Mechanical cues play a critical role in the development and maintenance of articular cartilage as well as in skeletal repair. Defining relationships between the mechanical environment and key cell and molecular events involved in cartilage formation has direct application in developing novel, regenerative approaches to articular cartilage repair that produce tissue with the requisite mechanical function. However, these relationships are not well understood. The long term goal of this research is to define the cellular, molecular and mechano-regulatory processes involved in the postnatal development of hyaline cartilage. Toward this end, we have developed an in vivo rat model of skeletal repair in which a cyclic bending motion applied daily to a mid-diaphyseal osteotomy gap results in robust cartilage formation within and surrounding the gap. Importantly, this newly generated cartilage has many characteristics of hyaline cartilage, as opposed to the fibrous cartilage typically formed during bone repair. The hypothesis of the work proposed here is that functional hyaline cartilage can be formed postnatally via mechano-regulated skeletal repair processes.
Three specific aims are proposed.
Aim #1 will characterize the mechanical function of trie newly generated cartilage. Nanoindentation, osmotic loading, and biochemical assays will be used to compare the biphasic material properties, swelling behavior, and fixed charge density of the newly generated cartilage to those of native articular cartilage.
Aim #2 will define the spatiotemporal patterns of gene expression and tissue structure induced by the mechanical stimulation using in situ hybridization, immunohistochemistry and histomorphometry.
Aim #3 will define the local mechanical environment induced during the mechanical stimulation via finite element analyses that use experimentally determined tissue material properties and geometry as input. Experimental validation of the finite element results will be performed. Integration of results from Aims #2 and #3 will allow direct assessment of correspondence between local mechanical cues and cell and molecular responses. The collective findings will in turn identify candidate pathways that can be targeted in future studies of articular cartilage repair and regeneration. Taken together, these experiments represent the first steps in defining the mechano-regulated processes involved in the postnatal formation of functional hyaline cartilage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR053353-04S1
Application #
7929028
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2009-09-18
Project End
2010-09-17
Budget Start
2009-09-18
Budget End
2010-09-17
Support Year
4
Fiscal Year
2009
Total Cost
$64,152
Indirect Cost
Name
Boston University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Miller, Gregory J; Gerstenfeld, Louis C; Morgan, Elise F (2015) Mechanical microenvironments and protein expression associated with formation of different skeletal tissues during bone healing. Biomech Model Mechanobiol 14:1239-53
Hayward, Lauren N M; de Bakker, Chantal M J; Gerstenfeld, Louis C et al. (2013) Assessment of contrast-enhanced computed tomography for imaging of cartilage during fracture healing. J Orthop Res 31:567-73
Hayward, Lauren Nicole Miller; de Bakker, Chantal Marie-Jeanne; Lusic, Hrvoje et al. (2012) MRT letter: Contrast-enhanced computed tomographic imaging of soft callus formation in fracture healing. Microsc Res Tech 75:7-14
Morgan, Elise F; Salisbury Palomares, Kristy T; Gleason, Ryan E et al. (2010) Correlations between local strains and tissue phenotypes in an experimental model of skeletal healing. J Biomech 43:2418-24
Salisbury Palomares, Kristy T; Gerstenfeld, Louis C; Wigner, Nathan A et al. (2010) Transcriptional profiling and biochemical analysis of mechanically induced cartilaginous tissues in a rat model. Arthritis Rheum 62:1108-18
Miller, G J; Morgan, E F (2010) Use of microindentation to characterize the mechanical properties of articular cartilage: comparison of biphasic material properties across length scales. Osteoarthritis Cartilage 18:1051-7
Hayward, Lauren Nicole Miller; Morgan, Elise F (2009) Assessment of a mechano-regulation theory of skeletal tissue differentiation in an in vivo model of mechanically induced cartilage formation. Biomech Model Mechanobiol 8:447-55
Morgan, Elise F; Mason, Zachary D; Chien, Karen B et al. (2009) Micro-computed tomography assessment of fracture healing: relationships among callus structure, composition, and mechanical function. Bone 44:335-44
Palomares, Kristy T Salisbury; Gleason, Ryan E; Mason, Zachary D et al. (2009) Mechanical stimulation alters tissue differentiation and molecular expression during bone healing. J Orthop Res 27:1123-32
Leong, Pui L; Morgan, Elise F (2009) Correlations between indentation modulus and mineral density in bone-fracture calluses. Integr Comp Biol 49:59-68

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