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.

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.

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.

Femoral Neurogram Before Transpsoas Spinal Access at L4-5 Intervertebral Disk Space: A Proposed Screening Tool.

STUDY DESIGN: Observational study. OBJECTIVE: To illustrate the variability of the course of the femoral nerve across the L4-5 disk space, and to present a novel application of transforaminal epidural steroid injections (TFESI) in the visualization of femoral nerve roots. SUMMARY OF BACKGROUND DATA: A concern regarding the lateral retroperitoneal transpsoas approach is the proximity of the lumbar plexus. Current techniques of assessing the proximity of neural tissue to the L4-5 disk space have limited capabilities. METHODS: A total of 100 patients were selected for L4-5 TFESI (L4 selective nerve root blocks) because of lumbar radiculopathy. L4 neurograms were obtained while performing L4-5 TFESI under flouroscopic guidance, using a retroneural technique. The course of the L4 root/femoral nerve was then evaluated under fluoroscopy in the anteroposterior and lateral planes. Images were then reviewed by a radiologist, physiatrist, and 2 orthopedic spine surgeons. RESULTS: Fluoroscopic evaluation revealed that the pattern of location of the femoral nerve was highly variable. In males, it was located 4.7% in zone 2, 32.5% in zone 3, 53.5% in zone 4, and 9.3% in zone P. In female patients, it was located 7.0% in zone 2, 14% in zone 3, 54.4% in zone 4, and 24.6% in zone P. CONCLUSIONS: An L4 neurogram will provide an accurate trajectory of L4 root/femoral nerve as it crosses the L4-5 intervertebral disk space. An accurate assessment is essential to help minimize the increasing frequency of thigh pain, paresthesias, and weakness associated with the lateral access to the L4-5 intervertebral disk space. Femoral nerves that fall within zones 2 and 3 will require more manipulation during retraction and may be better suited with a different surgical approach.

Prospective, Randomized Comparison of Cervical Total Disk Replacement Versus Anterior Cervical Fusion: Results at 48 Months Follow-up.

STUDY DESIGN: This was a prospective, randomized, controlled multicenter trial. OBJECTIVE: The purpose of this study was to compare clinical outcomes at 4-year follow-up of patients receiving cervical total disk replacement (TDR) with those receiving anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF has been the traditional treatment for symptomatic disk degeneration. Several studies found single-level TDR to be as safe and effective as ACDF at ≥2 years follow-up. METHODS: Patients from 23 centers were randomized in a 2:1 ratio with 164 receiving the investigational device (Mobi-C Cervical Disc Prosthesis) and 81 receiving ACDF using an anterior plate and allograft. Patients were evaluated preoperatively and 6 weeks, 3, 6, 12, 18, 24, 36, and 48 months postoperatively. Outcome assessments included a composite success score, Neck Disability Index, visual analog scales assessing neck and arm pain, patient satisfaction, major complications, subsequent surgery, segmental range of motion, and adjacent-segment degeneration. RESULTS: The composite success rate was similar in the 2 groups at 48-month follow-up. Mean Neck Disability Index, visual analog scale, and SF-12 scores were significantly improved in early follow-up in both groups with improvements maintained throughout 48 months. On some measures, TDR had significantly greater improvement during early follow-up. At no follow-up were TDR scores significantly worse than ACDF scores. Subsequent surgery rate was significantly higher for ACDF compared with TDR (9.9% vs. 3.0%, P<0.05). Range of motion was maintained with TDR having a mean baseline value of 8 degrees compared with 10 degrees at 48 months. The incidence of adjacent-segment degeneration was significantly higher with ACDF at inferior and superior segments compared with TDR (inferior: 50% vs. 30%, P<0.025; superior: 53% vs. 34%, P<0.025). CONCLUSIONS: Significant improvements were observed in pain and function. TDR patients maintained motion and had significantly lower rates of reoperation and adjacent-segment degeneration compared with ACDF. This study supports the safety and efficacy of TDR in appropriately selected patients.

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.

A Narrative Review on Recombinant Human Bone Morphogenetic Protein 2: Where Are We Now?

Spinal fusion is a prevalent surgical intervention for degenerative spinal diseases, with increasing demand driven by ageing populations. The coexistence of multiple chronic conditions, termed multimorbidity, often complicates surgical outcomes, making advanced bone grafts crucial for successful fusions. This paper reviews the development, clinical application, and controversies surrounding the use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries. A comprehensive narrative review was conducted, focusing on literature from January 1980 to January 2024, sourced from PubMed and Google Scholar. Studies included those examining rhBMP-2 specifically in spinal fusion contexts, excluding other bone morphogenetic proteins (BMPs) and non-spinal applications. This review presents an overarching synopsis of rhBMP-2, its development history and clinical efficacy, the emergence of side effects, and evolving patterns of clinical use. As discussed in this review, clinical practice has adjusted usage and dosages to mitigate adverse effects, yet the need for safer delivery mechanisms persists. rhBMP-2 remains a potent osteoinductive agent with comparable fusion success, as measured by radiographic fusion and good clinical outcomes, to autologous grafts but poses unique risks. This review sets out how further research is essential to optimise the delivery of rhBMP-2 to reduce side effects. Enhanced understanding and innovation of spatio-temporal presentation relative to endogenous BMP could significantly improve patient outcomes in spinal fusion surgeries. The review contributes to the growing body of literature on the use of rhBMP-2 in spine surgery and discusses changing patterns of clinical use over time.

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.

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats.

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.

Is There Clinical Improvement Associated With Intradiscal Therapies? A Comparison Across Randomized Controlled Studies.

STUDY DESIGN: Post hoc comparison using single-site data from 4 multicenter randomized controlled trials. OBJECTIVES: Discogenic back pain is associated with significant morbidity and medical cost. Several terminated, unreported randomized controlled trials have studied the effect of intradiscal biologic injections. Here we report single-center outcomes from these trials to determine if there is clinical improvement associated with these intradiscal injections. METHODS: Post hoc comparison was performed using single-site data from 4 similar multi-center randomized controlled trials. All trials evaluated an injectable therapy (growth factor, fibrin sealant, or stem cells) for symptomatic lumbar disc disease with near-identical inclusion and exclusion criteria. Demographics and patient reported outcomes were analyzed across treatment arms postinjection. RESULTS: A total of 38 patients were treated with biologic agents and 12 were treated with control saline injections. There was a significant decrease in visual analogue score (VAS) pain for both the investigational and saline groups up to 12 months postinjection (P < .01). There was no significant difference in VAS scores between the saline and investigational groups at 12 months. Similarly, there was significant improvement in patient-reported disability scores in both the investigational and saline groups at all time points. There were no significant differences in disability score improvement between the saline and investigational treatment groups at 12 months postinjection. CONCLUSIONS: A single-center analysis of 4 randomized controlled studies demonstrated no difference in outcomes between therapeutic intradiscal agents (growth factor, fibrin sealant, or stem cells) and control saline groups. In all groups, patient reported pain and disability scores decreased significantly. Future studies are needed to evaluate the therapeutic benefit of any intradiscal injections.

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.

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.

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.

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.

Intervertebral Disc Repair: Current Concepts.

STUDY DESIGN: Review article. OBJECTIVE: A review of the literature on current strategies utilized in intervertebral regeneration and repair efforts. METHODS: A review of the literature and analysis of the data to provide an updated review on current concepts of intervertebral disc repair and regeneration efforts. RESULTS: Multiple regenerative strategies for intervertebral disc regeneration are being employed to reduce pain and improve quality of life. Current promising strategies include molecular therapy, gene therapy, cell-based therapy, and augmentation with biomaterials. Multiple clinical trials studying biologic, cell-based, and scaffold-based injectable therapies are currently being investigated. CONCLUSION: Low back pain due to intervertebral disc disease represents a significant health and societal burden. Current promising strategies include molecular therapy, gene therapy, cell-based therapy, and augmentation with biomaterials. To date, there are no Food and Drug Administration-approved intradiscal therapies for discogenic back pain, and there are no large randomized trials that have shown clinically significant improvement with any investigational regenerative treatment. Multiple clinical trials studying biologic, cell-based, or scaffold-based injectable therapies are being currently investigated.

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.

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.

Optimization of a rat lumbar IVD degeneration model for low back pain.

INTRODUCTION: Intervertebral disc (IVD) degeneration is often associated with low back pain and radiating leg pain. The purpose of this study is to develop a reproducible and standardized preclinical model of painful lumbar IVD degeneration by evaluation of structural and behavioral changes in response to IVD injury with increasing needle sizes. This model can be used to develop new therapies for IVD degeneration. METHODS: Forty-five female Sprague Dawley rats underwent anterior lumbar disc needle puncture at levels L4-5 and L5-6 under fluoroscopic guidance. Animals were randomly assigned to four different experimental groups: needle sizes of 18 Gauge (G), 21G, 23G, and sham control. To monitor the progression of IVD degeneration and pain, the following methods were employed: µMRI, qRT-PCR, histology, and biobehavioral analysis. RESULTS: T1- and T2-weighted µMRI analysis showed a correlation between the degree of IVD degeneration and needle diameter, with the most severe degeneration in the 18G group. mRNA expression of markers for IVD degeneration markers were dysregulated in the 18G and 21G groups, while pro-nociceptive markers were increased in the 18G group only. Hematoxylin and Eosin (H&E) and Alcian Blue/Picrosirius Red staining confirmed the most pronounced IVD degeneration in the 18G group. Randall-Selitto and von Frey tests showed increased hindpaw sensitivity in the 18G group. CONCLUSION: Our findings demonstrate that anterior disc injury with an 18G needle creates severe IVD degeneration and mechanical hypersensitivity, while the 21G needle results in moderate degeneration with no increased pain sensitivity. Therefore, needle sizes should be selected depending on the desired phenotype for the pre-clinical model.

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.