Development of a small animal model to study tissue engineering strategies for growth plate defects

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Coleman, Rhima M.
Guldberg, Robert E.
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The growth plate is a cartilaginous tissue responsible for the longitudinal growth of long bones. It is a complex tissue composed of chondrocytes whose maturation and proliferation is tightly regulated by a biochemical feedback loop. Injury to this tissue can result in a limb length discrepancy or angular deformity that may lead to life long disability. Given the recent rise in the number of growth plate injuries and the variability in success of current therapies, there is a significant need for a greater understanding of growth plate injury pathology and the development of improved treatment strategies. Cartilage tissue engineering strategies offer an attractive alternative to regenerating growth plate tissue and restoring growth function. Bone marrow-derived stem cells (BMSCs) have been shown to be able to undergo chondrogenic differentiation and in vitro and in vivo and therefore offers an appealing and abundant cell resource for developing tissue engineering strategies for the treatment of growth plate defects. However, the dependence of chondrogenic differentiation and matrix accumulation on monolayer expansion protocols and three-dimensional (3D) culture environment has received little attention. Prior to developing treatment strategies for growth plate injury repair, it is essential to first understand the interconnection between alterations in growth plate morphology and subsequent limb deformities. To that end, we have established a surgical defect model of growth plate injury in Sprague Dawley rats and developed a novel technique to quantitatively monitor growth plate morphology in health and disease using microcomputed tomography (micro-CT) imaging. In an effort to develop a tissue engineering treatment strategy for growth plate injury, the role of monolayer expansion, 3D scaffold, and growth factor regimen in the chondrogenic differentiation of rat BMSCs was also examined. This research study has demonstrated the utility of micro-CT as a non-invasive imaging modality for assessing growth plate injury and repair. This work has also provided an improved understanding of the interrelationship of monolayer expansion, 3D culture environment, and growth factor regimen in BMSC chondrogenic differentiation. Finally, this work suggests that an injectable in situ gelling hydrogel is a feasible method for decreasing limb length discrepancies, however, neither implantation of agarose alone into the defect nor the inclusion of BMSCs fully corrects growth disruption.
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