Bone regeneration and vascularization with porous PLGA scaffolds loaded with VEGF (0.35 and 1.75 μg) and BMP-2 (3.5 and 17.5 μg), incorporated in PLGA microspheres, or the combination of either dose of BMP-2 with the low dose of VEGF were investigated in an intramedullary femur defect in rabbits. The system was designed to control growth factor (GF) release and maintain the GFs localized within the defect. An incomplete release was observed in vitro whereas in vivo VEGF and BMP-2 were totally delivered during 3 and 4 weeks, respectively. A weak synergistic effect of the dual delivery of VEGF and BMP-2 (high dose) was found by 4 weeks. However, the absence of an apparent synergistic long-term effect (12 weeks) of the combination over BMP-2 alone suggests that more work has to be done to optimize VEGF dose, sequential presentation, and the ratio of the two GFs to obtain a beneficial bone repair response.

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The aim of this work was to study the bone repair induced by bone morphogenetic protein-2 (BMP-2), rat mesenchymal stem cells (rMSCs), and platelet-derived growth factor (PDGF-BB) incorporated in a macroporous beta-tricalcium phosphate (β-TCP) system fabricated by robocasting, and to identify the most beneficial combination in a critical rat calvaria defect. BMP-2 was formulated in microspheres to provide a prolonged, local concentration, whereas PDGF-BB, which acts during the initial stage of defect repair, was incorporated in a thin layer of crosslinked alginate. Approximately 80% of PDGF-BB and 90% of BMP-2 were released into the defect during the first 2 d and 3 weeks, respectively. Histological analyses indicated a minor synergistic effect in the BMP-2-MSC groups. In contrast, significant antagonism was found with combined BMP-2 and PDGF-BB defect treatment. The high-grade repair induced by BMP-2 rules out any advantage from combining BMP-2 with PDGF-BB or MSCs, at least with this scaffold and defect model.

A sandwich-like system, fabricated with electrospun, poly(lactic-co-glycolic-acid) (PLGA) membranes incorporating either human recombinant bone morphogenetic protein 2 (BMP-2) enriched microspheres, rat bone marrow mesenchymal stem cells (rMSC), or rMSC with their Smurf1 (SMAD ubiquitin regulatory factor-1) expression knocked down by means of siRNA (rMSC573) at varying densities was evaluated in a rat calvarial, critical-size defect. The behavior of four membrane varieties, fabricated with different PLGA copolymers, was initially studied in rMSC cultures to decide on optimal membrane degradation and cell proliferation and differentiation characteristics. PLGA75:25 provided the most stable structure, and favored the cell environment. Radiological and histological analyses indicated bone repair in animals treated with the PLGA75:25 bioactivated systems. We found no synergist interaction between BMP-2 and rMSC 8 to 12 weeks postimplantation. By contrast, synergistic defect repair of around 85% was detected after 8 weeks of combined BMP-2 and rMSC573 treatment.

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