Controlled delivery of mitochondria for craniofacial bone healing

Georgia Institute Of Technology, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY Craniofacial bone defects result from trauma or congenital deformities. Although clinical approaches exist to fill these defects using bone grafts, poor graft take and incomplete closure of the defect (nonunion defects) remain a major clinical challenge. The recent discovery that osteoblasts donate their mitochondria to osteoprogenitor cells to drive osteogenic differentiation suggests that a new therapeutic approach to harness this phenomenon and promote osteogenesis exists. In particular, mitochondria from mesenchymal stem cells (MSCs) have been shown to provide a significant increase in oxidative phosphorylation required for both cell proliferation and differentiation. However, promoting sufficient levels of exogenous mitochondria transfer to osteoprogenitor cells to observe tissue level changes remains a major obstacle because 1) there is inefficient endocytosis of free mitochondria by cells and 2) mitochondrial “scavenging” by cells associated with the innate immune system reduces uptake by progenitor cells. As a first step, the objective of this proposal is to develop a biomaterial-based delivery platform that can facilitate the transfer of exogenous mitochondria to osteoprogenitor cells to promote bone regeneration. The central hypothesis of this work is that a strategy aimed to promote cellular uptake of mitochondria in co-delivered MSCs as they transition to bone-forming cells, while avoiding mitochondrial scavenging by inflammatory cells, will lead to improved bone regeneration in a calvarial defect. Towards this goal, three specific aims are proposed: 1) Evaluate the effect of transactivator of transcription peptide modification of exogenous mitochondria on cellular uptake and osteogenesis in vitro; 2) Examine the effect of mitochondria release kinetics from degradable hydrogel microparticles on uptake by co-delivered MSCs in a rat critical-sized calvarial defect model; 3) Determine the effect of controlled mitochondria delivery on bone healing in a rat critical-sized calvarial defect model. The proposed work is innovative because it will develop a novel biomaterials-based mitochondria release platform to increase uptake and temporally control delivery. Results from these studies are expected to have an important positive impact because they will lead to improved therapies for craniofacial bone defect regeneration as well as provide insight into the role of mitochondria transfer in bone regeneration.