Objectives. Interleukin 18 (IL-18) is a regulatory cytokine that degrades the disc matrix. Bone morphogenetic protein-2 (BMP-2) stimulates synthesis of the disc extracellular matrix. However, the combined effects of BMP-2 and IL-18 on human intervertebral disc degeneration have not previously been reported. The aim of this study was to investigate the effects of the anabolic cytokine BMP-2 and the catabolic cytokine IL-18 on human nucleus pulposus (NP) and annulus fibrosus (AF) cells and, therefore, to identify potential therapeutic and clinical benefits of recombinant human (rh)BMP-2 in intervertebral disc degeneration. Methods. Levels of IL-18 were measured in the blood of patients with intervertebral disc degenerative disease and in control patients. Human NP and AF cells were cultured in a NP cell medium and treated with IL-18 or IL-18 plus BMP-2. mRNA levels of target genes were measured by real-time polymerase chain reaction, and protein levels of aggrecan, type II collagen, SOX6, and matrix metalloproteinase 13 (MMP13) were assessed by western blot analysis. Results. The serum level of patients (IL-18) increased significantly with the grade of IVD degeneration. There was a dramatic alteration in IL-18 level between the advanced degeneration (Grade III to V) group and the normal group (p = 0.008) Furthermore, IL-18 induced upregulation of the catabolic regulator MMP13 and downregulation of the anabolic regulators aggrecan, type II collagen, and SOX6 at 24 hours, contributing to degradation of disc matrix enzymes. However, BMP-2 antagonised the IL-18 induced upregulation of aggrecan, type II collagen, and SOX6, resulting in reversal of IL-18 mediated disc degeneration. Conclusions. BMP-2 is anti-catabolic in human NP and AF cells, and its effects are partially mediated through provocation of the catabolic effect of IL-18. These findings indicate that BMP-2 may be a unique therapeutic option for prevention and reversal of disc degeneration. Cite this article: S. Ye, B. Ju, H. Wang, K-B. Lee. Bone morphogenetic protein-2 provokes interleukin-18-induced human intervertebral disc degeneration. Bone Joint Res 2016;5:412–418. DOI: 10.1302/2046-3758.59.BJR-2016-0032.R1

The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) for the treatment of congenital pseudarthrosis of the tibia has been investigated in only one previous study, with promising results. The aim of this study was to determine whether rhBMP-2 might improve the outcome of this disorder. We reviewed the medical records of five patients with a mean age of 7.4 years (2.3 to 21) with congenital pseudarthrosis of the tibia who had been treated with rhBMP-2 and intramedullary rodding. Ilizarov external fixation was also used in four of these patients. Radiological union of the pseudarthrosis was evident in all of them at a mean of 3.5 months (3.2 to 4) post-operatively. The Ilizarov device was removed after a mean of 4.2 months (3.0 to 5.3). These results indicate that treatment of congenital pseudarthrosis of the tibia using rhBMP-2 in combination with intramedullary stabilisation and Ilizarov external fixation may improve the initial rate of union and reduce the time to union. Further studies with more patients and longer follow-up are necessary to determine whether this surgial procedure may significantly enhance the outcome of congenital pseudarthrosis of the tibia, considering the refracture rate (two of five patients) in this small case series

We investigated the rates of expression of bone morphogenetic protein-2 (BMP-2) in 29 adult patients with high-grade malignant fibrous histiocytoma of soft tissue, using the BMP-2-specific monoclonal antibody, AbH3b2/17, and found that they ranged from 1.9% to 78.9%. The survival at five years of the groups expressing high (≥30%) and low (< 30%) levels of BMP-2 was 85.7% and 36.3%, respectively. Multivariable analysis showed that only BMP-2 had prognostic significance for continuous disease-free survival and for overall survival (p < 0.05). Our findings indicate that over-expression of BMP-2 in malignant fibrous histiocytoma of soft tissue is the most reliable prognostic indicator of the parameters assessed

To demonstrate the potential clinical benefits and safety of recombinant human bone morphogenetic protein-2 (rhBMP-2)/Absorbable Collagen Sponge (ACS) in the treatment of open tibial shaft fractures, as measured by the reduction of secondary interventions to promote fracture healing. In this prospective, controlled, multinational trial, patients were randomized to standard care (intramedullary nail and soft tissue management) or to standard care and rhBMP-2/ACS (0. 75mg/ml, 1. 5 mg/ml) implanted at definitive wound closure. 450 patients were enrolled at 49 centres. RhBMP-2 dose-dependently decreased the risk of secondary intervention for delayed union (p=0. 0004). Safety was similar among treatment groups

One hundred and thirty-eight patients from South Africa were part of an international study aimed to determine whether the rate of healing of compound tibial fractures treated with intramedullary nails improved with recombinant human bone morphogenetic protein-2 (rhBMP-2). There were 118 men and 20 women, with a mean age of 33.3 years. According to the Gustilo-Anderson classification, there were 32 type-I, 50 type-II, 38 type-IIA and 18 type-IIIB fractures. Patients were randomised to one of three groups: the standard care (SC) group, in which 47 patients were treated with intramedullary nail fixation and soft-tissue management, the group treated with SC and 0.75 mg/ml of rhBMP-2, which comprised 50 patients, and the group treated with SC and 1.50 mg/ml of rhBMP-2, which comprised 40 patients. At 20 and 26 weeks, there was a significant difference (p < 0.027) in the rate of fracture healing in the three groups. At one year follow-up union was achieved in 30 patients (63.8%) in the SC group and in 27 patients (54%) and 30 patients (73.2%) in the two rhBMP-2 groups respectively. All patients with type-IIIB fractures developed nonunion in the SC group, but 56% in the 0.75-mg/ml rhBMP-2 group and 50% in the 1.5-mg/ml rhBMP-2 group achieved union. Secondary intervention and medical costs were reduced in patients treated with rhBMP-2

Objectives. We performed a systematic review of the literature to determine the safety and efficacy of bone morphogenetic protein (BMP) compared with bone graft when used specifically for revision spinal fusion surgery secondary to pseudarthrosis. Methods. The MEDLINE, EMBASE and Cochrane Library databases were searched using defined search terms. The primary outcome measure was spinal fusion, assessed as success or failure in accordance with radiograph, MRI or CT scan review at 24-month follow-up. The secondary outcome measure was time to fusion. Results. A total of six studies (three prospective and three retrospective) reporting on the use of BMP2 met the inclusion criteria (203 patients). Of these, four provided a comparison of BMP2 and bone graft whereas the other two solely investigated the use of BMP2. The primary outcome was seen in 92.3% (108/117) of patients following surgery with BMP2. Although none of the studies showed superiority of BMP2 to bone graft for fusion, its use was associated with a statistically quicker time to achieving fusion. BMP2 did not appear to increase the risk of complication. Conclusion. The use of BMP2 is both safe and effective within the revision setting, ideally in cases where bone graft is unavailable or undesirable. Further research is required to define its optimum role. Cite this article: Mr P. Bodalia. Effectiveness and safety of recombinant human bone morphogenetic protein-2 for adults with lumbar spine pseudarthrosis following spinal fusion surgery: A systematic review. Bone Joint Res 2016;5:145–152. DOI: 10.1302/2046-3758.54.2000418

Open tibia fractures are often associated with delayed union and non-union. The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) to treat acute, open tibial shaft fractures has been approved in both Europe (InductOs) and the United States (INFUSE Bone Graft). These approvals were based on the results of a prospective, randomized study of 450 patients with open tibia fractures that has already been published (. Govender et al. 2002. ). Material and Methods: A sub-group of patients from the above study with Gustilo Grade IIIA and IIIB open tibia fractures was separately analyzed. Patients treated with the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]) were compared to those that received the standard of care and an implant containing the approved concentration of rhBMP-2 (1.50 mg/mL). The primary outcome measured was the incidence of secondary intervention to promote bone healing during the twelve months of follow-up. Fischer’s exact test was used to compare the two groups. Results: There were 55 patients in the control group and 59 patients in the rhBMP-2 group. The combined incidence of nail dynamization (those both performed and from broken screws) was higher in the control group 28/55 than the rhBMP-2 group 18/59. Significantly more control patients required autologous bone grafting because of delayed union or non-union as compared to the rhBMP-2 group [10/55 (18%) versus 1/59 (2%), respectively; p=0.0033]. More patients in the control group 15/55 required invasive secondary interventions to promote bone healing than those in the rhBMP-2 group 6/59 (p=0.0283). Fewer infections were observed in the rhBMP-2 group 14/59 as compared to the control group 23/55. In addition, the average time to full weight bearing for patients was 34 days sooner when rhBMP-2 was used (96 versus 130 days). Conclusions: The addition of rhBMP-2 to the treatment of open tibia fractures represents a significant improvement over the standard of care. Treatment of Grade III tibia fractures with rhBMP-2 was shown to reduce the incidence of both invasive secondary interventions and infections. The additional expense of using rhBMP-2 can be justified for these severe fractures, by the potential to eliminate of the cost required to treat these complications

This study was performed to evaluate the clinical and radiographic outcomes in patients undergoing anterior cervical discectomy and fusion (ACDF) with rhBMP-2 and polyetheretherketone (PEEK) cages with our standard treatment of allograft spacers and demineralised bone matrix.

Forty-six patients who underwent primary ACDF were included in the study. Twenty two patients with PEEK spacers and rhBMP-2 were compared to twenty four patients with allograft spacers and demineralised bone matrix all supplemented with an anterior locking plate. All patients were examined preoperatively and at two, six, twelve and twenty-four weeks and one and two years following surgery. Their cervical Oswestry scores,VAS for neck and arm pain and a pain diagram were recorded at every visit. A radiographic examination was also performed and patients were questioned for dysphagia, hoarseness of voice and any other difficulties. Radiographs were evaluated for prevertebral swelling, bone formation, subsidence and likelihood of fusion. CT scans were performed in any individual at twelve months if there was a concern of non union.

There was no significant difference in pain scores between rhBMP-2 and allograft spacer patients. There was improvement in both groups from their preoperative scores. Incidence of hoarseness of voice was also similar in both groups. There were statistically significant more patients with dysphagia in the rhBMP-2 group at two and six weeks following surgery. All patients in the rhBMP-2 group achieved a radiological diagnosis of probable fusion at their latest follow up (thirty-eight levels). In the allograft group 23/24 patients achieved a diagnosis of probable fusion (39/40 levels). End plate resorption was observed radiologically in 100% of the levels where rhBMP-2 was used. Prevertebral swelling on lateral radiographs was significantly greater in patients with rhBMP-2 causing dysphagia. The cost of implants was three times higher in patients with PEEK cage and rhBMP-2.

The use of rhBMP-2 leads to consistent fusion in the cervical spine. Significantly higher rates of prevertebral swelling, dysphagia and s higher cost are major drawbacks. End plate resorption was an unusual radiographic finding with the use of rhBMP-2.

In the treatment of bone non-unions an alternative to bone autografts is the use of bone morphogenetic proteins (BMP-2, BMP-7) with powerful osteoinductive and osteogenic properties. In clinical settings, BMPs are applied using absorbable collagen sponges. Supraphysiological doses are needed and major side effects may occur as induce ectopic bone formation, chronic inflammation and excessive bone resorption. In order to increase the efficiency of the delivered for BMPs we designed cryostructured collagen scaffolds functionalized with hydroxyapatite, mimicking the structure of cortical bone (aligned porosity, anisotropic, ANI) or trabecular bone (random distributed porosity, isotropic, ISO). We hypothesize that anisotropic structure would enhance osteoconductive properties of the scaffolds increasing rhBMP-2 regenerative properties. In vitro, both scaffolds presented similar mechanical properties, rhBMP-2 retention and delivery capacity. For in vivo testing, a rat femoral critical size defect model was created. Four groups were assessed depending on the implant applied to the bone defect: ISO, unloaded isotropic sponge; ISO-BMP, isotropic sponge loaded with 5 μg of hrBMP-2; ANI, unloaded anisotropic sponge; and ANI-BMP, anisotropic sponge loaded with 5 μg of hrBMP-2. Regeneration was allowed for 10 weeks. X-ray, μCT, biomechanical testing and histology were used to evaluate repair. Independently of their structure, sponges loaded with rhBMP-2 demonstrate increased bone volume, and biomechanical properties than their controls (p<0.01 and p<0.05 respectively). Globally, ANI-BMP group demonstrated better bone regeneration outputs with increased defect bridging (p<0.05 when compared ANI-BMP vs ISO-BMP groups). In conclusion, anisotropic cryostructured collagen scaffolds improve the efficiency of rhBMP-2 in bone regeneration.

Sustained release of BMP-2 is reported to be able to reduce the required dose of BMP-2 for bone induction. Nanohydroxyapatite (nHAp) has an osteoinduction capability which is lack in conventional hydroxyapatite. In this study, we combined PLA-PEG with nHAp and investigated the bone regenerative capacity of the newly established composite material of rhBMP-2/PLA-PEG/nHAp in a rat model of spinal fusion. The PLA-PEG was liquidized in acetone and mixed with nHAp and rhBMP-2. The sheet-shaped BMP-2/PLA-PEG (5mg)/nHAp (12.5mg) composites were prepared while evaporating the acetone. The release kinetics of rhBMP-2 from the composite was investigated by ELISA. In vivo bone formation was investigated by posterolateral spinal fusion in rats (the dosage of rhBMP-2; 0µg/ 0.5µg / 3µg). Bone formation was assessed by µCT and histology at post-op. 8 weeks. The composite showed the burst-release in the initial 24 hours (69% of total release) and the subsequent sustained-release for 25 days. According to µCT and histology of the spinal fusion experiment for all groups the bone formation was observed. While no bony bridging was observed in 0 µg and 0.5 µg BMP groups; in 3 µg group bony bridging and fusion were achieved. We developed a new technology for bone regeneration with rhBMP-2/PLA-PEG/nHAp composite. The reduction in the required dose of BMP-2 for bone induction was achieved. This result can be explained by the high bone induction ability of nHAp and sustainable release of BMP from PLA-PEG in the composite.

While new biomaterials for regenerative therapies are being reported in the literature, clinical translation is slow. Existing regenerative approaches rely on high doses of growth factors, such as BMP-2 in bone regeneration, which can cause serious side effects. We describe an ultra-low-dose growth factor technology yielding high bioactivity based on a simple polymer, poly (ethyl acrylate) (PEA), and report its translation to a clinical veterinary setting. This polymer-based technology triggers spontaneous fibronectin organization and stimulates growth factor signaling, enabling synergistic integrin and BMP-2 receptor activation in mesenchymal stem cells. To translate this technology, we use plasma-polymerized PEA on 2D and 3D substrates to enhance cell signaling in vitro, showing the complete healing of a critical-size bone injury in mice in vivo. We demonstrate its safety and efficacy in a Münsterländer dog with a non-healing humerus fracture, establishing the clinical translation of advanced ultra-low-dose growth factor treatment.

We have examined whether primary human muscle-derived cells can be used in ex vivo gene therapy to deliver BMP-2 and to produce bone in vivo. Two in vitro experiments and one in vivo experiment were used to determine the osteocompetence and BMP-2 secretion capacity of cells isolated from human skeletal muscle.

We isolated five different populations of primary muscle cells from human skeletal muscle in three patients. In the first in vitro experiment, production of alkaline phosphatase by the cells in response to stimulation by rhBMP-2 was measured and used as an indicator of cellular osteocompetence. In the second, secretion of BMP-2 was measured after the cell populations had been transduced by an adenovirus encoding for BMP-2. In the in vivo experiment, the cells were cotransduced with a retrovirus encoding for a nuclear localised β-galactosidase gene and an adenovirus encoding for BMP-2. The cotransduced cells were then injected into the hind limbs of severe combined immune-deficient (SCID) mice and analysed radiographically and histologically. The nuclear localised β-galactosidase gene allowed identification of the injected cells in histological specimens. In the first in vitro experiment, the five different cell populations all responded to in vitro stimulation of rhBMP-2 by producing higher levels of alkaline phosphatase when compared with non-stimulated cells. In the second, the five different cell populations were all successfully transduced by an adenovirus to express and secrete BMP-2. The cells secreted between 444 and 2551 ng of BMP-2 over three days. In the in vivo experiment, injection of the transduced cells into the hind-limb musculature of SCID mice resulted in the formation of ectopic bone at 1, 2, 3 and 4 weeks after injection. Retroviral labelling of the cell nuclei showed labelled human muscle-derived cells occupying locations of osteoblasts in the ectopic bone, further supporting their osteocompetence.

Cells from human skeletal muscle, because of their availability to orthopaedic surgeons, their osteocompetence, and their ability to express BMP-2 after genetic engineering, are an attractive cell population for use in BMP-2 gene therapy approaches.

The objective of this study was to investigate the effects of different doses rhBMP-2 on bone healing in an ovine lumbar interbody fusion model. In this study 22 sheep underwent two level lumbar interbody fusion using a ventrolateral approach with secondary dorsal fixation at L1/2 and L3/4. After randomization in one level a PEEK-cage was implanted filled with one of three doses rhBMP-2 (0,5mg; 1mg; 2mg) delivered on an ACS. The other level received an empty PEEK-cage or ACS filled cage. Animals were sacrificed after 3 and 6 months and decalcified histology was performed. This included histomorphological analysis well as histomorphometry of the tissues within the cage.

At 3 months after surgery the groups treated with rhBMP-2 showed higher amounts of bone tissue within the cage. At 6 months the amounts of bone tissue increased in all groups, were still lower in the groups without growth factor. At 3 months there was only one active osteolysis in the cage/ACS. 7 of 8 segments of the rhBMP-2 groups had a compromised bone structure around the implant. These areas were filled with fibrous tissue and fibrocartilage. This finding was not detected in the groups without rhBMP-2 at 3 months. At 6 months most of the segments with an empty cage or cage/ACS showed a chronic inflammation. Predominant cells were macrophages and giant cells. The groups treated with rhBMP-2 showed only a few mild chronic inflammatory reactions. The well-known dose dependent effect of rhBMP-2 on bone healing could also be recognized in our study. Attention has to be payed to the proinflammatory properties of the growth factor. Consistent with other studies we found 2 strong inflammatory reactions, each one in the lowest and highest dose group. Also, the potential for causing transient bone resorptions, according to the results of others, was demonstrated. At 3 months 7 of 8 segments treated with rhBMP-2 showed compromised peri-implant bone. Osteoblasts, but not osteoclasts, were seen in the periphery of these areas. It can be concluded that there where bone resorptions which already merged into an increased osteoblastic activity. Usually resorptions occur between 2 and 12 weeks and are followed by a period of increased osteoblastic activity. This finding wasn't recognized at 6 months anymore. Striking is that at 6 months most of the segments without rhBMP-2 showed a compromised bone structure around the implant with a mild to mainly moderate chronic inflammatory reaction. This cannot be attributed to the growth factor. Also, the ACS is degraded at 6 months and is unlikely a possible explanation. Therefore, the cage as a reason must be considered and it has to be questioned whether PEEK is the optimal material for interbody cages.

Aims: The present study examined the effect of ade-novirus-mediated recombinant human BMP-2 (RAd-BMP-2) gene therapy combined with bioactive glass (BG) microspheres in promotion of new bone formation. Methods: Harlan Dawley female rats (n=72) underwent unilateral surgery of right or left tibia in a random order. A round cortical window (⁻ 2.8 mm) was drilled into the anteromedial cortex of the proximal tibia. A smaller unicortical hole (⁻ 1.0 mm) was drilled 5 mm distally. Bone marrow was removed and the medullary space between the cortical holes was þlled with BG microspheres. Adenoviral vectors RAdBMP-2 carrying the BMP-2 gene or RAdLacZ harbouring the E. coli LacZ reporter gene were injected locally into the medullary spaces. The control defects were þlled with BG microspheres only. Empty control defects were left to heal without any þlling. The rats were killed 4 days, 2 and 8 weeks after surgery and the tibias were harvested for analyses. At each time point, six animals were used for pQCT, radiography, BEI-SEM and histomorphometric analyses. Results: All BG-þlled defects showed a time-related increase of intramedullary new bone. At 8 weeks, there was signiþcantly more new bone in defects treated with BG and RAdBMP-2 gene than in defects left to heal without þlling (p=0.003) (BG + RAdBMP-2: 25.0 ± 6.0% and empty control defects: 12.3 ± 3.8%). Also defects þlled with BG only showed higher new bone formation than empty control defects, but this was not statistically signiþcant (p=0.10) (BG: 19.9 ± 7.3%). Conclusions: The current study showed that local BMP-2 gene therapy enhances new bone formation on bioactive glass microspheres.

This article has been retracted, an editorial will follow.

Aims

Nonunion occurs when a fracture fails to heal permanently, often necessitating surgical intervention to stimulate the bone healing response. Current animal models of long-bone nonunion do not adequately replicate human pathological conditions. This study was intended as a preliminary investigation of a novel rat nonunion model using a two-stage surgical intervention, and to evaluate the efficacy of a selective prostaglandin E2 receptor 4 agonist (AKDS001) as a novel nonunion therapeutic agent compared with existing treatments.

Various approaches have been implemented to enhance bone regeneration, including the utilization of autologous platelet-rich plasma and bone morphogenetic protein-2. The objective of this study was to evaluate the impact of Marburg Bone Bank-derived bone grafts in conjunction with platelet-rich plasma (PRP), recombinant human bone morphogenetic protein-2 (rhBMP-2), and zoledronic acid (ZA) on osteogenesis within rabbit bone defects. Methodology. Bone defects (5mm in diameter) were created in the femurs of 96 male rabbits. The animals were allocated into five groups: (1) bone graft + PRP (BG + PRP), (2) bone graft + 5μg rhBMP-2 (BG + rhBMP-2), (3) bone graft + 5μg ZA (BG + ZA), (4) bone graft + 10μg rhBMP-2 + 5μg ZA (BG + rhBMP-2 + ZA), and (5) bone graft (BG). Marburg Bone Bank-processed human femoral head allografts were utilized for bone grafting. The rabbits were euthanized at 14-, 30-, and 60-days post-surgery, and their femurs underwent histopathological and histomorphometric assessments. Results. Histomorphometric analysis revealed significantly enhanced de novo osteogenesis within the bone allografts in the BG + PRP and BG + rhBMP-2 groups compared to the BG, BG + ZA, and BG + rhBMP-2 + ZA groups at 14 and 30 days (p < 0.05). However, on day 60, the BG + rhBMP-2 group exhibited elevated osteoclastic activity (early resorption). The local co-administration of ZA with thermally treated grafts impeded both bone graft resorption and new bone formation within the bone defect across all time points. The addition of ZA to BG + rhBMP-2 resulted in diminished osteogenic activity compared to the BG + rhBMP-2 group (p < 0.000). Conclusion. The study findings indicated that the combination of PRP and rhBMP-2 with Marburg bone grafts facilitates early-stage osteogenesis in bone defect healing. Incorporating ZA into the thermally treated bone graft hinders both graft resorption and de novo bone formation

Aims. Magnesium ions (Mg. 2+. ) play an important role in promoting cartilage repair in cartilage lesions. However, no research has focused on the role of Mg. 2+. combined with microfracture (MFX) in hyaline-like cartilage repair mediated by cartilage injury. This study aimed to investigate the beneficial effects of the combination of MFX and Mg. 2+. in cartilage repair. Methods. A total of 60 rabbits were classified into five groups (n = 12 each): sham, MFX, and three different doses of Mg. 2+. treatment groups (0.05, 0.5, and 5 mol/L). Bone cartilage defects were created in the trochlear groove cartilage of rabbits. MFX surgery was performed after osteochondral defects. Mg. 2+. was injected into knee joints immediately and two and four weeks after surgery. At six and 12 weeks after surgery, the rabbits were killed. Cartilage damage was detected by gross observation, micro-CT, and histological analysis. The expression levels of related genes were detected by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results. The histological results showed that the 0.5 mol/L Mg. 2+. group had deeper positive staining in haematoxylin-eosin (H&E), safranin O, Alcian blue, and type II collagen staining. The new cartilage coverage in the injury area was more complete, and the regeneration of hyaline cartilage was higher. The RT-qPCR results showed that sirtuin 1/bone morphogenetic protein-2/sex-determining region Y box 9 (SIRT1/BMP-2/SOX-9) and hypoxia-inducible factor 1-alpha (HIF-1α) messenger RNA levels were up-regulated after Mg. 2+. injection. Conclusion. MFX combined with Mg. 2+. treatment has a positive effect on cartilage repair. The Mg. 2+. injection dose of 0.5 mol/L is most effective in enhancing microfracture-mediated cartilage repair. Cite this article: Bone Joint Res 2025;14(1):20–32

Introduction. To develop an international guideline (AOGO) about use of osteobiologics in Anterior Cervical Discectomy and Fusion (ACDF) for treating degenerative spine conditions. Method. The guideline development process was guided by AO Spine Knowledge Forum Degenerative (KF Degen) and followed the Guideline International Network McMaster Guideline Development Checklist. The process involved 73 participants with expertise in degenerative spine diseases and surgery from 22 countries. Fifteen systematic reviews were conducted addressing respective key topics and evidence were collected. The methodologist compiled the evidence into GRADE Evidence-to-Decision frameworks. Guideline panel members judged the outcomes and other criteria and made the final recommendations through consensus. Result. Five conditional recommendations were created. A conditional recommendation is about the use of allograft, autograft or a cage with an osteobiologic in primary ACDF surgery. Other conditional recommendations are about use of osteobiologic for single or multi-level ACDF, and for hybrid construct surgery. It is suggested that surgeons use other osteobiologics rather than human bone morphogenetic protein-2 in common clinical situations. Surgeons are recommended to choose one graft over another or one osteobiologic over another primarily based on clinical situation, and the costs and availability of the materials. Conclusion. This AOGO guideline is the first to provide recommendations for the use of osteobiologics in ACDF. Despite the comprehensive searches for evidence, there were few studies completed with small sample sizes and primarily as case series with inherent risks of bias. Therefore high quality clinical evidence is demanded to improve the guideline

The efficacy of β-tricalcium phosphate (β-TCP) loaded with bone morphogenetic protein-2 (BMP-2)-gene-modified bone-marrow mesenchymal stem cells (BMSCs) was evaluated for the repair of experimentally-induced osteonecrosis of the femoral head in goats. Bilateral early-stage osteonecrosis was induced in adult goats three weeks after ligation of the lateral and medial circumflex arteries and delivery of liquid nitrogen into the femoral head. After core decompression, porous β-TCP loaded with BMP-2 gene- or β-galactosidase (gal)-gene-transduced BMSCs was implanted into the left and right femoral heads, respectively. At 16 weeks after implantation, there was collapse of the femoral head in the untreated group but not in the BMP-2 or β-gal groups. The femoral heads in the BMP-2 group had a normal density and surface, while those in the β-gal group presented with a low density and an irregular surface. Histologically, new bone and fibrous tissue were formed in the macropores of the β-TCP. Sixteen weeks after implantation, lamellar bone had formed in the BMP-2 group, but there were some empty cavities and residual fibrous tissue in the β-gal group. The new bone volume in the BMP-2 group was significantly higher than that in the β-gal group. The maximum compressive strength and Young’s modulus of the repaired tissue in the BMP-2 group were similar to those of normal bone and significantly higher than those in the β-gal group. Our findings indicate that porous β-TCP loaded with BMP-2-gene-transduced BMSCs are capable of repairing early-stage, experimentally-induced osteonecrosis of the femoral head and of restoring its mechanical function