The standard of care for augmenting surgical bone repair or regeneration remains bone graft harvested from the patient despite a lack of sufficient quantity or quality of graft in many clinical cases.  Bone morphogenetic protein (BMP) therapeutics have been successfully developed and commercially marketed as substitutes for bone graft.  Although the clinical success of BMP, especially in spinal fusion, is well-documented, safety issues related to the required therapeutic dose, sub-optimal delivery and off-label use have generated substantial controversy.  To address these issues and develop a next generation BMP product with improved efficacy and safety, we designed a series of novel recombinant human chimeric proteins with enhanced binding affinities to key cellular receptors involved in bone formation.  In parallel, a novel biomaterial scaffold was developed to improve the local retention time of these “designer” BMPs and reduce the risk of adverse events.  Through this combination of protein engineering and specialized biomaterial development, large animal studies have demonstrated efficacy at substantially lower doses than those required with existing BMP products and the potential to provide a safer and more effective option for surgeons and patients.