Project Summary Low back pain is the worldwide leading cause of disability, affecting more than half a billion people and increasing in prevalence alongside a growing and ageing population. Spinal fusion surgery, which immobilizes adjacent vertebrae, can effectively relieve low back pain and disability. Over 400,000 Americans annually undergo spinal fusion surgeries, at an aggregate hospital cost of around $13 billion, the highest of any surgical procedure. However, pseudo-arthrosis, or failed fusion, occurs in up to 40% of these procedures, even when the “gold- standard” treatment of grafting bone from the patient’s own iliac crest is used. We believe tissue engineering, which involves a combination of engineered scaffolds, growth factors, and/or cells to orchestrate new tissue formation, can solve the problem of pseudo-arthrosis. At present, the Infuse Bone Graft is the only tissue engineered product involving a growth factor that is FDA-approved for spinal fusion, though with significant design limitations: (1) non-controlled, supraphysiologic burst release of growth factors, (2) poor vascular induction, and (3) bio-disparate design; all of which limit new bone formation. Herein, we propose the development of a novel bone graft substitute specifically designed to overcome these limitations. The central hypothesis of this project is that a biomimetic, mussel-inspired, bioactive bone graft substitute can be engineered to provide controllable early and sustained release of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF), leading to superior fusion outcomes compared to the current gold standard and the Infuse Bone Graft in a preclinical animal model. In Aim 1, we will develop and optimize this material for maximal vascular ingrowth and bone formation in vitro, and in Aim 2 we will evaluate our material’s efficacy in a preclinical rabbit model of posterolateral lumbar spinal fusion in direct comparison to the current gold standard and the Infuse Bone Graft. We expect that our engineered graft will lead to superior fusion outcomes. Our research may inform the development of future materials and/or support clinical trials aimed at solving the problem of pseudo-arthrosis in spinal fusion.