A Developmentally-Based Tissue Engineering Approach to Improve Tendon Repair

项目摘要： 这个生物工程研究伙伴关系（BRP）的应用程序，从PI的生物医学系 辛辛那提大学的工程学和辛辛那提儿童医院的发育生物学部门 医院医学中心，是为了回应NIH PAR-07-352和NIAMS NOT-AR-002而编写的。大学 辛辛那提大学是牵头机构。本研究的目的是利用一个多 功能性组织工程策略，以刺激整个肌腱中间质和插入的修复 利用正常发育的基因模式该计划的目标是正常识别基因 在发育中的肌腱中表达，其将用作组织工程构建体的诊断工具。 (TEC)在培养物中成熟，以及控制细胞活性以指导肌腱TEC的信号传导途径 文化中的成熟。在每种情况下，我们将TEC成熟的程度与其生物力学 性质，以及其影响肌腱修复的能力。这将产生更多的功能性组织工程 加速肌肉骨骼修复的策略和设计标准。我们的中短期目标是：1） 确定FGF和BMP信号配体、受体和靶点表达的空间和时间模式 在正常小鼠髌腱发育的下游。将这些模式与表达的模式进行对比 成人PT愈合期间。2)确定TEC的体外机械刺激影响FGF的程度 和BMP信号传导以及由此产生的结构生物力学。将这些模式与 正常肌腱发育和自然成人愈合期间。3)确定是否调节 培养物中的鼠、兔和绵羊TEC内的候选标记物可以控制体外生物力学， 生物学，以及植入相应的兔TEC是否能改善兔的肌腱修复 模型我们已经有了一个关于骨髓来源的细胞结构修复能力的大型数据集。 损伤的肌腱我们将物种之间的TEC行为相关联，以便快速识别 为兔肌腱手术提供理想的候选人。到5年后，我们将产生 正常肌腱发育过程中基因表达的时空图， 在肌腱发育中的作用，以及这些信息可用于改善TEC成熟的程度， 培养和肌腱修复，以扩展到绵羊模型。三个主要咨询小组（研究指导 委员会、行业合作伙伴和临床医生-科学家）将定期参与监测进展， 确定研究的翻译方面。

Project Summary: 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.