The proposed studies will optimize mechanical stimuli applied to mesenchymal stem cell (MSC) constructs to test the global hypothesis that delivering in vivo strain simulations boths stiffens repairs and shortens healing time. This research addresses 3 important clinical problems: filling tendon defects with biological constructs to reduce pain and stiffness and to provide grafts for revision surgery; repairing large rotator cuff tears and augmenting ligament reconstructions; and repairing chronic degenerative tendon injuries. Using a functional tissue engineering or FTE roadmap with linked in vitro and in vivo studies, we will establish in vivo forces and displacements for 4 activities of daily living in the rabbit patellar tendon model (PT) (Aim 1). Using a novel design strategy, 6 mechanical treatment factors will then be varied in culture to optimize the construct's tangent stiffness before surgery (Aim 2). Constructs with significantly different tangent stiffness values will be implanted in rabbit PT defects to examine significant improvements in repair stiffness (Aim 3). We will thus test a series of related hypotheses: Hyp 1. The rabbit PT maintains non-zero tissue strain and force for all activities. Hyp 2. Increasing the grade or inclination of the gait surface increases in vivo force and strain parameters. Hyp 3. Rabbit and mouse constructs exposed to in vivo strain shapes develop higher tangent stiffness than constructs exposed to trapezoidal or sinusoidal profiles. Hyp 4. Increasing strain amplitude, within physiological limits, increases tangent stiffness in culture. Hyp. 5. Strain patterns with similar times to rise and fall and similar periods as in vivo signals exhibit the largest stiffness values in culture. Hyp 6. Mouse constructs having the largest tangent stiffness in culture exhibit the greatest increases in col I gene expression. Hyp 7. Increasing construct stiffness in culture increases repair stiffness after surgery and better aligns cells and extracellular matrix in the repair site. Our novel, interactive in vitro / in vivo study should help to develop in vitro predictors of in vivo repair outcome after surgery that also apply to other tissue systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046574-07
Application #
7122017
Study Section
Special Emphasis Panel (ZRG1-MTE (01))
Program Officer
Wang, Fei
Project Start
1999-11-01
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
7
Fiscal Year
2006
Total Cost
$396,264
Indirect Cost
Name
University of Cincinnati
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
041064767
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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