Sentinel lymph node biopsy is unreliable in predicting melanoma mortality for both younger and older patients.

BACKGROUND: Melanoma disease patterns vary with patient age. AIM: To evaluate sentinel lymph node biopsy (SLNB) in managing melanoma at differing patient ages. METHODS: Online prediction tools were applied to compare SLNB positivity (SLNB+) and survival risk at patient ages 20-80. Tübingen melanoma data were used to determine variations in the hazard ratio of SLNB+ for mortality at different patient ages. RESULTS: Regardless of tumour thickness, predicted SLNB+ rates were markedly higher than mortality rates for 20-year-old patients. For 80-year-old patients, it is the opposite. DISCUSSION: If 1000 20-year-olds with a 0.4 mm thickness non-ulcerated melanoma underwent SLNB, 100 would likely be positive. If all 100 were to be offered adjuvant drug therapy (ADT), fewer than three more melanoma deaths in those 1000 patients would be avoided. In total, 97 patients would have received medication they may never have needed. If 1000 80-year-olds with a 3 mm thickness non-ulcerated melanoma underwent SLNB, only 40 would likely be positive. In total, 274 patients would be predicted to die of melanoma, 245 being SLNB negative and 29 SLNB+. ADT linked to SLNB+ could deny treatment to 89% of these high-risk patients. LIMITATIONS: The authors relied on published risk data. CONCLUSION: SLNB has poor specificity at predicting mortality in young melanoma patients and poor sensitivity in older patients. SLNB is not indicated in managing cutaneous melanoma for patients under 40 or over 60 years of age. Many such patients could be managed with wide local excision alone in their clinician's office-based practice. For all cutaneous melanoma patients at all ages, linking ADT to BAUSSS biomarker, (an algorithm of Breslow thickness, age, ulceration, subtype, sex and Site) rather than SLNB+ is likely more appropriate. BAUSSS provides a more accurate melanoma-specific mortality risk assessment for patients without burdening them with added surgery, hospitalization, costs or morbidity risk.

Developmental morphogens direct human induced pluripotent stem cells toward an annulus fibrosus-like cell phenotype.

Introduction: Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown. Methods: iPSC-derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF-ß3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF-BB), insulin-like growth factor 1 (IGF-1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF-associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells. Results: TGF-ß3, in combination with PDGF-BB, CTGF, or IGF-1, induced an upregulation of key AF ECM genes in iPSC-derived sclerotome cells. In particular, treatment with a combination of TGF-ß3 with PDGF-BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF-ß3 and PDGF-BB for 14 days. Discussion: These findings represent an initial approach to guide human induced pluripotent stem cells toward an AF-like fate for cellular delivery strategies.

Injectable Radiopaque Hyaluronic Acid Granular Hydrogels for Intervertebral Disc Repair.

Injectable hydrogels offer minimally-invasive treatment options for degenerative disc disease, a prevalent condition affecting millions annually. Many hydrogels explored for intervertebral disc (IVD) repair suffer from weak mechanical integrity, migration issues, and expulsion. To overcome these limitations, an injectable and radiopaque hyaluronic acid granular hydrogel is developed. The granular structure provides easy injectability and low extrusion forces, while the radiopacity enables direct visualization during injection into the disc and non-invasive monitoring after injection. The radiopaque granular hydrogel is injected into rabbit disc explants to investigate restoration of healthy disc mechanics following needle puncture injury ex vivo and then delivered in a minimally-invasive manner into the intradiscal space in a clinically-relevant in vivo large animal goat model of IVD degeneration initiated through degradation by chondroitinase. The radiopaque granular hydrogel successfully halted loss of disc height due to degeneration. Further, the hydrogel not only enhanced proteoglycan content and reduced collagen content in the nucleus pulposus (NP) region compared to degenerative discs, but also helped to maintain the structural integrity of the disc and promote healthy segregation of the NP and annulus fibrosus regions. Overall, this study demonstrates the great potential of an injectable radiopaque granular hydrogel for treatment of degenerative disc disease.

Mechanical crosstalk between the intervertebral disc, facet joints, and vertebral endplate following acute disc injury in a rabbit model.

Background: Vertebral endplate sclerosis and facet osteoarthritis have been documented in animals and humans. However, it is unclear how these adjacent pathologies engage in crosstalk with the intervertebral disc. This study sought to elucidate this crosstalk by assessing each compartment individually in response to acute disc injury. Methods: Eleven New Zealand White rabbits underwent annular disc puncture using a 16G or 21G needle. At 4 and 10 weeks, individual compartments of the motion segment were analyzed. Discs underwent T 1 relaxation mapping with MRI contrast agent gadodiamide as well T 2 mapping. Both discs and facets underwent mechanical testing via vertebra-disc-vertebra tension-compression creep testing and indentation testing, respectively. Endplate bone density was quantified via µCT. Discs and facets were sectioned and stained for histology scoring. Results: Intervertebral discs became more degenerative with increasing needle diameter and time post-puncture. Bone density also increased in endplates adjacent to both 21G and 16G punctured discs leading to reduced gadodiamide transport at 10 weeks. The facet joints, however, did not follow this same trend. Facets adjacent to 16G punctured discs were less degenerative than facets adjacent to 21G punctured discs at 10 weeks. 16G facets were more degenerative at 4 weeks than at 10, suggesting the cartilage had recovered. The formation of severe disc osteophytes in 16G punctured discs between 4 and 10 weeks likely offloaded the facet cartilage, leading to the recovery observed. Conclusions: Overall, this study supports that degeneration spans the whole spinal motion segment following disc injury. Vertebral endplate thickening occurred in response to disc injury, which limited the diffusion of small molecules into the disc. This work also suggests that altered disc mechanics can induce facet degeneration, and that extreme bony remodeling adjacent to the disc may promote facet cartilage recovery through offloading of the articular cartilage.

Tension-activated nanofiber patches delivering an anti-inflammatory drug improve repair in a goat intervertebral disc herniation model.

Conventional microdiscectomy treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus, resulting in a high incidence of recurrent herniation and persistent dysfunction. The lack of repair and the acute inflammation that arise after injury can further compromise the disc and result in disc-wide degeneration in the long term. To address this clinical need, we developed tension-activated repair patches (TARPs) for annulus fibrosus repair and local delivery of the anti-inflammatory factor anakinra (a recombinant interleukin-1 receptor antagonist). TARPs transmit physiologic strain to mechanically activated microcapsules embedded within the patch, which release encapsulated bioactive molecules in direct response to spinal loading. Mechanically activated microcapsules carrying anakinra were loaded into TARPs, and the effects of TARP-mediated annular repair and anakinra delivery were evaluated in a goat model of annular injury in the cervical spine. TARPs integrated with native tissue and provided structural reinforcement at the injury site that prevented aberrant disc-wide remodeling resulting from detensioning of the annular fibrosus. The delivery of anakinra by TARP implantation increased matrix deposition and retention at the injury site and improved maintenance of disc extracellular matrix. Anakinra delivery additionally attenuated the inflammatory response associated with TARP implantation, decreasing osteolysis in adjacent vertebrae and preserving disc cellularity and matrix organization throughout the annulus fibrosus. These results demonstrate the therapeutic potential of TARPs for the treatment of intervertebral disc herniation.

Ezh2 promotes mammary tumor initiation through epigenetic regulation of the Wnt and mTORC1 signaling pathways.

The regulation of gene expression through histone posttranslational modifications plays a crucial role in breast cancer progression. However, the molecular mechanisms underlying the contribution of histone modification to tumor initiation remain unclear. To gain a deeper understanding of the role of the histone modifier Enhancer of Zeste homology 2 (Ezh2) in the early stages of mammary tumor progression, we employed an inducible mammary organoid system bearing conditional Ezh2 alleles that faithfully recapitulates key events of luminal B breast cancer initiation. We showed that the loss of Ezh2 severely impairs oncogene-induced organoid growth, with Ezh2-deficient organoids maintaining a polarized epithelial phenotype. Transcriptomic profiling showed that Ezh2-deficient mammary epithelial cells up-regulated the expression of negative regulators of Wnt signaling and down-regulated genes involved in mTORC1 (mechanistic target of rapamycin complex 1) signaling. We identified Sfrp1, a Wnt signaling suppressor, as an Ezh2 target gene that is derepressed and expressed in Ezh2-deficient epithelium. Furthermore, an analysis of breast cancer data revealed that Sfrp1 expression was associated with favorable clinical outcomes in luminal B breast cancer patients. Finally, we confirmed that targeting Ezh2 impairs mTORC1 activity through an indirect mechanism that up-regulates the expression of the tumor suppressor Pten. These findings indicate that Ezh2 integrates the mTORC1 and Wnt signaling pathways during early mammary tumor progression, arguing that inhibiting Ezh2 or therapeutically targeting Ezh2-dependent programs could be beneficial for the treatment of early-stage luminal B breast cancer.

A Tunable Calcium Phosphate Coating to Drive in vivo Osseointegration of Composite Engineered Tissues.

Varying degrees of hydroxyapatite (HA) surface functionalization have been implicated as the primary driver of differential osteogenesis observed in infiltrating cells. The ability to reliably create spatially controlled areas of mineralization in composite engineered tissues is of growing interest in the field, and the use of HA-functionalized biomaterials may provide a robust solution to this challenge. In this study, we successfully fabricated polycaprolactone salt-leached scaffolds with two levels of a biomimetic calcium phosphate coating to examine their effects on MSC osteogenesis. Longer duration coating in simulated body fluid (SBF) led to increased HA crystal nucleation within scaffold interiors as well as more robust HA crystal formation on scaffold surfaces. Ultimately, the increased surface stiffness of scaffolds coated in SBF for 7 days in comparison to scaffolds coated in SBF for 1 day led to more robust osteogenesis of MSCs in vitro without the assistance of osteogenic signaling molecules. This study also demonstrated that the use of SBF-based HA coatings can promote higher levels of osteogenesis in vivo. Finally, when incorporated as the endplate region of a larger tissue-engineered intervertebral disc replacement, HA coating did not induce mineralization in or promote cell migration out of neighboring biomaterials. Overall, these results verified tunable biomimetic HA coatings as a promising biomaterial modification to promote discrete regions of mineralization within composite engineered tissues.

Coordinated activation of c-Src and FOXM1 drives tumor cell proliferation and breast cancer progression.

Activation of the tyrosine kinase c-Src promotes breast cancer progression and poor outcomes, yet the underlying mechanisms are incompletely understood. Here, we have shown that deletion of c-Src in a genetically engineered model mimicking the luminal B molecular subtype of breast cancer abrogated the activity of forkhead box M1 (FOXM1), a master transcriptional regulator of the cell cycle. We determined that c-Src phosphorylated FOXM1 on 2 tyrosine residues to stimulate its nuclear localization and target gene expression. These included key regulators of G2/M cell-cycle progression as well as c-Src itself, forming a positive feedback loop that drove proliferation in genetically engineered and patient-derived models of luminal B-like breast cancer. Using genetic approaches and small molecules that destabilize the FOXM1 protein, we found that targeting this mechanism induced G2/M cell-cycle arrest and apoptosis, blocked tumor progression, and impaired metastasis. We identified a positive correlation between FOXM1 and c-Src expression in human breast cancer and show that the expression of FOXM1 target genes predicts poor outcomes and associates with the luminal B subtype, which responds poorly to currently approved therapies. These findings revealed a regulatory network centered on c-Src and FOXM1 that is a targetable vulnerability in aggressive luminal breast cancers.

Do Prophylactic Inferior Vena Cava Filters Affect the Rates of Venous Thromboembolism and Pulmonary Embolism in Patients Undergoing Major Spine Surgery?

STUDY DESIGN: Retrospective Analysis. BACKGROUND: Venous thromboembolism (VTE) represents a significant cause of morbidity and mortality in major spine surgery. Placement of prophylactic inferior vena cava filters (IVCF) in patients undergoing major spine surgery was previously adopted at our institution. This study reports our experience and compares VTE rates between patients with and without preoperative IVCF placement. METHODS: A Retrospective comparative study was conducted on adult patients who underwent IVCF placement and those who did not prior to their spinal fusion procedure, between 2013 and 2016. Thoracolumbar fusions (anterior and/or posterior) of 7 or more levels, spinal osteotomies, and a minimum of a 3-month follow-up were included. Traumatic, oncologic, and cervical pathology were excluded. Primary outcomes measured included the incidence of overall VTE (DVT/PE), death, IVCF related complications, and IVCF retrieval. RESULTS: 386 patients who underwent major spine surgery, 258 met the eligibility criteria. Of those patients, 105 patients (40.7%) had prophylactic IVCF placement. All patients had postoperative SCDs and chemoprophylaxis. The presence of an IVCF was associated with an increased rate of overall VTE (14.3% vs 6.5%, P ≤ .05) and DVT episodes (8.6% vs 2.6%, P = .04). The rate of PE for the IVCF group and non-IVCF group was 8.6% and 4.6%, respectively, which was not statistically significant (P = .32). The all-cause mortality rate overall of 2.3% was statistically similar between both groups (P = 1.0). The IVCF group had higher rates of hematoma/seroma vs the non-IVCF group (12.4% vs 3.9%, P ≤ .05). 99 IVCFs were retrievable designs, and 85% were successfully retrieved. Overall IVCF-related complication rate was 11%. CONCLUSIONS: No statistical difference in PE or mortality rates existed between the IVCF and the control group. Patients with IVCF placement experienced approximately twice the rate of VTE and three times the rate of DVT compared to those without IVCF. The IVCF-related complication rate was 11%. Based on the results of this study, the authors recommend against the routine use of prophylactic IVCFs in adults undergoing major spine surgery. LEVEL OF EVIDENCE: III.

Level dependent alterations in human facet cartilage mechanics and bone morphometry with spine degeneration.

The zygapophyseal joints of the spine, also known as the facet joints, are paired diarthrodial joints posterior to the intervertebral disc and neural elements. The pathophysiology of facet osteoarthritis (OA), as well as crosstalk between the disc and facets, remains largely understudied compared to disc degeneration. The purpose of this study was to characterize alterations to human facet cartilage and subchondral bone across a spectrum of degeneration and to investigate correlations between disc and facet degeneration. Human lumbar facet articular surfaces from six independent donors were subject to creep indentation mechanical testing to quantify cartilage mechanical properties, followed by microcomputed tomography (µCT) analyses for subchondral bone morphometry. The degenerative state of each articular surface was assessed via macroscopic scoring and via Osteoarthritis Research Society International histopathology scoring. Our data suggest reduced facet cartilage compressive and tensile moduli and increased permeability with increasing degenerative grade, particularly at the lower levels of the spine. µCT analyses revealed spinal level-dependent alterations to the subchondral bone, with an increase in trabecular bone at the L4-L5 level, but a decrease at the upper levels of the lumbar spine with increasing degenerative grade. Cortical bone volume fraction was generally decreased with increasing degenerative grade across spinal levels. Correlation analysis revealed several associations between quantitative measures of disc degeneration and facet OA. This study showed that alterations in the mechanical properties of facet cartilage and in the structural properties of facet subchondral bone correlated with aspects of disc degeneration and were highly dependent on spinal level.

Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα deficiency.

Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERRα activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERRα loss-of-function and doxorubicin treatment exhibit common features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.

Return to Play for Cervical and Lumbar Spine Conditions.

Although the safety of contact sports has improved over the years, participation in any sport always carries a risk of injury. When cervical or lumbar spine injuries do occur, prompt diagnosis is essential, and athletes must be held out of the sport if indicated to prevent further harm and allow for recovery. This article highlights some of the most common cervical spine pathologies (stinger/burners, strain, stenosis/cord neuropraxia, disc herniation, and fracture/instability) and lumbar spine pathologies (strain, disc degeneration, disc herniation, fracture, spondylolysis/spondylolisthesis, and scoliosis) encountered in sports and reviews the associated return to play guidelines and expectations for each condition.

A challenging playing field: Identifying the endogenous impediments to annulus fibrosus repair.

Intervertebral disc (IVD) herniations, caused by annulus fibrosus (AF) tears that enable disc tissue extrusion beyond the disc space, are very prevalent, especially among adults in the third to fifth decade of life. Symptomatic herniations, in which the extruded tissue compresses surrounding nerves, are characterized by back pain, numbness, and tingling and can cause extreme physical disability. Patients whose symptoms persist after nonoperative intervention may undergo surgical removal of the herniated tissue via microdiscectomy surgery. The AF, however, which has a poor endogenous healing ability, is left unrepaired increasing the risk for re-herniation and pre-disposing the IVD to degenerative disc disease. The lack of understanding of the mechanisms involved in native AF repair limits the design of repair systems that overcome the impediments to successful AF restoration. Moreover, the complexity of the AF structure and the challenging anatomy of the repair environment represents a significant challenge for the design of new repair devices. While progress has been made towards the development of an effective AF repair technique, these methods have yet to demonstrate long-term repair and recovery of IVD biomechanics. In this review, the limitations of endogenous AF healing are discussed and key cellular events and factors involved are highlighted to identify potential therapeutic targets that can be integrated into AF repair methods. Clinical repair strategies and their limitations are described to further guide the design of repair approaches that effectively restore native tissue structure and function.

Cell morphology and mechanosensing can be decoupled in fibrous microenvironments and identified using artificial neural networks.

Cells interpret cues from and interact with fibrous microenvironments through the body based on the mechanics and organization of these environments and the phenotypic state of the cell. This in turn regulates mechanoactive pathways, such as the localization of mechanosensitive factors. Here, we leverage the microscale heterogeneity inherent to engineered fiber microenvironments to produce a large morphologic data set, across multiple cells types, while simultaneously measuring mechanobiological response (YAP/TAZ nuclear localization) at the single cell level. This dataset describing a large dynamic range of cell morphologies and responses was coupled with a machine learning approach to predict the mechanobiological state of individual cells from multiple lineages. We also noted that certain cells (e.g., invasive cancer cells) or biochemical perturbations (e.g., modulating contractility) can limit the predictability of cells in a universal context. Leveraging this finding, we developed further models that incorporate biochemical cues for single cell prediction or identify individual cells that do not follow the established rules. The models developed here provide a tool for connecting cell morphology and signaling, incorporating biochemical cues in predictive models, and identifying aberrant cell behavior at the single cell level.

Restoration of sagittal alignment in high-grade isthmic spondylolisthesis using the reverse Bohlman technique with anterior lumbar interbody fusion using a hyperlordotic cage at L4-5: illustrative case.

BACKGROUND: Circumferential fusion with or without reduction is the preferred treatment for high-grade isthmic spondylolisthesis. Reduction presents significant risk of neurological injury. The authors present one case in which the "reverse Bohlman" technique was used with the addition of a hyperlordotic interbody cage at L4-5 as a means to correct sagittal malalignment while avoiding the reduction of L5 on S1. OBSERVATIONS: The patient was a 22-year-old woman with a long-term history of lower back pain and bilateral L5 radiculopathy secondary to high-grade isthmic lumbar spondylolisthesis. She underwent anterior lumbar interbody fusion using the reverse Bohlman technique plus a hyperlordotic interbody cage at L4-5, followed by decompression and posterior spinal instrumentation and fusion from L4 to the pelvis. At 2-year follow-up, she was found to have complete resolution of symptoms with clinical and radiographic evidence of fusion. Her spinopelvic parameters had significantly improved. LESSONS: The reverse Bohlman technique with the addition of a hyperlordotic interbody cage at L4-5 is a potential alternative treatment method to correct sagittal malalignment while avoiding possible injury to the L5 nerve roots that can be seen in the reduction of high-grade isthmic spondylolisthesis.

Putting the Pieces in Place: Mobilizing Cellular Players to Improve Annulus Fibrosus Repair.

The intervertebral disc (IVD) is an integral load-bearing tissue that derives its function from its composite structure and extracellular matrix composition. IVD herniations involve the failure of the annulus fibrosus (AF) and the extrusion of the nucleus pulposus beyond the disc boundary. Disc herniations can impinge the neural elements and cause debilitating pain and loss of function, posing a significant burden on individual patients and society as a whole. Patients with persistent symptoms may require surgery; however, surgical intervention fails to repair the ruptured AF and is associated with the risk for reherniation and further disc degeneration. Given the limitations of AF endogenous repair, many attempts have been made toward the development of effective repair approaches that reestablish IVD function. These methods, however, fail to recapitulate the composition and organization of the native AF, ultimately resulting in inferior tissue mechanics and function over time and high rates of reherniation. Harnessing the cellular function of cells (endogenous or exogenous) at the repair site through the provision of cell-instructive cues could enhance AF tissue regeneration and, ultimately, improve healing outcomes. In this study, we review the diverse approaches that have been developed for AF repair and emphasize the potential for mobilizing the appropriate cellular players at the site of injury to improve AF healing. Impact statement Conventional treatments for intervertebral disc herniation fail to repair the annulus fibrosus (AF), increasing the risk for recurrent herniation. The lack of repair devices in the market has spurred the development of regenerative approaches, yet most of these rely on a scarce endogenous cell population to repair large injuries, resulting in inadequate regeneration. This review identifies current and developing strategies for AF repair and highlights the potential for harnessing cellular function to improve AF regeneration. Ideal cell sources, differentiation strategies, and delivery methods are discussed to guide the design of repair systems that leverage specialized cells to achieve superior outcomes.

Degeneration alters structure-function relationships at multiple length-scales and across interfaces in human intervertebral discs.

Intervertebral disc (IVD) degeneration and associated back pain place a significant burden on the population. IVD degeneration is a progressive cascade of cellular, compositional, and structural changes, which results in a loss of disc height, disorganization of extracellular matrix architecture, tears in the annulus fibrosus which may involve herniation of the nucleus pulposus, and remodeling of the bony and cartilaginous endplates (CEP). These changes to the IVD often occur concomitantly, across the entire motion segment from the disc subcomponents to the CEP and vertebral bone, making it difficult to determine the causal initiating factor of degeneration. Furthermore, assessments of the subcomponents of the IVD have been largely qualitative, with most studies focusing on a single attribute, rather than multiple adjacent IVD substructures. The objective of this study was to perform a multiscale and multimodal analysis of human lumbar motion segments across various length scales and degrees of degeneration. We performed multiple assays on every sample and identified several correlations between structural and functional measurements of disc subcomponents. Our results demonstrate that with increasing Pfirrmann grade there is a reduction in disc height and nucleus pulposus T2 relaxation time, in addition to alterations in motion segment macromechanical function, disc matrix composition and cellular morphology. At the cartilage endplate-vertebral bone interface, substantial remodeling was observed coinciding with alterations in micromechanical properties. Finally, we report significant relationships between vertebral bone and nucleus pulposus metrics, as well as between micromechanical properties of the endplate and whole motion segment biomechanical parameters, indicating the importance of studying IVD degeneration as a whole organ.