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.
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.
|Arble, Jessica R; Lalley, Andrea L; Dyment, Nathaniel A et al. (2016) The LG/J murine strain exhibits near-normal tendon biomechanical properties following a full-length central patellar tendon defect. Connect Tissue Res 57:496-506|
|Liu, Han; Xu, Jingyue; Liu, Chia-Feng et al. (2015) Whole transcriptome expression profiling of mouse limb tendon development by using RNA-seq. J Orthop Res 33:840-8|
|Lalley, Andrea L; Dyment, Nathaniel A; Kazemi, Namdar et al. (2015) Improved biomechanical and biological outcomes in the MRL/MpJ murine strain following a full-length patellar tendon injury. J Orthop Res 33:1693-703|
|Dyment, Nathaniel A; Breidenbach, Andrew P; Schwartz, Andrea G et al. (2015) Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis. Dev Biol 405:96-107|
|Ratcliffe, Anthony; Butler, David L; Dyment, Nathaniel A et al. (2015) Scaffolds for tendon and ligament repair and regeneration. Ann Biomed Eng 43:819-31|
|Breidenbach, Andrew P; Dyment, Nathaniel A; Lu, Yinhui et al. (2015) Fibrin gels exhibit improved biological, structural, and mechanical properties compared with collagen gels in cell-based tendon tissue-engineered constructs. Tissue Eng Part A 21:438-50|
|Breidenbach, Andrew P; Aschbacher-Smith, Lindsey; Lu, Yinhui et al. (2015) Ablating hedgehog signaling in tenocytes during development impairs biomechanics and matrix organization of the adult murine patellar tendon enthesis. J Orthop Res 33:1142-51|
|Guilak, Farshid; Butler, David L; Goldstein, Steven A et al. (2014) Biomechanics and mechanobiology in functional tissue engineering. J Biomech 47:1933-40|
|Mow, Van C; Butler, David L; Nerem, Robert M (2014) A brief history of USNCB: motivation and formation. J Biomech Eng 136:060301|
|Gilday, Steven D; Casstevens, E Chris; Kenter, Keith et al. (2014) Murine patellar tendon biomechanical properties and regional strain patterns during natural tendon-to-bone healing after acute injury. J Biomech 47:2035-42|
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