Fractures are a significant problem in pediatric orthopedics. One third of childhood fractures involve the growth plate, a fragile, cartilaginous region in long bones that provides signaling for continued growth in children. Growth plate injuries occur from both high and low impact events, ranging from vehicular accidents to simple falls. Such injuries can result in the formation of a bony bar in which bony tissue replaces normal growth plate cartilage. This can result in angular deformities or complete growth cessation in the affected bone. Unfortunately, current growth plate injury treatments are invasive, prone to infections, and have low success rates. There is no treatment available that can fully regenerate the growth plate and ensure normal longitudinal bone growth. The long-term goal of this project is to develop a clinically useful biological therapy for growth plate regeneration. The objective of the current application is to prevent bony bar formation, replacing it instead with a cartilaginous tissue that more closely resembles the native growth plate and may restore normal longitudinal bone growth. Recent advances have elucidated mechanisms that affect bony bar formation as well as pathways that can promote regeneration. It has been shown that vascular endothelial growth factor (VEGF) and its associated angiogenesis in the injured growth plate can trigger bony bar formation. As well, it has been reported that mesenchymal stem cells (MSCs) infiltrate the injury site, express osteogenic markers, and participate in bony bar formation. In this project, we propose to prevent or replace bony bar formation in the injured growth plate by blocking angiogenesis and associated bone formation (Aim 1), recruiting more endogenous MSCs to the injured area by delivery of stem cell migratory factors (Aim 2), and promoting MSC chondrogenesis rather than osteogenesis by exposing them to a chondrogenic factor (Aim 3). This will be tested in a rat model of growth plate injury by using an injectable biomaterial delivery system that will sequentially release three therapeutic factors locally: (1) anti-VEGF antibody to block angiogenesis and bone formation, (2) a stem cell attracting factor such as SDF-1 or CCL25 to recruit endogenous MSCs to the injured area, and (3) TGF-?1 to direct the recruited stem cells down the cartilage lineage instead of the bone lineage. Overall, data from these studies will contribute new information to the basic biology of growth plate repair, and will also provide information on the translational potential of the proposed therapeutic approach. This will pave the way for further development of a novel treatment that not only prevents bony bar formation but also promotes formation of a functional tissue engineered growth plate that can prevent growth problems associated with growth plate injuries.
The growth plate is a region of cartilage found at the end of all long bones in children, providing signals for the bones to lengthen as a child grows. If the growth plate is injured, bone tissue is deposited in the injury site, forming a 'bony bar', which can stop bone growth completely or cause one side of the bone to grow more than the other, resulting in deformities. This project aims to develop a treatment for growth plate injuries in children by engineering an injectable biopolymer delivery system capable of blocking the formation of new blood vessels, recruiting stem cells to the area, and promoting the differentiation of these stem cells down the cartilage lineage, so as to prevent bony bar formation and associated growth problems.
| Shaw, Nichole; Erickson, Christopher; Bryant, Stephanie J et al. (2018) Regenerative Medicine Approaches for the Treatment of Pediatric Physeal Injuries. Tissue Eng Part B Rev 24:85-97 |
| Erickson, Christopher B; Shaw, Nichole; Hadley-Miller, Nancy et al. (2017) A Rat Tibial Growth Plate Injury Model to Characterize Repair Mechanisms and Evaluate Growth Plate Regeneration Strategies. J Vis Exp : |
| Riederer, Michael S; Requist, Brennan D; Payne, Karin A et al. (2016) Injectable and microporous scaffold of densely-packed, growth factor-encapsulating chitosan microgels. Carbohydr Polym 152:792-801 |
