Search Results (310)

Intervertebral disc disease remains the most common spinal pathology in dogs and is characterized by degeneration of the intervertebral disc, primarily through chondroid metaplasia of the nucleus pulposus. Current histological grading systems for disc degeneration do not include inflammation, despite its potential relevance in clinical presentation through extradural swelling and compression. In this retrospective study, surgically removed disc extrusion material from 74 dogs was histologically processed and evaluated using a semi-quantitative grading system for disc degeneration and inflammation. A high prevalence of chondroid metaplasia was observed, frequently accompanied by inflammatory infiltrates, hemorrhage, and necrosis. A significant positive correlation (correlation coefficient = 0.636, p < 0.001) was found between the degree of degeneration and the intensity of inflammation. Notably, thoracolumbar extrusions exhibited significantly higher inflammatory scores than cervical cases. In Dachshunds, more severe neurological deficits were associated with lower histological degeneration scores, indicating that neurological severity depends on multiple interacting factors that may differ between breeds. No significant associations were identified with age, sex, breed, body weight, neurological localization, or lesion severity in other groups. These findings suggest that inflammation is an active component in the pathophysiology of intervertebral disc disease. Incorporating inflammatory grading into histological grading systems could refine functional outcome predictions and guide therapeutic decisions. Full article

Background: Polyamide 6 microplastics (PA6-MPs), as emerging environmental pollutants, have attracted increasing attention due to their potential health risks. Their accumulation in human intervertebral disc tissue (86.4 particles/g) suggests a possible role in intervertebral disc degeneration (IVDD). However, direct evidence and mechanistic understanding remain limited. This study aimed to investigate the association between PA6-MPs exposure and IVDD, based on the hypothesis that PA6-MPs promote IVDD progression by targeting key regulatory molecules and disrupting cellular homeostasis. Methods: Potential PA6-related targets were predicted using multiple public databases, and IVDD-related differentially expressed genes were obtained from the GEO database. Overlapping targets were identified and analyzed through protein–protein interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to screen core targets and pathways. Molecular docking was performed to evaluate PA6–protein binding. In vitro validation was conducted using primary human nucleus pulposus cells exposed to PA6-MPs, with cell viability, proliferation, and phenotypic changes assessed by CCK-8, EdU, live/dead staining, and immunofluorescence (IF). Results: A total of 222 PA6-related targets and 1035 IVDD-associated genes were identified, yielding 10 overlapping targets. Four core targets, including NR3C1 and HDAC1, were selected. Molecular docking and experiments demonstrated stable binding and concentration-dependent inhibition of cell viability and proliferation. Conclusion: PA6-MPs may accelerate IVDD progression in a concentration-dependent manner by targeting key molecules and perturbing inflammatory homeostasis. These findings link environmental exposure to IVDD and provide a basis for future risk assessment and targeted intervention strategies. Full article

Low back pain is closely associated with intervertebral disc (IVD) degeneration, in which inflammation and neovascularization within the annulus fibrosus (AF) contribute to pain generation. Platelet-derived growth factor (PDGF)-BB plays a crucial role in tissue repair and cellular homeostasis, but its role in AF cell biology remains poorly understood. To investigate the effects of PDGF-BB on human AF cells, healthy and degenerated AF cells were treated with PDGF-BB for 3 or 5 days, followed by bulk RNA sequencing. Functional enrichment of differentially expressed genes, transcription factor activity analysis, and protein–protein interaction network analysis was performed. Publicly available single-cell RNA-seq data were used to compare the transcriptomic profiles of native healthy and degenerated AF samples. In addition, TNF-α stimulation was conducted to validate the anti-inflammatory effects of PDGF-BB. Our findings suggest that PDGF-BB induced both common and context-dependent transcriptional responses in healthy and degenerated AF cells. In healthy AF cells, PDGF-BB consistently upregulated genes associated with cell cycle and developmental growth. In degenerated AF cells, PDGF-BB also induced these responses, while additionally it downregulated the genes related to extracellular matrix remodeling and collagen degradation. Meanwhile, PDGF-BB showed common effects in both healthy and degenerated cells by modulating the expression of genes within G protein-coupled receptor (GPCR) networks that are linked to complement, inflammation, and neurotransmitter signaling. In addition, PDGF-BB also suppressed the expression of genes involved in inflammatory-neurogenic signaling, including nerve growth factor (NGF), C-X-C motif chemokine ligand 12 (CXCL12), and apolipoprotein E (APOE). To relate these PDGF-BB induced responses to disc degeneration, we reanalyzed publicly available single-cell RNA-seq datasets from native human AF tissues and found that NGF-positive cells showed increased tumor necrosis factor (TNF)-α signaling activity. When AF cells were stimulated with TNF-α, PDGF-BB treatment significantly inhibited the expression of NGF, endothelin-1 (EDN1), and interleukin 6 (IL6) under both baseline and TNF-α-stimulated conditions. These results suggest that PDGF-BB modulates gene expression associated with inflammatory and neurogenic signaling as well as ECM remodeling in human AF cells, providing a transcriptomic insight into the PDGF-BB’s function in AF biology. Full article

Objective: Posterior lumbar interbody fusion (PLIF), posterolateral fusion (PLF), and Hybrid fusion are widely used fusion procedures for lumbar degenerative diseases (LDDs). Postoperative complications dominated by cage migration (CM) and adjacent segment degeneration (ASD) remain major challenges. This study aimed to identify and compare the independent risk factors for CM and ASD in PLIF, PLF, and Hybrid fusion, so as to provide evidence-based references for preoperative evaluation, surgical selection, and complication prevention in clinical practice. Methods: A retrospective cohort study was conducted in patients who underwent PLIF, PLF, or Hybrid fusion for LDDs at our institution. Demographic data (age, gender, and body mass index [BMI]), lifestyle factors (smoking and insobriety), comorbidities (hypertension, diabetes, hyperuricemia, osteoporosis, and hypoalbuminemia), surgical parameters (operative time, intraoperative blood loss, fusion segments, and lumbar lordosis angle), radiological indices (Pfirrmann grading of intervertebral disc degeneration and relative disc height), and biological markers (C-reactive protein/lymphocyte ratio [CLR], procalcitonin [PCT], and serum amyloid A [SAA]) were collected. Patients were stratified into complication and non-complication groups based on the occurrence of CM or ASD. Univariate and binary logistic regression analyses were performed to determine independent risk factors for postoperative complications. Results: A total of 203 patients were enrolled, including 80 cases with complications in the PLIF group, 64 in the Hybrid group, and 59 in the PLF group. No significant differences were noted in the distribution of complication types among the three groups (p = 0.179). Univariate analysis revealed that BMI, osteoporosis, the Pfirrmann grading of superior adjacent disc degeneration, lumbar lordosis angle, operative time, and intraoperative blood loss were significantly associated with postoperative complications across all three surgical groups (p < 0.05). Binary logistic regression analysis confirmed that elevated BMI (PLIF: OR = 1.18, 95%CI: 1.05–4.38; PLF: OR = 1.19, 95%CI: 0.76–2.18; Hybrid: OR = 1.14, 95%CI: 1.07–2.54), osteoporosis (PLIF: OR = 6.86; PLF: OR = 7.62; Hybrid: OR = 5.62), advanced superior adjacent disc degeneration (PLIF: OR = 8.04; PLF: OR = 4.49; Hybrid: OR = 2.87), prolonged operative time, and increased intraoperative blood loss were independent risk factors for postoperative complications. In contrast, age, gender, smoking, insobriety, hypertension, diabetes, CLR, PCT, and SAA were not identified as risk factors (p* > 0.05). Conclusions: Elevated BMI, osteoporosis, pre-existing superior adjacent disc degeneration, prolonged operative time, and increased intraoperative blood loss are shared independent risk factors for CM and ASD following PLIF, PLF, and Hybrid fusion for LDDs. Targeted interventions addressing these factors may reduce postoperative complication rates and improve patient outcomes. Full article

Intervertebral disc degeneration (IVDD) is the leading cause of low back pain, a global public health burden for which current pharmacological and surgical treatments provide symptomatic relief but fail to reverse the underlying degenerative process. The uniquely avascular, hypoxic, acidic, and mechanically demanding disc microenvironment poses formidable barriers to the survival and function of therapeutic cells and genes, emphasizing the critical need for bioengineered delivery systems. In this review, we introduce the structure and microenvironment of the intervertebral disc, as well as the molecular mechanisms underlying IVDD. We then provide a critical comparative analysis of delivery platforms, including hydrogels, microspheres, nanoparticles, nanofibrous scaffolds, and viral and non-viral vectors, around five core delivery challenges: mechanical protection, retention and leakage prevention, targeted intracellular delivery, controlled release kinetics, and metabolic support. Furthermore, we examine the fabrication technologies and material considerations that determine platform performance, and we analyze the translational barriers that have impeded clinical adoption, such as the limitations of small-animal models and unresolved cell leakage. Finally, we highlight emerging strategies, including gene-cell combination therapy and endplate preconditioning, to accelerate the clinical translation of precision therapies for IVDD. Full article

The progressive decline in immune function during aging, termed immunosenescence, is increasingly recognized as a critical driver of skeletal fragility and impaired bone regeneration. This age-associated phenomenon—driven by thymic involution, inflammaging, and the accumulation of senescent immune cells—disrupts bone homeostasis primarily through the establishment of a pro-inflammatory milieu, wherein senescence-associated secretory phenotype (SASP) factors directly reprogram the function and fate of mesenchymal stem cells, osteoblasts, osteoclasts, and chondrocytes. Clinically, this immune-driven disruption of the bone microenvironment manifests across a spectrum of age-related skeletal disorders—including osteoporosis and osteoarthritis as prototypes of systemic and local bone loss, respectively, as well as delayed fracture healing, intervertebral disc degeneration, and periodontitis as paradigms of impaired regenerative and defensive responses. Despite advances in osteoimmunology revealing bidirectional immune-bone interactions, the mechanistic links between senescent immune cells and bone pathophysiology remain incompletely defined, presenting a significant barrier to therapeutic innovation. Herein, we synthesize current evidence to elucidate how immunosenescence, through the dysfunction of both innate and adaptive immunity, progressively dismantles bone homeostasis. We critically evaluate current challenges in dissecting the relative contributions of immunological memory accumulation versus fundamental aging processes to skeletal decline. We identify key knowledge gaps and propose strategic research directions, including longitudinal human immunophenotyping studies and innovative organoid-immune aging models. Such approaches hold the potential to transform the therapeutic landscape of age-related skeletal diseases by enabling precision interventions that target specific immunosenescence pathways to rejuvenate the aging skeleton. Full article

Intervertebral disc degeneration (IDD) is a fundamental pathological basis of low back pain, yet its pathogenic mechanisms remain incompletely understood. Infection by low-virulence anaerobic bacteria has recently been recognized as a potential etiological factor. In this study, Cutibacterium acnes (C. acnes) was detected in 13.7% of degenerated intervertebral disc (IVD) tissues, and its presence was significantly associated with younger patients and Modic changes. In vitro experiments demonstrated that C. acnes supernatant induces oxidative stress, apoptosis, and extracellular matrix (ECM) degradation in nucleus pulposus (NP) cells in a dose-dependent manner. RNA sequencing and functional validation further indicated that these pathological effects are mediated through activation of the p38 MAPK signaling pathway. Pharmacological inhibition of p38 with the specific inhibitor BIRB-796 effectively reversed the observed cellular damage. Wogonin exhibited negligible cytotoxicity toward NP cells and significantly attenuated C. acnes supernatant-induced oxidative stress, apoptosis, and ECM metabolic imbalance by inhibiting the phosphorylation of p38, JNK, and ERK1/2 within the MAPK pathway. Furthermore, in vivo experiments confirmed that Wogonin alleviated disc height loss, reduced T2-weighted signal attenuation, and mitigated histological damage induced by C. acnes in rat models, thereby restoring the balance between ECM synthesis and degradation. Collectively, this study demonstrates for the first time that C. acnes supernatant exacerbates IDD through activation of the p38 MAPK signaling pathway. It further shows that Wogonin can specifically inhibit this pathway and effectively ameliorate C. acnes-mediated IDD damage in both in vitro and in vivo models. These findings expand the theoretical framework of infection-related mechanisms underlying IDD and identify potential therapeutic targets and candidate agents for the treatment of IDD associated with C. acnes infection. Low back pain is a common health issue affecting populations worldwide, with intervertebral disc degeneration as its core etiology. However, the pathogenic causes in some patients, especially young individuals, remain incompletely understood. This study found that Cutibacterium acnes, a low-virulence bacterium commonly colonizing human skin and mucous membranes, produces metabolic products that can induce damage to the core cells of the intervertebral disc, exacerbate disc degeneration, and this process is associated with the abnormal activation of specific cellular signaling pathways. Through clinical sample detection, cell experiments, and animal model validation, we confirmed that infection with this bacterium is closely related to young patients and specific spinal imaging changes. Meanwhile, we identified Wogonin, a natural compound extracted from Scutellaria baicalensis, which can effectively inhibit the aforementioned abnormal signaling pathways, alleviate cell damage caused by bacterial metabolic products, and improve the pathological state of intervertebral disc degeneration. This study not only reveals the role of low-virulence bacterial infection in intervertebral disc degeneration and provides a new explanation for the pathogenic mechanism in young patients but also offers a natural antibiotic-free candidate for addressing bacterial resistance. It holds significant reference value for the clinical diagnosis and treatment of spinal diseases as well as the development of related drugs. Full article

Degenerative disc disease is a leading cause of chronic low back pain and disability worldwide, and current treatments primarily address symptoms rather than the underlying biological degeneration of the intervertebral disc. Mesenchymal stem cells (MSCs) have emerged as a promising regenerative approach due to their capacity for differentiation, immunomodulation, and secretion of bioactive factors that promote tissue repair. This review summarises findings from experimental and clinical studies investigating the therapeutic potential of MSC-based therapies for intervertebral disc regeneration, with particular focus on translational challenges that limit their clinical application. Preclinical studies generally show that MSC implantation can enhance extracellular matrix production, improve disc hydration, and modulate inflammatory processes within degenerated discs. Early clinical trials report improvements in pain and functional outcomes; however, consistent structural regeneration has not been reliably demonstrated. The limited clinical translation of MSC therapy is associated with several key challenges, including poor cell survival in the harsh disc microenvironment, variability in cell sources and manufacturing protocols, inadequate cell retention following intradiscal injection, and a lack of standardised outcome measures. In addition, regulatory and manufacturing barriers further complicate the development of reproducible and scalable MSC-based therapies. Although MSC-based therapies represent a promising strategy for the biological treatment of intervertebral disc degeneration, further research is required to improve cell survival, optimise delivery systems, standardise manufacturing procedures, and conduct large-scale controlled clinical trials to establish long-term safety and efficacy. Addressing these translational barriers will be essential for the successful integration of MSC-based therapies into clinical practice. Full article

Background: Intervertebral disc degeneration (IVDD) is driven by the interplay between inflammatory signaling, extracellular matrix (ECM) degradation, and impaired cellular adaptation. Although several nutraceutical compounds have been reported to exert protective effects in IVDD-related models, their multitarget mechanisms within integrated molecular networks remain incompletely characterized. Methods: An in silico framework integrating molecular docking with network-based analyses was employed to evaluate resveratrol, quercetin, melatonin, curcumin, and baicalein against a predefined panel of IVDD-associated targets, within an exploratory in silico framework. Binding affinities and interaction profiles were assessed using molecular docking, followed by protein–protein interaction (PPI) network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and hub gene identification. Results: Docking analyses revealed binding energies ranging from −4.59 to −13.25 kcal/mol, with curcumin and quercetin showing plausible docking poses across a subset of selected targets under the applied protocol. Network analysis showed a highly interconnected structure centered on key inflammatory regulators, including NFKB1, IL6, TNF, IL1B, STAT3, and NLRP3, together with ECM-associated components such as ACAN, COL2A1, SOX9, MMP13, and ADAMTS5. Enrichment analyses further suggested significant associations with inflammatory signaling pathways, cytokine regulation, and ECM organization. Conclusions: These findings are compatible with a distributed, multitarget interaction pattern of nutraceutical compounds within IVDD-associated molecular networks. By integrating molecular docking with network-based analyses, this study offers a system-level framework for interpreting previously reported effects within a disease-specific context. Docking-derived interaction patterns should be interpreted as qualitative and exploratory observations, as docking scores represent model-dependent estimates and do not establish comparable pharmacological effects across heterogeneous targets. The results should be considered hypothesis-generating and require experimental validation. Full article

Background and Objectives: Low back pain (LBP) is a leading cause of disability worldwide and is frequently associated with intervertebral disc degeneration (IVDD). Current therapeutic strategies are primarily symptomatic and do not restore native disc biology, largely due to the avascular nature of the intervertebral disc and the hostile inflammatory and mechanical microenvironment that characterizes degeneration. The aim of this study is to provide an updated and clinically oriented overview of the pathophysiology of IVDD and to evaluate the current evidence on mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP)-based therapies. Materials and Methods: A focused narrative literature review was performed to evaluate current evidence on MSC- and PRP-based therapies for intervertebral disc degeneration (IVDD). The search was conducted in PubMed. Only studies in English were considered eligible. Results: Mesenchymal stem cells (MSCs) demonstrated regenerative and immunomodulatory effects primarily through paracrine mechanisms, enhancing extracellular matrix synthesis and reducing inflammation and apoptosis. MSC-derived extracellular vesicles emerged as a promising cell-free alternative, potentially overcoming limitations related to cell survival and safety. Platelet-rich plasma (PRP) showed anabolic and anti-inflammatory properties, promoting disc cell proliferation and matrix production, particularly in early-stage degeneration. Clinical studies, including randomized trials, reported significant improvements in pain and function for both MSC and PRP therapies, with favourable safety profiles. However, heterogeneity in treatment protocols and limited long-term data remain significant limitations. Orthobiologic therapies represent a minimally invasive option for patients with discogenic low back pain refractory to conservative treatment. Patient selection is crucial and should consider degeneration stage, disc viability, and clinical presentation. PRP is primarily indicated in early-stage degeneration (Pfirrmann II–III), whereas MSC-based therapies may be considered in selected patients with more advanced but still viable discs. Based on current evidence, a stepwise approach is proposed, progressing from conservative management to PRP, MSCs, and ultimately surgery. Orthobiologics should be integrated within a multimodal strategy including rehabilitation. Conclusions: MSCs and PRP represent a promising and, eventually, complementary orthobiologic therapies for IVDD. PRP is primarily effective in early degenerative stages as a biologic stimulator, whereas MSCs may provide regenerative benefits in more advanced but still viable discs. Further studies are necessary to standardize protocols and confirm long-term efficacy and safety. Full article

Intervertebral disc degeneration is the most recognized cause of low back pain, characterized by the decline in tissue structure and mechanics. Image-based mechanical parameters (e.g., strain, stiffness) may provide an ideal assessment of disc function that is lost with degeneration, but unfortunately, these remain underdeveloped. Moreover, it is unknown whether strain or stiffness of the disc may be predicted by MRI relaxometry (e.g., T₁ or T₂), an increasingly accepted quantitative measure of disc structure. In this study, we quantified T₁ and T₂ relaxation times and compared to in-plane strains measured with displacement-encoded MRI within human cadaveric discs under physiological levels of compression and bending. Using a novel inverse approach, we then estimated shear modulus in orthogonal image planes and regionally compared these values to relaxation times and 2D strains. Intratissue strain depended on the loading mode, and shear modulus in the nucleus pulposus was typically an order of magnitude lower than the annulus fibrosus. Relative shear moduli estimated from strain data derived under compression generally did not correspond with those from bending experiments. Only one anatomical region showed a significant correlation between relative shear modulus and relaxometry (T₁ vs. µ_rel, coronal plane under bending). Together, these results suggest that future inverse analyses may be improved by incorporating multiple loading conditions into the same model and that image-based elastography and relaxometry should be viewed as complementary measures of disc structure and function to assess degeneration in future studies. Full article

Musculoskeletal disorders and injuries are highly prevalent and encompass a broad range of conditions, including bone fractures and segmental defects, tendinopathies and tendon injury, and cartilage disorders such as osteoarthritis, cartilage defects, and intervertebral disc disease. These conditions can arise from diverse causes including trauma and injury, tumor resection, congenital abnormalities, and age-related degeneration. In the past decades, administration of chemically modified mRNA (cmRNA) encoding growth factors and transcriptional regulators has demonstrated effectiveness in repairing musculoskeletal tissues in preclinical studies. This review summarizes recent advancements in bone, tendon, cartilage, intervertebral disc, and muscle regeneration achieved through the localized delivery of protein-encoding mRNAs to express therapeutic target proteins. Delivery of cmRNA encoding growth factors such as BMP-2, BMP-9, VEGF, FGF-18, and IGF-1, or transcriptional regulators including Runx1, to various animal models has shown beneficial effects on bone, tendon, cartilage, and muscle injury repair in preclinical models. Alongside these progresses, the advantages and disadvantages of applying chemically modified mRNA for musculoskeletal tissue regeneration are also discussed. While studies show the promise of cmRNA for therapeutic applications in orthopedic tissue regeneration, more research is required to optimize growth factors and delivery methods, as well as validate long-term safety and efficacy prior to successful translation into new therapies to benefit patients. Full article

Cervical spondylosis is a common cause of spinal cord dysfunction, and anterior cervical discectomy and fusion (ACDF) is widely employed when conservative treatment fails. Conventional implant systems such as the cervical cage with plate (CCP) and zero-profile stand-alone cage (ZPSC) are commonly used to enhance spinal stability and promote fusion, but they are associated with complications including dysphagia and adjacent segment degeneration. To address these limitations, a novel flexible plate cage system (FPCS) has been developed to optimize biomechanical performance while minimizing surgical risk. In this study, a finite element model of the C3–T1 cervical spine was constructed to simulate ACDF at the C5–C6 level using CCP, ZPSC, and FPCS implants. Under standardized loading conditions, von Mises stress was analyzed in the bone, intervertebral disc, endplates, cage, and screws, using the mean of the top 5% stress values to ensure accuracy. All surgical models showed increased stress compared to the intact reference spine. The ZPSC model exhibited the highest stress in the cage and screws, suggesting a more concentrated load path. The CCP model showed a more evenly distributed stress profile, particularly affecting the inferior adjacent segment. The FPCS model demonstrated moderate cage stress, reduced screw stress, and the highest plate stress, indicating a design that effectively redirects mechanical load from the screw-bone interface toward the anterior plate. This may be related to the unique structural configuration of the FPCS, which secures screws horizontally into the anterior vertebral body without penetrating the endplates. These findings suggest that the FPCS may offer a biomechanically favorable alternative to existing ACDF implants. Full article

In the body, mast cells are found in the circulation and located in tissues. These immune cells arise in the bone marrow and are often associated with conditions such as allergies and asthma. However, these cells also play roles in other inflammatory reactions, dysregulated wound healing and chronic conditions. Regarding their presence in tissues of the intervertebral disc (IVD), mast cells have been located in the normal nucleus pulposus, and reports indicate mast cell numbers are elevated in IVD degenerative conditions. As the integrity of the IVD is reported to decline with ageing as well as in sciatica and clinically defined degenerative conditions, targeting mast cell function may be a viable conservative treatment option for the ageing IVD in health and disease. This review discusses the possible involvement of mast cells in IVD health and disease, and the rationale for the use of mast cell stabilizers such as ketotifen as potential treatment options for conditions affecting IVD integrity. Such mast cell targeting treatments may be considered alone or in combination with other molecules such as specific proteinase inhibitors impacting proteinases known to be present in the affected tissues, such as MMP-3 and HTRA1. Thus, a multicomponent approach in such treatments may provide effectiveness in inhibiting progressive loss of IVD integrity and function in chronic degenerative conditions or adverse outcomes due to non-resorption of extruded nucleus pulposus in sciatica. Full article

Cervical Intervertebral Disc Degeneration (CIVDD) involves significant microenvironmental physical stiffening, forcing nucleus pulposus cells (NPCs) into a rigid phenotype via F-actin over-assembly. It remains unclear if cyclic tensile strain (CTS) can reverse this physical stiffening, particularly in severe degeneration. This study stratified 18 patients into Mild, Moderate, and Severe cohorts based on MRI. Primary NPCs were subjected to physiological 5% CTS (1 Hz, 24 h). Atomic Force Microscopy (AFM) and immunofluorescence were utilized to evaluate Young’s modulus and cytoskeletal remodeling. Results demonstrated that baseline cellular stiffness increased significantly with degeneration severity. Following CTS, all groups exhibited universal de-stiffening and F-actin depolymerization. Crucially, a “Degeneration Paradox” emerged: the Severe group displayed the highest relative elastic modulus recovery rate, significantly surpassing the Mild group. This microscopic recovery correlated inversely with preoperative disc height loss and range of motion. We conclude that severely degenerated cells are not metabolically quiescent but “physically locked” by a rigid cytoskeleton. Physiological CTS restores compliance via mechanical unloading, confirming that severe cells retain superior relative mechanoplasticity and may benefit from mechanotherapy-based “unlocking” strategies. Full article