Grants We Funded

Abstract

Project Summary: 13.8 million surgeries entering the skull occur annually for etiologies including trauma, stroke, cancer, and congenital anomalies. In each instance, skull reconstruction is required to prevent neurologic sequelae, cerebral protection, and potential psychosocial burdens particularly in large defects. The current clinically available materials for cranial defect reconstruction are limited by donor site morbidity for autologous bone and complications and cost for alloplastic materials, thereby providing an opportunity to develop strategies targeting skull regeneration. With the increasing knowledge of the instructive capabilities of the extracellular matrix, we previously demonstrated the potential for an extracellular matrix-inspired, synthetic material composed of nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) to serve as a materials-only regenerative strategy. MC-GAG was capable of regenerating massive calvarial defects in vivo without the addition of pre-expanded progenitor cells or exogenous growth factor supplementation. Mechanistically, we recently demonstrated that MC-GAG generates a temporospatial spike in phosphate ion equilibrium in the local microenvironment that is essential for its effects on osteoprogenitor cell differentiation via the activities of the type III sodium-phosphate cotransporters, SLC20A1/PiT-1 and SLC20A2/PiT-2. Given the necessity of phosphate ion, our central question is: could augmentation of phosphate elution improve MC-GAG-mediated osteoprogenitor differentiation and in vivo skull regeneration? In Aim 1, we will test the effects of a composite material combining MC-GAG and a phosphate eluting hydrogel (MCGPh) on in vitro osteogenic differentiation of primary human mesenchymal stem cells. We hypothesize that increasing the length of time for phosphate elution will improve osteogenic differentiation beyond that of the MC-GAG base material. In Aim 2, we will evaluate the efficacy of MCGPh in a rabbit calvarial defect model for biomechanical properties, vascularity, inflammation, bone healing, and local and systemic safety. We hypothesize that increasing the length of time for phosphate elution will improve in vivo calvarial healing in a manner that will surpass that of MC-GAG alone. The current proposal will allow us to generate preclinical safety and performance data for MCGPh as a first step in preparation for an IDE application to the FDA.

Impact Statement: 13.8 million surgeries that enter the skull occur globally every year for trauma, stroke, cancer, and birth defects. A complete repair of the skull is necessary to protect the brain and prevent neurological disorders, however, the current available materials for reconstruction have significant drawbacks in complications for patients as well as healthcare costs. Such limitations have demonstrated a need for new strategies, such as the development of targeted regenerative therapies that are safe and readily available during surgery. This proposal is focused on the development of a surgically practical, off-the-shelf, biomaterials-based regenerative solution for the treatment of skull defects.

Biography
Justine C. Lee, MD, PhD, FACS is the Bernard G. Sarnat Endowed Chair in Craniofacial Biology and Associate Chief of the Division of Plastic and Reconstructive Surgery at the UCLA David Geffen School of Medicine. Clinically, Dr. Lee is a craniofacial plastic and reconstructive surgeon who developed the facial gender affirmation surgery program at UCLA. Academically, Dr. Lee’s basic research program is focused on regenerative technologies for skeletal defects and her clinical research program is dedicated to understanding and improving outcomes of craniofacial reconstruction. Her research is currently funded by the National Institutes of Health/National Institute of Dental and Craniofacial Research, the Jean Perkins Foundation, the Aramont Foundation, and the Bernard G. Sarnat Endowment.