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Long-term posterolateral spinal fusion in rabbits induced by rhBMP6 applied in autologous blood coagulum with synthetic ceramics.

ABSTRACT: Autologous bone graft substitute (ABGS) containing rhBMP6 in autologous blood coagulum (Osteogrow) is a novel therapeutic solution for bone regeneration. This study is aimed to investigate the long-term outcome of ABGS with synthetic ceramics (Osteogrow-C) in rabbit posterolateral spinal fusion (PLF) model. Osteogrow-C implants were implanted bilaterally between rabbit lumbar transverse processes. We compared the outcome following implantation of ABGS with ceramic particles of different chemical composition (TCP and biphasic ceramics containing both TCP and HA) and size (500-1700 µm and 74-420 µm). Outcome was analyzed after 14 and 27 weeks by microCT, histology, and biomechanical analyses. Successful bilateral spinal fusion was observed in all animals at the end of observation period. Chemical composition of ceramic particles has impact on the PLF outcome via resorption of TCP ceramics, while ceramics containing HA were only partially resorbed. Moreover, persistence of ceramic particles subsequently resulted with an increased bone volume in implants with small particles containing high proportion of HA. ABGS (rhBMP6/ABC) with various synthetic ceramic particles promoted spinal fusion in rabbits. This is the first presentation of BMP-mediated ectopic bone formation in rabbit PLF model with radiological, histological, and biomechanical features over a time course of up to 27 weeks.

SUBMITTER: Stokovic N

PROVIDER: S-EPMC9270325 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Remodeling of the human bony skeleton is constantly occurring with up to 10% annual bone volume turnover from osteoclastic and osteoblastic activity. A shift toward resorption can result in osteoporosis and pathologic fractures, while a shift toward deposition is required after traumatic, or surgical injury. Spinal fusion represents one such state, requiring a substantial regenerative response to immobilize adjacent vertebrae through bony union. Autologous bone grafts were used extensively prior to the advent of advanced therapeutics incorporating exogenous growth factors and biomaterials. Besides cost constraints, these applications have demonstrated patient safety concerns. This study evaluated the regenerative ability of a nanostructured, magnesium-doped, hydroxyapatite/type I collagen scaffold (MHA/Coll) augmented by autologous platelet-rich plasma (PRP) in an orthotopic model of posterolateral lumbar spinal fusion. After bilateral decortication, rabbits received either the scaffold alone (Group 1) or scaffold with PRP (Group 2) to the anatomic right side. Bone regeneration and fusion success compared to internal control were assessed by DynaCT with 3-D reconstruction at 2, 4, and 6 weeks postoperatively followed by comparative osteogenic gene expression and representative histopathology. Both groups formed significantly more new bone volume than control, and Group 2 subjects produced significantly more trabecular and cortical bone than Group 1 subjects. Successful fusion was seen in one Group 1 animal (12.5%) and 6/8 Group 2 animals (75%). This enhanced effect by autologous PRP treatment appears to occur via astounding upregulation of key osteogenic genes. Both groups demonstrated significant gene upregulation compared to vertebral bone controls for all genes. Group 1 averaged 2.21-fold upregulation of RUNX2 gene, 3.20-fold upregulation of SPARC gene, and 3.67-fold upregulation of SPP1 gene. Depending on anatomical subgroup (cranial, mid, caudal scaffold portions), Group 2 had significantly higher average expression of all genes than both control and Group 1-RUNX2 (8.23-19.74 fold), SPARC (18.67-55.44 fold), and SPP1 (46.09-90.65 fold). Our data collectively demonstrate the osteoinductive nature of a nanostructured MHA/Coll scaffold, a beneficial effect of augmentation with autologous PRP, and an ability to achieve clinical fusion when applied together in an orthotopic model. This has implications both for future study and biomedical innovation of bone-forming therapeutics.

Project description:BackgroundPosterolateral spinal fusion with autologous bone graft is considered the "gold standard" for lumbar degenerative disc disease (DDD) when surgical treatment is indicated. The potential role of mesenchymal stromal cells (MSCs) to replace the bone graft in this setting has not been fully addressed.ObjectiveTo analyze the safety, feasibility and potential clinical efficacy of the implantation of autologous MSCs embedded with tricalcium phosphate as a therapeutic alternative to bone graft in patients with DDD during posterolateral spine fusion.Study designPhase I/II single-arm prospective clinical trial.MethodsEleven patients with monosegmental DDD at L4-L5 or L5-S1 level were included. Autologous bone marrow-derived MSC were expanded in our Good Manufacturing Practice (GMP) Facility and implanted during spinal surgery embedded in a tricalcium phosphate carrier. Monitoring of patients included a postoperative period of 12 months with four visits (after the 1st, 3rd, 6th, and 12th month), with clinical and radiological assessment that included the visual analog scale (VAS), the Oswestry disability index (ODI), the Short-Form Health Survey (SF-36), the vertebral fusion grade observed through a simple Rx, and the evaluation of possible complications or adverse reactions. In addition, all patients were further followed up to 5 years for outcome.ResultsMedian age of patients included was 44 years (range 30-58 years), and male/female ratio was (6/5) L4-L5 and L5-S1 DDD was present five and six patients, respectively. Autologous MSCs were expanded in all cases. There were no adverse effects related to cell implantation. Regarding efficacy, both VAS and ODI scores improved after surgery. Radiologically, 80% of patients achieved lumbar fusion at the end of the follow-up. No adverse effects related to the procedure were recorded.ConclusionsThe use of autologous MSCs for spine fusion in patients with monosegmental degenerative disc disease is feasible, safe, and potentially effective.Trial registrationno. EudraCT: 2010-018335-17 ; code Identifier: NCT01513694 ( clinicaltrials.gov ).

Project description:Bone morphogenetic proteins (BMPs) are potent osteogenic proteins that induce new bone formation in vivo. However, their effect on bone healing in the trabecular bone surfaces remains challenging. We evaluated the safety and efficacy of recombinant human BMP6 (rhBMP6) applied within an autologous blood coagulum (ABC) in a surgically created wedge defect of the proximal tibia in patients undergoing high tibial osteotomy (HTO) for varus deformity and medial osteoarthritis of the knee. We enrolled 20 HTO patients in a randomized, placebo-controlled, double-blinded phase I/II clinical trial. RhBMP6/ABC (1.0 mg/10 mL ABC prepared from peripheral blood) or placebo (10 mL ABC containing excipients) was administered into the tibial wedge defects. Patients were followed for 0 to 24 months by clinical examination (safety) and computed tomography (CT) and serial radiographic analyses (efficacy). The results show that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 20 patients at 14 weeks after implantation. During the 24 months of follow-up, there were no serious adverse reactions recorded. The CT scans from defects of patients treated with rhBMP6/ABC showed an accelerated bone healing compared with placebo at 9 weeks (47.8 ± 24.1 versus 22.2 ± 12.3 mg/cm3 ; p = 0.008) and at 14 weeks (89.7 ± 29.1 versus 53.6 ± 21.9 mg/cm3 ; p = 0.006) follow-up. Radiographic analyses at weeks 6 and 24 and months 12 and 24 suggested the advanced bone formation and remodeling in rhBMP6/ABC-treated patients. In conclusion, we show that rhBMP6/ABC at a dose of 100 μg/mL accelerated bone healing in patients undergoing HTO without serious adverse events and with a good tolerability compared with placebo alone. Overall, for the first time, a BMP-based osteogenic implant was examined against a placebo for bone healing efficacy in the trabecular bone surface, using an objective bone mineral density measurement system. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Project description:STUDY DESIGN:Two-year clinical and radiographic follow-up of a double-blind, multicenter, randomized, intra-patient controlled, non-inferiority trial comparing a bone graft substitute (AttraX Putty) with autograft in instrumented posterolateral fusion (PLF) surgery. OBJECTIVES:The aim of this study was to compare PLF rates between 1 and 2 years of follow-up and between graft types, and to explore the role of bone grafting based on the location of the PLF mass. SUMMARY OF BACKGROUND DATA:There are indications that bony fusion proceeds over time, but it is unknown to what extent this can be related to bone grafting. METHODS:A total of 100 adult patients underwent a primary, single- or multilevel, thoracolumbar PLF. After instrumentation and preparation for grafting, the randomized allocation side of AttraX Putty was disclosed. The contralateral posterolateral gutters were grafted with autograft. At 1-year follow-up, and in case of no fusion at 2 years, the fusion status of both sides of each segment was blindly assessed on CT scans. Intertransverse and facet fusion were scored separately. Difference in fusion rates after 1 and 2 years and between grafts were analyzed with a Generalized Estimating Equations (GEE) model (P?<?0.05). RESULTS:The 2-year PLF rate (66 patients) was 70% at the AttraX Putty and 68% at the autograft side, compared to 55% and 52% after 1 year (87 patients). GEE analysis demonstrated a significant increase for both conditions (odds ratio 2.0, 95% confidence interval 1.5-2.7, P?<?0.001), but no difference between the grafts (P?=?0.595). Ongoing bone formation was only observed between the facet joints. CONCLUSION:This intra-patient controlled trial demonstrated a significant increase in PLF rate between 1 and 2 years after instrumented thoracolumbar fusion, but no difference between AttraX Putty and autograft. Based on the location of the PLF mass, this increase is most likely the result of immobilization instead of grafting. LEVEL OF EVIDENCE:1.

Project description:IntroductionLocal steroid administration during anterior cervical spine surgery has been shown to improve postoperative dysphagia. However, concerns over potential complications remain. This study aims to evaluate the effect of local steroid administration on bone regeneration and spine fusion in a preclinical model, as well as the impact on osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) in a 3D culture system.Materials and methodsForty-five rats underwent bilateral L4-L5 posterolateral lumbar fusion (PLF) utilizing local delivery of low-dose recombinant human bone morphogenetic protein-2 (rhBMP-2; 0.5 μg/implant). Rats were divided into three groups: no steroid (control), low dose (0.5 mg/kg), and high dose (2.5 mg/kg) of triamcinolone. Bone growth and fusion were assessed using radiography, blinded manual palpation, and micro-CT analysis and were visualized by histology. The impact of triamcinolone exposure on osteogenic differentiation of hBM-MSCs was evaluated by gene expression analysis, alkaline phosphatase activity assay, and alizarin red staining.ResultsNo significant differences in fusion scores or rates were seen in the low- or high-dose steroid treatment groups relative to untreated controls. Quantification of new bone formation via micro-CT imaging revealed no significant between-group differences in the volume of newly regenerated bone. Triamcinolone also had no negative impact on pro-osteogenic gene transcript levels, and ALP activity was enhanced in the presence of triamcinolone. Mineral deposition appeared comparable in cultures grown with and without triamcinolone.ConclusionsLocal steroid application does not seem to inhibit rhBMP-2-mediated spine fusion in rats, though our study may not be adequately powered to detect differences in fusion as measured by manual palpation or bone volume as measured by micro-CT. These findings suggest that local triamcinolone may not increase pseudarthrosis in spine fusion procedures. Further large animal and clinical studies to verify its safety and efficacy are warranted.

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Long-term posterolateral spinal fusion in rabbits induced by rhBMP6 applied in autologous blood coagulum with synthetic ceramics.

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