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.

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.

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.

Racial and Sex Disparities in Resident Attrition Among Surgical Subspecialties.

Importance: Racial and sex disparities are prevalent in surgical trainees. Although retrospective studies on resident attrition have been conducted for individual specialties, this study analyzes racial and sex differences in resident attrition among all surgical subspecialties over an 18-year period. Objective: To evaluate the racial and sex differences in resident attrition among surgical specialties over an 18-year period. Design, Setting, and Participants: This was a large, cross-sectional, database study that analyzed program-reported resident censuses (program information, resident demographics, and attrition status) obtained by the Association of American Medical Colleges from 2001 to 2018 for trainees in surgical residency programs. Data were analyzed from March 20, 2021, to June 8, 2022. Main Outcomes and Measures: Demographic trends (including race and ethnicity and sex) for all surgical subspecialty training programs over an 18-year period. Resident attrition includes all-cause withdrawals, dismissals, and transfers to another specialty. Unintended attrition encompasses all withdrawals, dismissals, and transfers except for changing career plans. Results: This study included 407 461 program-reported resident years collected from 112 205 individual surgical residents (67 351 male individuals [60.0%]). The mean percentage of female trainees was 40.0% (44 835) and increased over the study period. Sex disparity remained greatest in orthopedic surgery. Residents who were underrepresented in medicine (URiM) comprised 14.9% (16 695) of all surgical trainees but demonstrated a 2.1% decrease over the study period. Overall attrition rate among all specialties was 6.9% (7759), with an unintended attrition rate of 2.3% (2556). Female residents had a significantly higher relative risk (RR) of attrition (RR, 1.16; 95% CI, 1.11-1.22; P < .001) and unintended attrition (RR, 1.17; 95% CI, 1.08-1.26; P < .001) compared with their male counterparts. URiM residents were at significantly higher RR for attrition (RR, 1.40; 95% CI, 1.32-1.48; P < .001) and unintended attrition (RR, 1.92; 95% CI, 1.75-2.11; P < .001) compared with non-URiM residents. The highest attrition (10.6% [746 of 7043]) and unintended attrition (5.2% [367 of 7043]) rates were in Black/African American residents. The lowest attrition and unintended attrition rates were seen in White residents at 6.2% (4300 of 69 323) and 1.8% (1234 of 69 323), respectively. Black/African American residents were at disproportionate risk for attrition (RR, 1.66; 95% CI, 1.53-1.80; P < .001) and unintended attrition (RR, 2.59; 95% CI, 2.31-2.90; P < .001) compared with all other residents. Orthopedic surgery had the highest attrition (RR, 3.80; 95% CI, 2.84-5.09; P < .001) and unintended attrition (RR, 7.20; 95% CI, 4.84-10.71; P < .001) for Black/African American residents. Conclusions and Relevance: Results of this cross-sectional study suggest that the percentage of female residents in surgical specialties has improved over the last 18 years, and the percentage of URiM residents has remained relatively unchanged. Risk for attrition and unintended attrition was significantly elevated for female and URiM residents, specifically Black/African Americans. These results highlight current racial and sex disparities in resident attrition and demonstrate the importance of developing strategies to recruit, retain, and support residents.

Racial and Sex Disparities in Resident Attrition in Orthopaedic Surgery.

Studies have suggested that female individuals and individuals from backgrounds under-represented in medicine (URiM) are at increased risk of attrition during residency. This likely exacerbates the lack of diversity in our field. The aims of this study were to (1) characterize demographic composition in orthopaedic residency from 2001 to 2018 and (2) determine the race/ethnicity and identify any disparities. Methods: Demographic and attrition data from 2001 to 2018 were obtained from the Association of American Medical Colleges. Attrition data comprised the following categories: withdrawals, dismissals, and transfers to another specialty. Analysis compared demographic composition and determined attrition rates with subgroup analysis by race/ethnicity and sex. Results: From 2001 to 2018, female orthopaedic residents increased from 8.77% to 15.54% and URiM residents from 9.49% to 11.32%. The overall and unintended attrition rates in orthopaedic surgery were 3.20% and 1.15%, respectively. Among female residents, the overall and unintended attrition rates were 5.96% and 2.09% compared with 2.79% and 1.01%, respectively, in male residents. URiM residents had overall and unintended attrition rates of 6.16% and 3.11% compared with 2.71% and 0.83%, respectively, for their White counterparts. Black/African American residents had an attrition rate of nearly 10%. Female residents averaged 12.9% of all residents but 24% of those leaving orthopaedics. URiM residents were 10.14% of all residents but 19.51% of those experiencing attrition. In logistic regression models, female residents had a relative risk (RR) of 2.20 (p < 0.001) for experiencing all-cause attrition and 2.09 (p < 0.001) for unintended attrition compared with male residents. Compared with their White male counterparts, URiM residents had a RR for overall and unintended attrition of 2.36 and 3.84 (p < 0.001), respectively; Black/African American residents had a RR for the same of 3.80 and 7.20 (p < 0.001), respectively. Conclusion: Although female resident percentage has increased, orthopaedics continues to train fewer female surgeons than all other fields. Female and URiM residents in orthopaedic surgery are disproportionately affected by attrition. While recruitment has been the primary focus of diversity, equity, and inclusion efforts, this study suggests that resident retention through appropriately supporting residents during training is equally critical.

Perioperative Complications Following Spine Surgery in Adult Patients with Achondroplasia.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To describe the common types of complications and their risk factors during spine surgery in patients with achondroplasia. METHODS: A retrospective review was performed of medical records of adult achondroplasia patients who underwent spine surgery at our institution between 2007 and 2021. Inclusion criteria were achondroplasia and age >16 years. Surgical encounters were evaluated for durotomy, postoperative neurologic deficit, wound compromise, medical complications, and return to the operating room. Statistical analysis included evaluation of relationships across complications and fisher exact test applied to bivariate/categorical variables and t-test/ANOVA for continuous variables. Multivariable analysis using logistic regression was performed to account for patient characteristics. RESULTS: Fifty-five patients with achondroplasia underwent 95 surgeries. Forty-nine percent of the surgeries involved a complication. These included durotomy (33.7%), neurologic deficit (11.6%), wound compromise (6.3%), and other medical complications (6.3%). Thirteen percent of surgeries required return to the operating room. The greatest number of complications occurred in thoracolumbar region (60.0%) compared to cervicothoracic (18.2%) and craniocervical junction (33.3%). Chronologically later surgical encounters had decreased complications and durotomies only occurred in thoracolumbar surgeries (45.7%). CONCLUSIONS: Adult patients with achondroplasia undergoing surgery chronologically later in this set of consecutive patients were at a decreased risk for complications. Thoracolumbar surgeries were at the greatest risk for durotomies. Male sex was a risk factor for durotomy, while age was a risk factor for neurologic deficit. The potential for adverse surgical events should be considered when evaluating patients with achondroplasia for spine surgery. .

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.

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.

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 effect of insulin dependent diabetes on bone metabolism and growth after spinal fusion.

STUDY DESIGN: Experimental animal model. OBJECTIVE: The purpose of this study was to evaluate the hypothesis that insulin dependent diabetes mellitus (IDDM) will inhibit the formation of a solid bony union after spinal fusion surgery via an alteration of the microenvironment at the fusion site in a rat model. SUMMARY OF BACKGROUND DATA: Previous studies report diabetes mellitus (DM) and specifically IDDM as a risk factor for complications and poor surgical outcomes following spinal fusion. METHODS: Twenty control and 22 diabetic rats were obtained at 5 weeks of age. At 20 weeks of age, all animals underwent posterolateral lumbar fusion surgery using a tailbone autograft with diabetic rats receiving an implantable time release insulin pellet. A subset of rats was sacrificed 1-week postsurgery for growth factor (PDGF, IGF-I, TGF-ß, and VEGF) and proinflammatory cytokine ELISA analysis. All other rats were sacrificed 3-months postsurgery for fusion evaluation via manual palpation and micro CT. Glycated hemoglobin (HbA1c) was measured at surgery and sacrifice on all animals. RESULTS: Compared with healthy rats undergoing spinal fusion, rats with IDDM demonstrated a significant reduction in manual palpation fusion rates (16.7% vs. 43%, p<.05). Average bone mineral density, bone volume, and bone volume fraction were also significantly reduced and negatively correlated to blood glucose levels. IL-1B, IL-5, IL-10, TNF-α, and KC/GRO were significantly elevated in fusion beds of IDDM rats. CONCLUSIONS: This study demonstrates that rats with IDDM demonstrate a reduced rate and quality of spinal fusion with increased local levels of inflammatory cytokines. Targeted modalities are required to improve bone healing in this growing, high-risk population. CLINICAL SIGNIFICANCE: This is the first translational animal model of IDDM to evaluate the rate and quality of spinal fusion while controlling for other surgical and patient-related risk factors. Our findings demonstrate the complex nature by which IDDM impairs bone healing and highlight the need for additional basic science research to further elucidate this mechanism in order to develop more effective therapeutic interventions.

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.

Electrospun, synthetic bone void filler promotes human MSC function and BMP-2 mediated spinal fusion.

INTRODUCTION: Synthetic bone grafts are often used to achieve a well-consolidated fusion mass in spinal fusion procedures. These bone grafts function as scaffolds, and ideally support cell function and facilitate protein binding. OBJECTIVE: The aim was to characterize an electrospun, synthetic bone void filler (Reb) for its bone morphogenetic protein (BMP)-2 release properties and support of human mesenchymal stem cell (hMSC) function in vitro, and its efficacy in promoting BMP-2-/bone marrow aspirate-(BMA)-mediated posterolateral spinal fusion (PLF) in vivo. METHODS: BMP-2 release kinetics from Reb versus standard absorbable collagen sponge (ACS) was determined. hMSC adhesion and proliferation on Reb was tested using cell counting, fluorescence microscopy and MTS. Cell osteogenic differentiation was quantified via cellular alkaline phosphatase (ALP) activity. For in vivo analysis, 18 Lewis rats were treated during PLF surgery with the following groups: (I) Reb + BMA, (II) Reb + BMA + BMP-2 and (III) BMA. A safe, minimally effective dose of BMP-2 was used. Fusion consolidation was followed for 3 months using radiography and micro-CT. After sacrifice, fusion rate and biomechanical stiffness was determined using manual palpation, biomechanical tests and histology. RESULTS: In vitro, BMP-2 release kinetics were similar between Reb versus ACS. MSC proliferation and differentiation were increased in the presence of Reb. At 3 months post-surgery, fusion rates were 29% (group I), 100% (group II), and 0% (group III). Biomechanical stiffness was higher in group II versus I. Micro-CT showed an increased bone volume and connectivity density in group II. Trabecular thickness was increased in group I versus II. H&E staining showed newly formed bone in group II only. CONCLUSIONS: Reb possesses a high protein binding affinity and promotes hMSC function. Combination with BMA and minimal dose BMP-2 allowed for 100% bone fusion in vivo. This data suggests that a minimally effective dose of BMP-2 can be used when combined with Reb.

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.

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.

Ten- and 20-year Survivorship of the Hip After Periacetabular Osteotomy for Acetabular Dysplasia.

INTRODUCTION: Acetabular dysplasia is a multifactorial condition characterized by a shallow hip socket with predisposition to osteoarthritis of the hip. The Bernese periacetabular osteotomy (PAO), developed by Reinhold Ganz in 1984, reorients the dysplastic hip joint to provide more uniform coverage of the femoral head and to extend the longevity of the native hip. Since 1987, the senior author performed the Bernese PAO on more than 430 patients. We performed a cross-sectional retrospective study on this cohort of patients to determine the 10- and 20-year survivorship after PAO in addition to assessing functional outcomes and radiographic parameters. METHODS: Four hundred thirty-four patients were treated for acetabular dysplasia with PAO by the senior surgeon from 1987 to 2014. Data were obtained for 302 hips in 258 patients in a retrospective fashion from medical records and/or mail-in/phone questionnaires. Functional outcome data consisted of postoperative Hip Osteoarthritis Outcome Score and University of California-Los Angeles Activity Score. Pre- and postoperative radiographs were used to determine lateral center-edge angle, anterior center-edge angle, Tönnis angle/grade, and head-to-ilioischial line distance. Survivorship of the native hip was determined by Kaplan-Meier analysis. RESULTS: Of the 302 hips analyzed, 248 were still surviving native hips and 54 had gone on to a total hip arthroplasty (THA) at the time of data acquisition. The average age of patients in the entire cohort at PAO was 32.7 years (range, 13 to 63 years). Of the 258 patients, 215 were female patients (83.3%) and 43 male patients (16.8%). The average age of patients in the surviving group at PAO was 32.3 years, and the average age of patients in the THA group was 36.6 years (P < 0.01). At the time of data acquisition, follow-up ranged from 2 to 27 years (average, 11.2 years). Hip Osteoarthritis Outcome Score and University of California-Los Angeles Activity Score are reported for the surviving native hips after PAO. Radiographic analyses for surviving and failed hips are described, with pre- and postoperative Tönnis grade being statistically significant predictors for conversion to THA (P < 0.01). Survivorship of the native hip was 86% at 10 years and 60% at 20 years in the surviving cohort. Survivorship stratified by age at the time of PAO demonstrated a 10-year survivorship of 93.3%, 90.1%, 81.6%, and 63.2% at ages 20, 30, 40, and 50 years, respectively. No notable difference exists in survivorship between male and female patients; however, male patients had a trend toward lower survivorship compared with female patients at 15 years. CONCLUSION: The 10- and 20-year survivorship of the native hip after PAO is approximately 86% and 60%, respectively, in our cohort of 302 hips. Older age at the time of PAO and higher Tönnis grade are negative prognostic factors for joint survival after PAO. Surviving hips after PAO have good functional outcomes even up to 20 years after surgery. This survivorship analysis represents one of the largest and longest survival studies of patients after PAO, and our results are consistent with other published studies. LEVEL OF EVIDENCE: Level III.

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.

The impact of type 2 diabetes on bone metabolism and growth after spinal fusion.

BACKGROUND CONTEXT: Some clinical reports suggest diabetes may have a negative effect on spinal fusion outcomes, although no conclusive experimental research has been conducted to investigate the causality, impact, and inherent risks of this growing patient population. PURPOSE: To analyze the hypothesis that type 2 diabetes (T2DM) inhibits the formation of a solid bony union after spinal fusion surgery by altering the local microenvironment at the fusion site through a reduction in growth factors critical for bone formation. STUDY DESIGN/SETTING: In vivo rodent model of type 2 diabetes. METHODS: Twenty control (Sprague Dawley, SD) and 30 diabetic (Zucker Diabetic Sprague Dawley, ZDSD) rats underwent posterolateral and laminar fusion surgery using a tailbone autograft implanted onto the L4/L5 transverse processes. A subset of animals was sacrificed 1-week postsurgery for growth factor analysis. Remaining rats were sacrificed 3-month postsurgery for fusion evaluation via manual palpation, micro-CT, and histology. RESULTS: There was no significant difference in the manual palpation fusion rate between ZDSD rats and SD control rats. Growth factor assay of fusion site explants at early sacrifice demonstrated PDGF was upregulated in the ZDSD rats. TGFB, IGF, and VEGF were not statistically different between groups. Bone mineral density as determined by micro-CT was significantly lower in ZDSD rats compared to SD controls and was a significant function of HbA1c. CONCLUSIONS: Data generated in this in vivo rat model of T2DM demonstrate that the metabolic dysregulation associated with the diabetic condition negatively impacts the quality and density of the formed fusion mass. Increased measures of diabetic status, as determined by blood glucose and HbA1c, were correlated with decreased quality of formed fusion, highlighting the importance of diabetic status monitoring and regulation to bone health, particularly during bone healing. CLINICAL RELEVANCE: T2DM rats demonstrated increased rates of infection, metabolic dysregulation, and a reduction in spinal fusion consolidation. Clinicians should consider these negative effects during preoperative care and treatment of this growing patient population.