Application Of Bone Morphogenetic Protein Research Articles

CALCIUM SULFATE/HYDROXYAPATITE-MEDIATED CONTROLLED CO-DELIVERY OF BMP-2 AND ZOLEDRONIC ACID ENHANCES SPINAL FUSION

Although bone morphogenetic protein 2 (BMP-2) has been FDA-approved for spinal fusion for decades, its disadvantages of promoting osteoclast-based bone resorption and suboptimal carrier (absorbable collagen sponge) leading to premature release of the protein limit its clinical applications. Our recent study showed an excellent effect on bone regeneration when BMP-2 and zoledronic acid (ZA) were co-delivered based on a calcium sulphate/hydroxyapatite (CaS/HA) scaffold in a rat critical-size femoral defect model. Therefore, the aim of this study was to evaluate whether local application of BMP-2 and ZA released from a CaS/HA scaffold is favorable for spinal fusion. We hypothesized that CaS/HA mediated controlled co-delivery of rhBMP-2 and ZA could show an improved effect in spinal fusion over BMP-2 alone. 120, 8-week-old male Wistar rats (protocol no. 25-5131/474/38) were randomly divided into six groups in this study (CaS/HA, CaS/HA + BMP-2, CaS/HA + systemic ZA, CaS/HA + local ZA, CaS/HA + BMP-2 + systemic ZA, CaS/HA + BMP-2 + local ZA). A posterolateral spinal fusion at L4 to L5 was performed bilaterally by implanting group-dependent scaffolds. At 3 weeks and 6 weeks, 10 animals per group were euthanized for µCT, histological staining, or mechanical testing. µCT and histological results showed that the CaS/HA + BMP-2 + local ZA group significantly promoted bone regeneration than other treated groups. Biomechanical testing showed breaking force in CaS/HA + BMP + local ZA group was significantly higher than other groups at 6 weeks. In conclusion, the CaS/HA-based biomaterial functionalized with bioactive molecules rhBMP-2 and ZA enhanced bone formation and concomitant spinal fusion outcomeAcknowledgements: Many thanks to Ulrike Heide, Anna-Maria Placht (assistance with surgeries) as well as Suzanne Manthey & Annett Wenke (histology).

Advances in the application of bone morphogenetic proteins and their derived peptides in bone defect repair

BMPs are members of the transforming growth factor-β (TGF-β) superfamily and have been extensively studied due to their excellent osteoinductive ability and multiple functions. Currently, research on the application of BMPs is primarily focused on the delivery system of BMPs to achieve local administration of BMPs and delay the decay of BMPs due to the short half-life of BMPs and their easy degradation in vivo. Meanwhile, to enhance the effect of BMPs, researchers have combined BMPs with other growth factors (GFs) during osteoinduction. The key issues encountered in these studies are the mechanisms of osteoinduction when BMPs are combined with delivery systems or GFs, and how to successfully translate the findings of basic research into clinical treatments for bone defect repair. In this paper, we review the progress of BMP research, including the structure and function of BMPs and BMP-related derived peptides, as well as the binding of BMPs to various loading materials, cells, and GFs. Finally, we summarize the applications of BMPs in bone defect repair and related disease treatment, and propose some improvements of BMPs which provide new ideas for better application of BMPs in clinical tissue defect repair.

Sequential deacetylation/self-gelling chitin hydrogels and scaffolds functionalized with fucoidan for enhanced BMP-2 loading and sustained release

Bone morphogenetic protein 2 (BMP-2) is a potent osteoinductive factor that promotes bone formation. A major obstacle to the clinical application of BMP-2 is its inherent instability and complications caused by its rapid release from implants. Chitin based materials have excellent biocompatibility and mechanical properties, making them ideal for bone tissue engineering applications. In this study, a simple and easy method was developed to spontaneously form deacetylated β-chitin (DAC-β-chitin) gels at room temperature through a sequential deacetylation/self-gelation process. The structural transformation of β-chitin to DAC-β-chitin leads to the formation of self-gelling DAC-β-chitin, from which hydrogels and scaffolds were prepared. Gelatin (GLT) accelerated the self-gelation of DAC-β-chitin and increased the pore size and porosity of the DAC-β-chitin scaffold. The DAC-β-chitin scaffolds were then functionalized with a BMP-2-binding sulfate polysaccharide, fucoidan (FD). Compared with β-chitin scaffolds, FD-functionalized DAC-β-chitin scaffolds showed higher BMP-2 loading capacity and more sustainable release of BMP-2, and thus had better osteogenic activity for bone regeneration.

Sclerostin deficiency effectively promotes bone morphogenetic protein-2-induced ectopic bone formation.

Severe periodontitis causes alveolar bone resorption, resulting in tooth loss. Developments of tissue regeneration therapy that can restore alveolar bone mass are desired for periodontal disease. The application of bone morphogenetic protein-2 (BMP-2) has been attempted for bone fractures and severe alveolar bone loss. BMP-2 reportedly induces sclerostin expression, an inhibitor of Wnt signals, that attenuates bone acquisition. However, the effect of sclerostin-deficiency on BMP-2-induced bone regeneration has not been fully elucidated. We investigated BMP-2-induced ectopic bones in Sost-knockout (KO) mice. rhBMP-2 were implanted into the thighs of C57BL/6 (WT) and Sost-KO male mice at 8 weeks of age. The BMP-2-induced ectopic bones in these mice were examined on days 14 and 28 after implantation. Immunohistochemical and quantitative RT-PCR analyses showed that BMP-2-induced ectopic bones expressed sclerostin in osteocytes on days 14 and 28 after implantation in Sost-Green reporter mice. Micro-computed tomography analysis revealed that BMP-2-induced ectopic bones in Sost-KO mice showed a significant increased relative bone volume and bone mineral density (WT = 468 mg/cm3 , Sost-KO = 602 mg/cm3 ) compared with those in WT mice on day 14 after implantation. BMP-2-induced ectopic bones in Sost-KO mice showed an increased horizontal cross-sectional bone area on day 28 after implantation. Immunohistochemical staining showed that BMP-2-induced ectopic bones in Sost-KO mice had an increased number of osteoblasts with osterix-positive nuclei compared with those in WT mice on days 14 and 28 after implantation. Sclerostin deficiency increased bone mineral density in BMP-2-induced ectopic bones.

Application of rhBMP in spinal fusion surgery: any correlation of cancer incidence? A systematic review and meta-analysis.

Safety concerns regarding the application of bone morphogenetic proteins (BMPs) have been highlighted in recent years. It is noted that both BMP and their receptors being identified as a trigger for cancer growth. Here, we aimed to determine the safety and efficacy of BMP for spinal fusion surgery. We conducted this systematic review on topics of spinal fusion surgery with rhBMP application from three database (PubMed, EuropePMC, and Clinicaltrials.gov) with MeSH phrases such as "rh-BMP," "rhBMP," "spine surgery," "spinal arthrodesis," and "spinal fusion" were searched (using the Boolean operators "and" and "or"). Our research includes all articles, as long as published in English language. In the face of disagreement between the two reviewers, we discussed it together until all authors reached a consensus. The primary key outcome of our study is the incidence of cancer following rhBMP implantation. Our study included a total of 8 unique studies (n = 37,682). The mean follow-up varies among all studies, with the longest follow-up is 66months. Our meta-analysis showed that exposure to rhBMP in spinal surgery did increase the risk of cancers (RR 1.85, 95%CI [1.05, 3.24], p = 0.03). Our study found that rhBMP was not associated with the increased risk of cancer incidence within the rhBMP cohort. Still, we did face several limitations, in which further studies are needed to confirm the result of our meta-analysis.

Synergistic Effect of QNZ, an Inhibitor of NF-κB Signaling, and Bone Morphogenetic Protein 2 on Osteogenic Differentiation in Mesenchymal Stem Cells through Fibroblast-Induced Yes-Associated Protein Activation.

Biomaterials carrying recombinant human bone morphogenetic protein 2 (BMP2) have been developed to enhance bone regeneration in the treatment of bone defects. However, various reports have shown that in the bone repair microenvironment, fibroblasts can inhibit BMP2-induced osteogenic differentiation in mesenchymal stem cells (MSCs). Thus, factors that can target fibroblasts and improve BMP2-mediated osteogenesis should be explored. In this project, we focused on whether or not an inhibitor of the NF-κB signaling pathway, QNZ (EVP4593), could play a synergistic role with BMP2 in osteogenesis by regulating the activity of fibroblasts. The roles of QNZ in regulating the proliferation and migration of fibroblasts were examined. In addition, the effect of QNZ combined with BMP2 on the osteogenic differentiation of MSCs was evaluated both in vitro and in vivo. Furthermore, the detailed mechanisms by which QNZ improved BMP2-mediated osteogenesis through the modulation of fibroblasts were analyzed and revealed. Interestingly, we found that QNZ inhibited the proliferation and migration of fibroblasts. Thus, QNZ could relieve the inhibitory effects of fibroblasts on the homing and osteogenic differentiation of mesenchymal stem cells. Furthermore, biomaterials carrying both QNZ and BMP2 showed better osteoinductivity than did those carrying BMP2 alone both in vitro and in vivo. It was found that the mechanism of QNZ involved reactivating YAP activity in mesenchymal stem cells, which was inhibited by fibroblasts. Taken together, our results suggest that QNZ may be a candidate factor for assisting BMP2 in inducing osteogenesis. The combined application of QNZ and BMP2 in biomaterials may be promising for the treatment of bone defects in the future.

Effect of local application of bone morphogenetic protein -2 on experimental tooth movement and biological remodeling in rats.

Background: This study attempts to detect the potential effects of local bone morphogenetic protein -2 (BMP-2) on orthodontic tooth movement and periodontal tissue remodeling. Methods: Forty adult SD rats were randomly divided into four groups: blank control group, unilateral injection of BMP-2 on the pressure side or tension side of orthodontic teeth and bilateral injection of BMP-2. Their maxillary first molar was moved by a 30g constant force closed coil spring. 60μL of BMP-2 with a concentration of 0.5μg/mL was injected into each part at a time. In addition, three rats were selected as healthy control rats without any intervention. Fluorescent labeled BMP-2 was used to observe the distribution of exogenous BMP-2 in tissues. Micro-CT was used to measure the microscopic parameters of tooth displacement, trabecular bone and root absorption volume. Three different histological methods were used to observe the changes of tissue remodeling, and then the number of osteoclasts and the content of collagen fibers were calculated. Results: Compared with the blank control group, BMP-2 injection reduced the movement distance and increased the collagen fiber content and bone mass (p < 0.01). There was no significant difference in tooth movement distance, BV/TV ratio and BMD between injection sites in unilateral injection group (p > 0.05). In the case of bilateral injection of BMP-2, the osteogenesis is enhanced. Unilateral injection of BMP-2 did not promote root resorption, but double injection showed root resorption (p < 0.01). Conclusion: Our study does show that the osteogenesis of BMP-2 is dose-dependent rather than site-dependent when a certain amount of BMP-2 is applied around orthodontic teeth. Local application of BMP-2 around orthodontic teeth in an appropriate way can enhance bone mass and tooth anchorage without increasing the risk of root absorption volume. However, high levels of BMP-2 may cause aggressive root resorption. These findings are of great significance, that is, BMP-2 is an effective target for regulating orthodontic tooth movement.

Application of bone morphogenetic protein 2 derived peptide loaded onto nano hydroxyapatite for periodontal bone regeneration

To explore the feasibility of utilizing a nano drug delivery system for the promotion of periodontal bone regeneration, we constructed a hydroxyapatite-bone morphogenetic protein-2 (HA-BMP-2) nanocomposite. Through characterization by X-ray diffraction and Fourier transform infrared spectroscopy, the synthesized nanocomposite was confirmed to be HA, and nano HA (nHA) could prolong the half-life of BMP-2 by 10 times. In the cell test, we found that compared with nHA, nHA-BMP-2 improved the activity and migration of human periodontal ligament stem cells (HPLSCs) to promote the reconstruction of bone defects. Moreover, nHA-BMP-2 could improve the mineralization of HPLSCs, including increased levels of alkaline phosphatase, collagen I, and osteocalcin, thus enhancing osteogenesis. In the animal experiments, nHA-BPM-2 was further confirmed to effectively improve the area of new bone formation, bone density, bone volume percentage, and trabecular number in periodontal bone defect areas and reduce the repair time. Therefore, nHA-BMP-2 shows great potential for periodontal bone regeneration.

Enhanced Bone Regeneration by Bone Morphogenetic Protein-2 after Pretreatment with Low-Intensity Pulsed Ultrasound in Distraction Osteogenesis.

Bone morphogenetic protein 2 (BMP-2) and low-intensity pulsed ultrasound (LIPUS) have been used to enhance bone healing in distraction osteogenesis (DO). The aim of this study was to assess the synergistic effect of BMP-2 and LIPUS on bone regeneration in DO and to determine the optimal treatment strategy for enhanced bone regeneration. Rat mesenchymal stromal cells were treated with various application protocols of BMP-2 and LIPUS, and cell proliferation, alkaline phosphatase activity, and osteogenesis-related marker expression were evaluated. In vivo experiments were performed in a rabbit DO model according to the application protocols with different timings of BMP-2 and LIPUS application. Application of BMP-2 after LIPUS pretreatment (BMP-2 after LIPUS) showed greater cell proliferation than LIPUS treatment alone, and higher ALP activity than all other treatment protocols. BMP-2 after LIPUS also exhibited increased gene expression levels of ALP, Cbfa1, and Osterix compared with LIPUS treatment alone. In vivo experiments revealed no significant differences in bone healing based on the timing of LIPUS treatment in DO. The combination of BMP-2 and LIPUS resulted in increased bone volume and bone mineral density compared with BMP-2 or LIPUS. Regarding the timing of BMP-2 application, the application of BMP-2 after LIPUS pretreatment led to greater bone volume than the application of BMP-2 before LIPUS. The results of this study suggest that the combined treatment of BMP-2 and LIPUS can lead to enhanced bone healing in DO and that effective bone healing can be achieved through the application of LIPUS before BMP-2.

Application of BMP in Bone Tissue Engineering.

At present, bone nonunion and delayed union are still difficult problems in orthopaedics. Since the discovery of bone morphogenetic protein (BMP), it has been widely used in various studies due to its powerful role in promoting osteogenesis and chondrogenesis. Current results show that BMPs can promote healing of bone defects and reduce the occurrence of complications. However, the mechanism of BMP in vivo still needs to be explored, and application of BMP alone to a bone defect site cannot achieve good therapeutic effects. It is particularly important to modify implants to carry BMP to achieve slow and sustained release effects by taking advantage of the nature of the implant. This review aims to explain the mechanism of BMP action in vivo, its biological function, and how BMP can be applied to orthopaedic implants to effectively stimulate bone healing in the long term. Notably, implantation of a system that allows sustained release of BMP can provide an effective method to treat bone nonunion and delayed bone healing in the clinic.

Orchestration of energy metabolism and osteogenesis by Mg2+ facilitates low-dose BMP-2-driven regeneration

The clinical application of bone morphogenetic protein-2 (BMP-2) is limited by several factors, including ineffectiveness at low doses and severe adverse effects at high doses. To address these efficacy and safety limitations, we explored whether orchestration of energy metabolism and osteogenesis by magnesium ion (Mg2+) could reduce the dose and thereby improve the safety of BMP-2. Our results demonstrated that rapid metabolic activation triggered by BMP-2 was indispensable for subsequent osteogenesis. Moreover, inadequate metabolic stimulation was shown to be responsible for the ineffectiveness of low-dose BMP-2. Next, we identified that Mg2+, as an ''energy propellant", substantially increased cellular bioenergetic levels to support the osteogenesis via the Akt-glycolysis-Mrs2-mitochondrial axis, and consequently enhanced the osteoinductivity of BMP-2. Based on the mechanistic discovery, microgel composite hydrogels were fabricated as low-dose BMP-2/Mg2+ codelivery system through microfluidic and 3D printing technologies. An in vivo study further confirmed that rapid and robust bone regeneration was induced by the codelivery system. Collectively, these results suggest that this bioenergetic-driven, cost-effective, low-dose BMP-2-based strategy has substantial potential for bone repair.

An Audit of the effect of Bone Morphogenetic Protein-2 Treatment in patients with non-union of long bone fractures.

To evaluate the outcomes, clinical and radiological application of Bone Morphogenetic Protein-2 alone versus Bone Morphogenetic Protein-2 with autograft in long bone non-unions. A prospective review of patients was done with fracture non-union admitted to Aga Khan University Hospital, Karachi, from January 2016 to January 2019. The patients were divided into two groups; those exposed to Bone Morphogenetic Protein-2 alone in group 1, and those exposed to Bone Morphogenetic Protein-2 plus autologous graft in group 2. Background characteristics of both the groups were analysed. Patients were followed up at 6, 12 and 24 weeks through their medical records. The primary outcome was postoperative union at 6, 12 and 24. Union was defined by having the clinical union as well as the radiological union at the same time of assessment. Of the 80 patients enrolled, 13(16.25%) were excluded, and 5(6.25%) were lost to follow-up. The final sample had 62(77.5%) patients; 35(56.5%) in group 1, and 27(43.5%) in group 2. Union at 6 weeks was observed in 13(21%) patients; 8(62%) in group 1, and 5(38%) in group 2. Union at 12 weeks was observed in 38(61%) patients; 20(53%) in group 1, and 18(47%) in group 2. Results showed that using the adjuvant treatment alone was not worse than using it along with bone autologous graft.

Application of Bone Morphogenetic Protein 7 Enhanced the Osteogenic Differentiation and Mineralization of Bone Marrow-Derived Stem Cells Cultured on Deproteinized Bovine Bone

The growth of bone morphogenetic protein 7 (BMP-7) has been applied for tissue regeneration due to its osteoinductive properties. The aim of this research is to analyze the enhancing effects of BMP-7 on the osteogenic differentiation and mineralization of human bone marrow-derived stem cells cultured on the bovine bone particle. After the stem cells were loaded onto the bone graft material, their morphology was observed on day 7. Viability assays based on the application of fluorescent stains were used for qualitative analyses. Alkaline phosphatase activity assays and Alizarin red staining were used for the assessment of osteogenic differentiation on days 7 and 14. Next-generation mRNA sequencing was applied to evaluate global gene expression. Gene ontology and pathway analysis was used to propose the underlying mechanism. Fibroblast-like morphology was attained with the stem cells. The cells were shown to be firmly attached to the bone particle. Most of the stem cells produced an intense green fluorescence. The relative cellular viability assay values for BMP-7 groups at 0, 10, and 100 ng/mL on day 7 were 0.295 ± 0.003, 0.250 ± 0.002, and 0.240 ± 0.003, respectively (p &lt; 0.05). Alkaline phosphatase activity was significantly higher in BMP-7 groups at concentration of 100 ng/mL compared to the control on days 7 and 14 (p &lt; 0.05). The results of the mineralization assay showed significantly higher values for BMP-7 groups at 100 ng/mL concentration when compared with the control (p &lt; 0.05). The expression of RUNX2 was increased with application of BMP-7 and mitogen-activated protein kinase pathway was associated with the target genes. Overall, this study shows that in vitro application of BMP-7 increases alkaline phosphorylase activity and mineralization of stem cells culture on deproteinized bovine bone mineral. The study suggests that combining stem cells with osteoinductive growth factors with scaffolds can have synergy effects on osteogenic differentiation.

Inhibitory Effects of Combined Bone Morphogenetic Protein 2, Vascular Endothelial Growth Factor, and Basic Fibroblast Growth Factor on Osteoclast Differentiation and Activity.

Bone morphogenetic protein 2 (BMP-2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factors (bFGF) are important regulators of bone development and bone remodeling involving the coordination of osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The synergistic promotions of these growth factors on osteogenesis in the appropriate combination have been confirmed by a lot of studies, but the effect of this combined application on osteoclastogenesis still remains ambiguous. On the basis of comparing the osteoclastic potentials under stimulation of BMP-2, VEGF, or bFGF alone, this study focused on their combined effects on the differentiation and activity of osteoclasts. Our results showed that osteoclastogenesis was enhanced to some extent under the stimulation of BMP-2, VEGF, or bFGF alone, and the potential of these three growth factors to stimulate osteoclastogenesis was VEGF > BMP-2 > bFGF. However, the treatment with the combination of BMP-2 (50 ng/mL), VEGF (1 ng/mL), and bFGF (10 ng/mL), the most suitable dose combination for osteogenesis optimized in our previous study, weakened osteoclast differentiation confirmed by smaller tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells, lower TRAP activity, and lower expression of dendritic cell-specific transmembrane protein, an important molecule regulating osteoclast fusion. Moreover, BMP-2, VEGF, and bFGF in combination also moderately inhibited the bone-resorbing activity of mature osteoclasts by suppressing the expression of osteoclast-specific genes cathepsin K, and matrix metalloproteinase-9. The underlying molecular mechanisms involved the suppression of the receptor activator of nuclear factor-κB ligand-induced c-Fos levels and the activation of nuclear factor of activated T cells c1, two major transcription factors in osteoclast differentiation. Taken together, our study showed that the combination of BMP-2 (50 ng/mL), VEGF (1 ng/mL), and bFGF (10 ng/mL) promoted osteoblastogenesis but inhibited osteoclastogenesis. Thus, the simultaneous use of BMP-2 (50 ng/mL), VEGF (1 ng/mL), and bFGF (10 ng/mL) in an appropriate combination might improve efficacious bone regeneration in a clinical setting. Impact statement Few studies have addressed the combined effects of multiple growth factors on osteoclasts. This study demonstrated that the simultaneous use of bone morphogenetic protein 2 (BMP-2; 50 ng/mL), vascular endothelial growth factor (VEGF; 1 ng/mL), and basic fibroblast growth factors (bFGF; 10 ng/mL), the most suitable dose combination for osteogenesis optimized in our previous study, showed inhibitory effects on the differentiation and activity of osteoclasts. Our results suggest that the growth factor signaling pathways in osteoclasts may interact with each other. Furthermore, this study could provide new insights into the optimal application of BMP-2, VEGF, and bFGF for bone repair and regeneration.

Role and application of bone morphogenetic proteins in articular cartilage regeneration

Role and application of bone morphogenetic proteins in articular cartilage regeneration

The application of bone morphogenetic proteins in medicine, dentistry, sport and rehabilitation: A review of literature

Bone tissue is a mineralized structure with a complicated metabolism and due to its mechanical functions its structure must be adapted to the bone function. The BMP protein group stimulates the formation of bone and cartilage and influences numerous non-osteogenic processes. As a result of their osteogenic effect, BMP proteins are used in numerous areas of medicine, including dentistry and orthopaedics, as well as sport and rehabilitation. The publications used in this paper were sourced from the PubMed and the Google Scholar databases. The index entries used to search the databases included BMP, bone morphogenetic proteins, medicine, dentistry and sport. BMP proteins have a wide range of applications, particularly in dentistry and sports medicine. The study demonstrates that autogenous material is the best for bone regeneration as a result of using resources of BMP proteins and bone-forming cells. Undeniably, the condition of the patient's body undergoing treatment with BMP is not without significance. According to the authors of the article, all applications and treatment options with the use of BMPs are yet to be known. Perhaps further development of medicine will make their discovery possible.

Bone Morphogenetic Protein-2 in Development and Bone Homeostasis.

Bone morphogenetic proteins (BMPs) are multi-functional growth factors belonging to the Transforming Growth Factor-Beta (TGF-β) superfamily. These proteins are essential to many developmental processes, including cardiogenesis, neurogenesis, and osteogenesis. Specifically, within the BMP family, Bone Morphogenetic Protein-2 (BMP-2) was the first BMP to be characterized and has been well-studied. BMP-2 has important roles during embryonic development, as well as bone remodeling and homeostasis in adulthood. Some of its specific functions include digit formation and activating osteogenic genes, such as Runt-Related Transcription Factor 2 (RUNX2). Because of its diverse functions and osteogenic potential, the Food and Drug Administration (FDA) approved usage of recombinant human BMP-2 (rhBMP-2) during spinal fusion surgery, tibial shaft repair, and maxillary sinus reconstructive surgery. However, shortly after initial injections of rhBMP-2, several adverse complications were reported, and alternative therapeutics have been developed to limit these side-effects. As the clinical application of BMP-2 is largely implicated in bone, we focus primarily on its role in bone. However, we also describe briefly the role of BMP-2 in development. We then focus on the structure of BMP-2, its activation and regulation signaling pathways, BMP-2 clinical applications, and limitations of using BMP-2 as a therapeutic. Further, this review explores other potential treatments that may be useful in treating bone disorders.

Immediate versus delayed application of bone morphogenetic protein-2 solution in damaged extraction sockets: a preclinical in vivo investigation

To compare the clinical, radiographic, and histological healing patterns between the immediate and delayed applications of bone morphogenetic protein-2 (BMP-2) in damaged extraction sockets in dogs. The distal roots of the fourth premolars of the mandible were extracted bilaterally in five beagle dogs, and buccal bone defects (4mm wide and 9mm high) were surgically created. Collagenated biphasic calcium phosphate (CBCP) soaked for 10min in 100μL of BMP-2 solution was applied immediately to the defect site in the control group. In the test group, the BMP-2 solution of same dose was injected into the grafted site 2weeks after grafting with a saline-soaked CBCP. The dogs were sacrificed 2weeks later. Clinical, histological, and radiographic analyses were followed. Swelling and inflammatory reactions were predominantly observed in the control group at 2weeks. The area of new bone formation was significantly larger in the control group compared with the test group (10.8 ± 7.0 mm2 [mean ± SD] and 6.3 ± 3.1 mm2, respectively; p = 0.043). No significant difference was found in ridge width at 2mm, 4mm and 6mm below the lingual bone crest between the control (2.6 ± 1.0mm, 3.2 ± 0.9mm and 4.5 ± 0.5mm, respectively) and test group (3.3 ± 1.0mm, 3.7 ± 1.3mm and 4.2 ± 1.0mm; all p > 0.05). Delayed application of BMP-2 2weeks after surgery did not show any advantage over immediate application of BMP-2 in terms of new bone formation. This study suggests that it might be better to apply BMP-2 immediately in alveolar ridge preservation, instead of delayed application, in order to enhance new bone formation.

Injectable hydrogel delivering bone morphogenetic protein-2, vascular endothelial growth factor, and adipose-derived stem cells for vascularized bone tissue engineering

We aimed to evaluate the integration of stem cells with injectable microspheres loaded with growth factors using a chitosan (CS) scaffold to promote healthy bone regeneration. We prepared and injected CS scaffolds containing adipose-derived stem cell (ADSC)-, vascular endothelial growth factor (VEGF)-, and bone morphogenetic protein-2 (BMP-2)-loaded nanohydroxyapatite (nHA)/poly lactic-co-glycolic acid microspheres (PLGAs) into critical-sized mandibular bone defects in rabbits. This injectable hydrogel displayed excellent physicochemical properties and degradability and achieved sustainable release and bioactivity preservation for both BMP-2 and VEGF. Computed tomography imaging and gross and histological observations indicated that bone defect cavities in the control group did not narrow and were filled with granulation tissue. Limited new bone formation for the first 12 weeks post-operation was observed in the defect cavities of the VEGF group; the scaffold degraded gradually and was replaced with fibrous connective tissue. In the BMP-2 or BMP-2/VEGF groups, bone defect cavities narrowed with time and healed completely after 12 weeks; scaffolds gradually degraded and infiltrated tightly into the surrounding tissues. Overall, the BMP-2/VEGF group demonstrated greater new bone formation, faster healing, and better callus remodeling. Simultaneous application of VEGF and BMP-2, therefore, promoted ossification and vascularization in critical-sized rabbit mandibular bone defects.

CLINICAL APPLICATION OF BONE MORPHOGENETIC PROTEIN ON FRACTURE HEALING PROCESS

Delayed union or non-union often occurs in bone healing fracture process. The clinical application of Bone Morphogenetic Proteins (BMPs) has helped an increasing number of patients achieve bone regeneration in clinical area lacking simple solutions for difficult bone healing situations. Many researches has proved that BMPs improved fracture healing regeneration. In this review article, introduction and current clinical issues are summarized on efficacy and function of BMPs. Currently, rhBMP-2 and rhBMP-7 have shown clinical significance but other subfamily members of BMPs still lacked of evidence.