A Developmentally-Based Tissue Engineering Approach to Improve Tendon Repair

描述（由申请人提供）：这份生物工程研究伙伴关系（BRP）申请，来自辛辛那提大学生物医学工程系的PI和辛辛那提儿童医院医学中心的发育生物学部门，是为了响应NIH PAR-07-352和NIAMS NOT-AR-002而写的。辛辛那提大学是牵头机构。本研究的目的是使用多功能组织工程策略，利用正常发育的遗传模式来刺激整个肌腱中间物质和插入物的修复。该项目的目标是鉴定在发育中的肌腱中正常表达的基因，这些基因将被用作组织工程构建体（TEC）在培养中成熟的诊断工具，以及控制细胞活动的信号通路，从而指导培养中的肌腱TEC成熟。在每种情况下，我们将把TEC的成熟程度与其生物力学特性及其影响肌腱修复的能力联系起来。这将产生更多的功能性组织工程策略和设计标准，以加速肌肉骨骼修复。我们的短期和中期目标是：1)确定正常小鼠髌腱发育过程中FGF和BMP信号配体、受体和下游靶点的时空表达模式。将这些模式与成人PT愈合期间表达的模式进行对比。2)确定体外机械刺激tec对FGF和BMP信号传导的影响程度以及由此产生的构建生物力学。将这些模式与正常肌腱发育和成人自然愈合期间表达的模式进行比较。3)确定在培养的小鼠、兔和羊TECs中调节候选标记物的表达是否可以控制体外生物力学和生物学，进而确定植入相应的兔TECs是否可以改善兔模型的肌腱修复。我们已经有了一个关于骨髓来源的细胞结构修复兔子肌腱损伤能力的大型数据集。我们将把不同物种之间的TEC行为联系起来，以便快速确定兔肌腱手术的理想候选者。5年后，我们将绘制出正常肌腱发育过程中基因表达的时空图谱、肌腱发育过程中涉及的信号通路，以及这些信息在多大程度上可用于提高TEC在培养和肌腱修复中的成熟程度，并将其推广到羊模型中。三个关键咨询小组（研究指导委员会、行业合作伙伴和临床科学家）将定期参与监测进展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%，并极大地影响娱乐和工作场所的生活质量。我们试图识别在肌腱发育过程中表达的基因，并使用这些数据来控制“组织工程构建体”的产生，在培养中制造，目标是在小型和大型动物模型中使用这些来修复受损的肌腱，并从长远来看，加速患者肌腱损伤的修复。

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.