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: 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
• 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

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）：这份生物工程研究合作伙伴 (BRP) 申请由辛辛那提大学生物医学工程系和辛辛那提儿童医院医学中心发育生物学部的 PI 撰写，是为了响应 NIH PAR- 07-352 和 NIAMS NOT-AR-002。辛辛那提大学是牵头机构。拟议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质的修复和使用正常发育的遗传模式的插入。该项目的目标是识别发育中肌腱中正常表达的基因，这些基因将用作组织工程构建体（TEC）在培养物中成熟的诊断工具，以及控制细胞活动的信号传导途径，从而指导肌腱 TEC 成熟在文化中。在每种情况下，我们都会将 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。我们的短期到中期目标是：1) 确定正常小鼠髌腱发育过程中 FGF 和 BMP 信号配体、受体和下游靶标的空间和时间表达模式。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 TEC 的体外机械刺激对 FGF 和 BMP 信号传导以及由此产生的构建生物力学的影响程度。将这些模式与正常肌腱发育和成人自然愈合过程中表达的模式进行比较。 3) 确定调节培养物中的鼠、兔和羊 TEC 中候选标记的表达是否可以控制体外生物力学和生物学，此外，确定植入相应的兔 TEC 是否可以改善兔模型中的肌腱修复。我们已经拥有关于骨髓来源的细胞结构修复兔子受损肌腱能力的大型数据集。我们将关联物种之间的 TEC 行为，以便快速识别适合兔肌腱手术的候选者。到 5 年底，我们将生成正常肌腱发育过程中基因表达的时空图、肌腱发育中涉及的信号通路，以及这些信息可在多大程度上用于改善培养中的 TEC 成熟和肌腱修复。延伸至绵羊模型。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。 公共健康相关性：该 BRP 应用程序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%，并且极大地影响娱乐和工作环境中的生活质量。我们寻求鉴定肌腱发育过程中表达的基因，并使用这些数据来控制培养中制造的“组织工程构建体”的生成，目标是使用这些基因来修复小型和大型动物模型以及更长时间内受损的肌腱。短期内，加速患者肌腱损伤的修复。