Inducing Skeletal Repair by Mechanical Stimulation

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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.