Spinal Fusion Rates Research Articles

Low-Intensity Pulsed Ultrasound Promotes Spinal Fusion by Regulating the Macrophage Polarization

Background: Spinal fusion is regarded as the gold standard procedure for treating spinal degeneration, tumors, and trauma. Inflammatory response is an important part in bone repair. We want to investigate the role of inflammatory macrophage (M1) and resident macrophage (M2) during spinal fusion. Methods: Thirty male Sprague Dawley rats (age: 12 weeks; weight: 300 g) were involved in the study. Spinal fusion model of SD rats was established by surgical procedures. LIPUS treatment (20 min/d, 5 d/wk) was performed three days after surgery. The rats were randomly divided into control group and LIPUS group and sacrificed on day 3 (n=6), day 5 (n=6), day 7 (n=6), day 10 (n=6) and day 14 (n=6) after spinal fusion surgery. Bone volume was measured by Micro-CT, fusion region was examined by Histological analyses, types of macrophages in the fusion area were examined by Immunohistochemical staining. Raw264.7 and BMDM cells were used in cell experiments. The cells were divided into control group and LIPUS group, control group were treated control and LIPUS group. Flow Cytometer was used to examine the rate of resident macrophages, real-time PCR was used to examine the mRNA level of anti-inflammation genes. The data was analyzed by SPSS version 22.0. Findings: Analyzing the presence of two different types of macrophages in a rat spinal fusion model, we found that LIPUS could promote spinal fusion and stimulate transition of the expression from F4-80+/Mac-2+ (M1) to F4-80+/Mac-2- (M2), leading to early appearance of resident macrophage. And cell experiments showed that the rate of CD206+ macrophages (M2) were significantly increased after LIPUS treatment. The anti-inflamation factors were increaed after LIPUS treatment. Interpretation: The earlier transition from inflammatory to resident macrophage might be one reason for the positive effect of LIPUS on spinal fusion. Funding: Young talents cultivating plan of Shanghai municipal medical and health system (2018YQ26). Changhai Hospital Youth Startup Fund (2018QNA013). Declaration of Interest: None. Ethical Approval: All procedures in this study were in accordance with the guidelines and were approved by the Laboratory Animal Ethics Center of the Second Military Medical University.

Collagen/β-TCP composite as a bone-graft substitute for posterior spinal fusion in rabbit model: a comparison study

β-TCP bioceramic, as a kind of biocompatible and biodegradable artificial bone scaffolds, is increasingly used to supplement lamina autografts when performing instrumented or non-instrumented spinal fusion, clinically, although solid fusion is not always achieved. The addition of collagen to β-TCP appears to be a potential strategy to improve bone regeneration, thereby enhancing the rate of spinal fusion. This study aimed to compare the fusion in collagen/β-TCP composite, β-TCP and autologous bone in a posterior spinal fusion model. The fusion grade evaluated radiography was greater in the collagen/β-TCP group than in the β-TCP group (p < 0.05). Stiffness and yield strength of the fused segments in collagen/β-TCP group were comparable to that in autogenous bone group. Histological analysis revealed that the proportion of new bone formation in collagen/β-TCP group were significantly greater than in β-TCP group (p < 0.05). In addition, bone deposition rate in the collagen/β-TCP group was greater than in the β-TCP group (p < 0.05) and comparable to that in the autogenous bone group. We therefore concluded that collagen/β-TCP is superior to β-TCP alone in facilitating posterior spinal fusion. The addition of collagen to β-TCP represents a simple strategy that couples the osteogenic effect, providing a promising alternative to autologous bone in the clinical treatment of spinal disorders.

Comparison of platelet quality and the effect of platelet collection in single donor platelet collected by 2 brands of apheresis machines

Posterolateral fusion (PLF) with autogenous iliac bone graft is one of the most common surgical procedures for lumbar spinal disease. However, its limited success demands new biologically competent graft enhancers or substitutes. Although the use of direct current (DC) electrical stimulation has been shown to increase rate of successful spinal fusions, little is known about the effect of the type of current in DC stimulation.To evaluate the effects of various DC stimulators on the strength and success rate of posterolateral fusion facilitated by using a nitinol mesh container, in rats.This was an experimental animal study.A conductive, tubular nitinol mesh container was used to carry small pieces of bone grafts. The nitinol mesh container received electrical stimulation via a lead that connected the container to different types of DC stimulators. Sixty male Sprague-Dawley rats were divided into three groups (N=20 in each): a control group that underwent PLF with a nitinol container filled with autograft, a constant DC group that received a nitinol container and constant DC (100 μA), and a pulsed DC group that received a nitinol container and pulsed DC (100 μA, 100 Hz, 200 μs). The rats underwent PLF between L4 and L5, and transverse processes were grafted with bilateral iliac grafts. A stimulator was implanted subcutaneously. The rats were sacrificed 8 weeks postsurgery, and lumbar spines were removed. Spinal fusion was evaluated by microcomputed tomography, manual testing, biomechanical testing, histologic examination, and molecular analysis.All animals in the DC stimulation groups displayed solid fusion, whereas only 70% of control animals showed solid fusion. Radiographic images, biomechanical testing, histologic examination, and molecular analysis revealed improved fusion in the order control group<constant DC group<pulsed DC group. The volume of new bone mass was significantly higher in the pulsed DC group (p<.05). Fusion was more solid in the pulsed DC group than in control group (p<.05). The pulsed DC group displayed the lowest inflammatory responses.Pulsed DC electrical stimulation is efficacious in improving both strength and fusion rate in a rat spinal fusion model. In addition, tubular nitinol mesh, made of conductive suture, appears useful for holding small pieces of bone grafts and maintaining a good environment for bone fusion.Pulsed DC electrical stimulation may be potentially useful to increase the fusion rate after spinal fusion in humans. Future research is required to evaluate the safety and efficacy of tubular nitinol mesh and pulsed DC electrical stimulation in humans.

Investigational growth factors utilized in animal models of spinal fusion: Systematic review.

BACKGROUNDOver 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current “gold standard” treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors (e.g., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion.AIMTo review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation.METHODSWe conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29th, 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review.RESULTSTwenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 (n = 1); angiopoietin 1 (n = 1); calcitonin (n = 3); erythropoietin (n = 1); basic fibroblast growth factor (n = 1); growth differentiation factor 5 (n = 4), combined insulin-like growth factor 1 + transforming growth factor beta (n = 4); insulin (n = 1); NELL-1 (n = 5); noggin (n = 1); P-15 (n = 1); peptide B2A (n = 2); and secreted phosphoprotein 24 (n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P-15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP-2, or other internal control in some studies. Large heterogeneity in animal species, fusion method, and experimental groups and time points was observed across the included studies, limiting the direct comparison of the growth factors identified herein.CONCLUSIONSeveral promising investigational growth factors for spinal fusion have been identified herein; directly comparing the fusion efficacy and safety of these agents may inform clinical translation.

Positive effect on spinal fusion by the combination of platelet-rich plasma and collagen-mineral scaffold using lumbar posterolateral fusion model in rats

BackgroundPlatelet-rich plasma (PRP) is autologous in origin and contains a high concentration of platelets which is a source of various growth factors. Previous studies have suggested that PRP has a positive effect in accelerating fusion by an autologous bone graft in a lumbar fusion. The role of PRP on artificial bone grafts in spinal fusion remains controversial. In this study, positive effect on spinal fusion by PRP was hypothesized; in vitro and in vivo studies were designed to test this hypothesis.MethodsPRP was produced from peripheral blood of Sprague-Dawley (SD) rats. A lumbar posterolateral arthrodesis model was used to test the efficacy of PRP on spinal fusion. Thirty SD rats were divided into three groups by different implants: the PRP group, PRP plus collagen-mineral carrier; the platelet-poor plasma (PPP) group, PPP plus collagen-mineral carrier; and the control group, collagen-mineral only. Spinal fusion was examined using plain radiographs, micro-computed tomography (micro-CT), manual palpation, and histological analysis. The fusion rate by micro-CT and that by manual palpation in groups were compared.ResultsIn the micro-CT results, 16 fused segments were observed in the PRP group (80%, 16/20), 2 in the PPP group (10%, 2/20), and 2 in the control group (10%, 2/20). The fusion rate, determined by manual palpation, was 60% (6/10) in the PRP group, 0% (0/10) in the PPP group, and 0% (0/10) in the control group. Histology showed that the PRP group had more new bone and matured marrow formation.ConclusionsThe results of this study demonstrated that PRP on an artificial bone carrier had positive effects on lumbar spinal fusion in rats. In the future, this composite could be potentially used as a bone graft in humans.

Comparison of synthetic bone graft ABM/P-15 and allograft on uninstrumented posterior lumbar spine fusion in sheep

BackgroundSpinal fusion is a commonly used procedure in spinal surgery. To ensure stable fusion, bone graft materials are used. ABM/P-15 (commercial name i-Factor™ Flex) is an available synthetic bone graft material that has CE approval in Europe. This peptide has been shown to improve bone formation when used in devices with fixation or on bone defects. However, the lack of external stability and large graft size make posterolateral lumbar fusion (PLF) a most challenging grafting procedure. This prospective randomized study was designed to evaluate early spinal fusion rates using an anorganic bovine-derived hydroxyapatite matrix (ABM) combined with a synthetic 15 amino acid sequence (P-15)–ABM/P-15 bone graft, and compared with allograft in an uninstrumented PLF model in sheep. The objective of this study was to assess fusion rates when using ABM/P-15 in uninstrumented posterolateral fusion in sheep.MethodsTwelve Texas/Gotland mixed breed sheep underwent open PLF at 2 levels L2/L3 and L4/L5 without fixation instruments. The levels were randomized so that sheep received an ABM graft either with or without P15 coating. Sheep were euthanized after 4.5 months and levels were harvested and evaluated with a micro-CT scanner and qualitative histology. Fusion rates were assessed by 2D sections and 3D reconstruction images and fusion was defined as intertransverse bridging.ResultsThere was 68% fusion rate in the allograft group and an extensive migration of graft material was noticed with a fusion rate of just 37% in the ABM/P-15 group. Qualitative histology showed positive osteointegration of the material and good correlation to scanning results.ConclusionsIn this PLF fusion model, ABM/P15 demonstrated the ability to migrate when lacking external stability. Due to this migration, reported fusion rates were significantly lower than in the allograft group. The use of ABM/P15 as i-Factor™ Flex may be limited to devices with fixation and bone defects.

The effect of ketorolac on posterior thoracolumbar spinal fusions: a prospective double-blinded randomised placebo-controlled trial protocol

IntroductionKetorolac has been shown to provide quality postoperative pain control and decrease opioid requirement with minimal side effects following spinal surgery. However, the literature addressing its use in spinal fusions...

Assessment of spinal arthrodesis in dorsolumbar spine trauma using hydroxyapatite, tricalcium phosphate, and 60% hydroxyapatite + 40% tricalcium phosphate: A comparative study

Study Design: Open level experimental design. Purpose: Ceramics are effective, safe, and good alternatives of iliac crest autograft for spinal fusion. There were not enough study available to compare among ceramics for fusion in spinal surgery. Our aim was comparative assessment of posterolateral spinal arthrodesis radiologically and clinically in dorsolumbar spine trauma using hydroxyapatite (HA), tricalcium phosphate (TCP), and 60% HA + 40% TCP. Overview of Literature: Surgical management of thoracolumbar spine injury has encouraged early rehabilitation and avoided adverse effects of prolonged recumbency. Instrumentation enhanced spinal fusion which was the main technique of spinal stabilization. Although iliac crest autograft is the gold standard for spinal fusion,the procedure is not devoid of major and minor complications. A variety of ceramics are available as good alternatives for spinal arthrodesis. There are not any studies in the literature comparing spinal fusion rate among commonly used ceramics. Materials and Methods: Patients having Thoraco Lumbar Injury Classification and Severity score ≥4 underwent pedicle screw fixation and decompression (if required). We applied chips of HA, TCP, or 60% HA + 40% TCP for fusion. At 12-month follow-up, computed tomography scan of involved spine was done to assess posterolateral fusion by Lenke classification. Clinical follow-up was done evaluating pain status (visual analog scale). Mean follow-up duration was 27.8 months. Radiological and clinical parameters were compared among three groups. Results: A total of 45 patients (16 received HA, 15 received TCP, and 14 received [60%HA + 40%TCP]) were analyzed. About 28.88% of total patients had Lenke Grade A fusion and 51.11% had Grade B, but no statistically significant difference (P = 0.09) among three groups. Although reduction of pain score occurred individually in all three groups,no significant difference (P = 0.3)was noted among three groups. Conclusions: There was no statistically significant difference in fusion rate and change in pain perception with applied ceramics (HA/TCP/[60%HA + 40%TCP]).

An inception cohort study of patients in a military clinic treated for lower back pain with lumbar fusion and SIGNAFUSE® with a systematic review of the literature

Background: Use of synthetic bone graft substitutes for spinal fusion has increased sharply over the past 20 years. SIGNAFUSE® is one such synthetic graft material that provides an osteostimulatory effect for spinal fusion. Because clinical trials are not required for commercialization of synthetic bone graft substitutes in the United States, fusion rates attained using SIGNAFUSE for lumbar fusion are not well documented. The goal of the current study is to determine the rate of spinal fusion in a military clinic following lumbar fusion surgery augmented with SIGNAFUSE. Methods: We report a retrospective chart review of 8 patients who received lumbar spinal fusion surgery augmented with SIGNAFUSE. All patients were assessed by computed tomographic (CT) imaging at least 1-year post-surgery to determine whether bony fusion had occurred. We also systematically reviewed literature sources that report fusion rate following spinal fusion surgery, for broader context. Results: An average of 1.6 spinal levels were treated with SIGNAFUSE-loaded interbody cages. All patients had stabilization hardware via pedicle screws or integrated cage fixation. Seven of 8 patients successfully fused, for an overall fusion rate of 87.5% (95% confidence interval: 47.4% to 99.7%). Systematic review of 26 recent publications that included 1,126 patients treated with synthetic bone graft showed that the overall fusion rate in the literature is 84.4%. Conclusions: Fusion was achieved in 87.5% of patients treated with SIGNAFUSE. This is comparable to the fusion rate in a systematic review of 1,126 patients treated with synthetic bone graft materials.

Effect of the type of electrical stimulation on spinal fusion in a rat posterolateral spinal fusion model

BACKGROUND CONTEXTPosterolateral fusion (PLF) with autogenous iliac bone graft is one of the most common surgical procedures for lumbar spinal disease. However, its limited success demands new biologically competent graft enhancers or substitutes. Although the use of direct current (DC) electrical stimulation has been shown to increase rate of successful spinal fusions, little is known about the effect of the type of current in DC stimulation. PURPOSETo evaluate the effects of various DC stimulators on the strength and success rate of posterolateral fusion facilitated by using a nitinol mesh container, in rats. STUDY DESIGNThis was an experimental animal study. METHODSA conductive, tubular nitinol mesh container was used to carry small pieces of bone grafts. The nitinol mesh container received electrical stimulation via a lead that connected the container to different types of DC stimulators. Sixty male Sprague-Dawley rats were divided into three groups (N=20 in each): a control group that underwent PLF with a nitinol container filled with autograft, a constant DC group that received a nitinol container and constant DC (100 μA), and a pulsed DC group that received a nitinol container and pulsed DC (100 μA, 100 Hz, 200 μs). The rats underwent PLF between L4 and L5, and transverse processes were grafted with bilateral iliac grafts. A stimulator was implanted subcutaneously. The rats were sacrificed 8 weeks postsurgery, and lumbar spines were removed. Spinal fusion was evaluated by microcomputed tomography, manual testing, biomechanical testing, histologic examination, and molecular analysis. RESULTSAll animals in the DC stimulation groups displayed solid fusion, whereas only 70% of control animals showed solid fusion. Radiographic images, biomechanical testing, histologic examination, and molecular analysis revealed improved fusion in the order control group<constant DC group<pulsed DC group. The volume of new bone mass was significantly higher in the pulsed DC group (p<.05). Fusion was more solid in the pulsed DC group than in control group (p<.05). The pulsed DC group displayed the lowest inflammatory responses. CONCLUSIONSPulsed DC electrical stimulation is efficacious in improving both strength and fusion rate in a rat spinal fusion model. In addition, tubular nitinol mesh, made of conductive suture, appears useful for holding small pieces of bone grafts and maintaining a good environment for bone fusion. CLINICAL RELEVANCEPulsed DC electrical stimulation may be potentially useful to increase the fusion rate after spinal fusion in humans. Future research is required to evaluate the safety and efficacy of tubular nitinol mesh and pulsed DC electrical stimulation in humans.

The impact of collagen sponge composite bone marrow mesenchymal stem cells (BMSCs) in inducing interbody fusion.

To assess the effectiveness of bone mesenchymal stem cells (BMSCs) in the induction of interbody fusion. The 3rd generation BMSCs were seeded on collagen sponge scaffold and cultured in osteoblast induction medium for 3 weeks to prepare cell-scaffold complex. Thirty patients were randomly divided into three groups to establish the L4/L5 interbody fusion model. The cell-scaffold complex was implanted in the intervertebral space in group I, the collagen sponge scaffold was implanted in group II, and the autologous iliac crest spongy bone was implanted in group III. Palpation, radiography, micro-CT, and histology were performed on the 12th weeks after operation to evaluate osteogenesis and spinal fusion. BMSCs differentiated into osteoblasts in the cell-scaffold complex after osteogenic induction for 3 weeks. The spinal fusion rates in group I, II, and III were 40%, 0%, and 70%, respectively. Micro-CT and histological examination showed mature bone marrow and trabecular bone formation in the fusion segments. The new bone was integrated with the upper and lower vertebral body. The bone trabecula in group III was stronger than group I. The surgical segments in group II was scar tissue without collagen sponge residue. BMSCs can induce osseous fusion in the lumbar vertebra.

Friday, September 28, 2018 4:05 PM–5:05 PM abstracts: basic science of spinal fusion: 238. The effects of varenicline (Chantix) on lumbar spinal fusion in a rat model

BACKGROUND CONTEXT Smoking is detrimental to obtaining a solid spinal fusion mass with previous studies demonstrating that tobacco use is associated with pseudoarthrosis in patients undergoing spinal fusions. Additionally, smoking is an important predictor of increased dissatisfaction, decreased walking ability, increased pain medication use, and poorer quality of life scores in patients after spine surgery when compared to nonsmokers. Accordingly, physicians make significant efforts toward helping patients discontinue their use of nicotine products. Varenicline is a nonscheduled prescription medication that works as a partial agonist of nicotinic acetylcholine receptors, the same receptors activated during smoking and tobacco use, and is used as a pharmacologic adjunct to aid patients in smoking cessation. However, no clinical or basic science studies to date have characterized if varenicline has the same negative effects as nicotine on spinal fusion, consolidation, and bone healing. PURPOSE As a partial agonist of nicotine receptors, our study aimed to elucidate whether varenicline affects the rate or quality of spinal fusion. STUDY DESIGN/SETTING Manual, radiographic, and biomechanical testing. PATIENT SAMPLE A total of 14 Lewis rats undergoing L4-5 lumbar spinal fusion. OUTCOME MEASURES Gross motion, radiographic density, peak load, and stiffness of fusion mass METHODS According to our IACUC approved protocol, fourteen male Lewis rats underwent tail amputation to create an autogenous bone graft from the tailbone followed by a lumbar L4-5 posterior spinal fusion procedure. Postsurgery, rats were randomly separated into two experimental groups receiving either daily subcutaneous injections of human dose (1mg/kg daily in saline) varenicline or saline (placebo) for 12 weeks postsurgery. Spine samples were then explanted and fusion was determined via manual palpation of segments by two independent blinded observers. Radiographic analysis of fusion was performed via high-resolution radiographs evaluating bridging fusion mass. Rat lumbar spinal fusion units were then tested in 4-point bending to evaluate stiffness and peak load before failure. Comparisons were made between groups (significance at p RESULTS At three months postsurgery, twelve out of fourteen rats demonstrated lumbar spine fusion (86% fused) with no difference in fusion rate between the varenicline and control groups (6/7, 86%). Fusion rate as detected by manual palpation indicated no motion in the desired fusion segment. Findings were further supported with faxitron radiography demonstrating six out of seven rats (86%) having complete fusion consisting of contiguous transverse processes bilaterally at a single level in each of the varenicline and placebo control groups. Of the six successfully fused specimens, five from each group underwent successful biomechanical testing. The average stiffness at the fusion site of the varenicline group and control group was 49.2±17.5N/mm and 69.1±32.6N/mm, respectively (p=.271). The average peak load at the fusion site of the varenicline group and control group was 51.9±25.2N and 60.5±20.4N, respectively (p=.574). CONCLUSIONS Varenicline has no significant effect on the rate and quality of spinal fusions and remains an appropriate pharmaceutical adjunct for tobacco cessation in individuals undergoing spinal fusion.

Ketogenic diet delays spinal fusion and decreases bone mass in posterolateral lumbar spinal fusion: an in vivo rat model.

Ketogenic diet (KD), a low-carbohydrate-and-high-fat diet, causes a metabolic state of ketogenesis and has been used to treat drug-resistance epilepsy. Our recent studies showed KD neuroprotective after spinal cord injury and causing bone loss. Effects of KD on spinal fusion were still unknown. This study was aimed to evaluate effects of KD on spinal fusion in rats. Thirty-two Sprague-Dawley rats were randomly divided into KD and standard diet (SD) groups. The KD group was fed with food of 1:4 carbohydrates to fat. All rats were subjected to L4/5 posterolateral lumbar spinal fusion. The blood ketone, and serum calcium, phosphorus, and insulin-like growth factor-1 (IGF-1) were measured, as well as the fusion rates, bone mass (BV), and bone mineral contents (BMC) of fusion sites were estimated at 4 and 8weeks. There was no significant difference in serum calcium or phosphorus levels between groups at 4 or 8weeks. However, there was a significant increase of blood ketone (1.02mmol/L vs 0.38mmol/L at 4weeks; 0.83mmol/L vs 0.32mmol/L, at 8weeks) and decrease of serum IGF-1 (339.4ng/mL vs 630.6ng/mL at 4weeks; 418.8ng/mL vs 628.6ng/mL, at 8weeks) in theKD group compared with theSD group. The spinal fusion occurred less inthe KD group (1/16 vs 6/16 at 4weeks; 7/16 vs 10/16, at 8weeks), particularly at 4weeks after surgery. The BV and BMC were lower in theKD group than that in theSD group at 4weeks, but not different between groups at 8weeks. This study demonstrated that KD delayed spinal fusion and decreased bone mass in posterolateral lumbar spinal fusionin rats.

The efficacy of electrical spinal fusion stimulators on fusion rates: a meta-analysis

Background: Previous studies have investigated the clinical effectiveness of electrical stimulation. However, minimal aggregate data from randomized controlled trials (RCT) exist to determine the overall efficacy of stimulators on spinal fusion outcomes. Thus, a meta-analysis of RCTs was undertaken to elucidate the effect of spinal fusion stimulators on fusion rates after spinal fusion procedures. Methods: This meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RCTs that compared fusion rates between cohorts receiving either electrical stimulation or a placebo/control following spinal fusion were included. Studies were obtained from literature searches of PubMed and MEDLINE databases. Articles without 1 yr follow-up or complete randomization were excluded. The primary outcome was fusion rate. A meta-analysis on relative risks for fusion was performed. The summary estimate was derived using Mantel-Haenszel methods. Results: Out of six RCTs, fusion rates ranged from 35.4% to 90.6% in stimulation groups, and 33.3% to 92.8% in control groups. There was no significant difference in fusion rates between spinal stimulator and control groups (P=0.067). Four of six studies exhibited a variety of study population characteristics, including a mixture of primary and revision spinal fusions, single-level and multi-level procedures, and electrical stimulation types. Conclusions: The results from the present study suggest no significant effect of spinal fusion stimulators on rates of spinal fusion when compared to control treatments. Physicians should use caution when interpreting these studies. Further RCTs demonstrating uniformity are necessary to better understand the effects of electrical stimulators on spinal fusion.

PLGA/β-TCP composite scaffold incorporating salvianolic acid B promotes bone fusion by angiogenesis and osteogenesis in a rat spinal fusion model

Spinal disorders often require surgical treatment called spinal fusion to restore a stabilized spine where bone grafts are implanted for the fusion of adjacent vertebras. In this study, we developed a bioactive composite scaffold incorporated with salvianolic acid B (SB), an active component extracted from Danshen. This study aimed to evaluate the effects of SB-incorporated porous scaffold on spinal fusion models. The composite scaffolds composed of poly (lactic-co-glycolic acid) and tricalcium phosphate (PLGA/β-TCP) were fabricated with low-temperature rapid prototyping technique, which incorporated SB at low (SB-L), middle (SB-M), high (SB-H) doses, and pure PLGA/β-TCP as blank control (Con). The release profile of SB from the scaffolds was determined by high performance liquid chromatography. Osteoconductive and osteoinductive properties of the scaffolds were reflected by the osteogenic differentiation ability of rat primary mesenchymal stem cells. The angiogenesis was determined by the forming of tube-like structures resembling capillaries using endothelial cell line (EA hy9.26). A well-established spinal fusion model was used to evaluate the in vivo bony fusion. Animals were transplanted with scaffolds, or autografts from iliac crest as positive controls. Micro-computed tomography (CT) analysis, CT-based angiography, manual palpation test, histomorphometry, and histology were performed after 8 weeks of transplantation. Results revealed that incorporated SB was steadily released from the scaffolds. The aliquot of released SB promoted osteogenesis and angiogenesis in vitro in a dose-dependent manner. In animal study, a dose-dependent effect of SB on new bone formation, mineral apposition rate, and vessel density within the scaffold were demonstrated. Manual palpation test showed little numerical improvement in fusion rate when compared with the blank controls. In summary, our results suggested that SB-incorporated PLGA/β-TCP composite scaffold could enhance bony fusion through the promotion of osteogenesis and angiogenesis.

The local cytokine and growth factor response to recombinant human bone morphogenetic protein-2 (rhBMP-2) after spinal fusion

Background ContextThe systemic response regarding cytokine expression after the application of recombinant human bone morphogenetic protein-2 (rhBMP-2) in a rat spinal fusion model has recently been defined, but the local response has not been defined. Defining the local cytokine and growth factor response at the fusion site will help explain the roles of these molecules in the fusion process, as well as that of rhBMP-2. Our hypothesis is that the application of rhBMP-2 to the fusion site will alter the local levels of cytokines and growth factors throughout the fusion process, in a manner that is different from the systemic response, given the tissue-specific effects of rhBMP-2. PurposeThe purpose of this study was to evaluate the local cytokine and growth factor response after the application of rhBMP-2 in a rat spinal fusion model. Study Design/SettingThis was a basic science animal model study. MethodsThis study was partially funded by a physician-sponsored grant from Medtronic. A total of 135 Wistar rats (age 8 weeks, weighing approximately 300–400 g) underwent L4–L5 posterolateral intertransverse fusion with demineralized bone graft (approximately 0.4-cm3 rat demineralized bone matrix [DBM] per side). In the first group, 10 µg of rhBMP-2 on an allograft collagen sponge (ACS) was added to the fusion site with approximately 0.4-cm3 rat DBM per side. In the second group, 100 µg of rhBMP-2 on an ACS was added to the fusion site with approximately 0.4-cm3 rat DBM per side, and the third experiment was the control group, which consisted of only an ACS plus 0.4-cm3 DBM per side. There were nine groups of five animals each per experiment. Each group was sacrificed at time points up to 4 weeks (1, 6, 24, and 48 hours, and 4, 7, 14, 21, and 28 days after surgery). At sacrifice, the DBM, transverse processes, and any new bone formed were harvested, immediately frozen in liquid nitrogen, and prepared for protein extraction. ELISA was performed to compare the levels of various cytokines (interleukin [IL]-1β, tumor necrosis factor alpha, IL-6, IL-1RA [IL-1 receptor antagonist], IL-4, and IL-10) and growth factors (vascular endothelial growth factor [VEGF], endothelia growth factor [EGF], insulin-like growth factor-1 [IGF-1], platelet derived growth factor [PDGF], transforming growth factor beta [TGF-β]) that are known to be involved in the fusion-fracture healing process. Fusion was evaluated on the rats sacrificed at 28 days by manual palpation and microcomputed tomography (microCT) by two independent observers. ResultsThe expression of cytokines and growth factors varied throughout the fusion process at each time point. In the groups treated with rh-BMP-2, IL-6 and IL-1RA had higher expression in the early time points (1 and 6 hours). Tumor necrosis factor alpha demonstrated significantly lower expression in the groups treated with rhBMP-2 at Days 1, 2, and 4. At the early time points (1 and 6 hours), in the groups treated with rhBMP-2, all of the growth factors IGF-1, VEGF, platelet derived growth factor AB (PDGF-AB), TGF-β had equal or lower expression compared with controls. At 24 hours, there was a peak in IGF-1, VEGF, and PDGF-AB. These growth factors then declined, with IGF-1 and PDGF-AB having a second peak at Day 7. At 4 weeks, all of the rhBMP-2-treated animals fused based on manual palpation and microCT. The control group had four of five rats fused based on manual palpation and two of five rats based on microCT. ConclusionsThere is significant variability in the expression of cytokines throughout the fusion process after treatment with rhBMP-2. The inflammatory response appears to peak early (1 and 6 hours), followed by a significant decrease with rhBMP-2 treatment. However, the growth factor expression appears to be suppressed early (1 and 6 hours), followed by a peak at 24 hours, and a second peak at Day 7.

Clinical efficacy of one-stage posterior debridement, Smith-Petersen osteotomy, compressive fusion and instrumentation for treatment of thoracolumbar tuberculosis

Objective To discuss the clinical efficacy and surgical indications of one-stage posterior debridement, Smith-Petersen osteotomy(SPO), compressive fusion and instrumentation for treatment of thoracolumbar tuberculosis. Methods All of 32 patients with thoracolumbar spinal tuberculosis were retrospectively analyzed, treated by one-stage posterior debridement, SPO, compressive fusion and instrumentation from March 2010 to October 2016, including 23 males and 9 females, aged 2 to 77 years old, average (39.2±17.8) years. All patients were treated by preoperative quadruple anti-tuberculosis drugs therapy for 2-4 weeks, postoperative regular chemotherapy for 12-18 months. Preoperative and postoperative changes in clinical symptoms, nervous function, the situation of the erythrocyte sedimentation rate (ESR) and C-reactive protein(CRP) with strict follow-up, as well as other related complications were observed. The spinal fusion rate and fusion situation, changing of the physiological curvature, as well as loosening or breaking of the internal fixation device were detected through regular imaging examination. Results The surgery duration time was 90-150 min, average (120±19.6) min, and the blood loss was 150-600 ml, average (320±88.9) ml. Postoperative follow-up time was 1 to 3 years, average 2.3 years. The symptoms of tuberculosis poisoning in all patients were obviously relieved and the nutritional status was improved gradually. The visual analogue scale(VAS) improvement rate was about 92%. The VAS score in the preoperative and the last follow-up was statistically significant. All patients' ESR and CRP returned to normal levels at the last follow-up. The Kirkaldy-Willis function score showed that the total fine rate was 93.75%. 9 patients with spinal neurological impairment were postoperative improved significantly. Except 1 patient’s Asia grade improved from the B to C, others returned to normal condition. 30 cases recovered. Pleural effusion was observed in 3 cases treated with closed thoracic drainage and antibiotics. The drainage tube was removed after 5-7 d. Incision fistula were observed in 1 patient at 1 month after discharge and recovered after debridement and drugs adjustment. Internal fixation loosening was found in 1 elderly patient after 6 months after surgery which was treated with hyperextended brace and anti-osteoporosis drugs. No tuberculosis recurrence was found. Conclusion One-stage posterior debridement, SPO, compressive fusion and instrumentation is a simple, effective and safety surgical approach, which has great application value for surgical treatment of patients with thoracolumbar spinal tuberculosis. Key words: Thoracic vertebrae; Lumbar vertebrae; Tuberculosis, spinal; Spinal fusion

Cervical Spinal Fusion: 16-Year Trends in Epidemiology, Indications, and In-Hospital Outcomes by Surgical Approach.

The rate of cervical spinal fusion has been increasing significantly. However, there is a paucity of literature describing trends based on surgical approach using complete population databases. We investigated the approach-based trends in epidemiology, indications, and in-hospital outcomes of cervical spinal fusion. New York's Statewide Planning and Research Cooperative System database was queried to identify patients who underwent primary subaxial cervical fusion from 1997 to 2012. Demographic and clinical information was obtained. Subgroup analyses were performed based on surgical approach: anterior (A), posterior (P), and circumferential (C). A total of 87,045 cervical fusions were included. Over the study period, the population-adjusted annual fusion rate increased from 23.7 to 50.6 per 100,000 population (P < 0.001). A fusion was most common (85.2%), followed by P (12.3%), and C (2.5%). Mean ages were 49.8 ± 11.9, 59.9 ± 15.2, and 55.1 ± 14.5 years (P < 0.001), respectively. Although rates remained steady among younger patients, they increased for older patients. Overall, degenerative conditions were the predominant indications for surgery and increased in rate over time. The mean length of stay was: A, 3.1 ± 10.5; P, 9.1 ± 14.1; and C, 14.1 ± 22.5 days (P < 0.001). Rates of in-hospital complications were A, 3.0%; P, 10.5%; and C, 18.9% (P < 0.001), and mortality was A, 0.3%, P, 1.8%, and C, 2.5% (P < 0.001). The rate of subaxial spinal fusions increased 114% from 1997 to 2012 in New York State. Rates remained stable in younger patients but increased in the older population. Preoperative indications and postoperative courses differed significantly among the various approaches, with patients undergoing anterior fusion having better short-term outcomes.

Rapid Osteogenic Enhancement of Stem Cells in Human Bone Marrow Using a Glycogen-Synthease-Kinase-3-Beta Inhibitor Improves Osteogenic Efficacy In Vitro and In Vivo.

Non‐union defects of bone are a major problem in orthopedics, especially for patients with a low healing capacity. Fixation devices and osteoconductive materials are used to provide a stable environment for osteogenesis and an osteogenic component such as autologous human bone marrow (hBM) is then used, but robust bone formation is contingent on the healing capacity of the patients. A safe and rapid procedure for improvement of the osteoanabolic properties of hBM is, therefore, sought after in the field of orthopedics, especially if it can be performed within the temporal limitations of the surgical procedure, with minimal manipulation, and at point‐of‐care. One way to achieve this goal is to stimulate canonical Wingless (cWnt) signaling in bone marrow‐resident human mesenchymal stem cells (hMSCs), the presumptive precursors of osteoblasts in bone marrow. Herein, we report that the effects of cWnt stimulation can be achieved by transient (1–2 hours) exposure of osteoprogenitors to the GSK3β‐inhibitor (2′Z,3′E)‐6‐bromoindirubin‐3′‐oxime (BIO) at a concentration of 800 nM. Very‐rapid‐exposure‐to‐BIO (VRE‐BIO) on either hMSCs or whole hBM resulted in the long‐term establishment of an osteogenic phenotype associated with accelerated alkaline phosphatase activity and enhanced transcription of the master regulator of osteogenesis, Runx2. When VRE‐BIO treated hBM was tested in a rat spinal fusion model, VRE‐BIO caused the formation of a denser, stiffer, fusion mass as compared with vehicle treated hBM. Collectively, these data indicate that the VRE‐BIO procedure may represent a rapid, safe, and point‐of‐care strategy for the osteogenic enhancement of autologous hBM for use in clinical orthopedic procedures. stem cells translational medicine 2018;7:342–353

Local delivery of a novel PTHrP via mesoporous bioactive glass scaffolds to improve bone regeneration in a rat posterolateral spinal fusion model.

With the development of tissue engineering, bone defects, such as fractured long bones or cavitary lesions, may be efficiently repaired and reconstructed using bone substitutes. However, high rates of fusion failure remain unavoidable in spinal fusion surgery owing to the lack of appropriate materials for bone regeneration under such challenging conditions. Parathyroid hormone (PTH), a major regulator of bone remodeling, exerts both anabolic and catabolic effects. In this study, we modified PTH(1–34) and designed and synthesized a novel PTH-related peptide, namely PTHrP-1. Further, we fabricated a local PTHrP delivery device from mesoporous bioactive glass (MBG) to address the need for a suitable material in spinal fusion surgery. Using MBG scaffolds as a control, the biological properties of PTHrP-MBG scaffolds were evaluated in terms of attachment, proliferation, and alkaline phosphatase activity, as well as osteogenic gene and angiogenic gene expression in co-cultured rat bone marrow mesenchymal stem cells (rBMSCs) in vitro. Furthermore, PTHrP-1-MBG scaffolds were tested in a rat posterolateral spinal fusion model. Our data showed that PTHrP-1-MBG scaffolds possessed good ability to facilitate attachment and stimulation of rBMSC proliferation and differentiation. Importantly, the in vivo results revealed that the PTHrP-1-MBG scaffolds facilitated faster new bone formation and a higher rate and quality of spinal fusion. Therefore, the results suggest that devices consisting of the present novel PTHrP and MBG possess wider potential applications in bone regeneration and should serve as a promising bone substitute for spinal fusion.