title: Stimulation of bone regeneration following the controlled release of water-insoluble oxysterol from biodegradable hydrogel.
abstract: Recently bone graft substitutes using bone morphogenetic proteins (BMPs) have been heralded as potential alternatives to traditional bone reconstruction procedures. BMP-based products, however, are associated with significant and potentially life-threatening side effects when used in the head and neck region and furthermore, are exorbitantly priced. Oxysterols, products of cholesterol oxidation, represent a class of molecules that are favorable alternatives or adjuncts to BMP therapy due to their low side effect profile and cost. In order to establish the optimal clinical utility of oxysterol, an optimal scaffold must be developed, one that allows the release of oxysterol in a sustained and efficient manner. In this study, we prepare a clinically applicable bone graft substitute engineered for the optimal release of oxysterol. We first solubilized oxysterol in water by making use of polymeric micelles using l-lactic acid oligomer (LAo) grafted gelatin. Then, the water-solubilized oxysterol was incorporated into a biodegradable hydrogel that was enzymatically degraded intracorporeally. In this manner, oxysterol could be released from the hydrogel in a degradation-driven manner. The water-solubilized oxysterol incorporated biodegradable hydrogel was implanted into rat calvarial defects and induced successful bone regeneration. The innovative significance of this study lies in the development of a bone graft substitute that couples the osteogenic activity of oxysterol with a scaffold designed for optimized oxysterol release kinetics, all of which lead to better repair of bone defects.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90025, USA.
authors.forename: Akishige
authors.initials: A
authors.lastname: Hokugo
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90025, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Biomaterials, Field of Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA 90025, USA. Electronic address: rjarrahy@mednet.ucla.edu.
authors.forename: Reza
authors.initials: R
authors.lastname: Jarrahy
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D001861:Bone Regeneration / Q000187:drug effects*; D018786:Bone Substitutes / Q000494:pharmacology; D002478:Cells, Cultured; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D005780:Gelatin / Q000737:chemistry / Q000494:pharmacology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000494:pharmacology*; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008823:Micelles; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D014867:Water / Q000737:chemistry
chemical_list: D019485:Bone Morphogenetic Proteins; D018786:Bone Substitutes; D003692:Delayed-Action Preparations; D008823:Micelles; D011108:Polymers; D014867:Water; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D019344:Lactic Acid; D005780:Gelatin
keywords: Bone regeneration; Controlled release; Gelatin hydrogel; Hydroxycholesterol; Oxysterol; Water-insoluble drug