Hard Tissues and Materials Biodegradable hypoxia biomimicry microspheres for bone tissue regeneration Lina Hadidi 1 , Justine Constantin 1 , Benjamin Dalisson 2 , Daniela Vieira 1 , Edward Harvey 3 and Geraldine Merle 3 Abstract The iron chelator deferoxamine is a hypoxia biomimicry and has received interest as a potential therapeutic in tissue engineering and regenerative medicine. Recently, local injection of this iron chelator deferoxamine has proven to increase bone healing through the activation of the hypoxia-inducible factor-1 signaling pathway that augments angiogenesis and osteogenesis. Repeated injections of deferoxamine are required to achieve local therapeutic levels at fracture site. To achieve local therapeutic levels at fracture site without the use of multiples injections and associated pain and infection issues, we designed and prepared polymeric microspheres made of polycaprolactone and poly (ethylene oxide), in which deferoxamine was encapsulated, via a melting process. The application of this process has enabled to obtain spheres of different poly(ethylene oxide) concentrations for optimizing the drug release rate. The effective local release carrier offers a predetermined rate that can mimic the effect of repeated deferoxamine injections over a 14-day period to selectively stimulate bone repair and thus improve the biological performance to the point where ideally synthetics begin to challenge autograft dominance as the bone replacement of choice. Keywords Microsphere, drug release, deferoxamine mesylate, osteogenesis, angiogenesis Introduction The ability of fractured bone to regenerate and under- go repair is often compromised. 1 Although only 10% of fractures fail to heal (40% have delay in healing) for the general population, the incidence rises to 30% in the elderly or impaired resulting in permanent disabil- ities related to mal-union, joint stiffness, muscular atro- phy, or reflex sympathetic dystrophy. The accepted gold standard treatment is based on bone grafts, spe- cifically autografts, which are not always feasible or appropriate. As alternatives to autografts, research activity has been directed toward osteoconductive or osteoinductive synthetic materials including different forms and compositions of bioceramics that can poten- tially deliver added growth factor like bone morphoge- netic protein (BMP) for local stimulation of osteoprogenitor cell differentiation. Because bone growth is regulated by an interplay of various factors such as cells and vascular networks, different avenues can be triggered to successfully regenerate bone. Both osteoinduction and vascularization are critical to promote bone tissue regeneration and remodeling. Indeed, vascularization is crucial not only to facilitate substance exchange, but most importantly to allow migration of essential cells and factors required for skeletal regeneration. 2 Tissue hypoxia is a key player in the activation of angiogenesis after injury. In response to low oxygen pressure (hypoxia), hypoxia- inducible factor-1 (HIF-1) pathway is modulated, which results in the translocation of HIF-1a into the 1 Experimental Surgery, Faculty of Medicine, McGill University, Montreal General Hospital, Montreal, Quebec, Canada 2 Faculty of Dentistry, McGill University, Montreal, Quebec, Canada 3 Department of Surgery, Faculty of Medicine, McGill University, Montreal General Hospital, Montreal, Quebec, Canada Corresponding author: Geraldine Merle, Department of Surgery, Faculty of Medicine, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec H3G 1Y6, Canada. Email: geraldine.merle@mcgill.ca Journal of Biomaterials Applications 0(0) 1–10 ! The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0885328219884023 journals.sagepub.com/home/jba