To Cross the Cervicothoracic Junction? Terminating Posterior Cervical Fusion Constructs Proximal to the Cervicothoracic Junction Does Not Impart Increased Risk of Reoperation in Patients With Cervical Spondylotic Myelopathy.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To evaluate the effect of caudal instrumentation level on revision rates following posterior cervical laminectomy and fusion. METHODS: A retrospective review of a prospectively collected database was performed. Minimum follow-up was one year. Patients were divided into two groups based on the caudal level of their index fusion construct (Group 1-cervical and Group 2- thoracic). Reoperation rates were compared between the two groups, and preoperative demographics and radiographic parameters were compared between patients who required revision and those who did not. Multivariate binomial regression analysis was performed to determine independent risk factors for revision surgery. RESULTS: One hundred thirty-seven (137/204) patients received fusion constructs that terminated at C7 (Group 1), while 67 (67/204) received fusion constructs that terminated at T1 or T2 (Group 2). The revision rate was 8.33% in the combined cohort, 7.3% in Group 1, and 10.4% in Group 2. There was no significant difference in revision rates between the 2 groups (P = .43). Multivariate regression analysis did not identify any independent risk factors for revision surgery. CONCLUSION: This study shows no evidence of increased risk of revision in patients with fusion constructs terminating in the cervical spine when compared to patients with constructs crossing the cervicothoracic junction. These findings support terminating the fusion construct proximal to the cervicothoracic junction when indicated. LEVEL OF EVIDENCE: III.

The Mandated Publication of Individual Hospital Charge Description Masters Does Not Permit the Estimation of Complex Procedure Charges.

BACKGROUND: As healthcare spending continues to rise, price transparency is crucial for patients to calculate a reasonable cost estimate for tests and procedures. Legislative efforts have been successful at mandating increased hospital price transparency, including publishing charge description masters (CDMs), but their usefulness in permitting patients to assess the cost for complex procedures is unclear. We sought to determine CDM and diagnosis-related group (DRG) prevalence and evaluate whether these are effective tools for patients to preemptively ascertain the costs for simple and complex tests and procedures. METHODS: Cross-sectional analysis of publicly available 2019 CDMs and DRGs from 122 hospitals in the United States, including the top-20 as ranked by the US News & World Report Honor Roll and two top-ranked hospitals per state. We first determined the availability of CDMs and DRGs and then determined the ability to estimate the hospital charge for a three-view knee radiograph and a primary total knee arthroplasty (TKA) using CDM and DRG data. RESULTS: One hundred fifteen of 122 (94.3%) hospitals published a CDM, and 78 (63.9%) published a DRG. Top-ranked hospitals published DRGs more frequently than those outside of the Honor Roll designation (P = 0.04). The estimated charge for a three-view knee radiograph could be calculated from 113/115 (98.3%) CDMs. The estimated total charge for a primary TKA could not be obtained from any of the available CDMs. By comparison, the estimated charge for a primary TKA could be obtained from 76/78 (97.4%) of the available DRGs. DISCUSSION: CDMs are available as currently mandated for most hospitals and generally can be used to identify the charges for simple procedures, but they are ineffective tools for patients to estimate the charges associated with a multifaceted healthcare procedure, such as TKA. Although DRGs are less frequently available, they are a more effective resource for patients to estimate charges.

Ex-vivo biomechanics of repaired rat intervertebral discs using genipin crosslinked fibrin adhesive hydrogel.

Microdiscectomy is the current standard surgical treatment for intervertebral disc (IVD) herniation, however annulus fibrosus (AF) defects remain unrepaired which can alter IVD biomechanical properties and lead to reherniation, IVD degeneration and recurrent back pain. Genipin-crosslinked fibrin (FibGen) hydrogel is an injectable AF sealant previously shown to partially restore IVD motion segment biomechanical properties. A small animal model of herniation and repair is needed to evaluate repair potential for early-stage screening of IVD repair strategies prior to more costly large animal and eventual human studies. This study developed an ex-vivo rat caudal IVD herniation model and characterized torsional, axial tension-compression and stress relaxation biomechanical properties before and after herniation injury with or without repair using FibGen. Injury group involved an annular defect followed by removal of nucleus pulposus tissue to simulate a severe herniation while Repaired group involved FibGen injection. Injury significantly altered axial range of motion, neutral zone, torsional stiffness, torque range and stress-relaxation biomechanical parameters compared to Intact. FibGen repair restored the stress-relaxation parameters including effective hydraulic permeability indicating it effectively sealed the IVD defect, and there was a trend for improved tensile stiffness and axial neutral zone length. This study demonstrated a model for studying IVD herniation injury and repair strategies using rat caudal IVDs ex-vivo and demonstrated FibGen sealed IVDs to restore water retention and IVD pressurization. This ex-vivo small animal model may be modified for future in-vivo studies to screen IVD repair strategies using FibGen and other IVD repair biomaterials as an augment to additional large animal and human IVD testing.

Correction: Dietary polyphenols as a safe and novel intervention for modulating pain associated with intervertebral disc degeneration in an in-vivo rat model.

[This corrects the article DOI: 10.1371/journal.pone.0223435.].

Dietary polyphenols as a safe and novel intervention for modulating pain associated with intervertebral disc degeneration in an in-vivo rat model.

Developing effective therapies for back pain associated with intervertebral disc (IVD) degeneration is a research priority since it is a major socioeconomic burden and current conservative and surgical treatments have limited success. Polyphenols are naturally occurring compounds in plant-derived foods and beverages, and evidence suggests dietary supplementation with select polyphenol preparations can modulate diverse neurological and painful disorders. This study tested whether supplementation with a select standardized Bioactive-Dietary-Polyphenol-Preparation (BDPP) may alleviate pain symptoms associated with IVD degeneration. Painful IVD degeneration was surgically induced in skeletally-mature rats by intradiscal saline injection into three consecutive lumbar IVDs. Injured rats were given normal or BDPP-supplemented drinking water. In-vivo hindpaw mechanical allodynia and IVD height were assessed weekly for 6 weeks following injury. Spinal column, dorsal-root-ganglion (DRG) and serum were collected at 1 and 6 weeks post-operative (post-op) for analyses of IVD-related mechanical and biological pathogenic processes. Dietary BDPP significantly alleviated the typical behavioral sensitivity associated with surgical procedures and IVD degeneration, but did not modulate IVD degeneration nor changes of pro-inflammatory cytokine levels in IVD. Gene expression analyses suggested BDPP might have an immunomodulatory effect in attenuating the expression of pro-inflammatory cytokines in DRGs. This study supports the idea that dietary supplementation with BDPP has potential to alleviate IVD degeneration-related pain, and further investigations are warranted to identify the mechanisms of action of dietary BDPP.

Sex Differences in Rat Intervertebral Disc Structure and Function Following Annular Puncture Injury.

STUDY DESIGN: A rat puncture injury intervertebral disc (IVD) degeneration model with structural, biomechanical, and histological analyses. OBJECTIVE: To determine if males and females have distinct responses in the IVD after injury. SUMMARY OF BACKGROUND DATA: Low back pain (LBP) and spinal impairments are more common in women than men. However, sex differences in IVD response to injury have been underexplored, particularly in animal models where sex differences can be measured without gender confounds. METHODS: Forty-eight male and female Sprague Dawley rats underwent sham, single annular puncture with tumor necrosis factor α (TNFα) injection (1×), or triple annular puncture with TNFα injection (3×) surgery. Six weeks after surgery, lumbar IVDs were assessed by radiologic IVD height, spinal motion segment biomechanical testing, histological degeneration grading, second harmonic generation (SHG) imaging, and immunofluorescence for fibronectin and α-smooth muscle actin. RESULTS: Annular puncture injuries significantly increased degenerative grade and IVD height loss for males and females, but females had increased degeneration grade particularly in the annulus fibrosus (AF). Despite IVD height loss, biomechanical properties were largely unaffected by injury at 6 weeks. However, biomechanical measures sensitive to outer AF differed by sex after 3× injury-male IVDs had greater torsional stiffness, torque range, and viscoelastic creep responses. SHG intensity of outer AF was reduced after injury only in female IVDs, suggesting sex differences in collagen remodeling. Both males and females exhibited decreased cellularity and increased fibronectin expression at injury sites. CONCLUSION: IVD injury results in distinct degeneration and functional healing responses between males and females. The subtle sex differences identified in this animal model suggest differences in response to IVD injury that might explain some of the variance observed in human LBP, and demonstrate the need to better understand differences in male and female IVD degeneration patterns and pain pathogenesis. LEVEL OF EVIDENCE: N/A.

Biomechanical test protocols to detect minor injury effects in intervertebral discs.

Intervertebral discs (IVDs) maintain flexibility of the spine and bear mechanical load. Annulus fibrosus (AF) defects are associated with IVD degeneration and herniation which disrupt biomechanical function and can cause pain. AF puncture injuries can induce IVD degeneration but are needed to inject therapies. Identifying small AF defects with biomechanical testing can be difficult because IVDs have a complex, composite structure and nonlinear biomechanical properties that are dependent on AF fiber tension. It remains unclear how choice of biomechanical testing protocols affect the sensitivity of biomechanical properties to AF injuries. This study determined whether axial preload or magnitude of cyclic axial or torsional testing affected the ability to detect minor AF defects in rat caudal motion segments using ex vivo biomechanical testing. Intact and injured motion segments were subjected to a repeated measures study design with multiple biomechanical testing protocols that varied axial tension-compression force amplitude (±1.6 N, ±8.0 N, ±16.0 N), axial preload (-1.6 N, -8.0 N, -16.0 N, corresponding to -0.1 MPa, -0.5 MPa, and -1.0 MPa, respectively), and torsional rotation angle (±10°, ±15°, and ±20°). Biomechanical properties obtained from the lowest force testing conditions for axial tension-compression (±1.6 N), axial preload (-1.6 N), and angular rotation (±10°) exhibited the largest differences in biomechanical properties between intact and injured conditions. Biomechanical properties determined under low axial force or torsion amplitudes involve less AF fiber tension and were most sensitive to injury. Low force testing protocols are recommended for detecting minor structural AF defects and may enable more precise assessments of IVD injuries, healing or repair.

Inhibiting tumor necrosis factor-alpha at time of induced intervertebral disc injury limits long-term pain and degeneration in a rat model.

BACKGROUND: Painful intervertebral disc (IVD) degeneration has tremendous societal costs and few effective therapies. Intradiscal tumor necrosis factor-alpha (TNFα) is commonly associated with low back pain, but the direct relationship remains unclear. PURPOSE: Treatment strategies for low back pain require improved understanding of the complex relationships between pain, intradiscal pro-inflammatory cytokines, and structural IVD degeneration. A rat in vivo lumbar IVD puncture model was used to 1) determine the role of TNFα in initiating painful IVD degeneration, and 2) identify statistical relationships between painful behavior, IVD degeneration, and intradiscal pro-inflammatory cytokine expression. METHODS: Lumbar IVDs were punctured anteriorly and injected with TNFα, anti-TNFα, or saline and compared with sham and naive controls. Hindpaw mechanical hyperalgesia was assayed weekly to determine pain over time. 6-weeks post-surgery, animals were sacrificed, and IVD degeneration, IVD height, and intradiscal TNFα and interleukin-1 beta (IL-1ß) expressions were assayed. RESULTS: Intradiscal TNFα injection increased pain and IVD degeneration whereas anti-TNFα alleviated pain to sham level. Multivariate step-wise linear regression identified pain threshold was predicted by IVD degeneration and intradiscal TNFα expression. Pain threshold was also linearly associated with IVD height loss and IL-1ß. DISCUSSION: The significant associations between IVD degeneration, height loss, inflammation, and painful behavior highlight the multifactorial nature of painful IVD degeneration and the challenges to diagnose and treat a specific underlying factor. We concluded that TNFα is an initiator of painful IVD degeneration and its early inhibition can mitigate pain and degeneration. Intradiscal TNFα inhibition following IVD injury may warrant investigation for its potential to alter downstream painful IVD degeneration processes.

Hyperosmolarity induces notochordal cell differentiation with aquaporin3 upregulation and reduced N-cadherin expression.

The nucleus pulposus (NP) of intervertebral discs (IVD) undergoes dramatic changes with aging including loss of its gelatinous structure and large, vacuolated notochordal cells (NCs) in favor of a matrix-rich structure populated by small NP cells (sNPCs). NP maturation also involves a loading-pattern shift from pressurization to matrix deformations, and these events are thought to predispose to degeneration. Little is known of the triggering events and cellular alterations involved with NP maturation, which remains a fundamental open spinal mechanobiology question. A mouse IVD organ culture model was used to test the hypotheses that hyperosmotic overloading will induce NP maturation with transition of NCs to sNPCs while also increasing matrix accumulation and altering osmoregulatory and mechanotransductive proteins. Results indicated that static hyperosmolarity, as might occur during growth, caused maturation of NCs to sNPCs and involved a cellular differentiation process since known NC markers (cytokeratin-8, -19, and sonic hedgehog) persisted without increased cell apoptosis. Osmosensitive channels Aquaporin 3 (Aqp3) and transient receptor potential vanilloid-4 (TRPV4) expression were both modified with altered osmolarity, but increased Aqp3 with hyperosmolarity was associated with NC to sNPC differentiation. NC to sNPC differentiation was accompanied by a shift in cellular mechanotransduction proteins with decreased N-cadherin adhesions and increased Connexin 43 connexons. We conclude that hyperosmotic overloading can promote NC differentiation into sNPCs. This study identified osmolarity as a triggering mechanism for notochordal cell differentiation with associated shifts in osmoregulatory and mechanotransductive proteins that are likely to play important roles in intervertebral disc aging. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:788-798, 2018.

Looking beyond the intervertebral disc: the need for behavioral assays in models of discogenic pain.

Orthopedic research into chronic discogenic back pain has commonly focused on aging- and degeneration-related changes in intervertebral disc structure, biomechanics, and biology. However, the primary spine-related reason for physician office visits is pain. The ambiguous nature of the human condition of discogenic low back pain motivates the use of animal models to better understand the pathophysiology. Discogenic back pain models must consider both emergent behavioral changes following pain induction and changes in the nervous system that mediate such behavior. Looking beyond the intervertebral disc, we describe the different ways to classify pain in human patients and animal models. We describe several behavioral assays that can be used in rodent models to augment disc degeneration measurements and characterize different types of pain. We review rodent models of discogenic pain that employed behavioral pain assays and highlight a need to better integrate neuroscience and orthopedic science methods to extend current understanding of the complex and multifactorial pathophysiology of discogenic back pain.