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However, controlling the release of these growth factors on demand and within the desired localized area is a significant challenge and the associated high costs and side effects of uncontrolled delivery have proven increasingly problematic in clinical orthopedics. Gene therapy may be a valuable tool to avoid the limitations of local delivery of growth factors. Following a series of setbacks in the 1990s, the field of gene therapy is now seeing improvements in safety and efficacy resulting in substantial clinical progress and a resurgence in confidence. Biomaterial scaffold\u2010mediated gene therapy provides a template for cell infiltration and tissue formation while promoting transfection of cells to engineer therapeutic proteins in a sustained but ultimately transient fashion. Additionally, scaffold\u2010mediated delivery of RNA\u2010based therapeutics can silence specific genes associated with orthopedic pathological states. This review will provide an overview of the current state\u2010of\u2010the\u2010art in the field of gene\u2010activated scaffolds and their use within orthopedic tissue engineering applications. \u00a9 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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