The goal of this interdisciplinary project is to design a materials-based approach to gene therapy that improves the healing of large bone defects. More than 2 million orthopedic procedures per year use bone grafts to repair damaged bone, at a cost exceeding $30 billion. Despite this need, there are limited supplies of bone tissue for grafts. Recombinant (artificially produced) proteins can be used as an alternative to grafts, but they are expensive and have potential adverse side effects. In collaboration with researchers in Northern Ireland and the Republic of Ireland, this research will develop innovative gene-activated materials that encourage the body's own cells to produce the proteins needed for bone tissue repair. This will advance the nation's health and promote the progress of science by developing material systems that can be used to promote the healing of many tissues in the body, in addition to bone. The educational outreach component of this proposal will help students understand how biological materials behave mechanically and how this knowledge can be used to develop replacement materials for clinical use. Interactive STEM research kits will be developed for middle and high school students to enhance understanding of the measurement techniques used to quantify mechanical behavior of biological materials, including bone and synthetic materials used to replace biological materials clinically.
The overall goal of this project is to design a materials-based approach for the controlled delivery of novel osteoanabolic genetic cargos using non-viral vectors combined with osteoconductive scaffolds to promote healing of large bone defects. To achieve this goal, a hybrid material system will be designed and validated; the system will consist of a peptide vector to deliver genetic cargo and a collagen/hydroxyapatite scaffold to present the genetic cargo to cells in the healing space and provide osteoconductive surfaces. The material system will be validated by assessing its ability to promote bone formation activity in vitro and bone healing in vivo. The novel therapeutic genetic cargos for local delivery are parathyroid hormone (PTH), microRNA 26A mimic (miR-26a), and an inhibitor to microRNA133a (antagomiR-133a). The RALA peptide is a non-viral vector that will be used to deliver the therapeutic cargos using a collagen-based scaffold designed specifically for bone repair. The efficacy of the gene activated scaffolds at promoting osteoanabolic activity in mesenchymal stem cells in vitro will be evaluated by quantifying gene expression of key osteogenic and angiogenic markers. The safety of the gene-activated scaffolds will be evaluated in vivo by assessing the distribution of the genetic cargos in tissues and organs. The efficacy will be evaluated by quantifying bone formation in a critical size femoral defect using micro-computed tomography and histomorphometry.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
