Periodontal disease and malignant neoplasms are devastating complications often leading to the resection of large segments of the mandible. Various osteoinductive growth factor-based therapies have been developed in an attempt to find an effective and safer method of bone regeneration. In particular, bone morphogenetic proteins (BMPs) are currently approved for spinal fusion, tibial fracture repair, and alveolar ridge or maxillary sinus augmentation. However, BMPs are highly pleiotropic molecules and their supra-physiological high dose requirement leads to adverse side effects such as cyst formation, and inefficient bone formation. Thus, there is a need to develop alternative growth factor therapeutic strategies using osteoinductive factors with more specific osteogenic effects. Nell-1 (Nel-like protein-1) is a novel osteogenic protein originally identified in active bone forming sites of human craniosynostosis patients, and is believed to specifically target cells committed to the osteogenic lineage. To provide effective and safer bone regeneration for the repair of large, complex and structural defects, we propose a novel computer-designed, biomimetic scaffolding system for controlled local delivery of Nell-1. This system will consist of three-dimensional (3D) chitosan/alginate (Chi/Al) scaffolds with well-defined geometries on the macro- and micro-scales created from an indirect 3D printing technique in conjunction with biomimetic processing strategy to confer bone mineral-mimicking apatite microenvironment and osteogenic signaling molecules (Nell-1). To maximize bone regeneration, Nell-1 will be employed also in combination with platelet-derived growth factor-BB (PDGF-BB) in clinical use for the treatment of periodontal osseous defects. The specific hypothesis of this proposal is that controlled delivery of Nell-1+PDGF from computer-designed biomimetic scaffolds can enhance repair of alveolar bone defects. To investigate this hypothesis, we propose the following aims: 1) To develop biomimetic apatite-coated Chi/Al scaffolds with controlled architectures and delivery of osteogenic molecules (Nell-1+PDGF-BB); 2) To enhance alveolar bone regeneration by biomimetic scaffolds delivering Nell-1+PDGF-BB. Chi/Al scaffold architectures that facilitate mass transport and vessel ingrowth will be created from an indirect 3D printing technique. In this construct, we will create a biomimetic apatite coating and determine if apatite layer can increase Nell-1 and PDGF delivery efficiency. The bone formation efficacy of Nell-1 from the fabricated biomimetic scaffolds will be evaluated in a larger mandibular segmental defect model. In addition, we will also incorporate PDGF into the scaffolds and assess the effects of combined Nell-1+ PDGF on bone regeneration to maximize bone formation. The results from this proposal will be critical towards clinical translation of Nell-1 mediated therapeutics to augment alveolar bone regeneration while minimizing potential adverse effects of current osteoinductive therapeutics. PUBLIC HEALTH RELEVANCE: Loss of alveolar ridge due to periodontal disease, trauma, tooth loss or reconstructive surgery often leads to clinical situations exhibiting limited alveolar bone availability for dental implant placement. The proposed research provides effective and safer bone regeneration strategies combining a novel osteogenic protein with biomimetic scaffolding/delivery systems while minimizing potential adverse effects of current osteoinductive therapeutics.