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Autologous blood coagulum is a physiological carrier for BMP6 to induce new bone formation and promote posterolateral lumbar spine fusion in rabbits.

ABSTRACT: In the present study, we describe autologous blood coagulum (ABC) as a physiological carrier for BMP6 to induce new bone formation. Recombinant human BMP6 (rhBMP6), dispersed within ABC and formed as an autologous bone graft substitute (ABGS), was evaluated either with or without allograft bone particles (ALLO) in rat subcutaneous implants and in a posterolateral lumbar fusion (PLF) model in rabbits. ABGS induced endochondral bone differentiation in rat subcutaneous implants. Coating ALLO by ABC significantly decreased the formation of multinucleated foreign body giant cells (FBGCs) in implants, as compared with ALLO alone. However, addition of rhBMP6 to ABC/ALLO induced a robust endochondral bone formation with little or no FBGCs in the implant. In rabbit PLF model, ABGS induced new bone formation uniformly within the implant resulting in a complete fusion when placed between two lumbar transverse processes in the posterolateral gutter with an optimum dose of 100-?g rhBMP6 per ml of ABC. ABGS containing ALLO also resulted in a fusion where the ALLO was replaced by the newly formed bone via creeping substitution. Our findings demonstrate for the first time that rhBMP6, with ABC as a carrier, induced a robust bone formation with a complete spinal fusion in a rabbit PLF model. RhBMP6 was effective at low doses with ABC serving as a physiological substratum providing a permissive environment by protecting against foreign body reaction elicited by ALLO.

SUBMITTER: Vukicevic S

PROVIDER: S-EPMC7027565 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Autologous blood coagulum is a physiological carrier for BMP6 to induce new bone formation and promote posterolateral lumbar spine fusion in rabbits.

Vukicevic Slobodan S Grgurevic Lovorka L Erjavec Igor I Pecin Marko M Bordukalo-Niksic Tatjana T Stokovic Nikola N Lipar Marija M Capak Hrvoje H Maticic Drazen D Windhager Reinhard R Sampath T Kuber TK Gupta Munish M

Journal of tissue engineering and regenerative medicine 20191110 1

In the present study, we describe autologous blood coagulum (ABC) as a physiological carrier for BMP6 to induce new bone formation. Recombinant human BMP6 (rhBMP6), dispersed within ABC and formed as an autologous bone graft substitute (ABGS), was evaluated either with or without allograft bone particles (ALLO) in rat subcutaneous implants and in a posterolateral lumbar fusion (PLF) model in rabbits. ABGS induced endochondral bone differentiation in rat subcutaneous implants. Coating ALLO by ABC ...[more]

PMID: 31671243

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Project description:Background contextPseudarthrosis following spinal fusion remains problematic despite modern surgical and grafting techniques. In surgical spinal fusion, new bone forms via intramembranous and endochondral ossification, with endochondral ossification occurring in the hypoxic zones of the fusion bed. During bone development and fracture healing, the key cellular mediator of endochondral ossification is the hypertrophic chondrocyte given its ability to function in hypoxia and induce neovascularization and ossification. We therefore hypothesize that hypertrophic chondrocytes may be an effective bone graft alternative.PurposeSpinal fusion procedures have increased substantially; yet 5% to 35% of all spinal fusions may result in pseudoarthrosis. Pseudoarthrosis may occur because of implant failure, infection, or biological failure, among other reasons. Advances in surgical techniques and bone grafting have improved fusion; however pseudarthrosis rates remain unacceptably high. Thus, the goal of this study is to investigate hypertrophic chondrocytes as a potential biological graft alternative.MethodsUsing a validated murine fracture model, hypertrophic chondrocytes were harvested from fracture calluses and transplanted into the posterolateral spines of identical mice. New bone formation was assessed by X-ray, microcomputed tomography (μCT), and in vivo fluorescent imaging. Results were compared against a standard iliac crest bone graft and a sham surgery control group. Funding for this work was provided by the Department of Orthopaedics and Rehabilitation, the OREF (Grant #16-150), and The Caitlin Lovejoy Fund.ResultsRadiography, μCT, and in vivo fluorescent imaging demonstrated that hypertrophic chondrocytes promoted bone formation at rates equivalent to iliac crest autograft. Additionally, μCT analysis demonstrated similar fusion rates in a subset of mice from the iliac crest and hypertrophic chondrocyte groups.ConclusionsThis proof-of-concept study indicates that hypertrophic chondrocytes can promote bone formation comparable to iliac crest bone graft. These findings provide the foundation for future studies to investigate the potential therapeutic use of hypertrophic chondrocytes in spinal fusion.

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: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:Study Design Randomized controlled trial. Objective Despite a large number of publications of outcomes after spinal fusion surgery, there is still no consensus on the efficacy of the several different fusion methods. The aim of this study was to determine whether transforaminal lumbar interbody fusion (TLIF) results in an improved clinical outcome compared with uninstrumented posterolateral fusion (PLF) in the surgical treatment for chronic low back pain. Methods This study included 135 patients with degenerative disk disease (n = 96) or postdiskectomy syndrome (n = 39). Inclusion criteria were at least 1 year of back pain with or without leg pain in patients aged 20 to 65 with one- or two-level disease. Exclusion criteria were sequestration of disk hernia, psychosocial instability, isthmic spondylolisthesis, drug abuse, and previous spine surgery other than diskectomy. Pain was assessed by visual analog scale (pain index). Functional disability was quantified by the disability rating index and Oswestry Disability Index. The global outcome was assessed by the patient and classified as much better, better, unchanged, or worse. The patients were randomized to conventional uninstrumented PLF (n = 67) or TLIF (n = 68). PLF was performed in a standardized fashion using autograft. TLIF was performed with pedicle titanium screw fixation and a porous tantalum interbody spacer with interbody and posterolateral autograft. The clinical outcome measurements were obtained preoperatively and at 12 and 24 months postoperatively. The 2-year follow-up rate was 98%. Results The two treatment groups improved significantly from preoperatively to 2 years' follow-up. At final follow-up, the results in the TLIF group were significantly superior to those in the PLF group in pain index (2.0 versus 3.9, p = 0.007) and in disability rating index (22 versus 36, p = 0.003). The Oswestry Disability Index was better in the TLIF group (20 versus 28, p = 0.110, not significant). The global assessment was clearly superior in the TLIF group: 63% of patients scored "much better" in the TLIF group as compared with 48% in the PLF group (p = 0.017). Conclusions The results of the current study support the use of TLIF rather than uninstrumented PLF in the surgical treatment of the degenerative lumbar spine. The less optimal outcome after uninstrumented PLF may be explained by the much higher reoperation rate.

Dataset Information

Autologous blood coagulum is a physiological carrier for BMP6 to induce new bone formation and promote posterolateral lumbar spine fusion in rabbits.

Publications

Autologous blood coagulum is a physiological carrier for BMP6 to induce new bone formation and promote posterolateral lumbar spine fusion in rabbits.

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