Our global hypothesis is that """"""""functional"""""""" tissue-engineered constructs containing mesenchymal stem cells can be used in models of tendon injury to improve repair biomechanics, structure, and biochemistry. Implants will be designed in vitro with appropriate contraction characteristics and initial biomechanics to improve tendon repair. Functional tissue engineering or FTE will be used to mechanically stimulate the tissue engineered (TE) implants in culture and to establish thresholds of in vivo forces that the implants will be expected to transmit after surgery. We will address four research questions. First, can we significantly improve repair outcome by varying the in vitro culture conditions? Second, what are the thresholds of in vivo force transmitted by normal tendons and how are these forces distributed through the repair site after implant surgery? Third, would altering the mechanical signals applied to the constructs in vitro enhance repair biomechanics after surgery? Finally, do in vitro markers exist that correlate with in vivo outcome, both short and long term? In a series of in vitro and in vivo studies, the following Specific Aims will be examined: 1. Create MSC constructs for up to 6 weeks in culture using selected combinations of cell-seeding density, collagen concentration, and collagen braids as suture replacements. Evaluate in vitro contraction characteristics, initial biomechanical properties, cell morphology, collagen synthesis, and expression of alkaline phosphatase and osteocalcin. 2. Establish in vivo loading regimens on normal Achilles and patellar tendons for various activities. 3. Estimate load distributions in the repair tissues for different combinations of implant conditions using finite element modeling. 4. Evaluate in vivo selected combinations from SA1 in light of design criteria derived from SA2 and SA3 to determine the success of the implant in replacing the injured tissue. 5. Assess the potential benefits of continuous and intermittent cyclic strain on construct contraction, initial biomechanical properties, cell morphology, and biochemistry in vitro. 6. Evaluate in vivo the most promising combinations from SA5 in light of the previous aims to determine the potential benefits of in vitro mechanical stimulation on repair biomechanics, histology, and biochemistry after surgery. 7. Identify possible predictors of in vivo outcome by correlating in vitro biomechanical, histological, and biochemical results with early and long-term in vivo outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR046574-01A1
Application #
6193937
Study Section
Special Emphasis Panel (ZRG1-SSS-M (01))
Program Officer
Panagis, James S
Project Start
2000-07-19
Project End
2005-06-30
Budget Start
2000-07-19
Budget End
2001-06-30
Support Year
1
Fiscal Year
2000
Total Cost
$269,700
Indirect Cost
Name
University of Cincinnati
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Dyment, Nathaniel A; Liu, Chia-Feng; Kazemi, Namdar et al. (2013) The paratenon contributes to scleraxis-expressing cells during patellar tendon healing. PLoS One 8:e59944
Butler, David L; Dyment, Nathaniel A; Shearn, Jason T et al. (2013) Evolving strategies in mechanobiology to more effectively treat damaged musculoskeletal tissues. J Biomech Eng 135:020301
Chaubey, Aditya; Grawe, Brian; Meganck, Jeffrey A et al. (2013) Structural and biomechanical responses of osseous healing: a novel murine nonunion model. J Orthop Traumatol 14:247-57
Kinneberg, Kirsten R C; Galloway, Marc T; Butler, David L et al. (2013) The native cell population does not contribute to central-third graft healing at 6, 12, or 26 weeks in the rabbit patellar tendon. J Orthop Res 31:638-44
Dyment, Nathaniel A; Kazemi, Namdar; Aschbacher-Smith, Lindsey E et al. (2012) The relationships among spatiotemporal collagen gene expression, histology, and biomechanics following full-length injury in the murine patellar tendon. J Orthop Res 30:28-36
Liu, Chia-Feng; Aschbacher-Smith, Lindsey; Barthelery, Nicolas J et al. (2012) Spatial and temporal expression of molecular markers and cell signals during normal development of the mouse patellar tendon. Tissue Eng Part A 18:598-608
Torzilli, Peter A; Bourne, Jonathan W; Cigler, Tessa et al. (2012) A new paradigm for mechanobiological mechanisms in tumor metastasis. Semin Cancer Biol 22:385-95
Herfat, Safa T; Shearn, Jason T; Bailey, Denis L et al. (2011) Effect of surgery to implant motion and force sensors on vertical ground reaction forces in the ovine model. J Biomech Eng 133:021010
Maye, Peter; Fu, Yu; Butler, David L et al. (2011) Generation and characterization of Col10a1-mcherry reporter mice. Genesis 49:410-8
Kinneberg, Kirsten R C; Galloway, Marc T; Butler, David L et al. (2011) Effect of implanting a soft tissue autograft in a central-third patellar tendon defect: biomechanical and histological comparisons. J Biomech Eng 133:091002

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