Due to the limitations of autograft and allograft transplantation in the clinical bone reconstruction settings, scaffold-based tissue engineering strategies has drawn great attention in the search of bone graft substitutes during the past decades. We developed polymeric scaffolds for bone tissue regeneration here at NJCBM. By screening candidates from the tyrosine-derived polycarbonate library, we were able to identify the proper polycarbonate (i.e. E1001(1k)) for bone scaffold fabrication. Trabecular bone mimetic polymer scaffolds can be custom-shaped for critical size calvarial defect models in rats, rabbits and goats as well as a critical size tibial defect model in sheep. Moreover, the scaffolds can be modified with calcium phosphates such as tricalcium phosphate (b-TCP) and dicalcium phosphate dihydrate (DCPD) for enhanced osteoconductivity in vivo. It has been demonstrated that our E1001(1k) scaffold modified with DCPD can promote bridging in a 20 mm goat calvarial model at 16 weeks without any additional biological cues. Recombinant morphogenetic protein 2 (rhBMP-2) has also been applied in our bone regeneration strategy. We established a reliable rhBMP-2 bioactivity assay based on cellular ALP expression and performed thorough bioactivity analyses on commercially available rhBMP-2 in US. It was found that E1001(1k) scaffolds with b-TCP and 212 ng/mm3 rhBMP-2 promoted full void filling in a 20 mm critical size goat calvarial model, whereas the same long tubular scaffold loaded with 281 ng/mm3 rhBMP-2 could trigger bridging of 30 mm defect in a critical size sheep tibial model. The large animal studies showed that the composite scaffolds supplemented with extremely low doses of rhBMP-2 could trigger satisfactory new bone formation and thus make those scaffolds promising for clinical trials.