Research Project
9456096
Project Summary Every year, a substantial number of children injure a growth plate, a cartilaginous region found at the end of all long bones in children that provides signals for the bones to lengthen. The growth plate is the most fragile structure in a child?s developing bones, making it prone to injury. Damaged cartilage within the growth plate is often replaced by unwanted bone, forming a ?bony bar?, which can lead to angular deformities or halt bone growth completely. Current surgical methods to correct bone growth defects are invasive, prone to infections and have low success rates. There is no current treatment that leads to complete repair of an injured growth plate. Innovative treatment strategies that prevent bony bar formation, restore functional growth plate cartilage, and permit normal longitudinal bone growth in affected individuals are greatly needed. This proposal seeks to develop an injectable hydrogel biomaterial system that could prevent bony bar formation and promote the formation of cartilage tissue, and which could ultimately be examined for its ability to heal growth plate injuries in children. It has been shown that mesenchymal stem cells (MSCs) infiltrate the injured growth plate and undergo osteogenic differentiation. Here, two important areas for inhibiting the osteogenesis of MSCs via a biomaterial system will be studied: (1) the role of biopolymer hydrogel substrate mechanics in preventing osteogenesis, and (2) the delivery of short interfering RNA (siRNA) from biopolymer hydrogels that can block osteogenic differentiation. We hypothesize that hydrogel systems that are less stiff and that provide sustained exposure of MSCs to p38 MAPK siRNA will inhibit osteogenesis. This proposal seeks to engineer hydrogel systems with these characteristics as a first step towards creating new technologies for helping to heal growth plate injuries in children. This will be accomplished as by two Aims: Aim 1 - To engineer a hydrogel system with mechanical cues that prevent osteogenic differentiation of MSCs. Aim 2 - To design a hydrogel that would provide sustained release of siRNA targeting p38 MAPK to prevent osteogenesis of MSCs. The p38 MAPK pathway has been linked to osteogenesis in various cell types, including MSCs. Local inhibition of this pathway by siRNA could prevent MSC osteogenesis from occurring after growth plate injury. For both Aims, these studies will be conducted in vitro and also in vivo in a rat growth plate injury model. This project is a first step towards successful development of a biomaterial system that can prevent MSC osteogenesis, which could ultimately aid in growth plate tissue repair.
