ORTHOPEDIC MANAGEMENT OF FRACTURES (S BUKATA AND L GERSTENFELD, SECTION EDITORS) Recent Advances and Future of Gene Therapy for Bone Regeneration Galina Shapiro 1 & Raphael Lieber 1 & Dan Gazit 1,2,3,4,5,6 & Gadi Pelled 1,2,3,5,6 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Purpose of Review The purpose of this review is to discuss the recent advances in gene therapy as a treatment for bone regeneration. While most fractures heal spontaneously, patients who present with fracture nonunion suffer from prolonged pain, disability, and often require additional operations to regain musculoskeletal function. Recent Findings In the last few years, BMP gene delivery by means of electroporation and sonoporation resulted in repair of nonunion bone defects in mice, rats, and minipigs. Ex vivo transfection of porcine mesenchymal stem cells (MSCs) resulted in bone regeneration following implantation in vertebral defects of minipigs. Sustained release of VEGF gene from a collagen- hydroxyapatite scaffold to the mandible of a human patient was shown to be safe and osteoinductive. Summary In conclusion, gene therapy methods for bone regeneration are systematically becoming more efficient and show proof-of-concept in clinically relevant animal models. Yet, on the pathway to clinical use, more investigation is needed to determine the safety aspects of the various techniques in terms of biodistribution, toxicity, and tumorigenicity. Keywords Fracture . Nonunion . Gene therapy . Gene-activated matrix . Regenerative medicine . Orthobiologics Introduction The lifetime risk of any fracture at 50 years old is 53% among women and 21% among men [1]. Although most fractures heal spontaneously, they are associated with sig- nificant mortality, disability, emotional distress, and medi- cal costs [2, 3]. As the world population ages and patients with complex medical conditions live longer, the frequen- cy of fractures is expected to rise, further increasing the socioeconomic burden of fractures. Therefore, the preva- lence of fracture nonunion, which is currently estimated to be 4.9% [4], may increase [5]. The risk of nonunion across all bones is related to patient-specific risk factors including multiple concurrent fractures, prescription nonsteroidal anti-inflammatory drug and opioid use, open fracture, anticoagulant use, and oste- oarthritis with rheumatoid arthritis [4]. However, progres- sion to nonunion is not fully explained by these risk factors alone. Preventing nonunion is an important clinical objec- tive because patients with nonunion experience more pain, disability, and medical treatment costs as well as a slower return to normal work productivity [6]. Yet, no effective treatment for preventing nonunion is currently available. Acute management of fractures involves immobiliza- tion, pain management, and evaluation for an indication for a surgical intervention. The latter includes the applica- tion of internal or external stabilization systems to improve the stability of fixation and thereby enhance fracture healing. Both immobilization and surgical interventions mostly modify the mechanical environment, which is now considered an element in the “Diamond model of This article is part of the Topical Collection on Orthopedic Management of Fractures * Gadi Pelled gadi.pelled@cshs.org 1 Skeletal Biotech Laboratory, The Hebrew University–Hadassah Faculty of Dental Medicine, Ein Kerem, 91120 Jerusalem, Israel 2 Department of Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd., AHSP-8304, Los Angeles, CA 90048, USA 3 Cedars-Sinai Medical Center, Board of Governors Regenerative Medicine Institute, Los Angeles, CA 90048, USA 4 Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 5 Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 6 Cedars-Sinai Medical Center, Biomedical Imaging Research Institute, Los Angeles, CA 90048, USA Current Osteoporosis Reports https://doi.org/10.1007/s11914-018-0459-3