BMP Group Research Articles

The use of biphasic calcium phosphate with or without bone morphogenic protein-2 for bone regeneration during immediate implant placement in a micropig model: A pilot study

PurposeThe aim of this pilot study is to investigate bone regeneration in a three wall defect during immediate implant placement, using porous biphasic calcium phosphate (BCP) granules with or without recombinant human bone morphogenetic protein – 2 (rhBMP-2). Materials and MethodsAlveolar defects were created in the mandible of five female, adult micropigs. The lower right 4th premolar was extracted and the buccal cortex removed. Immediate implants were placed and the defect was grafted. Control group (n = 2), received BCP granules and fibrin sealant. The test group (n = 3) received BCP granules in combination with fibrin sealant and rhBMP-2. A collagen membrane was placed over the graft and primary closure of the wound was achieved. The pigs were all euthanized at 6 months after the first surgery. Histology evaluation and histomorphometry analyses calculating % bone implant contact (%BIC) and % bone area (%BA) were performed. ResultsOne pig in the BMP group died prematurely at 3 months after the first surgery. At specimen harvest, there were no dehiscence of all surgical sites and implant survival rate was 100%. The control group demonstrated no new bone formation at the buccal surface of the dental implants at 6 months. The mean %BIC for the BMP group at 6 months was 75.53 ± 12.52%. The mean %BA for the BMP group 6 months was 52.82 ± 3.27%. ConclusionWithin the limitations of this pilot study, the use of rhBMP-2 resulted in significant new bone formation in a non-contained defect around an immediate implant.

Experimental Study on Construction of Tissue Engineered Bone by Autologous Oxygen Release Nano-Bionic Scaffold Combined with Bone Morphogenetic Protein-2 Induced Bone Marrow Mesenchymal Stem Cells

Bone marrow mesenchymal stem cells (BMSCs) are used for bone tissue engineering. BMP-2 and autologous oxygen-releasing nano-bionic scaffolds promote bone differentiation of BMSCs. Our study intends to evaluate the role of autologous oxygen-releasing nano-bionic scaffolds combined with BMP-2-induced BMSCs in the construction of tissue engineered bone. Rat BMSCs were isolated and transfected with NC (negative control group) and BMP-2 (BMP-2 plasmid group), respectively. Healthy male SD rats were randomly and equally divided into fracture group, negative control group and the BMP-2 group which was implanted with autologous oxygen-releasing nano-bionic scaffolds to synthesize BMSCs and transfected with BMP-2 plasmids respectively followed by analysis of osteophytes growth, ALP activity, expression of BMP-2, type II collagen, Runx2 and OC by real time PCR, TGF-β1 secretion by ELISA and BMP-2 protein expression by western blot. BMSCs induced by autologous oxygen release nano-bionic scaffold combined with BMP-2 can significantly promote the increase of bone mineral density, increase the expression of Runx2 and OC, promote ALP activity, upregulate type II collagen, BMP-2 mRNA and protein, and TGF-β1 secretion compared to fracture group (P < 0.05). The BMSCs induced by autologous oxygen-releasing nanobionic scaffolds transfected with BMP-2 had a more significant effect on bone repair. Autologous oxygen-releasing nano-bionic scaffolds combined with BMP-2-induced BMSCs can promote bone healing by regulating BMP-2 and increasing osteogenesis at the bone defect.

Correction to: NELL-1, HMGB1, and CCN2 Enhance Migration and Vasculogenesis, But Not Osteogenic Differentiation Compared to BMP2 by Fahmy-Garcia S, van Driel M, Witte-Buoma J, Walles H, van Leeuwen JPTM, van Osch GJVM, and Farrell E. Tissue Eng Part A 2018;24(3-4):207-218. DOI: 10.1089/ten.tea.2016.0537.

Tissue Engineering Part AVol. 25, No. 15-16 CorrectionsFree AccessCorrection to: NELL-1, HMGB1, and CCN2 Enhance Migration and Vasculogenesis, But Not Osteogenic Differentiation Compared to BMP2 by Fahmy-Garcia S, van Driel M, Witte-Buoma J, Walles H, van Leeuwen JPTM, van Osch GJVM, and Farrell E. Tissue Eng Part A 2018;24(3-4):207-218. DOI: 10.1089/ten.tea.2016.0537Published Online:5 Aug 2019https://doi.org/10.1089/ten.tea.2016.0537.correxAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail In the February 2018 issue of Tissue Engineering, Part A (vol. 24, no. 3-4; 207-218) the article entitled “NELL-1, HMGB1, and CCN2 Enhance Migration and Vasculogenesis, But Not Osteogenic Differentiation Compared to BMP2” by Fahmy-Garcia et al. requires correction.The authors discovered that the incorrect image was used as a representative picture of the BMP2 group condition (10 ng/ml) in Figure 3A. This image is from another experimental group but was mistakenly used as representative picture of MSC mineralization under BMP2 treatment. The authors have revised Figure 3A as below:As the images are representative, and were not used for the quantification of the mineral deposition, this error does not change the results shown in Figure 3 nor the overall message of the article in any way.The online version of the article has been corrected to reflect this. The authors apologize for this error.FiguresReferencesRelatedDetails Volume 25Issue 15-16Aug 2019 InformationCopyright 2019, Mary Ann Liebert, Inc., publishersTo cite this article:Correction to: NELL-1, HMGB1, and CCN2 Enhance Migration and Vasculogenesis, But Not Osteogenic Differentiation Compared to BMP2 by Fahmy-Garcia S, van Driel M, Witte-Buoma J, Walles H, van Leeuwen JPTM, van Osch GJVM, and Farrell E. Tissue Eng Part A 2018;24(3-4):207-218. DOI: 10.1089/ten.tea.2016.0537.Tissue Engineering Part A.Aug 2019.1188-1188.http://doi.org/10.1089/ten.tea.2016.0537.correxPublished in Volume: 25 Issue 15-16: August 5, 2019PDF download

BMP-2 gene delivery in cell-loaded and cell-free constructs for bone regeneration.

To induce osteogenicity in bone graft substitutes, plasmid-based expression of BMP-2 (pBMP-2) has been successfully applied in gene activated matrices based on alginate polymer constructs. Here, we investigated whether cell seeding is necessary for non-viral BMP-2 gene expression in vivo. Furthermore, to gain insight in the role of BMP-producing cells, we compared inclusion of bone progenitor cells with non-osteogenic target cells in gene delivery constructs. Plasmid DNA encoding GFP (pGFP) was used to trace transfection of host tissue cells and seeded cells in a rat model. Transgene expression was followed in both cell-free alginate-ceramic constructs as well as constructs seeded with syngeneic fibroblasts or multipotent mesenchymal stromal cells (MSCs). Titration of pGFP revealed that the highest pGFP dose resulted in frequent presence of positive host cells in the constructs. Both cell-loaded groups were associated with transgene expression, most effectively in the MSC-loaded constructs. Subsequently, we investigated effectiveness of cell-free and cell-loaded alginate-ceramic constructs with pBMP-2 to induce bone formation. Local BMP-2 production was found in all groups containing BMP-2 plasmid DNA, and was most pronounced in the groups with MSCs transfected with high concentration pBMP-2. Bone formation was only apparent in the recombinant protein BMP-2 group. In conclusion, we show that non-viral gene delivery of BMP-2 is a potentially effective way to induce transgene expression in vivo, both in cell-seeded as well as cell-free conditions. However, alginate-based gene delivery of BMP-2 to host cells or seeded cells did not result in protein levels adequate for bone formation in this setting, calling for more reliable scaffold compatible transfection methods.

Evaluation of Heterotopic Ossification After Using Recombinant Human Bone Morphogenetic Protein-2 in Transforaminal Lumbar Interbody Fusion: A Computed Tomography Review of 996 Disc Levels.

Study Design:Retrospective cohort study.Objectives:Reported incidences and complications of heterotopic ossification (HO) after using recombinant human bone morphogenetic protein–2 (rhBMP-2) in transforaminal lumbar interbody fusion (TLIF) have been inconclusive. This study was designed to evaluate both incidences of radiologic and symptomatic HO in a large series of TLIFs using rhBMP-2.Methods:A total of 996 disc levels in 927 consecutive TLIF patients were retrospectively evaluated at 6-month postoperative follow-up in a single surgical practice. Subjects were separated into the BMP group and the control group. Operative reports, pre- and postoperative medical records were reviewed. Computed tomography (CT) scans were analyzed and graded independently for ossification at each disc level of TLIF.Results:A total of 933 disc levels were in the BMP group, and 63 were in the control group. Six-month fusion rate of interbody was 92.5% in the BMP group, which was significantly higher in contrast to 71.4% in the control group (P < .001). The incidence of radiologic HO in the BMP group was 13.5%, which was significantly higher than 1.6% in the control group (P = .006). After controlling for basic demographics and comorbidities, the presence of radiologic HO was significantly associated with the use of rhBMP-2 (P = .026). However, only one case in the BMP group (0.11%) developed a symptomatic HO (mild-medium left buttock pain, treated nonsurgically) involving left foramen of L5-S1.Conclusions:rhBMP-2 can be safely used in TLIF with regard to HO. There was a low rate of radiologic HO and minimal symptomatic HO, with high fusion rates at 6 months postoperative.

Recombinant Human Bone Morphogenic Protein-2 Combined With Autogenous Bone Graft for Reconstruction of Alveolar Cleft

Recombinant human bone morphogenic proteins (rhBMPs) have been introduced for reconstruction of alveolar defects. The volume of the bone formed at the cleft region may be related to rhBMP-2 dose. Greater side effects have been reported with increased doses of rhBMP-2. The aim of the present study was to assess the bone at the cleft area using low dose of rhBMP-2 combined with autogenous bone graft for reconstruction of the alveolar cleft. Patients with unilateral cleft lip and palate between the 11 to 14 years old were enrolled. After palatal expansion, autogenous graft was placed at the side of cleft in the control group (n = 6). In the BMP group, the rhBMP-2 was injected into the autogenous bone graft at the defect site (n = 5). Cone beam computed tomography (CBCT) images were taken of all patients immediately and 3 months after graft surgery to compare the density, thickness, and height of the bone graft between the 2 groups. Intermolar and interpremolar widths were also measured. The authors found less diminish of density and height of the bone graft 3 months postsurgery in patients with autogenous bone graft combined with rhBMP-2. However, significant difference in the relapse tendency of transverse dimension of the arch or thickness of the bone graft was not observed between the 2 groups. Thus, low dose rhBMP-2 combined with autogenous bone graft can be promising to reach predictable results after alveolar reconstruction in cleft lip and palate patients.

Application of Hydroxycholesterols for Alveolar Cleft Osteoplasty in a Rodent Model.

Bone morphogenetic proteins (BMPs) have played a central role in the regenerative therapies for bone reconstruction, including alveolar cleft and craniofacial surgery. However, the high cost and significant adverse effect of BMPs limit their broad application. Hydroxycholesterols, naturally occurring products of cholesterol oxidation, are a promising alternative to BMPs. The authors studied the osteogenic capability of hydroxycholesterols on human mesenchymal stem cells and the impact of hydroxycholesterols on a rodent alveolar cleft model. Human mesenchymal stem cells were treated with control medium or osteogenic medium with or without hydroxycholesterols. Evaluation of cellular osteogenic activity was performed. A critical-size alveolar cleft was created and one of the following treatment options was assigned randomly to each defect: collagen sponge incorporated with hydroxycholesterols, BMP-2, or no treatment. Bone regeneration was assessed by means of radiologic and histologic analyses and local inflammation in the cleft evaluated. Moreover, the role of the hedgehog signaling pathway in hydroxycholesterol-mediated osteogenesis was examined. All cellular osteogenic activities were significantly increased on human mesenchymal stem cells treated with hydroxycholesterols relative to others. The alveolar cleft treated with collagen sponge with hydroxycholesterols and BMP-2 demonstrated robust bone regeneration. The hydroxycholesterol group revealed histologically complete bridging of the alveolar defect with architecturally mature new bone. The inflammatory responses were less in the hydroxycholesterol group compared with the BMP-2 group. Induction of hydroxycholesterol-mediated in vitro osteogenesis and in vivo bone regeneration were attenuated by hedgehog signaling inhibitor, implicating involvement of the hedgehog signaling pathway. Hydroxycholesterols may represent a viable alternative to BMP-2 in bone tissue engineering for alveolar cleft.

Injectable Scaffold for Bone Marrow Stem Cells and Bone Morphogenetic Protein-2 to Repair Cartilage.

The limits of the microfracture (MFX) treatment in terms of lesion size and long-term tissue functionality makes it necessary to investigate different alternatives to repair focal cartilage lesions. The present study aims at evaluating the efficacy of a minimally invasive approach against the conventional MFX to repair a chondral defect in rabbits. An injectable scaffold of BMP-2 pre-encapsulated in PLGA microspheres dispersed in a Pluronic F-127 solution is proposed as support of cells and controlled delivery system for the growth factor. MFX was compared versus the injectable system seeded with mesenchymal stem cells (MSCs), both without BMP-2 and under controlled release of BMP-2 at 2 different doses (3 and 12 µg/scaffold). The different treatments were evaluated on a 4-mm diameter chondral defect model using 9 experimental groups of 4 rabbits (8 knees) each, throughout 24 weeks. Histologically, all the treated groups, except MFX treated, responded significantly better than the control group (nontreated defect). Although no significant differences were found between the treated groups, only BMP(12), MSC-BMP(12), and MFX-BMP(3) groups showed nonsignificant differences when compared with the normal cartilage. The hydrogel system proposed to control the release rate of the BMP-2 was safe, easily injectable, and also provided good support for cells. Treatments with MSCs or BMP-2 repaired efficiently the chondral lesion created in rabbits, being less invasive than MFX treatment.

Synergistic effect of stem cells from human exfoliated deciduous teeth and rhBMP-2 delivered by injectable nanofibrous microspheres with different surface modifications on vascularized bone regeneration

To provide a suitable 3D microenvironment for bone regeneration, we selected the injectable poly (l-lactic acid) nanofibrous microspheres (PLLA NF-Ms) with different surface modifications to serve as cell micro-carriers or protein vehicles on-demand. Results showed that polydopamine (PDA) modified NF-Ms (PDA-NF-Ms) exhibited good affinity for stem cells from human exfoliated deciduous teeth (SHED), and Heparin-Dopamine (Hep-Dopa) conjugated with NF-Ms (Hep-Dopa NF-Ms) are able to immobilize and slowly release recombinant human bone morphogenic protein-2 (rhBMP-2) efficiently. In vivo evaluations were carried out in both ectopic subcutaneous implantation and orthotopic cranial bone defect nude mouse models (φ = 4 mm). The results suggested that PDA-NF-Ms could support SHED survival over 4 weeks. All experimental groups with SHED/PDA-NF-Ms engraftment showed angiogenesis activity. But, no effect of SHED/PDA-NF-Ms on osteogenesis was found in ectopic implantation, which is different from the result in cranial defect. The rhBMP-2 released from Hep-Dopa NF-Ms could significantly guide bone tissue regeneration in both ectopic and orthotopic site. At 8 weeks, both BMP-2 group and dual group showed large amounts of bone formation in situ, despite the fact that quantitative results of micro-CT did not demonstrate significant difference between them. More blood vessels were observed in SHED and Dual groups, which verifies the quality improvement of regenerated osseous tissues. Regeneration of vascularized bone tissue was, thus, highly expected upon implanting SHED/PDA-NF-Ms and rhBMP-2-loaded Hep-Dopa NF-Ms together. The strategy developed in this study represents a promising method for satisfactorily promoting bone regeneration.

Prospective Evaluation of Radiculitis following Bone Morphogenetic Protein-2 Use for Transforaminal Interbody Arthrodesis in Spine Surgery.

Study DesignProspective observational cohort study.PurposeThis study aims to evaluate the safety and efficacy of bone morphogenetic protein-2 (BMP-2) in transforaminal lumbar interbody fusion (TLIF) with regard to postoperative radiculitis.Overview of LiteratureBone morphogenetic protein (BMP) is being used increasingly as an alternative to iliac crest autograft in spinal arthrodesis. Recently, the use of BMP in TLIF has been examined, but concerns exist that the placement of BMP close to the nerve roots may cause postoperative radiculitis. Furthermore, prospective studies regarding the use of BMP in TLIF are lacking.MethodsThis prospective study included 77 patients. The use of BMP-2 was determined individually, and demographic and operative characteristics were recorded. Leg pain was assessed using the Visual Analog Scale (VAS) for pain and the Sciatica Bothersome Index (SBI) with several secondary outcome measures. The outcome data were collected at each follow-up visit.ResultsAmong the 77 patients, 29 were administered with BMP. Postoperative leg pain significantly improved according to VAS leg and SBI scores for the entire cohort, and no clinically significant differences were observed between the BMP and control groups. The VAS back, Oswestry Disability Index, and Short-Form 36 scores also significantly improved. A significantly increased 6-month fusion rate was noted in the BMP group (82.8% vs. 55.3%), but no significant differences in fusion rate were observed at the 12- and 24-month follow-up. Heterotopic ossification was observed in seven patients: six patients and one patient in the BMP and control groups, respectively (20.7% vs. 2.1%). However, no clinical effect was observed.ConclusionsIn this prospective observational trial, the use of BMP in TLIF did not lead to significant postoperative radiculitis, as measured by VAS leg and SBI scores. Back pain and other functional outcome scores also improved, and no differences existed between the BMP and control groups. The careful use of BMP in TLIF appears to be both safe and effective.

Microcalcification and BMP-2 in breast cancer: correlation with clinicopathological features and outcomes.

BackgroundMicrocalcification is a very important diagnostic information in breast cancer. The purpose of this study was to determine the relationship of clinicopathological features and prognosis of breast cancer with microcalcification and to detect biomarkers related to the possible mechanisms of microcalcifications.Patients and methodsAll 529 subjects with microcalcifications were selected from patients who had been examined using breast mammography. The control group did not have detectable microcalcifications, and was matched in a ratio of 1:3. The clinicopathological factors, progression-free survival (PFS), and overall survival were evaluated by SPSS.ResultsThere was a significant difference in tumor size between the two groups, with larger tumors in the calcification group than the control group, and the proportion of patients in the calcification group with tumors of >5 cm was 20.4% vs 17.2% in the control group (P=0.041). The proportion of patients with lymph node metastasis in the calcification group was higher than that of the control group (35% vs 27.9%, P=0.027). The recurrence rate in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) patients with microcalcification was higher than that in the control group (P=0.035 and 0.044). BMP-2 expression was higher in breast cancer tissues, especially in breast cancer tissues with microcalcifications. The recurrence rate in the BMP-2(+) group was higher than that in the BMP-2(−) group both in DCIS and IDC (P=0.044 and 0.049). Microcalcifications and the positive expression of BMP-2 were independent factors affecting the PFS of the breast cancer patients.ConclusionThrough the analysis of this study, it was found that the prognosis of the patients with microcalcification was relatively poor. BMP-2 was highly expressed in the breast cancer with microcalcification and was associated with poor prognosis.

Predictive Factors and Rates of Fusion in Minimally Invasive Transforaminal Lumbar Interbody Fusion Utilizing rhBMP-2 or Mesenchymal Stem Cells.

Several fusion adjuncts exist to enhance fusion rates during minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). The objective of this study was to compare fusion rates in patients undergoing MI-TLIF with either rhBMP-2 or cellularized bone matrix (CBM). We conducted a single surgeon retrospective cohort study of patients who underwent MI-TLIF with either rhBMP-2 or CBM placed in an interbody cage. Single and multilevel procedures were included. Fusion was assessed on computed tomography scans at 12-month follow-up by an independent, blinded, board-certified neuroradiologist. Fusion rates and rate of revision surgery were compared with a Fisher exact test between the 2 groups. A multivariate regression analysis was performed to identify patient factors that were predictive of radiographic nonunion after MI-TLIF. A total of 93 fusion levels in 78 patients were reviewed. Thirty-nine patients received CBM, and 39 patients received rhBMP-2. The patients receiving rhBMP-2 were older on average (61.4 vs 55.6, P = .03). The overall fusion rate was 68% in the CBM group (32/47 levels) and 78% in the rhBMP-2 group (36/46) (P = .35). Only preoperative hypertension was predictive of radiographic nonunion (odds ratio = 3.5, P = .05). There were 3 smokers in the CBM group and 4 smokers in the BMP group, and 1 in each group experienced radiographic pseudarthrosis. A total of 4 patients, 3 in the CBM group and 1 in the BMP group (P = .61), required revision for symptomatic pseudarthrosis. All of these patients had a single-level index procedure. There were no differences in radiographic fusion and rate of revision surgery in patients who underwent MI-TLIF with either rhBMP-2 or CBM as fusion adjuncts. 3. Both rhBMP-2 and CBMs can be used as effective fusion adjuncts without any clear advantage of one over the other.

Combination Use of BMP2 and VEGF165 Promotes Osseointegration and Stability of Titanium Implants in Irradiated Bone.

Background Clinical data demonstrated that failure rate of titanium implant in irradiated bone was 2-3 times higher than that in nonirradiated bone and it is difficult to get the ideal results in irradiated bone. Purpose The aim of the study was to investigate the effects of HBO, BMP2, VEGF165, and combined use of BMP2/VEGF165 on osseointegration and stability of titanium implant in irradiated bone. Materials and Methods Sixty rabbits were randomly assigned to 5 groups (control group, HBO group, VEGF165 group, BMP2 group, and BMP2/VEGF165 group) after receiving 15 Gy radiation. Implant surgery was performed on tibias eight weeks later. They were sacrificed at two or eight weeks after operation. Implant stability, calcium, and ALP activity in serum, the ratio of bone volume to total volume, the rate of bone growth, and gene expression were assessed. Result There was no mortality and no implants failed during the experiment. Implant stability was significantly compromised in the control group compared to the other four experimental groups, and the BMP2/VEGF165 group had the highest implant stability. HBO, BMP2, and VEGF165 significantly increased BV/TV and the rate of bone growth, while the BMP2/VEGF165 showed the best effect among groups. The expression of RUNX2 in HBO, BMP2, and VEGF165/BMP2 group was higher than that in the VEGF165 and control groups at two weeks. The expression of OCN in HBO, BMP2, VEGF165, and VEGF165/BMP2 groups was higher than that in the control group, and the gene expression of CD31 was higher in HBO, VEGF165, and BMP2/VEGF165 groups than that in control and BMP2 groups. Conclusion HBO, BMP2, and VEGF165 could increase bone formation around the implant and improved the implant stability in irradiated bone. The combination use of BMP2 and VEGF165 may be promising in the treatment of implant patients with radiotherapy.

Overaugmentation to compensate for postextraction ridge atrophy using a putty-type porcine bone substitute material with recombinant bone morphogenetic protein-2: 4weeks of healing in a canine model.

The aims of the present study were (i) to determine the short-term effects of putty-type porcine bone substitute material (PB) with recombinant bone morphogenetic protein-2 (rhBMP-2) for alveolar ridge preservation (ARP) and (ii) evaluate the early healing of labial overaugmentation. Two groups were randomly assigned to the extraction sockets in mandibular incisors of eight dogs: labial overaugmentation with (i) PB (control) or (ii) rhBMP-2-loaded PB (BMP). Microcomputed tomography (micro-CT), and histologic and histomorphometric analyses were performed after 4weeks. Micro-CT revealed that some of the overaugmented PB was dispersed in both groups. The new bone volume was significantly larger in the BMP group than in the control group (18.4 ± 3.3 vs. 15.5 ± 3.0mm3, mean ± SD, P < 0.05). Labial bone resorption was generally found histologically. No signs of mineralization were observed in the overaugmented area despite significantly increased ridge width, as compared to the adjacent tooth area. The area of new bone formation was larger in the BMP group than in the control group overall (23.7 ± 18.8 vs. 18.3 ± 21.2mm2) and in three parts (apical, middle, and coronal), although the difference was statistically significant only in the coronal part (7.7 ± 7.9 vs. 4.6 ± 6.4mm2, P < 0.05). The addition of rhBMP-2 enhanced ossification in the coronal part of the extraction socket relative to using PB alone. Overaugmentation increased the ridge dimension with no evidence of ossification in situ at 4weeks. In early healing following ARP, rhBMP-2 enhances bone formation within the socket, but ossification in the overaugmented area needs to be studied further.

Does Recombinant Human Bone Morphogenic Protein 2 Affect Perioperative Blood Loss after Lumbar and Thoracic Spinal Fusion?

Study DesignRetrospective cohort design.PurposeThis study aimed to determine whether recombinant human bone morphogenic protein 2 (rhBMP-2) reduces total perioperative blood loss during lumbar and thoracic fusion.Overview of LiteraturePrevious studies on rhBMP-2 versus iliac crest bone grafting in thoracic and lumbar fusions have yielded mixed results regarding reductions in blood loss and have largely neglected the postoperative period when analyzing total blood loss. Additionally, these studies have been limited by heterogeneity and sample size.MethodsWe analyzed the blood loss patterns of 617 consecutive adult patients undergoing lumbar and/or thoracic fusions requiring subfascial drain placement at a single institution from January 2009 to December 2016. Patients were divided into BMP and non-BMP cohorts, and a propensity score analysis was conducted to account for the differences between cohorts.ResultsAt a per-level fused basis, the BMP group exhibited a significant reduction in the intraoperative (66.1 mL per-level fused basis; 95% confidence interval [CI], 127.9 to 4.25 mL; p=0.036) and total perioperative blood loss (100.7 mL per-level fused basis; 95% CI, 200.9 to 0.5 mL; p=0.049). However, no significant differences were observed in an analysis when not controlling for the number of levels or when examining the postoperative drain output.ConclusionRhBMP-2 appears to reduce both intraoperative and total blood loss during lumbar and thoracic fusions on a per-level fused basis. This total reduction in blood loss was achieved via intraoperative effects because RhBMP-2 had no significant effect on the postoperative drain output.

Osseointegrative effect of rhBMP-2 covalently bound on a titan-plasma-spray-surface after modification with chromosulfuric acid in a large animal bone gap-healing model with the G\xf6ttingen minipig

BackgroundBone morphogenetic proteins play an important role as osseointegrative factors. It is used widely in orthopedic research and surgery to enhance the osseointegrative potential of implants, e.g., in spinal fusion or alveolar socket augmentation. The aim of the present study was to investigate the benefit of rhBMP-2 on a titan plasma spray (TPS) layer after a special modification with chromosulfuric acid (CSA) at different postoperative times, regarding osseoconduction and osseoinduction.MethodsWe allocated 27 Göttinger minipigs into three groups consisting of nine animals each. They received four dumbbell-shaped implants in the metaphyseal parts of the femora. The implants had a TPS surface with (CSA group) and without a CSA treatment (TPS group). The former received an additional layer of BMP-2 (BMP-2 group). For the assessment of osseointegration after healing periods of 4, 8, and 12 weeks, histomorphometry was applied to undecalcified specimens after staining according to Masson-Goldner. An intravital labeling with different fluorochromes was used in the gap model. A multivariable analysis with repeated measurement design was performed for statistical evaluation.ResultsWe observed several statistical differences in a three-way ANOVA. The comparison between the BMP-2 and the TPS group (two-way ANOVA) showed statistically significant differences in terms of the osseoinduction (osteoid volume), and pronounced for the osseoconduction (bone and osteoid ongrowth), in favor of the BMP-2 group. In the pairwise comparison between BMP-2 and CSA (two-way ANOVA), no statistical significance occurred. The intravital staining with tetracycline, calcein green, and xylenol orange revealed no considerable differences between the groups.ConclusionBMP-2, covalently bound on a CSA-treated TPS surface, has positive effects on the osseointegration in the large animal bone gap-healing model over the observation period of 12 weeks.

Effect of guided bone regeneration on bone quality surrounding dental implants

Bone quality as well as its quantity at the implant interface is responsible for determining stability of the implant system. The objective of this study is to examine the nanoindentation based elastic modulus (E) at different bone regions adjacent to titanium dental implants with guided bone regeneration (GBR) treated with DBM and BMP-2 during different post-implantation periods. Six adult male beagle dogs were used to create circumferential defects with buccal bone removal at each implantation site of mandibles. The implant systems were randomly assigned to only GBR (control), GBR with demineralized bone matrix (DBM), and GBR with DBM + recombinant human bone morphogenetic protein-2 (rhBMP-2) (BMP) groups. Three animals were sacrificed at each 4 and 8 weeks of post-implantation healing periods. Following buccolingual dissection, the E values were assessed at the defects (Defect), interfacial bone tissue adjacent to the implant (Interface), and pre-existing bone tissue away from the implant (Pre-existing). The E values of BMP group had significantly higher than control and DBM groups for interface and defect regions at 4 weeks of post-implantation period and for the defect region at 8 weeks (p < 0.043). DBM group had higher E values than control group only for the defect region at 4 weeks (p < 0.001). The current results indicate that treatment of rhBMP-2 with GBR accelerates bone tissue mineralization for longer healing period because the GBR likely facilitates a microenvironment to provide more metabolites with open space of the defect region surrounding the implant.

Escherichia coli-derived BMP-2-absorbed β-TCP granules induce bone regeneration in rabbit critical-sized femoral segmental defects.

This study investigated whether Escherichia coli-derived bone morphogenetic protein (BMP)-2 (E-BMP-2) adsorbed onto β-tricalcium phosphate (β-TCP) granules can induce bone regeneration in critical-size femoral segmental defects in rabbits. Bone defects 20mm in size and stabilized with an external fixator were created in the femur of New Zealand white rabbits, which were divided into BMP-2 and control groups. E-BMP-2-loaded β-TCP granules were implanted into defects of the BMP-2 group, whereas defects in the controls were implanted with β-TCP granules alone. At 12 and 24weeks after surgery, radiographs were obtained of the femurs and histological and biomechanical assessments of the defect area were performed. Bone regeneration was quantified using micro-computed tomography at 24weeks. Radiographic and histologic analyses revealed bone regeneration in the BMP-2 group but not the control group; no fracturing of newly formed bone occurred when the external fixator was removed at 12weeks. At 24weeks, tissue mineral density, the ratio of bone volume to total volume, and volumetric bone mineral density of the callus were higher in the BMP-2 group than in control animals. In the former, ultimate stress, extrinsic stiffness, and failure energy measurements for the femurs were higher at 24weeks than at 12weeks. E-BMP-2-loaded β-TCP granules can effectively promote bone regeneration in long bone defects.

The effect of bone morphogenetic protein-6 on chondrocyte formation from periosteum derived cells

Objective To observe the influence of cytokines of bone morphogenetic protein-6 (BMP-6) on the process of chondrocyte formation from rabit periosteum derived cells (PDCs). Methods Periosteum was obtained from tibia of rabit, and isolated periosteum derived cells by tissue culture method. The passage 3 PDCs were used for experiment. Experiment was divided into control group, chondrogenic differentiation and BMP-6 group. PDCs were expanded and differentiated in the presence or absence of BMP-6 and common culture medium. PDCs were observed by inverted microscope for morphological changes. Then collagen type Ⅱ (COL2A1) immunohistochemistry staining and toluidine blue staining detected collagen and aggrecan (ACAN) expression of these cells after 14 days. Reverse transcriptase-polymerase chain reaction (RT-PCR) were using to detect the expression of ACAN, COL2A1 and sex determining region Y 9 (Sox-9) mRNA of these cells. Results PDCs in chondrogenic differentiation group and BMP-6 group were changing into chondrocyte-like cells. Collagen type Ⅱ immunohistochemistry staining and toluidine blue staining were positive in chondrogenic differentiation group and BMP-6 group with relatively deeper staining in BMP-6 group, while the results were negative in control group. RT-PCR indicated that the relative expressions of ACAN, COL2A1 and Sox-9 mRNA in BMP-6 group (0.813±0.042, 1.621±0.156, 0.927±0.218) were higher than those in chondrogenic differentiation group (0.443±0.086, 0.652±0.126, 0.513±0.172) and control group (0.181±0.042, 0.272±0.062, 0.214±0.062) (P=0.000). Western blotting revealed that the expressions of ACAN, COL2A1 and Sox-9 in BMP group (0.347±0.091, 0.782±0.214, 0.381±0.108) were higher than those in chondrogenic differentiation group (0.205±0.065, 0.513±0.128, 0.223±0.054) and control group (0.105±0.036, 0.268±0.072, 0.125±0.041) (P=0.000). Conclusion PDCs can differentiate into chondrocyte-like cells under induction condition, and BMP-6 can significantly promote this process. Key words: Bone morphogenetic protein-6; Periosteum derived cells; Differentiation; Chondrocytes; Tissue engineering

Wednesday, September 26, 2018 7:35 AM–9:00 AM ePosters: P1. NF-κB inhibitor suppresses edema and promotes rhBMP-2-mediated bone formation in spinal fusion

BACKGROUND CONTEXT Loading of absorbable collagen sponges (ACS) with recombinant human bone morphogenic protein-2 (rhBMP-2) has been successfully used to enhance bone formation and to induce spinal fusion. However, side effects, such as soft-tissue edema and inflammation, have been reported. NEMO binding domain peptide (NBD) inhibits activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a central regulator of immune response. PURPOSE To investigate NBD's potential to reduce rhBMP-2-induced soft-tissue inflammation and to stimulate spinal fusion. STUDY DESIGN/SETTING To evaluate inflammation, ACS containing either high dose rhBMP-2, rhBMP-2+NBD, NBD only or buffer were only implanted into intramuscular fusion beds of 32 rats. To analyze new bone formation in the presence of NBD, posterolateral intertransverse lumbar fusion procedures were performed on 16 rats. ACS implants were loaded with rhBMP-2 or rhBMP-2+NBD. PATIENT SAMPLE No patients, animal study. OUTCOME MEASURES T2-weighted relaxation time (T2-RT), histological analysis (HE appropriate post hoc tests for multiple comparisons using Tukey's honestly significant was applied. p≤.05 was considered significant. RESULTS T2-RT values were increased in the BMP-2 group compared to BMP-2+NBD, NBD and ACS groups. No difference was detected between BMP-2+NBD versus NBD and ACS controls. Histological analysisof the implant-surrounding zones showed an increase in cellular activity in the BMP-2 group compared to BMP-2+NBD and controls. Presence of rhBMP-2 increased relative NF-κB binding and gene expression of inflammatory markers, interleukin (IL)1β, IL6, IL18, chemokine ligand (CCL)2 and CCL3 compared to controls. In the BMP-2+NBD group, cytokine expression was blocked. No differences were found between BMP-2+NBD and control groups. BMP-2+NBD resulted in a higher bone volume and reduced trabecular spacing compared to BMP-2, a higher number of levels fused, and similar structural properties of the bone tissue. CONCLUSIONS In summary, NBD reduces soft-tissue edema formation, reduces recruitment of inflammatory cells, diminishes NF-κB binding and blocks transcription of NF-κB-regulated cytokines in response to high-dose rhBMP-2 in rats. Furthermore, NBD stimulates bone formation in rhBMP-2-mediated spinal fusion, potentially through cross-talk of the NF-κB pathway with other pathways. The results of this study might provide the basis to develop new therapeutic approaches for spinal fusion using graft material with a combinatory administration of rhBMP-2 and NBD.