Project Summary As bone substitutes for autografts and allografts, synthetic porous scaffolds have limitations in the repair of critical-sized craniofacial bone defects due to insufficient vascularization and bone formation. To address these issues, in this project we propose to construct a new vasculature-like channels internal structure and add manganese dioxide (MnO2) hollow nanoparticles in a porous beta-tricalcium phosphate (b-TCP) scaffold to facilitate new blood vessel growth and stimulate osteogenesis. This strategy harnesses the new mimicking vasculature-like channels to stimulate cell recruitment and promote the invasion of new blood vessels, and utilizes the new inorganic Mn-containing nanoparticles to promote osteogenesis. Specifically, a template-casting technique combining 3D printing will be employed to develop vasculature-like channeled porous MnO2/b-TCP scaffolds. The concentrations of MnO2 nanoparticles in the b-TCP, the optimal channel size of the vasculature-like channels, and the in vivo cell infiltration, tissue biocompatibility, and vascularization of the new scaffold will be fully investigated. To achieve this goal, we will pursue the following three specific aims. Aim 1: Investigate the effect of MnO2 nanoparticles on the mechanical, physicochemical, and biological properties of porous b-TCP scaffolds. Aim 2: Investigate the effect of 3D channels on the mechanical, physicochemical, and biological properties of porous MnO2/b-TCP scaffolds. Aim 3: Examine the tissue biocompatibility, pro-angiogenic, cell-instructive functions of the channeled scaffold in a mouse subcutaneous model. After we complete this three-years proposed project, we will generate a new scaffold with mimicking structures and osteogenesis-stimulating components for craniofacial bone tissue regeneration. This proposed project will be the foundation for our long-term goal to translate this synthetic porous scaffold for the regeneration of large craniofacial bone defects.