Comparison of Surgical Outcomes After Posterior Decompression by Junior or Senior Surgeons for Patients With Cervical Ossification of the Posterior Longitudinal Ligament: Results From Retrospective Multicenter Cohort Study.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVES: To investigate surgical outcomes following posterior decompression for cervical ossification of the posterior longitudinal ligament (OPLL) when performed by board-certified spine (BCS) or non-BCS (NBCS) surgeons. METHODS: We included 203 patients with cervical OPLL who were followed for a minimum of 1 year after surgery. Demographic information, medical history, and imaging findings were collected. Clinical outcomes were assessed preoperatively and at the final follow-up using the Japanese Orthopedic Association (JOA) score and the visual analog scale (VAS) for the neck. We compared outcomes between BCS surgeons, who must meet several requirements, including experience in more than 300 spinal surgeries, and NBCS surgeons. RESULTS: BCS surgeons performed 124 out of 203 cases, while NBCS surgeons were primary in 79 cases, with 73.4% were directly supervised by a BCS surgeon. There was no statistically significant difference in surgical duration, estimated blood loss, and perioperative complication rates between the BCS and NBCS groups. Moreover, no statistically significant group differences were observed in each position of the C2-7 angle and cervical range of motion at preoperation and the final follow-up. Preoperative and final follow-up JOA scores, VAS for the neck, and JOA score recovery rate were comparable between the two groups. CONCLUSIONS: Surgical outcomes, including functional recovery, complication rates, and cervical dynamics, were comparable between the BCS and NBCS groups. Consequently, posterior decompression for cervical OPLL is considered safe and effective when conducted by junior surgeons who have undergone training and supervision by experienced spine surgeons.

Quantitative evaluation of natural progression of fatty infiltration and muscle atrophy in chronic rotator cuff tears without tear extension using magnetic resonance imaging.

Background: The pathology of and mechanisms underlying muscle degeneration remain unclear. We aimed to quantitatively evaluate the natural changes in fatty infiltration and muscle atrophy in patients with chronic rotator cuff tears using 3-dimensional 2-point Dixon magnetic resonance imaging. Methods: Thirty patients with nonoperatively observed rotator cuff tears without tear extension were evaluated using multiple magnetic resonance imaging examinations with a minimum interval of 2 years. The fatty infiltration ratio (%fat) and muscle volume of the rotator cuff muscles were compared between the 2 examinations in those with supraspinatus (SSP) tear <2 cm (<2 cm SSP group), SSP tear ≥2 cm (≥2 cm SSP group), and massive tear (massive group). The SSP) infraspinatus, and teres minor (ISP + TM), and subscapularis muscles were evaluated. Results: The massive group showed a significantly greater %fat than the <2 and ≥2 cm SSP groups in the SSP (P = .002) and ISP + TM muscles (P < .001). The total muscle volume did not differ among the 3 groups for all rotator cuff muscle components. The %fat values did not change in any rotator cuff components during the follow-up period in all groups. The total muscle volume in the massive group significantly decreased in the SSP (P = .018) and ISP + TM muscles (P = .013). Conclusion: The present results indicate that fatty infiltration of the torn muscle occurs in the early phase after a rotator cuff tear, whereas muscle atrophy appears to progress gradually in chronic rotator cuff tears. Early intervention before muscle degeneration should be considered if the tear involves the infraspinatus tendon.

Effect of Alaska pollock-gelatin sheet on repair strength and regeneration of nerve.

The aim of the study was to investigate the repair strength and the biocompatibility of Alaska pollock-derived gelatin (ApGltn) sheet for nerve repair. Cadaveric digital nerves were repaired with double suture, single suture + ApGltn sheet, single suture + fibrin glue, single suture, ApGltn sheet and fibrin. Maximum failure loads were measured (20 nerves each). Rat sciatic nerves were repaired with double suture, single suture + ApGltn sheet, single suture, ApGltn sheet, fibrin glue and resection (10 nerves each). Macroscopic appearance, muscle weight and histopathological findings were examined 8 weeks postoperatively. The mean failure load of ApGltn sheet (0.39 N) was significantly higher than that of a fibrin (0.05 N), and that of single suture + ApGltn sheet (1.32 N) was significantly higher than that of a single suture alone (0.97 N). Functional and histological assessments showed similar nerve recovery among the suture, ApGltn and fibrin groups. ApGltn sheet has potential for clinical application as an alternative to fibrin.

The significance of cerebrospinal fluid dynamics in adolescent idiopathic scoliosis using time-SLIP MRI.

Adolescent idiopathic scoliosis (AIS) affects approximately 3% of the global population. Recent studies have drawn attention to abnormalities in the dynamics of the CSF as potential contributors. This research aims to employ the Time-Spatial Labeling Inversion Pulse (Time-SLIP) MRI to assess and analyze cerebrospinal fluid (CSF) dynamics in AIS patients. 101 AIS patients underwent Time-SLIP MRI. Images were taken at the mid-cervical and craniocervical junction regions. The sum of the maximum movement distances of CSF on the ventral and dorsal sides of the spinal canal within a single timeframe was defined and measured as Travel Distance (TD). Correlations between TD, age, Cobb angle, and Risser grade were analyzed. TD comparisons were made across Lenke classifications. TD for all patients was a weak correlation with the Cobb angle (r = - 0.16). Comparing TD between Lenke type 1 and 5, type 5 patients display significantly shorter TD (p < 0.05). In Risser5 patients with Lenke type 5 showed a significant negative correlation between Cobb angle and TD (r = - 0.44). Lenke type 5 patients had significantly shorter CSF TD compared to type1, correlating with worsening Cobb angles. Further analysis and exploration are required to understand the mechanism of onset and progression.

Clinical application and potential pluripotent effects of hepatocyte growth factor in spinal cord injury regeneration.

INTRODUCTION: Spinal cord injury (SCI) is a condition in which the spinal cord parenchyma is damaged by various factors. The mammalian central nervous system has been considered unable to regenerate once damaged, but recent progress in basic research has gradually revealed that injured neural cells can indeed regenerate. Drug therapy using novel agents is being actively investigated as a new treatment for SCI. One notable treatment method is regeneration therapy using hepatocyte growth factors (HGF). AREA COVERED: HGF has pluripotent neuroregenerative actions, as indicated by its neuroprotective and regenerative effects on the microenvironment and damaged cells, respectively. This review examines these effects in various phases of SCI, from basic research to clinical studies, and the application of this treatment to other diseases. EXPERT OPINION: In regenerative medicine for SCI, drug therapies have tended to be more likely to be developed compared to cell replacement treatment. Nevertheless, there are still challenges to be addressed for these clinical applications due to a wide variety of pathology and animal experimental models of basic study, but HGF could be an effective treatment for SCI with expanded application.

Gender differences in spinal mobility during postural changes: a detailed analysis using upright CT.

Lumbar spinal alignment is crucial for spine biomechanics and is linked to various spinal pathologies. However, limited research has explored gender-specific differences using CT scans. The objective was to evaluate and compare lumbar spinal alignment between standing and sitting CT in healthy individuals, focusing on gender differences. 24 young and 25 elderly males (M) and females (F) underwent standing and sitting CT scans to assess lumbar spinal alignment. Parameters measured and compared between genders included lumbar lordosis (LL), sacral slope (SS), pelvic tilt (PT), pelvic incidence (PI), lordotic angle (LA), foraminal height (FH), and bony boundary area (BBA). Females showed significantly larger changes in SS and PT when transitioning from standing to sitting (p = .044, p = .038). A notable gender difference was also observed in the L4-S LA among the elderly, with females showing a significantly larger decrease in lordotic angle compared to males (- 14.1° vs. - 9.2°, p = .039*). Females consistently exhibited larger FH and BBA values, particularly in lower lumbar segments, which was more prominent in the elderly group (M vs. F: L4/5 BBA 80.1 mm2 [46.3, 97.8] vs. 109.7 mm2 [74.4, 121.3], p = .019 in sitting). These findings underline distinct gender-related variations in lumbar alignment and flexibility, with a focus on noteworthy changes in BBA and FH in females. Gender differences in lumbar spinal alignment were evident, with females displaying greater pelvic and sacral mobility. Considering gender-specific characteristics is crucial for assessing spinal alignment and understanding spinal pathologies. These findings contribute to our understanding of lumbar spinal alignment and have implications for gender-specific spinal conditions and treatments.

IL-33-ST2 signaling in fibro-adipogenic progenitors alleviates immobilization-induced muscle atrophy in mice.

BACKGROUND: The regenerative and adaptive capacity of skeletal muscles reduces with age, leading to severe disability and frailty in the elderly. Therefore, development of effective therapeutic interventions for muscle wasting is important both medically and socioeconomically. In the present study, we aimed to elucidate the potential contribution of fibro-adipogenic progenitors (FAPs), which are mesenchymal stem cells in skeletal muscles, to immobilization-induced muscle atrophy. METHODS: Young (2-3 months), adult (12-14 months), and aged (20-22 months) mice were used for analysis. Muscle atrophy was induced by immobilizing the hind limbs with a steel wire. FAPs were isolated from the hind limbs on days 0, 3, and 14 after immobilization for transcriptome analysis. The expression of ST2 and IL-33 in FAPs was evaluated by flow cytometry and immunostaining, respectively. To examine the role of IL-33-ST2 signaling in vivo, we intraperitoneally administered recombinant IL-33 or soluble ST2 (sST2) twice a week throughout the 2-week immobilization period. After 2-week immobilization, the tibialis anterior muscles were harvested and the cross-sectional area of muscle fibers was evaluated. RESULTS: The number of FAPs increased with the progression of muscle atrophy after immobilization in all age-groups. Transcriptome analysis of FAPs collected before and after immobilization revealed that Il33 and Il1rl1 transcripts, which encode the IL-33 receptor ST2, were transiently induced in young mice and, to a lesser extent, in aged mice. The number of FAPs positive for ST2 increased after immobilization in young mice. The number of ST2-positive FAPs also increased after immobilization in aged mice, but the difference from the baseline was not statistically significant. Immunostaining for IL-33 in the muscle sections revealed a significant increase in the number of FAPs expressing IL-33 after immobilization. Administration of recombinant IL-33 suppressed immobilization-induced muscle atrophy in aged mice but not in young mice. CONCLUSIONS: Our data reveal a previously unknown protective role of IL-33-ST2 signaling against immobilization-induced muscle atrophy in FAPs and suggest that IL-33-ST2 signaling is a potential new therapeutic target for alleviating disuse muscle atrophy, particularly in older adults.

Dysregulation of Inflammatory Pathways in Adult Spinal Deformity Patients with Frailty.

Background/Objectives: An important aspect of the pathophysiology of frailty seems to be the dysregulation of inflammatory pathways and the coagulation system. However, an objective assessment of the impact of frailty on the recovery from surgery is not fully studied. This study sought to assess how frailty affects the recovery of adult spinal deformity (ASD) surgery using blood biomarkers. Methods: 153 consecutive ASD patients (age 64 ± 10 yr, 93% female) who had corrective spine surgery in a single institution and reached 2y f/u were included. The subjects were stratified by frailty using the modified frailty index-11 (robust [R] group or prefrail and frail [F] group). Results of commonly employed laboratory tests at baseline, 1, 3, 7, and 14 post-operative days (POD) were compared. Further comparison was performed in propensity-score matched-39 paired patients between the groups by age, curve type, and baseline alignment. A correlation between HRQOLs, major complications, and biomarkers was performed. Results: Among the propensity-score matched groups, CRP was significantly elevated in the F group at POD1,3(POD1; 5.3 ± 3.1 vs. 7.9 ± 4.7 p = 0.02, POD3; 6.6 ± 4.6 vs. 8.9 ± 5.2 p = 0.02). Transaminase was also elevated in the F group at POD3(ASD: 36 ± 15 vs. 51 ± 58 U/L, p = 0.03, ALT: 32 ± 16 vs. 47 ± 55 U/L, p = 0.04). Interestingly, moderate correlation was observed between transaminase at POD1 and 2 y SRS22 (AST; function r = -0.37, mental health r = -0.39, satisfaction -0.28, total r = -0.40, ALT; function r = -0.37, satisfaction -0.34, total r = -0.39). Conclusions: Frailty affected the serum CRP and transaminase differently following ASD surgery. Transaminase at early POD was correlated with 2 y HRQOLs. These findings support the hypothesis that there is a specific physiological basis to the frailty that is characterized in part by increased inflammation and that these physiological differences persist.

Human-Induced Pluripotent Stem Cell-Derived Neural Progenitor Cells Showed Neuronal Differentiation, Neurite Extension, and Formation of Synaptic Structures in Rodent Ischemic Stroke Brains.

Ischemic stroke is a major cerebrovascular disease with high morbidity and mortality rates; however, effective treatments for ischemic stroke-related neurological dysfunction have yet to be developed. In this study, we generated neural progenitor cells from human leukocyte antigen major loci gene-homozygous-induced pluripotent stem cells (hiPSC-NPCs) and evaluated their therapeutic effects against ischemic stroke. hiPSC-NPCs were intracerebrally transplanted into rat ischemic brains produced by transient middle cerebral artery occlusion at either the subacute or acute stage, and their in vivo survival, differentiation, and efficacy for functional improvement in neurological dysfunction were evaluated. hiPSC-NPCs were histologically identified in host brain tissues and showed neuronal differentiation into vGLUT-positive glutamatergic neurons, extended neurites into both the ipsilateral infarct and contralateral healthy hemispheres, and synaptic structures formed 12 weeks after both acute and subacute stage transplantation. They also improved neurological function when transplanted at the subacute stage with γ-secretase inhibitor pretreatment. However, their effects were modest and not significant and showed a possible risk of cells remaining in their undifferentiated and immature status in acute-stage transplantation. These results suggest that hiPSC-NPCs show cell replacement effects in ischemic stroke-damaged neural tissues, but their efficacy is insufficient for neurological functional improvement after acute or subacute transplantation. Further optimization of cell preparation methods and the timing of transplantation is required to balance the efficacy and safety of hiPSC-NPC transplantation.

Extra-Articular Stabilization for the Treatment of Recurrent Sternoclavicular Joint Instability: A Report of Two Cases.

CASE: A 22-year-old man and a 14-year-old adolescent boy, who exhibited moderate general joint laxity, experienced recurrent sternoclavicular joint instability without traumatic events. The patients were successfully treated with extra-articular stabilization using autologous tendon grafts without surgical exposure of the sternoclavicular joint. CONCLUSION: Atraumatic instability of the sternoclavicular joint is rare but often results in recurrent instability accompanied by discomfort, pain, and limitations in activities. Extra-articular stabilization, which reinforces the anterior capsule of the sternoclavicular joint and prevents anterior displacement of the proximal clavicle at the elevated arm position, could be a viable surgical option for this pathological condition.

Local alternating heat and cold stimulation affects hemodynamics and oxygenation in fatigued muscle tissue and autonomic nervous activity: a single-arm interventional study.

BACKGROUND: Local alternating heat and cold stimulation as an alternative to contrast bath may cause intermittent vasoconstriction and vasodilation, inducing a vascular pumping effect and consequently promoting increased tissue blood flow and oxygenation. This study aimed to examine the effects of local alternating heat and cold stimulation, using a wearable thermal device, on the hemodynamics of fatigued muscle tissue and autonomic nervous activity. METHODS: Twenty healthy individuals experienced fatigue in the periarticular muscles of the shoulder joint due to a typing task. Local alternating heat and cold stimulations were then applied to the upper trapezius muscle. Muscle hardness was measured using a muscle hardness meter, and muscle tissue hemodynamics and oxygenation were evaluated using near-infrared spectroscopy before and after the stimulation. Autonomic nervous activity was also evaluated using heart rate variability. RESULTS: Alternating heat and cold stimulation decreased muscle hardness of the fatigued trapezius muscle from 1.38 ± 0.15 to 1.31 ± 0.14 N (P < 0.01). The concentration of total hemoglobin in the trapezius muscle tissue increased from - 0.21 ± 1.36 to 2.29 ± 3.42 µmol/l (P < 0.01), and the tissue hemoglobin oxygen saturation also increased from 70.1 ± 5.4 to 71.1 ± 6.0% (P < 0.05). Additionally, the heart rate variability parameter, which is an index of sympathetic nervous activity, increased from 3.82 ± 2.96 to 6.86 ± 3.49 (P < 0.01). A correlation was found between increased tissue hemoglobin oxygen saturation and increased parameters of sympathetic nervous activity (r = 0.50, P < 0.05). CONCLUSIONS: Local alternating heat and cold stimulation affected the hemodynamic response in fatigued muscle tissue and autonomic nervous activity. This stimulation is more efficient than conventional contrast baths in terms of mobility and temperature control and has potential as a new versatile therapeutic intervention for muscle fatigue. TRIAL REGISTRATION: UMIN-CTR (UMIN000040087: registered on April 7, 2020, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045710 . UMIN000040620: registered on June 1, 2020, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046359 ).

Visually assessing work performance using a smartwatch via day-to-day fluctuations in heart rate variability.

Objective: To optimize workplace health promotion, a simple method for quantifying allostatic load response is needed. This study examines the feasibility of optimizing objective anxiety and presenteeism monitoring using daily smartwatch-measured ultra-short heart rate variability (HRV). Methods: Office workers without diagnosed disease prospectively performed 30 s HRV self-measurement each morning for two months and responded to the State-Trait Anxiety Inventory (STAI) and Work Limitation Questionnaire (WLQ). Logistic regression analysis examined daily HRV parameters in the high-trait anxiety group (HTA, STAI ≥ 40) using mean and variance HRV, age, self-reported gender, and body mass index (BMI). The ideal cutoff value enabled comparison of WLQ using the Mann-Whitney U test. Heart rate variability data were collected for 279 participants (male ratio, 83.9%; age, 42 ± 10 years) who completed questionnaires and monitored HRV for 30+ days. Results: Compared to the low-trait anxiety group, HTA exhibited higher variance of the log-transformed coefficient of component variance of high-frequency component (LnccvHF) and low-frequency per HF (Lnccv L/H), in addition to differences in the means of these HRV parameters. In addition to BMI (odds ratio [OR] = 0.92, p = 0.02) and mean LnccvL/H (OR = 10.75, p < 0.01), the variance of Lnccv L/H was an independent predictor of HTA (OR = 2.39E + 8, p = 0.011). The daily Lnccv L/H dispersion group had a lower WLQ productivity loss score (p = 0.02, r = 0.17). Conclusions: By focusing on HRV dispersion status, this simple and instantly applicable daily HRV monitoring system enables optimized quantitative monitoring of anxiety and productivity.

Alaska Pollock-derived Gelatin Sealant has Higher Sealing Strength than, and Comparable Biocompatibility with, Fibrin Sealant in Porcine and Rat Dural Injury Models.

STUDY DESIGN: Burst strength study in porcine dural models and functional and histological study in rat dural models. OBJECTIVE: This study aimed to investigate the sealing strength and biocompatibility of Alaska pollock-derived gelatin (ApGltn) and fibrin sealants in disrupted dural injuries. SUMMARY OF BACKGROUND DATA: Disruption of the dura mater occurs during spine surgery, leading to cerebrospinal fluid leakage. Fibrin sealant is usually applied to ruptured sites; however, it lacks sealing strength. A novel biocompatible sealant composed of ApGltn was recently demonstrated to have good burst strength and biocompatibility in the porcine aorta. METHODS: Ten porcine dura maters with central holes were covered with ApGltn and fibrin sealants (five samples per group). The maximum burst strength of each sealant was measured, and histological examination was performed after burst testing. Twenty-seven dura maters of male Wistar rats were used for functional and histopathological evaluations. The rats were treated with three surgical interventions: defect + ApGltn sealant; defect + fibrin sealant; defect alone (nine rats per group). Macroscopic confirmation of the sealant, hindlimb motor function analysis, and histopathological examination were performed at 2, 4, and 8 weeks after the procedure. RESULTS: The maximum burst strength of the ApGltn sealant was approximately 4.4 times higher than that of the fibrin sealant (68.1±12.1 vs. 15.6±8.7 mmHg; P<0.001). Histological examination confirmed that the ApGltn sealant showed tight adhesion to the dural surface, whereas a gap was observed between the fibrin sealant and the dura mater. In the rat model, the ApGltn sealant resulted in spinal function and dural histological findings similar to those of the fibrin sealant. CONCLUSIONS: The ApGltn sealant had a higher sealing strength than, and comparable effect on dura regeneration with, the fibrin sealant.

The tibial tubercle-to-trochlear groove distance changes in standing weight-bearing condition: An upright weight-bearing computed tomography analysis.

BACKGROUND: The tibial tubercle-to-trochlear groove (TT-TG) distance and Insall-Salvati (I/S) ratio are widely used to determine the need for distal realignment in conjunction with medial patellofemoral ligament (MPFL) reconstruction in patients with recurrent patellar dislocation. A TT-TG distance >20 mm and an I/S ratio >1.3 are significant anatomical risk factors for patellar instability. However, these parameters have traditionally been measured using non-weight-bearing (NWB) imaging modalities. As patellar dislocation occurs during weight-bearing actions, these two parameters should be measured under weight-bearing conditions. Thus, this study aimed to measure the TT-TG distance and I/S ratio using upright full-weight-bearing (FWB) computed tomography (CT) scans and compare the data with NWB CT scans. METHODS: This study included 49 knee joints of 26 healthy volunteers. CT images were obtained under both FWB and NWB standing conditions using a 320-detector row upright CT scanner. TT-TGs in the axial plane and I/S ratios in the sagittal plane were measured and compared. RESULTS: The average FWB TT-TG distance was 20.3 ± 3.9 mm, whereas the average NWB TT-TG distance was 12.3 ± 4.7 mm. The TT-TG level was significantly higher in the FWB condition than that in the NWB condition (P < 0.001). The I/S ratios were comparable between the FWB and NWB conditions (P = 0.29). CONCLUSIONS: The TT-TG distance in the standing weight-bearing condition was larger than the conventional TT-TG distance and surpassed the historical cutoff value of TT-TG, which may affect the indication of additional distal realignment in MPFL reconstruction for patellar instability.

Do Pharmacological Treatments Act in Collaboration with Rehabilitation in Spinal Cord Injury Treatment? A Review of Preclinical Studies.

There is no choice other than rehabilitation as a practical medical treatment to restore impairments or improve activities after acute treatment in people with spinal cord injury (SCI); however, the effect is unremarkable. Therefore, researchers have been seeking effective pharmacological treatments. These will, hopefully, exert a greater effect when combined with rehabilitation. However, no review has specifically summarized the combinatorial effects of rehabilitation with various medical agents. In the current review, which included 43 articles, we summarized the combinatorial effects according to the properties of the medical agents, namely neuromodulation, neurotrophic factors, counteraction to inhibitory factors, and others. The recovery processes promoted by rehabilitation include the regeneration of tracts, neuroprotection, scar tissue reorganization, plasticity of spinal circuits, microenvironmental change in the spinal cord, and enforcement of the musculoskeletal system, which are additive, complementary, or even synergistic with medication in many cases. However, there are some cases that lack interaction or even demonstrate competition between medication and rehabilitation. A large fraction of the combinatorial mechanisms remains to be elucidated, and very few studies have investigated complex combinations of these agents or targeted chronically injured spinal cords.

Chronological transitions of hepatocyte growth factor treatment effects in spinal cord injury tissue.

Inflammatory responses are known to suppress neural regeneration in patients receiving stem cell-based regenerative therapy for spinal cord injury (SCI). Consequently, pathways involved in neurogenesis and immunomodulation, such as the hepatocyte growth factor (HGF)/MET signaling cascade, have garnered significant attention. Notably, various studies, including our own, have highlighted the enhanced recovery of locomotor functions achieved in SCI animal models by combining HGF pretreatment and human induced stem cell-derived neural stem/progenitor cell (hiPSC-NS/PC) transplantation. However, these studies implicitly hypothesized that the functionality of HGF in SCI would be time consistent and did not elucidate its dynamics. In the present article, we investigated the time-course of the effect of HGF on SCI, aiming to uncover a more precise mechanism for HGF administration, which is indispensable for developing crystallizing protocols for combination therapy. To this end, we performed a detailed investigation of the temporal variation of HGF using the RNA-seq data we obtained in our most recent study. Leveraging the time-series design of the data, which we did not fully exploit previously, we identified three components in the effects of HGF that operate at different times: early effects, continuous effects, and delayed effects. Our findings suggested a concept where the three components together contribute to the acceleration of neurogenesis and immunomodulation, which reinforce the legitimacy of empirically fine-tuned protocols for HGF administration and advocate the novel possibility that the time-inconsistent effects of HGF progressively augment the efficacy of combined therapy.

Human-induced pluripotent stem cell-derived neural stem/progenitor cell ex vivo gene therapy with synaptic organizer CPTX for spinal cord injury.

The transplantation of neural stem/progenitor cells (NS/PCs) derived from human induced pluripotent stem cells (hiPSCs) has shown promise in spinal cord injury (SCI) model animals. Establishing a functional synaptic connection between the transplanted and host neurons is crucial for motor function recovery. To boost therapeutic outcomes, we developed an ex vivo gene therapy aimed at promoting synapse formation by expressing the synthetic excitatory synapse organizer CPTX in hiPSC-NS/PCs. Using an immunocompromised transgenic rat model of SCI, we evaluated the effects of transplanting CPTX-expressing hiPSC-NS/PCs using histological and functional analyses. Our findings revealed a significant increase in excitatory synapse formation at the transplantation site. Retrograde monosynaptic tracing indicated extensive integration of transplanted neurons into the surrounding neuronal tracts facilitated by CPTX. Consequently, locomotion and spinal cord conduction significantly improved. Thus, ex vivo gene therapy targeting synapse formation holds promise for future clinical applications and offers potential benefits to individuals with SCI.

Regenerative Medicine for Spinal Cord Injury Using Induced Pluripotent Stem Cells.

Spinal cord injury (SCI) is a devastating injury that causes permanent neurological dysfunction. To develop a new treatment strategy for SCI, a clinical trial of transplantation of human-induced pluripotent stem cell-derived neural precursor cells (NPCs) in patients in the subacute phase of SCI was recently initiated. The formation of synaptic connections with host neural tissues is one of the therapeutic mechanisms of cell transplantation, and this beneficial efficacy has been directly demonstrated using a chemogenetic tool. This research focuses on the establishment of cell therapy for chronic SCI, which is more challenging owing to cavity and scar formation. Thus, neurogenic NPC transplantation is more effective in forming functional synapses with the host neurons. Furthermore, combinatory rehabilitation therapy is useful to enhance the efficacy of this strategy, and a valid rehabilitative training program has been established for SCI animal models that received NPC transplantation in the chronic phase. Therefore, the use of regenerative medicine for chronic SCI is expected to increase.

Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury.

BACKGROUND: Severe peripheral nerve damage always requires surgical treatment. Autologous nerve transplantation is a standard treatment, but it is not sufficient due to length limitations and extended surgical time. Even with the available artificial nerves, there is still large room for improvement in their therapeutic effects. Novel treatments for peripheral nerve injury are greatly expected. METHODS: Using a specialized microfluidic device, we generated artificial neurite bundles from human iPSC-derived motor and sensory nerve organoids. We developed a new technology to isolate cell-free neurite bundles from spheroids. Transplantation therapy was carried out for large nerve defects in rat sciatic nerve with novel artificial nerve conduit filled with lineally assembled sets of human neurite bundles. Quantitative comparisons were performed over time to search for the artificial nerve with the therapeutic effect, evaluating the recovery of motor and sensory functions and histological regeneration. In addition, a multidimensional unbiased gene expression profiling was carried out by using next-generation sequencing. RESULT: After transplantation, the neurite bundle-derived artificial nerves exerted significant therapeutic effects, both functionally and histologically. Remarkably, therapeutic efficacy was achieved without immunosuppression, even in xenotransplantation. Transplanted neurite bundles fully dissolved after several weeks, with no tumor formation or cell proliferation, confirming their biosafety. Posttransplant gene expression analysis highlighted the immune system's role in recovery. CONCLUSION: The combination of newly developed microfluidic devices and iPSC technology enables the preparation of artificial nerves from organoid-derived neurite bundles in advance for future treatment of peripheral nerve injury patients. A promising, safe, and effective peripheral nerve treatment is now ready for clinical application.

Non-lesional white matter changes depicted by q-space diffusional MRI correlate with clinical disabilities in multiple sclerosis.

BACKGROUND: We previously developed an optimized q-space diffusional MRI technique (normalized leptokurtic diffusion [NLD] map) to delineate the demyelinated lesions of multiple sclerosis (MS) patients. Herein, we evaluated the utility of NLD maps to discern the white matter abnormalities in normal-appearing white matter (NAWM) and the abnormalities' possible associations with physical and cognitive disabilities in MS. METHODS: We conducted a retrospective observational study of MS patients treated at our hospital (Jan. 2012 to Dec. 2022). Clinical and MRI data were collected; Processing Speed Test (PST) data were obtained when possible. For a quantitative analysis of the NLD maps, we calculated the NLD index as GVROI/GVREF, where GV is a mean grayscale value in the regions of interest (ROIs) and the reference area (REF; cerebrospinal fluid). RESULTS: One hundred-one individuals with MS were included. The lower corpus callosum and non-lesional WM NLD index were associated with worse Expanded Disability Status Scale (EDSS) and PST scores. The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly reduced in progressive MS compared to relapsing-remitting MS. We categorized MS severity as moderate/severe (EDSS score ≥ 4 points) and mild (EDSS score < 4 points). The NLD indexes in the corpus callosum (p < 0.0001) and non-lesional white matter (p < 0.0001) were significantly lower in the moderate/severe MS group compared to the mild MS group. CONCLUSION: The NLD map revealed abnormalities in the non-lesional white matter, providing valuable insights for evaluating manifestations in MS patients.