Abstract
Healthy bone metabolism is a tightly coupled dynamic process that relies on a balance between bone resorption (catabolism) by osteoclasts and bone formation (anabolism) by osteoblasts. Traditionally, tissue-engineering approaches for non-union fracture repair employ local anabolic therapeutic delivery strategies that target mesenchymal stem cells (MSCs) and osteoblasts to induce bone formation, however, the challenge of healing non-union defects depends on the cause of defect e.g. trauma or disease, and targeting bone formation alone is often not sufficient. Our research focuses on utilising both anabolic therapeutics, including recombinant human bone morphogenic protein (rhBMP) −2 and parathyroid hormone (PTH)(1–34), and anti-catabolic bisphosphonates (BPs) to target bone metabolism. A major challenge with harnessing a combined dosing regimen is controlling the release of the individual therapeutics to target cells. We have developed a number of polymer-ceramic based biomaterial delivery systems, including injectable and implantable scaffolds, for the controlled release of rhBMP-2 and the BP zoledronic acid (ZA) and demonstrated their efficacy in vivo. A dual therapeutic load provided a synergistic enhancement of bone regeneration, demonstrating significantly increased bone formation and remodelling compared to anabolic therapies alone. Utilising hydroxyapatite as the ceramic phase in our scaffolds further increased bone formation, demonstrating the polymer-ceramic scaffolds to be osteoconductive in the absence of therapeutics. In addition, we have demonstrated the manipulation of bone metabolism through a specific dosing regimen of PTH(1–34), a therapeutic traditionally used as an anabolic, to induce bone remodelling and drive healing in BP loaded fractures. Our research to date has shown that optimising the delivery and regimen of anabolic and anti-catabolic therapeutics to control bone metabolism, augments the bone regenerative potential of these therapeutics in orthopaedic applications.
