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

• 批准号: 8490162
• 负责人: JASON T SHEARN
• 金额: $ 57.7万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-10 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490162
• 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; Gene Expression; Gene Expression Profile; 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; 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; receptor; repaired; research study; response; scaffold; scleraxis; soft tissue; spatiotemporal; stem cell differentiation; success; thrombospondin 4; tissue repair; tool; transcription factor; wound

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.

项目总结： 生物工程研究伙伴关系(BRP)的应用，来自生物医学系的PI‘s 辛辛那提大学工程学和辛辛那提儿童发育生物学分部 医院医疗中心，是为响应NIH PAR-07-352和NIAMS NOT-AR-002而编写的。这所大学 辛辛那提大学是牵头机构。拟议研究的目的是使用多个- 功能组织工程策略促进整个肌腱中间物质的修复和植入 使用正常发育的遗传模式。该计划的目标是正常识别基因 在发育中的肌腱中表达，这将被用作组织工程构造的诊断工具 (TEC)在培养中成熟，以及控制细胞活动以指导肌腱TEC的信号通路 在培养中成熟。在每一种情况下，我们都会将TEC的成熟程度与其生物力学联系起来。 性能，以及其修复肌腱的能力。这将产生更多的功能组织工程 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) 确定成纤维细胞生长因子和骨形态发生蛋白信号配体、受体和靶点表达的时空模式 在正常的小鼠膝盖腱发育过程中。将这些模式与所表达的模式进行对比 在成人PT愈合过程中。2)确定体外机械刺激TECs对成纤维细胞生长因子的影响程度 以及BMP信号和由此产生的构建生物力学。将这些模式与在 肌腱正常发育和成人自然愈合过程中。3)确定是否调节表达 小鼠、兔和绵羊TECs培养中的候选标志物可以控制体外生物力学和 生物学以及是否植入相应的兔TECs促进兔肌腱修复 模特。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 兔子的肌腱受损。我们将关联物种之间的TEC行为，以便快速识别 兔肌腱手术的理想人选。到五年结束时，我们将产生 正常肌腱发育过程中基因表达的时空图谱，涉及的信号通路 在肌腱发育中，以及这些信息可以在多大程度上促进TEC的成熟 培养和肌腱修复用于绵羊模型的推广。三个关键咨询小组(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和 确定研究的翻译方面。

项目成果

A role for hedgehog signaling in the differentiation of the insertion site of the patellar tendon in the mouse.

刺猬信号传导在小鼠the骨肌腱插入位点的分化中的作用。

• DOI: 10.1371/journal.pone.0065411
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Liu CF;Breidenbach A;Aschbacher-Smith L;Butler D;Wylie C
• 通讯作者: Wylie C

The LG/J murine strain exhibits near-normal tendon biomechanical properties following a full-length central patellar tendon defect.

• DOI: 10.1080/03008207.2016.1213247
• 发表时间: 2016-11
• 期刊: Connective tissue research
• 影响因子: 2.9

Improved biomechanical and biological outcomes in the MRL/MpJ murine strain following a full-length patellar tendon injury.

• DOI: 10.1002/jor.22928
• 发表时间: 2015-11
• 期刊: JOURNAL OF ORTHOPAEDIC RESEARCH
• 影响因子: 2.8
• 作者: Lalley, Andrea L.;Dyment, Nathaniel A.;Kazemi, Namdar;Kenter, Keith;Gooch, Cynthia;Rowe, David W.;Butler, David L.;Shearn, Jason T.
• 通讯作者: Shearn, Jason T.

A brief history of USNCB: motivation and formation.

USNCB 简史：动机和形成。

• DOI: 10.1115/1.4027332
• 发表时间: 2014
• 期刊: Journal of biomechanical engineering
• 作者: Mow,VanC;Butler,DavidL;Nerem,RobertM
• 通讯作者: Nerem,RobertM