Abstract
Patients with diabetes mellitus (DM) have defective healing of bone fractures. It was previously shown that nonviral gene delivery of plasmid DNA (pDNA) that independently encodes bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor-2 (FGF-2), acts synergistically to promote bone regeneration in a DM animal model. Additionally, both insulin (INS) and the hormonally active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1α,25(OH)(2) D(3) ) (VD3) have independently been shown to play key roles in regulating bone fracture healing in DM patients. However, these individual therapies fail to adequately stimulate bone regeneration, illustrating a need for novel treatment of bone fractures in diabetic patients. Here, the ability of local delivery of INS and VD3 along with BMP-2 and FGF-2 genes is investigated to promote bone formation ectopically in Type-2 diabetic rats. A composite consisting of VD3 and INS is developed that contains poly(lactic-co-glycolic acid) microparticles (MPs) embedded in a fibrin gel surrounded by a collagen matrix that is permeated with polyethylenimine (PEI)-(pBMP-2+pFGF-2) nanoplexes. Using a submuscular osteoinduction model, it is demonstrated that local delivery of INS, VD3, and PEI-(pBMP-2+pFGF-2) significantly improves bone generation compared to other treatments, thusimplicating this approach as a method to promote bone regeneration in DM patients with bone fractures.