The Effects of Longer Use of Teriparatide on Clinical and Radiographic Outcomes after Spinal Fusion in Geriatric Patients.

Background: Teriparatide is an anabolic agent for osteoporosis and is believed to improve the bone healing process. Previous studies showed that teriparatide could enhance not only fracture healing but also spine fusion. It has been reported that use of teriparatide could promote the spine fusion process and decrease mechanical complications. However, there was no consensus regarding optimal treatment duration. The purpose of this study was to compare surgical outcomes between short-duration and long-duration teriparatide treatment after lumbar fusion surgery in elderly patients. Materials and Methods: All consecutive patients older than 60 years who underwent 1-level lumbar fusion surgery for degenerative diseases between January 2015 and December 2019 were retrospectively reviewed. Based on the duration of teriparatide treatment (daily subcutaneous injection of 20 µg teriparatide), patients were subdivided into two groups: a short-duration (SD) group (<6 months) and a long-duration (LD) group (≥6 months). Mechanical complications, such as screw loosening, cage subsidence, and adjacent vertebral fractures, were investigated. Postoperative 1-year union rate was also evaluated on computed tomography. Clinical outcomes were recorded using visual analog scale (VAS) and Oswestry Disability Index (ODI). Between-group differences for these radiographic and clinical outcomes were analyzed. Results: Ninety-one patients were reviewed in this study, including sixty patients in the SD group and thirty-one patients in the LD group. Their mean age was 72.3 ± 6.2 years, and 79 patients were female. Mean T-score was -3.3 ± 0.8. Cage subsidence (6.7% vs. 3.2%), screw loosening (28.3% vs. 35.5%), and adjacent vertebral fracture (6.7% vs. 9.7%) were not significantly different between the SD and LD groups. Union rate at 1-year postoperative was 65.0% in the SD group and 87.1% in the LD group (p = 0.028). Both groups showed improvement in VAS and ODI after surgery. However, the differences of VAS from preoperative to 6 months and 1 year postoperative were significantly higher in the LD group. Conclusions: Longer teriparatide treatment after lumbar fusion surgery resulted in a higher union rate at 1-year postoperative than the shorter treatment. Also, it could be more beneficial for clinical outcomes.

Risk Factors for Reoperation Following Single-Level Cervical Disc Arthroplasty as Utilized in a Representative Sample of United States Clinical Practice: A Retrospective PearlDiver Study.

STUDY DESIGN: Retrospective Cohort. OBJECTIVES: Most data regarding cervical disc arthroplasty (CDA) outcomes are from highly controlled clinical trials with strict inclusion/exclusion criteria. This study aimed to identify risk factors for CDA reoperation, in "real world" clinical practice using a national insurance claims database. METHODS: The PearlDiver database was queried for patients (2010-2020) who underwent a subsequent cervical procedure following a single-level CDA. Patients with less than 2 years follow-up were excluded. Primary outcome was to evaluate risk factors for reoperation. Secondary outcome was to evaluate the types of reoperations. Risk factors were compared using descriptive statistics. Multivariate regression analyses were used to ascertain the association among risk factors and reoperation. RESULTS: Of 14,202 patients who met inclusion criteria, 916 (6.5%) underwent reoperation. Patients undergoing reoperation were slightly older with higher Elixhauser Comorbidity Index (ECI) scores, however both were not risk factors for reoperation. Patients with diagnoses such as smoking, myelopathy, inflammatory disorders, spinal deformity, trauma, or a history of prior cervical surgery were at greater risk for reoperation. No association was found between the year of index surgery and reoperation risk. The most common reoperation procedure was cervical fusion. CONCLUSIONS: As billed for in the United States since 2010, CDA was associated with a 6.5% reoperation rate over a mean follow-up time of 5.3 years. Smoking, myelopathy, inflammatory disorders, spinal deformity, and a history of prior cervical surgery or trauma are risk factors for reoperation following CDA. Though patients who underwent a reoperation were older, age was not found to be an independent risk factor for a subsequent procedure.

Is single-level cervical disc arthroplasty associated with a lower reoperation rate than anterior cervical discectomy and fusion?

OBJECTIVE: Long-term meta-analysis of cervical disc arthroplasty (CDA) trials report lower rates of subsequent cervical spine surgical procedures with CDA compared with anterior cervical discectomy and fusion (ACDF). The objective of this study was to compare the rate of subsequent cervical spine surgery in single-level CDA-treated patients to that of a matched cohort of single-level ACDF-treated patients by using records from 2010 to 2021 included in a large national administrative claims database (PearlDiver). METHODS: This retrospective matched-cohort study used a large national insurance claims database; 525,510 patients who had undergone a single-level ACDF or CDA between 2010 and 2021 were identified. Patients with other same-day spine procedures, as well as those for trauma, infection, or tumor, were excluded, yielding 148,531 patients. ACDF patients were matched 2:1 to CDA patients on the basis of clinical and demographic characteristics. The primary outcome was the overall incidence of all-cause cervical reoperation after index surgery. Secondary outcomes included readmission, any adverse event within 90 days, and overall reintervention after index surgery. Multivariable logistic regression analyses were adjusted for covariates and were employed to estimate the effect of the index ACDF or CDA procedure on patient outcomes. Survival was assessed using Kaplan-Meier estimation, and differences between ACDF- and CDA-treated patients were compared using log-rank tests. RESULTS: After the patients were matched, 28,795 ACDF patients to 14,504 CDA patients were included. ACDF patients had higher rates of 90-day adverse events (18.4% vs 14.6%, adjusted odds ratio [aOR] 0.77, 95% CI 0.73-0.82, p < 0.001) and readmission (11.5% vs 9.7%, aOR 0.87, 95% CI 0.81-0.93, p < 0.001). Over a mean 4.3 years of follow-up, 5.0% of ACDF patients and 5.4% of CDA patients underwent reoperation (aOR 1.09, 95% CI 1.00-1.19, p = 0.059). The rate of aggregate reintervention was higher in CDA patients than in ACDF patients (11.7% vs 10.7%, aOR 1.10, p = 0.002). The Kaplan-Meier 10-year reoperation-free survival rate was worse for CDA than ACDF (91.0% vs 92.0%, p = 0.05), as was the rate of reintervention-free survival (81.2% vs 82.0%, p = 0.003). CONCLUSIONS: Single-level CDA was associated with a similar rate of reoperation and higher rate of subsequent injections when compared with a matched cohort that underwent single-level ACDF. CDA was associated with lower rates of 90-day adverse events and readmissions.

Evolution of Bioactive Implants in Lateral Interbody Fusion.

Lateral lumbar interbody fusion (LLIF) is an advantageous approach for spinal arthrodesis for a wide range of spinal disorders including degenerative, genetic, and traumatic conditions. LLIF techniques have evolved over the past 15 years regarding surgical approach, with concomitant improvements in implant material design. Bioactive materials have been a focus in the development of novel methods, which reduce the risk of subsidence and pseudarthrosis. Historically, polyetheretherketone and titanium cages have been selected for their advantageous biomechanical properties; however, both have their limitations, regarding optimal modulus or osseointegrative properties. Recent modifications to these 2 materials have focused on devising bioactive implants, which may enhance the rate of bony fusion in spinal arthrodesis by addressing the shortcomings of each. Specific emphasis has been placed on developing improvements in surface coating, porosity, microroughness, and nanotopography of interbody cages. This has been coupled with advances in additive manufacturing to generate cages with ideal biomechanical properties. Three-dimensional-printed titanium cages may be particularly beneficial in spinal arthrodesis during LLIF and reduce the historical rates of subsidence and pseudarthrosis by combining a number of these putatively beneficial biomaterial properties.

Allografts and Spinal Fusion.

BACKGROUND: Back pain is a common chief complaint within the United States and is caused by a multitude of etiologies. There are many different treatment modalities for back pain, with a frequent option being spinal fusion procedures. The success of spinal fusion greatly depends on instrumentation, construct design, and bone grafts used in surgery. Bone allografts are important for both structural integrity and providing a scaffold for bone fusion to occur. METHOD: Searches were performed using terms "allografts" and "bone" as well as product names in peer reviewed literature Pubmed, Google Scholar, FDA-510k approvals, and clinicaltrials.gov. RESULTS: This study is a review of allografts and focuses on currently available products and their success in both animal and clinical studies. CONCLUSION: Bone grafts used in surgery are generally categorized into 3 main types: autogenous (from patient's own body), allograft (from cadaveric or living donor), and synthetic. This paper focuses on allografts and provides an overview on the different subtypes with an emphasis on recent product development and uses in spinal fusion surgery.

Stem Cells and Spinal Fusion.

BACKGROUND: This manuscript is a review of the literature investigating the use of mesenchymal stem cells (MSCs) being applied in the setting of spinal fusion surgery. We mention the rates of pseudarthrosis, discuss current bone grafting options, and examine the preclinical and clinical outcomes of utilizing MSCs to assist in successfully fusing the spine. METHODS: A thorough literature review was conducted to look at current and previous preclinical and clinical studies using stem cells for spinal fusion augmentation. Searches for PubMed/MEDLINE and ClinicalTrials.gov through January 2021 were conducted for literature mentioning stem cells and spinal fusion. RESULTS: All preclinical and clinical studies investigating MSC use in spinal fusion were examined. We found 19 preclinical and 17 clinical studies. The majority of studies, both preclinical and clinical, were heterogeneous in design due to different osteoconductive scaffolds, cells, and techniques used. Preclinical studies showed promising outcomes in animal models when using appropriate osteoconductive scaffolds and factors for osteogenic differentiation. Similarly, clinical studies have promising outcomes but differ in their methodologies, surgical techniques, and materials used, making it difficult to adequately compare between the studies. CONCLUSION: MSCs may be a promising option to use to augment grafting for spinal fusion surgery. MSCs must be used with appropriate osteoconductive scaffolds. Cell-based allografts and the optimization of their use have yet to be fully elucidated. Further studies are necessary to determine the efficacy of MSCs with different osteoconductive scaffolds and growth/osteogenic differentiation factors. LEVEL OF EVIDENCE: 3.

Single-Level Cervical Disc Replacement Using a PEEK-on-Ceramic Implant: Results of a Multicenter FDA IDE Trial With 24-Month Follow-up.

BACKGROUND: Many early cervical total disc replacements (TDRs) produced motion through a ball-and-socket action, with metal endplates articulating with a plastic core. Polyetheretherketone (PEEK) is used increasingly for spinal implants due to its mechanical properties and lack of artifacts on imaging. A TDR was designed with titanium-coated PEEK endplates and a ceramic core. The purpose of this study was to compare this TDR with anterior cervical discectomy and fusion (ACDF) to treat single-level cervical disc degeneration. METHODS: This was a prospective, nonrandomized, historically controlled, multicenter US Food and Drug Administration (FDA) Investigational Device Exemption (IDE) trial. Patients received the PEEK-on-ceramic Simplify® Cervical Artificial Disc (n = 150). The historic control group included 117 propensity-matched ACDF patients from an earlier IDE trial. The primary outcome was a composite success classification at the 24-month follow-up. Outcome measures included the Neck Disability Index (NDI), neurological status, adverse events, subsequent surgery, a visual analog scale assessing neck and arm pain, and the Dysphagia Handicap Index. Radiographic assessment included flexion/extension range of motion and heterotopic ossification. Facet joints were assessed at 24 months using MRI. RESULTS: The success rate was significantly greater in the TDR group vs the ACDF group (93.0% vs 73.6%; P < .001). Mean NDI, neck pain, and arm pain scores improved significantly in both groups at all follow-up points. Mean NDI scores in the TDR group were significantly lower than ACDF scores at all follow-up points. There were no significant differences in the rates of serious adverse events. The range of motion of the TDR level had increased significantly by 3 months and remained so throughout follow-up. Facet joint assessment by MRI in the TDR group showed little change from preoperation. CONCLUSIONS: The TDR had an acceptable safety profile and a significantly greater composite success rate than ACDF. These results support that the PEEK-on-ceramic TDR is a viable alternative to ACDF for single-level symptomatic disc degeneration. CLINICAL RELEVANCE: This study found that the PEEK-on-ceramic TDR is a viable treatment for symptoms related to cervical disc degeneration and offers similar or superior outcomes compared with fusion. LEVEL OF EVIDENCE: 2.

Neural crest-derived mesenchymal progenitor cells enhance cranial allograft integration.

Replacement of lost cranial bone (partly mesodermal and partly neural crest-derived) is challenging and includes the use of nonviable allografts. To revitalize allografts, bone marrow-derived mesenchymal stromal cells (mesoderm-derived BM-MSCs) have been used with limited success. We hypothesize that coating of allografts with induced neural crest cell-mesenchymal progenitor cells (iNCC-MPCs) improves implant-to-bone integration in mouse cranial defects. Human induced pluripotent stem cells were reprogramed from dermal fibroblasts, differentiated to iNCCs and then to iNCC-MPCs. BM-MSCs were used as reference. Cells were labeled with luciferase (Luc2) and characterized for MSC consensus markers expression, differentiation, and risk of cellular transformation. A calvarial defect was created in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice and allografts were implanted, with or without cell coating. Bioluminescence imaging (BLI), microcomputed tomography (µCT), histology, immunofluorescence, and biomechanical tests were performed. Characterization of iNCC-MPC-Luc2 vs BM-MSC-Luc2 showed no difference in MSC markers expression and differentiation in vitro. In vivo, BLI indicated survival of both cell types for at least 8 weeks. At week 8, µCT analysis showed enhanced structural parameters in the iNCC-MPC-Luc2 group and increased bone volume in the BM-MSC-Luc2 group compared to controls. Histology demonstrated improved integration of iNCC-MPC-Luc2 allografts compared to BM-MSC-Luc2 group and controls. Human osteocalcin and collagen type 1 were detected at the allograft-host interphase in cell-seeded groups. The iNCC-MPC-Luc2 group also demonstrated improved biomechanical properties compared to BM-MSC-Luc2 implants and cell-free controls. Our results show an improved integration of iNCC-MPC-Luc2-coated allografts compared to BM-MSC-Luc2 and controls, suggesting the use of iNCC-MPCs as potential cell source for cranial bone repair.

Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats.

Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD degeneration, lumbar disc injury or sham surgery was performed on Zucker Diabetic Sprague Dawley (ZDSD) or control Sprague Dawley (SD) rats. Post-surgery, IVD-injured ZDSD rats received daily PM dissolved in drinking water or water only. The resulting groups were SD uninjured, SD injured, ZDSD uninjured, ZDSD injured, and ZDSD injured + PM. Levels of blood glycation and disc degeneration were investigated. At week 8 post-surgery, glycated serum protein (GSP) levels were increased in ZDSDs compared to SDs. PM treatment attenuated this increase. Micro-MRI analysis demonstrated IVD dehydration in injured versus uninjured SDs and ZDSDs. In the ZDSD injured + PM group, IVD dehydration was diminished compared to ZDSD injured. AGE levels were decreased and aggrecan levels increased in ZDSD injured + PM versus ZDSD injured rats. Histological and immunohistochemical analyses further supported the beneficial effect of PM. In summary, PM attenuated GSP levels and IVD degeneration processes in ZDSD rats, demonstrating its potential to attenuate IVD degeneration in addition to managing glycemia in T2DM.

NF-κB inhibitor, NEMO-binding domain peptide attenuates intervertebral disc degeneration.

BACKGROUND CONTEXT: Nonphysiological mechanical loading and inflammation are both critically involved in intervertebral disc (IVD) degeneration, which is characterized by an increase in cytokines and matrix metalloproteases (MMPs) in the nucleus pulposus (NP). This process is known to be mediated by the NF-κB pathway. CLINICAL SIGNIFICANCE: Current clinical treatments for IVD degeneration focus on the alleviation of symptoms rather than targeting the underlying mechanism. Injection of an NF-κB inhibitor may attenuate the progression of IVD degeneration. PURPOSE: To investigate the ability of the NF-κB inhibitor, NEMO binding domain peptide (NBD), to alter IVD degeneration processes by reducing IL-1ß- and mechanically-induced cytokine and MMP levels in human nucleus pulposus cells in vitro, and by attenuating IVD degeneration in an in vivo rat model for disc degeneration. STUDY DESIGN: Experimental in vitro and animal model. PATIENT SAMPLE: Discarded specimens of lumbar disc from 21 patients, and 12 Sprague Dawley rats. OUTCOME MEASURES: Gene and protein expression, cell viability, µMRI and histology. METHODS: IL-1ß-prestimulated human nucleus pulposus cells embedded into fibrin constructs were loaded in the Flexcell FX-5000 compression system at 5 kPa and 1 Hz for 48 hours in the presence and absence of NBD. Unloaded hNPC/fibrin constructs served as controls. Cell viability in loaded and unloaded constructs was quantified, and gene and protein expression levels determined. For in vivo testing, a rat needle disc puncture model was employed. Experimental groups included injured discs with and without NBD injection and uninjured controls. Levels of disc degeneration were determined via µMRI, qPCR and histology. Funding sources include $48,874 NASS Young Investigator Research Grant and $119,174 NIH 5K01AR071512-02. There were no applicable financial relationships or conflicts of interest. RESULTS: Mechanical compression of hNPC/fibrin constructs resulted in upregulation of MMP-3 and IL-8. Supplementation of media with 10 µM NBD during loading increased cell viability, and decreased MMP-3 gene and protein levels. IVD injury in rat resulted in an increase in MMP-3, IL-1ß and IL-6 gene expression. Injections of 250 µg of NBD during disc injury resulted in decreased IL-6 gene expression. µMRI analysis demonstrated a reduction of disc hydration in response to disc needle injury, which was attenuated in NBD-treated IVDs. Histological evaluation showed NP and AF lesion in injured discs, which was attenuated by NBD injection. CONCLUSIONS: The results of this study show NBD peptide's capacity to reduce IL-1ß- and loading-induced MMP-3 levels in hNPC/fibrin constructs while increasing the cells' viability, and to attenuate IVD degeneration in rat, involving downregulation of IL-6. Therefore, NBD may be a potential therapeutic agent to treat IVD degeneration.

The effects of varenicline on lumbar spinal fusion in a rat model.

BACKGROUND CONTEXT: Smoking is detrimental to obtaining a solid spinal fusion mass with previous studies demonstrating its association with pseudoarthrosis in patients undergoing spinal fusion. Varenicline is a pharmacologic adjunct used in smoking cessation which acts as a partial agonist of the same nicotinic receptors activated during tobacco use. However, no clinical or basic science studies to date have characterized if varenicline has negative effects on spinal fusion and bone healing by itself. PURPOSE: Our study's aim was to elucidate whether varenicline affects the frequency or quality of posterolateral spinal fusion in a rodent model at an endpoint of 12 weeks. STUDY DESIGN: Randomized control trial. PATIENT SAMPLE: Fourteen male Lewis rats randomly separated into two experimental groups. OUTCOME MEASURES: Manual palpation of fusion segment, radiography, µCT imaging, and four-point bend. METHODS: Fourteen male Lewis rats were randomly separated into two experimental groups undergoing L4-L5 posterior spinal fusion procedure followed by daily subcutaneous injections of human dose varenicline or saline (control) for 12 weeks postsurgery. Spine samples were explanted, and fusion was determined via manual palpation of segments by two independent observers. High-resolution radiographs were obtained to evaluate bridging fusion mass. µCT imaging was performed to characterize fusion mass and consolidation. Lumbar spinal fusion units were tested in four-point bending to evaluate stiffness and peak load. Study funding sources include $5000 OREF Grant. There were no applicable financial relationships or conflicts of interest. RESULTS: At 3 months postsurgery, 12 out of 14 rats demonstrated lumbar spine fusion (86% fused) with no difference in fusion frequency between the varenicline and control groups as detected by manual palpation. High-resolution radiography revealed six out of seven rats (86%) having complete fusion in both groups. µCT showed no significant difference in bone mineral density or bone fraction volume between groups in the region of interest. Biomechanical testing demonstrated no significant different in the average stiffness or peak loads at the fusion site of the varenicline and control groups. CONCLUSION: Based on the results of our rat study, there is no indication that varenicline itself has a detrimental effect on the frequency and quality of spinal fusion.

Omega-3 Fatty Acid Supplementation Reduces Intervertebral Disc Degeneration.

BACKGROUND Intervertebral disc (IVD) degeneration is a common cause of lower back pain, which carries substantial morbidity and economic cost. Omega-3 fatty acids (n-3 FA) are known to reduce inflammatory processes with a relatively benign side effect profile. This study aimed to investigate the effect of n-3 FA supplementation on IVD degeneration. MATERIAL AND METHODS Two non-contiguous lumbar discs of 12 Sprague Dawley rats were needle-punctured to induce disc degeneration. Post-surgery, rats were randomly assigned to either a daily n-3 FA diet (530 mg/kg/day of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in a 2: 1 ratio, administered in sucrose solution) or control diet (sucrose solution only), which was given for the duration of the study. After 1 month, blood serum arachidonic acid/eicosapentaenoic acid (AA/EPA) ratios were analyzed. After 2 months, micro-MRI (magnetic resonance imaging) analysis and histological staining of disc explants were performed to analyze the IVD. RESULTS A reduction of blood AA/EPA ratios from 40 to 20 was demonstrated after 1 month of daily supplementation with n-3 FA. Micro-MRI analysis showed an injury-induced reduction of IVD hydration, which was attenuated in rats receiving n-3 FA. Histological evaluation demonstrated the destruction of nucleus pulposus tissue in response to needle puncture injury, which was less severe in the n-3 FA diet group. CONCLUSIONS The results of this study suggest that n-3 FA dietary supplementation reduces systemic inflammation by lowering AA/EPA ratios in blood serum and has potential protective effects on the progression of spinal disc degeneration, as demonstrated by reduced needle injury-induced dehydration of intervertebral discs and reduced histological signs of IVD degeneration.

Comparative Efficacy of Commonly Available Human Bone Graft Substitutes as Tested for Posterolateral Fusion in an Athymic Rat Model.

BACKGROUND: Insufficient data exist on bone graft substitute materials efficacy; two thirds lack any clinical data.1,2 This prospective animal study identified efficacy differences among commercially available materials of several classes. METHODS: Historically validated muscle pouch osteoinduction study (OIS) and posterolateral fusion (PLF) were performed in an athymic rat model. Grafting material products implanted were demineralized bone matrix (DBM)-based allografts (Accell EVO3, DBX Mix, DBX Strip, Grafton Crunch, Grafton Flex, Grafton Matrix, Grafton Putty, Magnifuse, and Progenix Plus), allografts (OsteoSponge, MinerOss), cellular allograft (Osteocel Plus), ceramics (Mozaik Strip), or activated ceramics (Actifuse ABX Putty, Vitoss BA). After 4 weeks, OIS specimens were evaluated ex vivo by histologic osteoinductivity. After 8 weeks, PLF ex vivo specimens were evaluated for fusion by manual palpation (FMP), radiography (FXR), and histology (FHISTO). RESULTS: OIS: No materials exhibited a rejection reaction on histology. All DBM-based materials exhibited osteoinductive potential as new bone formation at > 88% of implanted sites. One plain allograft (OsteoSponge) formed bone at 25% of sites. No bone formed for one ceramic (Mozaik Strip), three activated ceramics (Actifuse ABX Putty), or one cellular allograft, regardless of human bone marrow aspirate (hBMA) when added. PLF: Among the 10 DBMs, 6 had FMP of 100% (Accell EVO3, DBX Mix, DBX Strip, Grafton Flex, Grafton Putty, Magnifuse), 2 had FMP of 94% (Grafton Crunch, Grafton Matrix), and 2 conditions had FMP of 0% (Progenix Plus, Progenix Plus + athymic rat iliac crest bone graft [arICBG]). Ceramics (Mozaik Strip), activated ceramics (Actifuse ABX Putty, Vitoss BA), plain allograft (OsteoSponge, MinerOss (PLF study), and cellular allograft (Osteocel Plus) demonstrated 0% FMP. ArICBG demonstrated 13% FMP. CONCLUSIONS: Eight DBM-based materials (Accell EVO3, DBX Mix, DBX Strip, Grafton Crunch, Grafton Flex, Grafton Matrix, Grafton Putty, Magnifuse) demonstrated excellent (> 90% FMP) efficacy in promoting fusion via bone healing. Two DBM conditions (Progenix Plus, Progenix Plus + arICBG) showed no manual palpation fusion (FMP). Systematically, over the 2 studies (OIS and PLF), cellular (Osteocel Plus), plain allografts (OsteoSponge, MinerOss; PLF study), ceramic (Mozaik Strip), and activated ceramics (Actifuse ABX Putty, Vitoss BA) demonstrated poor FMP efficacy (< 10%). CLINICAL RELEVANCE: When selecting DBMs, clinicians must be cognizant of variability in DBM efficacy by product and lot. While theoretically osteoinductive, cellular allograft and activated ceramics yielded poor in vivo efficacy. Whole allograft and ceramics may provide osteoconductive scaffolding for mixed-material grafting; however, surgeons should be cautious in using them alone. Direct clinical data are needed to establish efficacy for any bone graft substitute.

Anti-Inflammatory Peptide Attenuates Edema and Promotes BMP-2-Induced Bone Formation in Spine Fusion.

Recombinant human bone morphogenic protein-2 (BMP-2)-loaded absorbable collagen sponges (ACS) have been successfully used to enhance bone formation and to induce spinal fusion in humans. However, side effects, such as soft tissue edema and inflammation, have been reported. NEMO binding domain peptide (NBD) inhibits activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a central regulator of immune response. In this study, we investigated NBD's potential to reduce BMP-2-induced soft tissue inflammation without affecting BMP-2-mediated spinal fusion in rat. For evaluation of soft tissue inflammation, ACS containing BMP-2, BMP-2+NBD, NBD, or ACS only were implanted into intramuscular paraspinal sites of 32 rats. At day 2 postsurgery, edema formation at the implant sites was assessed using magnetic resonance imaging. T2-weighted relaxation time (T2-RT) values were increased in the BMP-2 group compared with BMP-2+NBD, NBD, and ACS groups. No difference in T2-RT values was detected between BMP-2+NBD versus NBD and ACS controls. Postsacrifice, histological analysis of the implant-surrounding zones showed increased mononuclear cell infiltration in the BMP-2 group compared with BMP-2+NBD and controls. The presence of BMP-2 increased relative NF-κB binding and gene expression of inflammatory markers, interleukin (IL)1ß, IL6, IL18, and chemokine ligand (CCL)2 and CCL3 compared with controls. In the BMP-2+NBD group, cytokine expression was blocked. No differences were found between BMP-2+NBD and control groups. For evaluation of spinal fusion, posterolateral intertransverse lumbar fusion procedures were performed on 16 rats. ACS were loaded with BMP-2 or BMP-2+NBD. After sacrifice at week 12, microcomputed tomographic assessment of the fusion site detected a higher bone volume and reduced trabecular spacing in the BMP-2+NBD group compared with BMP-2. Histological analysis did not show any differences in newly formed bone microarchitecture. In summary, addition of NBD to BMP-2-loaded ACS reduces BMP-2-induced soft tissue edema formation and mononuclear cell infiltration, diminishes NF-κB binding, and thus blocks transcription of NF-κB-regulated cytokines in rat. Furthermore, NBD stimulates bone formation in BMP-2-mediated spinal fusion, possibly through crosstalk of the NF-κB pathway with other pathways. The results of this study might provide the basis to develop new therapeutic bone grafting approaches with combinatory administration of BMP-2 and NBD for spinal fusion.

In situ bone tissue engineering via ultrasound-mediated gene delivery to endogenous progenitor cells in mini-pigs.

More than 2 million bone-grafting procedures are performed each year using autografts or allografts. However, both options carry disadvantages, and there remains a clear medical need for the development of new therapies for massive bone loss and fracture nonunions. We hypothesized that localized ultrasound-mediated, microbubble-enhanced therapeutic gene delivery to endogenous stem cells would induce efficient bone regeneration and fracture repair. To test this hypothesis, we surgically created a critical-sized bone fracture in the tibiae of Yucatán mini-pigs, a clinically relevant large animal model. A collagen scaffold was implanted in the fracture to facilitate recruitment of endogenous mesenchymal stem/progenitor cells (MSCs) into the fracture site. Two weeks later, transcutaneous ultrasound-mediated reporter gene delivery successfully transfected 40% of cells at the fracture site, and flow cytometry showed that 80% of the transfected cells expressed MSC markers. Human bone morphogenetic protein-6 (BMP-6) plasmid DNA was delivered using ultrasound in the same animal model, leading to transient expression and secretion of BMP-6 localized to the fracture area. Micro-computed tomography and biomechanical analyses showed that ultrasound-mediated BMP-6 gene delivery led to complete radiographic and functional fracture healing in all animals 6 weeks after treatment, whereas nonunion was evident in control animals. Collectively, these findings demonstrate that ultrasound-mediated gene delivery to endogenous mesenchymal progenitor cells can effectively treat nonhealing bone fractures in large animals, thereby addressing a major orthopedic unmet need and offering new possibilities for clinical translation.

Long-term Evaluation of Cervical Disc Arthroplasty with the Mobi-C© Cervical Disc: A Randomized, Prospective, Multicenter Clinical Trial with Seven-Year Follow-up.

BACKGROUND: Cervical total disc replacement (TDR) is an increasingly accepted procedure for the treatment of symptomatic cervical degenerative disc disease. Multiple Level I evidence clinical trials have established cervical TDR to be a safe and effective procedure in the short-term. The objective of this study is to provide a long-term assessment of TDR versus anterior discectomy and fusion for the treatment of one- and two-level disc disease. METHODS: This study was a continuation of a prospective, multicenter, randomized, US FDA IDE clinical trial comparing cervical TDR with the Mobi-C© Cervical Disc versus ACDF through 7 years follow-up. Inclusion criteria included a diagnosis of symptomatic cervical degenerative disc disease at one or two cervical levels. TDR patients were treated using a Mobi-C© artificial disc (Zimmer Biomet, Austin TX, USA). ACDF with allograft and anterior plate was used as a control treatment. Outcome measures were collected preoperatively and postoperatively at 6 weeks, at 3, 6, 12, 18 months, annually through 60 months, and at 84 months. Measured outcomes included Overall success, Neck Disability Index (NDI), VAS neck and arm pain, segmental range of motion (ROM), patient satisfaction, SF-12 MCS/PCS, major complications, and subsequent surgery rate. The primary endpoint was an FDA composite definition of success comprising clinical improvement and an absence of major complications and secondary surgery events. RESULTS: A total of 599 patients were enrolled and treated, with 164 treated with one-level TDR, 225 treated with two-level TDR, 81 treated with one-level ACDF, and 105 treated with two-level ACDF. At seven years, follow-up rates ranged from 73.5% to 84.4% (overall 80.2%).The overall success rates of two level TDR and ACDF patients were 60.8% and 34.2%, respectively (p<0.0001). The overall success rates of one level TDR and ACDF patients were 55.2% and 50%, respectively (p>0.05). Both the single and two level TDR and ACDF groups showed significant improvement from baseline NDI scores, VAS neck and arm pain scores, and SF-12 MCS/PCS scores (p<0.0001). In the single level cohort, there was an increased percentage of TDR patients who reported themselves as "very satisfied" (TDR 90.9% vs ACDF 77.8%; p= 0.028). There was a lower rate of adjacent level secondary surgery in the single level TDR patients (3.7%) versus the ACDF patients (13.6%; p = 0.007).In the two level TDR group, the NDI success rate was significantly greater in the TDR group (TDR: 79.0% vs. ACDF: 58.0%; p=0.001). There was significantly more improvement in NDI change score at 7 years in the TDR patients versus ACDF. The TDR group had a significantly higher rate of patients who were "very satisfied" with their treatment compared to the ACDF group (TDR: 85.9% vs. ACDF: 73.9%). The rate of subsequent surgery at the index level was significantly lower in the TDR group compared to the ACDF group (TDR: 4.4% vs. ACDF: 16.2%; p=0.001). The rate of adjacent level secondary surgery was significantly lower in the two level TDR (4.4%) patients compared to the ACDF (11.3%; p=0.03) patients. In both single and two level cohorts, the percentage of patients with worse NDI (2.5%-3.8% of two level surgeries and 1.2%-2.5% of single level surgeries) or worse neck pain (5%-6.8% of the two level surgeries and 1.3% - 3.8% of the single level surgeries) was strikingly low in both groups but trended lower in the TDR patients. CONCLUSIONS: At seven years, the composite success analysis demonstrated clinical superiority of two level TDR over ACDF and non-inferiority of single level TDR versus ACDF. There were lower rates of secondary surgery and higher adjacent level disc survivorship in both groups. Both surgeries were remarkably effective in alleviating pain relative to baseline and the rate of patients with worse disability or neck pain was surprisingly low. Overall, greater than 95% of patients (from both groups) who underwent TDR and 88% of patients who underwent ACDF were "very satisfied" at seven years. The differences in clinical effectiveness of TDR versus ACDF becomes more apparent as treatment increases from one to two levels, indicating a significant benefit for TDR over ACDF for two-level procedures. ETHICAL STANDARDS: The Mobi-C Clinical Trial (ClinicalTrials.gov registration number: NCT00389597) was conducted at 24 sites in the US and was approved by the Institutional Review Board, Research Ethics Committee, or local equivalent of each participating site. LEVEL OF EVIDENCE: 1.

Transient Local Bone Remodeling Effects of rhBMP-2 in an Ovine Interbody Spine Fusion Model.

BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a powerful osteoinductive morphogen capable of stimulating the migration of mesenchymal stem cells (MSCs) to the site of implantation and inducing the proliferation and differentiation of these MSCs into osteoblasts. Vertebral end-plate and vertebral body resorption has been reported after interbody fusion with high doses of rhBMP-2. In this study, we investigated the effects of 2 rhBMP-2 doses on peri-implant bone resorption and bone remodeling at 7 time points in an end-plate-sparing ovine interbody fusion model. METHODS: Twenty-one female sheep underwent an end-plate-sparing discectomy followed by interbody fusion at L2-L3 and L4-L5 using a custom polyetheretherketone (PEEK) interbody fusion device. The PEEK interbody device was filled with 1 of 2 different doses of rhBMP-2 on an absorbable collagen sponge (ACS): 0.13 mg (1×) or 0.90 mg (7×). Bone remodeling and interbody fusion were assessed via high-resolution radiography and histological analyses at 1, 2, 3, 4, 8, 12, and 20 weeks postoperatively. RESULTS: Peri-implant bone resorption peaked between 3 and 8 weeks in both the 1× and the 7× rhBMP-2/ACS-dose group. Osteoclastic activity and corresponding peri-implant bone resorption was dose-dependent, with moderate-to-marked resorption at the 7×-dose level and less resorption at the 1×-dose level. Both dose (p < 0.0007) and time (p < 0.0025) affected bone resorption significantly. Transient bone-resorption areas were fully healed by 12 weeks. Osseous bridging was seen at all but 1 spinal level at 12 and at 20 weeks. CONCLUSIONS: In the ovine end-plate-sparing interbody fusion model, rhBMP-2 dose-dependent osteoclastic resorption is a transient phenomenon that peaks at 4 weeks postoperatively. CLINICAL RELEVANCE: Using the U.S. Food and Drug Administration (FDA)-approved rhBMP-2 concentration and matching the volume of rhBMP-2/ACS with the volume of desired bone formation within the interbody construct may limit the occurrence of transient bone resorption.

Prospective, Randomized Comparison of One-level Mobi-C Cervical Total Disc Replacement vs. Anterior Cervical Discectomy and Fusion: Results at 5-year Follow-up.

INTRODUCTION: There is increasing interest in the role of cervical total disc replacement (TDR) as an alternative to anterior cervical discectomy and fusion (ACDF). Multiple prospective randomized studies with minimum 2 year follow-up have shown TDR to be at least as safe and effective as ACDF in treating symptomatic degenerative disc disease at a single level. The purpose of this study was to compare outcomes of cervical TDR using the Mobi-C(®) with ACDF at 5-year follow-up. METHODS: This prospective, randomized, controlled trial was conducted as a Food and Drug Administration regulated Investigational Device Exemption trial across 23 centers with 245 patients randomized (2:1) to receive TDR with Mobi-C(®) Cervical Disc Prosthesis or ACDF with anterior plate and allograft. Outcome assessments included a composite overall success score, Neck Disability Index (NDI), visual analog scales (VAS) assessing neck and arm pain, Short Form-12 (SF-12) health survey, patient satisfaction, major complications, subsequent surgery, segmental range of motion, and adjacent segment degeneration. RESULTS: The 60-month follow-up rate was 85.5% for the TDR group and 78.9% for the ACDF group. The composite overall success was 61.9% with TDR vs. 52.2% with ACDF, demonstrating statistical non-inferiority. Improvements in NDI, VAS neck and arm pain, and SF-12 scores were similar between groups and were maintained from earlier follow-up through 60 months. There was no significant difference between TDR and ACDF in adverse events or major complications. Range of motion was maintained with TDR through 60 months. Device-related subsequent surgeries (TDR: 3.0%, ACDF: 11.1%, p<0.02) and adjacent segment degeneration at the superior level (TDR: 37.1%, ACDF: 54.7%, p<0.03) were significantly lower for TDR patients. CONCLUSIONS: Five-year results demonstrate the safety and efficacy of TDR with the Mobi-C as a viable alternative to ACDF with the potential advantage of lower rates of reoperation and adjacent segment degeneration, in the treatment of one-level symptomatic cervical degenerative disc disease. CLINICAL RELEVANCE: This prospective, randomized study with 5-year follow-up adds to the existing literature indicating that cervical TDR is a viable alternative to ACDF in appropriately selected patients. LEVEL OF EVIDENCE: This is a Level I study.

Evaluation of Decompression and Interlaminar Stabilization Compared with Decompression and Fusion for the Treatment of Lumbar Spinal Stenosis: 5-year Follow-up of a Prospective, Randomized, Controlled Trial.

INTRODUCTION: If nonoperative treatment for lumbar stenosis fails, surgery may be considered. This traditionally includes decompression often combined with fusion. Desire for less extensive surgery led to developing new techniques and implants, including an interlaminar device designed with the goal of providing segmental stability without fusion, following decompression. The purpose of this study was to investigate 5-year outcomes associated with an interlaminar device. METHODS: This prospective, randomized, controlled trial was conducted at 21 centers. Patients with moderate to severe lumbar stenosis at one or two contiguous levels and up to Grade I spondylolisthesis were randomized (2:1 ratio) to decompression and interlaminar stabilization (D+ILS; n=215) using the coflex(®) Interlaminar Stabilization(®) device (Paradigm Spine, LLC) or decompression and fusion with pedicle screws (D+PS; n=107). Clinical evaluations were made preoperatively and at 6 weeks and 3, 6, 12, 18, 24, 36, 48, and 60 months postoperatively. Overall Food and Drug Administration success criteria required that a patient meet 4 criteria: 1) >15 point improvement in Oswestry Disability Index (ODI) score; 2) no reoperation, revision, removal, or supplemental fixation; 3) no major device-related complication; and 4) no epidural steroid injection after surgery. RESULTS: At 5 years, 50.3% of D+ILS vs. 44% of D+PS patients (p>0.35) met the composite success criteria. Reoperation/revision rates were similar in the two groups (16.3% vs. 17.8%; p >0.90). Both groups had statistically significant improvement through 60 months in ODI scores with 80.6% of D+ILS patients and 73.2% of D+PS patients demonstrating >15 point improvement (p>0.30). VAS, SF-12, and ZCQ scores followed a similar pattern of maintained significant improvement throughout follow-up. On the SF-12 and ZCQ, D+ILS group scores were statistically significantly better during early follow-up compared to D+PS. In the D+ILS group, foraminal height, disc space height, and range of motion at the index level were maintained through 5 years. CONCLUSION: Both treatment groups achieved and maintained statistically significant improvements on multiple outcome assessments throughout 5-year follow-up. On some clinical measures, there were statistically significant differences during early follow-up favoring D+ILS. At no point were there significant differences favoring D+PS. Results of this 5-year follow-up study demonstrate that decompression and interlaminar stabilization with coflex is a viable alternative to traditional decompression and fusion in the treatment of patients with moderate to severe stenosis at one or two lumbar levels. LEVEL OF EVIDENCE AND ETHICAL STATEMENTS: This is a Level I study. Institutional approval was received at each of the sites participating in the trial. Each patient gave informed consent to participate in the trial.