Dual Delivery Of Bone Morphogenetic Protein-2 Research Articles

Dual Delivery of BMP2 and IGF1 Through Injectable Hydrogel Promotes Cranial Bone Defect Healing.

Critical-sized cranial bone defect remains a great clinical challenge. With advantages in regenerative medicine, injectable hydrogels incorporated with bioactive molecules show great potential in promoting cranial bone repair. Recently, we developed a dual delivery system by sequential release of bone morphogenetic protein 2 (BMP2) followed by insulin-like growth factor 1 (IGF1) in microparticles (MPs), and an injectable alginate/collagen (alg/col)-based hydrogel. In this study, we aim to evaluate the effect of dual delivery of BMP2 and IGF1 in MPs through the injectable hydrogel in critical-sized cranial bone defect healing. The gelatin MPs loaded with BMP2 and poly(lactic-co-glycolic acid)-poly(ethylene glycol)-carboxyl (PLGA-PEG-COOH) MPs loaded with IGF1 were prepared, respectively. The encapsulation efficiency and release profile of growth factors in MPs were measured. A cranial defect model was applied to evaluate the efficacy of the dual delivery system in bone regeneration. Adult Sprague Dawley rats were subjected to osteotomy to make an ⌀8-mm cranial defect. The injectable hydrogel containing MPs loaded with BMP2 (2 μg), IGF1 (2 μg), or a combination of BMP2 (1 μg) and IGF1 (1 μg) were injected to the defect site. New bone formation was evaluated by microcomputed tomography, histological analysis, and immunohistochemistry after 4 or 8 weeks. Data showed that dual delivery of the low-dose BMP2 and IGF1 in MPs through alg/col-based hydrogel successfully restored cranial bone as early as 4 weeks after implantation, whose effect was comparable to the single delivery of high-dose BMP2 in MPs. In conclusion, this study suggests that dual delivery of BMP2 and IGF1 in MPs in alg/col-based hydrogel achieves early bone regeneration in critical-sized bone defect, with advantage in reducing the dose of BMP2. Impact Statement Sequential release of bone morphogenetic protein 2 (BMP2) followed by insulin-like growth factor 1 (IGF1) in two different microparticles promotes critical-sized bone defect healing. This dual delivery system reduces the dose of BMP2 by supplementing IGF1, which may diminish the potential side effects of BMP2.

Delivery of bone morphogenetic protein-2 and substance P using graphene oxide for bone regeneration.

In this study, we demonstrate that graphene oxide (GO) can be used for the delivery of bone morphogenetic protein-2 (BMP-2) and substance P (SP), and that this delivery promotes bone formation on titanium (Ti) implants that are coated with GO. GO coating on Ti substrate enabled a sustained release of BMP-2. BMP-2 delivery using GO-coated Ti exhibited a higher alkaline phosphatase activity in bone-forming cells in vitro compared with bare Ti. SP, which is known to recruit mesenchymal stem cells (MSCs), was co-delivered using Ti or GO-coated Ti to further promote bone formation. SP induced the migration of MSCs in vitro. The dual delivery of BMP-2 and SP using GO-coated Ti showed the greatest new bone formation on Ti implanted in the mouse calvaria compared with other groups. This approach may be useful to improve osteointegration of Ti in dental or orthopedic implants.

Dual Delivery of BMP-2 and bFGF from a New Nano-Composite Scaffold, Loaded with Vascular Stents for Large-Size Mandibular Defect Regeneration

The aim of this study was to investigate the feasibility and advantages of the dual delivery of bone morphogenetic protein-2 (BMP-2) and basic fibroblast growth factor (bFGF) from nano-composite scaffolds (PLGA/PCL/nHA) loaded with vascular stents (PLCL/Col/nHA) for large bone defect regeneration in rabbit mandibles. Thirty-six large bone defects were repaired in rabbits using engineering bone composed of allogeneic bone marrow mesenchymal stem cells (BMSCs), bFGF, BMP-2 and scaffolds composed of PLGA/PCL/nHA loaded with PLCL/Col/nHA. The experiments were divided into six groups: BMSCs/bFGF/BMP-2/scaffold, BMSCs/BMP-2/scaffold, BMSCs/bFGF/scaffold, BMSCs/scaffold, scaffold alone and no treatment. Sodium alginate hydrogel was used as the carrier for BMP-2 and bFGF and its features, including gelling, degradation and controlled release properties, was detected by the determination of gelation and degradation time coupled with a controlled release study of bovine serum albumin (BSA). AlamarBlue assay and alkaline phosphatase (ALP) activity were used to evaluate the proliferation and osteogenic differentiation of BMSCs in different groups. X-ray and histological examinations of the samples were performed after 4 and 12 weeks post-implantation to clarify new bone formation in the mandible defects. The results verified that the use of sodium alginate hydrogel as a controlled release carrier has good sustained release ability, and the combined application of bFGF and BMP-2 could significantly promote the proliferation and osteogenic differentiation of BMSCs (p < 0.05 or p < 0.01). In addition, X-ray and histological examinations of the samples exhibited that the dual release group had significantly higher bone formation than the other groups. The above results indicate that the delivery of both growth factors could enhance new bone formation and vascularization compared with delivery of BMP-2 or bFGF alone, and may supply a promising way of repairing large bone defects in bone tissue engineering.

Combined delivery of BMP-2 and bFGF from nanostructured colloidal gelatin gels and its effect on bone regeneration in vivo

During the process of bone regeneration, a multitude of morphogenetic signaling factors regulate cellular behavior and ultimately tissue response. These factors are presented to cells under strong spatial and temporal control, which stresses the relevance of controlled delivery of multiple growth factors for bone tissue regeneration. This demand for biomimetic delivery has prompted the development of a novel generation of biomaterials that is capable of delivering multiple growth factors in a controlled manner. Therefore, the current study has exploited the strong capacity of colloidal gels solely made of oppositely charged gelatin nanospheres to obtain controlled release of angiogenic and osteogenic growth factors. The release kinetics of dual delivery of osteogenic bone morphogenetic protein-2 (BMP-2) and angiogenic basic fibroblast growth factor (bFGF) were investigated in vitro by radiolabeling the respective growth factors and monitoring their release in vitro. Furthermore, the effect of single or dual delivery of BMP-2 and bFGF on bone regeneration was evaluated in vivo using a rat femoral condyle defect model. The in vitro results confirmed that the delivery kinetics of BMP-2 and/or bFGF are more dependent on the degree of crosslinking than on the type of gelatin. Sequential release characterized by rapid release of angiogenic bFGF and more sustained release of BMP-2 was obtained by loading bFGF onto cationic nanospheres of low crosslinking density and BMP-2 onto anionic nanospheres of high crosslinking density. The in vivo study demonstrated the biocompatibility and biodegradability of bare colloidal gelatin gels, and did not show any adverse effects on the process of bone healing after 4week of implantation since the volumes of new bone formation were comparable to empty control defects. An obvious stimulatory effect on bone regeneration was observed for the colloidal gels loaded with BMP-2, whereas bFGF-loaded colloidal gelatin gels did not influence the rate of bone regeneration. In contrast, the combined delivery of BMP-2 and bFGF resulted into an inhibitory effect on osteogenesis under the current experimental conditions. Summarizing, the current study proved that nanostructured colloidal gelatin gels are suitable carriers for programmed and sustained release of multiple therapeutic proteins for tissue regeneration.