Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Physeal cartilage tissue engineering using mesenchymal stem cells directed towards chondrogenesis

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Physeal injuries account for 30% of all pediatric fractures and can result in impaired bone growth. The physis (or ?growth plate?) is a cartilage region at the end of children's long bones that is responsible for longitudinal bone growth. Once damaged, cartilage tissue within the physis is often replaced by unwanted bony tissue, forming a ?bony bar? that can lead to angular deformities or even completely halt longitudinal bone growth. Children with a bony bar that spans less than half of the physis usually undergo bony bar resection and insertion of a permanent interpositional material, such as a fat graft, to prevent bony bar recurrence and allow the surrounding uninjured physeal tissue to restore longitudinal bone growth. Clinical success for this procedure is <35% and often the bony bar and associated growth impairments return. Children who are not candidates for bony bar resection due to a physeal bar that spans greater than half of their physis, undergo corrective osteotomy or bone lengthening procedures. These approaches are complex and result in multiple hospitalizations. There is a critical need to develop effective treatments that prevent bony bar formation and regenerate physeal cartilage in order to restore normal bone elongation. Mesenchymal stem cells (MSCs) from the underlying subchondral bone have been shown to migrate into the injured physis, undergo osteogenesis, and form the bony bar. This suggests that MSCs play a central role in bony bar formation, and are a potential target for treatment strategies directed towards physeal injuries. Our hypothesis is that a cartilage- biomimetic hydrogel that provides cartilage-specific physiochemical cues to MSCs prevents bony bar formation by directing MSCs towards chondrogenesis and not osteogenesis, restores the physis by promoting cartilage-specific repair tissue, and allows normal bone elongation after physeal injury. This hypothesis will be tested in two aims. In Aim 1, we will evaluate a temporary biomimetic hydrogel, which has chondrogenic physiochemical cues, for its ability to direct endogenous MSCs towards chondrogenesis, thus preventing bony bar formation in a rat model of physeal injury when compared to a hydrogel without chondrogenic cues and to an untreated injured model. In Aim 2, we will deliver exogenous syngeneic MSCs within the cartilage-biomimetic hydrogel to facilitate rapid and robust cartilage repair tissue formation and evaluate its ability to serve as a template for bone elongation after physeal injury in a rat model. Findings from each aim have clinical significance. Children who are candidates for bony bar resection would benefit from the implantation of a temporary interpositional material that prevents bony bar formation and augments the surrounding healthy physis to continue longitudinal bone growth. On the other hand, children that are not candidates for resection would benefit from the delivery of a cartilage-biomimetic hydrogel with MSCs to form robust cartilage formation within the injured site to restore longitudinal bone growth. Ultimately this work will have a high impact on the clinical management of physeal injuries and the quality of life of affected children.
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