Chronic low back pain caused by intervertebral disc (IVD) degeneration, also termed chronic discogenic low back pain (CD-LBP), is one of the most prevalent musculoskeletal diseases. Degenerative processes in the IVD, such as inflammation and extra-cellular matrix breakdown, result in neurotrophin release. Local elevated neurotrophin levels will stimulate sprouting and innervation of sensory neurons. Furthermore, sprouted sensory nerves that are directly connected to adjacent dorsal root ganglia have shown to increase microglia activation, contributing to the maintenance and chronification of pain. Current pain treatments have shown to be insufficient or inadequate for long-term usage. Furthermore, most therapeutic approaches aimed to target the underlying pathogenesis of disc degeneration focus on repair and regeneration and neglect chronic pain. How biomolecular therapies influence the degenerative IVD environment, pain signaling cascades, and innervation and excitability of the sensory neurons often remains unclear. This review addresses the relatively underexplored area of chronic pain treatment for CD-LBP and summarizes effects of therapies aimed for CD-LBP with special emphasis on chronic pain. Approaches based on blocking pro-inflammatory mediators or neurotrophin activity have been shown to hamper neuronal ingrowth into the disc. Furthermore, the tissue regenerative and neuro inhibitory properties of extracellular matrix components or transplanted mesenchymal stem cells are potentially interesting biomolecular approaches to not only block IVD degeneration but also impede pain sensitization. At present, most biomolecular therapies are based on acute IVD degeneration models and thus do not reflect the real clinical chronic pain situation in CD-LBP patients. Future studies should aim at investigating the effects of therapeutic interventions applied in chronic degenerated discs containing established sensory nerve ingrowth. The in-depth understanding of the ramifications from biomolecular therapies on pain (chronification) pathways and pain relief in CD-LBP could help narrow the gap between the pre-clinical bench and clinical bedside for novel CD-LBP therapeutics and optimize pain treatment.

Although several methods are being applied to treat peripheral nerve injury, a perfect treatment that leads to full functional recovery has not yet been developed. SMAD (Suppressor of Mothers Against Decapentaplegic Homolog) plays a crucial role in nerve regeneration by facilitating the survival and growth of nerve cells following peripheral nerve injury. We conducted a systematic literature review on the role of SMAD in this context. Following peripheral nerve injury, there was an increase in the expression of SMAD1, -2, -4, -5, and -8, while SMAD5, -6, and -7 showed no significant changes; SMAD8 expression was decreased. Specifically, SMAD1 and SMAD4 were found to promote nerve regeneration, whereas SMAD2 and SMAD6 inhibited it. SMAD exerts its effects by promoting neuronal survival and growth through BMP/SMAD1, BMP/SMAD4, and BMP/SMAD7 signaling pathways. Furthermore, it activates nerve regeneration programs via the PI3K/GSK3/SMAD1 pathway, facilitating active regeneration of nerve cells and subsequent functional recovery after peripheral nerve damage. By leveraging these mechanisms of SMAD, novel strategies for treating peripheral nerve damage could potentially be developed. We aim to further elucidate the precise mechanisms of nerve regeneration mediated by SMAD and explore the potential for developing targeted nerve treatments based on these findings.

BACKGROUND: Zygapophysial joints (Z joints) can be a source of back pain and of neck pain, but the cause of pain is not known. Some authors attribute the pain to osteoarthritis but without citing evidence.
OBJECTIVE: The present review was undertaken to determine if there was sufficient evidence of association between spinal pain and osteoarthritis of Z joints to justify osteoarthritis being held to be the cause of pain. The null hypothesis was that osteoarthritis of Z joints does not cause back pain or neck pain.
METHODS: Relevant studies were ones that provided primary data on the association between pain and osteoarthritis of Z joints. These could be population studies, diagnostic studies, or case-control studies.
METHODS: The database of PubMed was searched using the terms: lumbar or cervical, zygapophysial or facet, pain, and osteoarthritis or degeneration or degenerative.
METHODS: Data pertinent to the research question were extracted from original articles and tabulated for reporting. Odds ratios for associations were calculated, as were the prevalence rates of osteoarthritis in subjects with pain, and conversely the prevalence rates of pain in subjects with osteoarthritis.
RESULTS: The searches retrieved 11 population studies, four diagnostic studies, and three cases control studies. No study showed any positive association between osteoarthritis of Z joints and pain. All studies found pain to be independent of the presence or severity of osteoarthritis. Osteoarthritis was as common in subjects with no pain as in subjects with pain. The null hypothesis was not refuted.
CONCLUSIONS: The published evidence does not support the belief that osteoarthritis causes Z joint pain. All the evidence contradicts this belief.

OBJECTIVE: This study aims to assess the impact of surgical approaches and other factors on the incidence of Adjacent Segment Degeneration (ASD) following Spinal Fusion for Adolescent Idiopathic Scoliosis (AIS).
METHODS: We conducted a comprehensive search of four electronic databases from their inception until March 30, 2023. Two independent reviewers screened titles, abstracts, and full texts and evaluated the methodological quality of the studies. A random-effects model was used to calculate the incidence of ASD.
RESULTS: Our analysis included 14 studies involving 651 individuals. The overall incidence of ASD was 47% (95%CI: 0.37, 0.56). Subgroup analyses revealed that the prevalence of ASD increased with postoperative time (53% (95%CI: 0.31, 0.75) versus 48% (95%CI: 0.36, 0.60) versus 39% (95%CI: 0.22, 0.56)). For the number of fused segments, a group with more than 10 segments had a higher prevalence (49% (95%CI: 0.38, 0.60) versus 44% (95%CI: 0.21, 0.69)). In terms of regions, East Asia had the highest prevalence, followed by Occident and West Asia (52% (95%CI: 0.41, 0.62) versus 43% (95%CI: 0.20, 0.68) versus 37% (95%CI: 0.17, 0.59)). However, the surgical approach, male ratio, and the position of the lowest instrumented vertebra (LIV) did not show significant differences between groups. Funnel plots and Egger\'s test did not reveal any significant publication bias (Egger\'s test: t = 1.62, p-value = .1274).
CONCLUSIONS: This meta-analysis found that nearly half of AIS patients following spinal fusion surgery experienced ASD. Long-term follow-up, regular screening, and timely interventions are essential to reduce the prevalence of ASD.

The cartilaginous endplates (CEP) are key components of the intervertebral disc (IVD) necessary for sustaining the nutrition of the disc while distributing mechanical loads and preventing the disc from bulging into the adjacent vertebral body. The size, shape, and composition of the CEP are essential in maintaining its function, and degeneration of the CEP is considered a contributor to early IVD degeneration. In addition, the CEP is implicated in Modic changes, which are often associated with low back pain. This review aims to tackle the current knowledge of the CEP regarding its structure, composition, permeability, and mechanical role in a healthy disc, how they change with degeneration, and how they connect to IVD degeneration and low back pain. Additionally, the authors suggest a standardized naming convention regarding the CEP and bony endplate and suggest avoiding the term vertebral endplate. Currently, there is limited data on the CEP itself as reported data is often a combination of CEP and bony endplate, or the CEP is considered as articular cartilage. However, it is clear the CEP is a unique tissue type that differs from articular cartilage, bony endplate, and other IVD tissues. Thus, future research should investigate the CEP separately to fully understand its role in healthy and degenerated IVDs. Further, most IVD regeneration therapies in development failed to address, or even considered the CEP, despite its key role in nutrition and mechanical stability within the IVD. Thus, the CEP should be considered and potentially targeted for future sustainable treatments.

Low back pain caused by disc herniation and spinal stenosis imposes an enormous medical burden on society due to its high prevalence and refractory nature. This is mainly due to the long-term inflammation and degradation of the extracellular matrix in the process of intervertebral disc degeneration (IVDD), which manifests as loss of water in the nucleus pulposus (NP) and the formation of fibrous disc fissures. Biomaterial repair strategies involving hydrogels play an important role in the treatment of intervertebral disc degeneration. Excellent biocompatibility, tunable mechanical properties, easy modification, injectability, and the ability to encapsulate drugs, cells, genes, etc. make hydrogels good candidates as scaffolds and cell/drug carriers for treating NP degeneration and other aspects of IVDD. This review first briefly describes the anatomy, pathology, and current treatments of IVDD, and then introduces different types of hydrogels and addresses \"smart hydrogels\". Finally, we discuss the feasibility and prospects of using hydrogels to treat IVDD.

UNASSIGNED: Meniscal pathology constitutes a major reason for a vast number of patients suffering from knee pain. It is, in general, attributed either to meniscal tearing or degeneration. Debridement and partial meniscectomy, or repair, when possible, is the mainstay surgical approach for refractory knee pain from meniscal degeneration or tears. Sometimes, the patient has clinical symptoms of meniscal pathology, but despite those highly suggestive clinical symptoms, the patient turns out, during knee arthroscopy, to have meniscal degeneration and hardening of the meniscus without frank tearing of the meniscus.
UNASSIGNED: To initiate meniscal trephination, we first conduct a diagnostic knee arthroscopy to examine the suprapatellar space, the gutters, and the anterior knee space for any pathologies. Following this, both menisci are inspected for any signs of tearing or hardening. For the purposes of our study, the medial meniscus is considered pathological if it shows signs of degeneration or hardening, which then justifies our intervention. An 18-gauge spinal needle, manually bent for the procedure, is inserted through the portal to perform trephination on the hardened menisci. Care is taken to adequately space the needle insertion points to prevent accidental tearing. Our trephination technique aims to soften the meniscus, facilitating its ability to compact and compress when patients ambulate. Additionally, the needle insertion points help attract blood flow to the meniscus, thereby enriching it with growth factors and stem cells that may aid in improving the degenerative condition.
UNASSIGNED: Meniscal trephination is benign and effective for meniscal degenerative pathologies. The procedure allows for a healthier meniscus, free from degeneration, that would otherwise disable patients. The intervention does not have long-term adverse effects. To this end, more comparative trials are required to confirm the effectiveness of the technique and to ensure minimal to no associated side effects.

Background: The meta-analysis aimed to estimate the efficacy of mesenchymal stem cells on lumbar discogenic pain in patients with intervertebral disc degeneration. Methods: A comprehensive literature search was conducted in the PubMed, Web of Science, Embase and Cochrane Library databases with predetermined search strategy up to 18 September 2022. The clinical studies focusing on evaluating the efficacy and safety of mesenchymal stem cells in patients with intervertebral disc degeneration were identified. The primary outcomes were changes of pain score and Oswestry Disability Index. The Newcastle-Ottawa Scale for cohort studies was used for quality assessment. Review Manager was used to conduct the statistical analysis. Pooled risk ratios were calculated based on the random effect model. Heterogeneity, subgroup, and publication bias analyses were also performed. Results: There were 2,392 studies were identified in the initial search, and 9 eligible studies with 245 patients were eventually included in this review. The Visual Analogue Scale score was significantly lower in patients after receiving mesenchymal stem cells therapy (mean difference = 41.62; 95% confidence interval 24.32 to 58.93; Heterogeneity: I2 = 98%; p < 0.01). And the pooled mean difference of Oswestry Disability Index was 22.04 from baseline to final follow-up points (95% confidence interval 8.75 to 35.33; p = 0.001; Heterogeneity: I2 = 98%; p < 0.001). The pooled reoperation proportion was 0.074 (95% confidence interval 0.009 to 0.175; Heterogeneity: I2 = 72%; p < 0.01). There were no serious related adverse events associated with the therapy. Conclusion: The findings of this meta-analysis indicated that mesenchymal stem cells therapy may be effective in relieving pain and improving Oswestry Disability Index significantly in patients with lumbar discogenic pain. Mesenchymal stem cells therapy may also be associated with a lower risk of adverse events and reoperation rates.

UNASSIGNED: Intraepidermal nerve fiber density (IENFD) has become an important biomarker for neuropathy diagnosis and research. The consequences of reduced IENFD can include sensory dysfunction, pain, and a significant decrease in quality of life. We examined the extent to which IENFD is being used as a tool in human and mouse models and compared the degree of fiber loss between diseases to gain a broader understanding of the existing data collected using this common technique.
UNASSIGNED: We conducted a scoping review of publications that used IENFD as a biomarker in human and non-human research. PubMed was used to identify 1,004 initial articles that were then screened to select articles that met the criteria for inclusion. Criteria were chosen to standardize publications so they could be compared rigorously and included having a control group, measuring IENFD in a distal limb, and using protein gene product 9.5 (PGP9.5).
UNASSIGNED: We analyzed 397 articles and collected information related to publication year, the condition studied, and the percent IENFD loss. The analysis revealed that the use of IENFD as a tool has been increasing in both human and non-human research. We found that IENFD loss is prevalent in many diseases, and metabolic or diabetes-related diseases were the most studied conditions in humans and rodents. Our analysis identified 73 human diseases in which IENFD was affected, with 71 reporting IENFD loss and an overall average IENFD change of -47%. We identified 28 mouse and 21 rat conditions, with average IENFD changes of -31.6% and -34.7%, respectively. Additionally, we present data describing sub-analyses of IENFD loss according to disease characteristics in diabetes and chemotherapy treatments in humans and rodents.
UNASSIGNED: Reduced IENFD occurs in a surprising number of human disease conditions. Abnormal IENFD contributes to important complications, including poor cutaneous vascularization, sensory dysfunction, and pain. Our analysis informs future rodent studies so they may better mirror human diseases impacted by reduced IENFD, highlights the breadth of diseases impacted by IENFD loss, and urges exploration of common mechanisms that lead to substantial IENFD loss as a complication in disease.

How back pain is related to intervertebral disc degeneration, spinal loading or sports-related overuse remains an unanswered question of biomechanics. Coupled MBS and FEM simulations can provide a holistic view of the spine by considering both the overall kinematics and kinetics of the spine and the inner stress distribution of flexible components. We reviewed studies that included MBS and FEM co-simulations of the spine. Thereby, we classified the studies into unidirectional and bidirectional co-simulation, according to their data exchange methods. Several studies have demonstrated that using unidirectional co-simulation models provides useful insights into spinal biomechanics, although synchronizing the two distinct models remains a key challenge, often requiring extensive manual intervention. The use of a bidirectional co-simulation features an iterative, automated process with a constant data exchange between integrated subsystems. It reduces manual corrections of vertebra positions or reaction forces and enables detailed modeling of dynamic load cases. Bidirectional co-simulations are thus a promising new research approach for improved spine modeling, as a main challenge in spinal biomechanics is the nonlinear deformation of the intervertebral discs. Future studies will likely include the automated implementation of patient-specific bidirectional co-simulation models using hyper- or poroelastic intervertebral disc FEM models and muscle forces examined by an optimization algorithm in MBS. Applications range from clinical diagnosis to biomechanical analysis of overload situations in sports and injury prediction.