-352和NIAMS NOT-AR-AR-AR-AR-002编写的。辛辛那提大学正在担任主要机构。拟议的研究的目的是使用多功能组织工程策略来刺激整个肌腱中固有的修复，并使用正常发育的遗传模式刺激整个肌腱中的插入。该程序的目的是识别通常在发育中的肌腱中表达的基因，该基因将用作培养物中组织工程结构（TEC）成熟的诊断工具，以及控制细胞活性的信号传导途径，从而导致培养中肌腱TEC成熟。在每种情况下，我们将将TEC成熟度的程度与其生物力学特性及其实现肌腱修复的能力相关联。这将产生更多功能的组织工程策略和设计标准，以加快肌肉骨骼修复。我们的短期至中期目标是：1）在正常的鼠tellar肌腱发育过程中，确定FGF和BMP信号配体，受体和靶标的空间和时间模式。将这些模式与成人PT愈合过程中表达的模式进行对比。 2）确定TEC的体外机械刺激在多大程度上影响FGF和BMP信号传导以及由此产生的构建生物力学。将这些模式与在正常肌腱发育和自然成年愈合过程中表达的模式进行比较。 3）确定培养物中候选标记的表达是否是否可以控制体外生物力学和生物学，此外，植入相应的兔子TEC是否可以改善兔模型中的腱修复。我们已经有一个关于骨髓衍生的细胞构建体能够修复兔子中受损肌腱的能力的大数据集。我们将将物种之间的TEC行为相关联，以便迅速识别理想的候选者，以提出兔肌腱手术。到5年结束时，我们将在正常肌腱发育期间生成基因表达的时空图，涉及肌腱发育的信号传导途径以及该信息可用于改善培养和肌腱修复的TEC成熟程度，以扩展到绵羊模型。三个关键咨询小组（研究指导委员会，行业伙伴和临床医生科学家）将定期参与监视进度并确定研究的转化方面。公共卫生相关性：该BRP应用将使用多功能组织工程策略来更好地修复肌腱损伤。肌腱和韧带损伤几乎占所有肌肉骨骼损伤的45％，并极大地影响了休闲和工作场所环境的生活质量。我们试图鉴定在肌腱发育过程中表达的基因，并使用这些数据来控制文化中制造的“组织工程结构”的产生，目的是使用这些数据来修复大小动物模型中的受损肌腱，从而加速患者肌腱损伤的修复。