Qu, Wenchun

Background Lumbar facet arthropathy (LFA) is a degenerative, arthritic joint disorder and a common specific cause of axial low back pain and functional impairment. Currently, no disease-modifying therapies are available for symptomatic LFA. Mesenchymal stem/stromal cell (MSC)-based therapy represents an emerging regenerative treatment modality with the promise to target the underlying pathophysiology of LFA. Despite encouraging clinical evidence supporting the safety and efficacy of MSC therapy in other osteoarthritis, its therapeutic utility in LFA remains largely unexplored. We recently completed a prospective, single-arm, open-label phase I clinical trial that demonstrated a favourable safety profile and preliminary clinical benefit following intra-articular administration of bone marrow-derived MSCs (BMSCs) in patients with symptomatic LFA. Building on these findings, we present the protocol for CellKine II , a prospective, randomised, double-blind, placebo-controlled, cross-over phase II clinical trial to evaluate the safety and preliminary efficacy of intra-articular delivery of allogeneic, culture-expanded BMSCs in patients with painful LFA. Methods and analysis This study is a single-centre, randomised, double-blind, placebo-controlled, cross-over phase II trial with a target accrual of 40 patients. Eligible patients will be randomly assigned in a 1:1 ratio to receive a single intra-articular injection of either Arm A: BMSC or Arm B: Placebo (dimethyl sulfoxide). At the 6-month follow-up, all patients will be unblinded. Patients initially randomised to Arm A will continue follow-up for up to 12 months. Patients initially randomised to Arm B may cross over to receive the BMSC treatment, followed by an additional 12 months of post-BMSC treatment follow-up, or they may continue observation for another 6 months without BMSC treatment. Overall, each patient will be followed up to 12 months after BMSC treatment. The primary endpoints are back pain, functional outcomes and adverse events at 6 months post-randomisation. Ethics and dissemination This study will be conducted in compliance with U.S. federal regulations and Mayo Clinic institutional research policies and procedures. The protocol has been approved by the Mayo Clinic Institutional Review Board (IRB) and the Data Safety Monitoring Board (IRB No. 21-013278). The results of this trial will be disseminated through publication in peer-reviewed journals and on ClinicalTrials.gov. Trial registration number NCT06001853 .

Abstract Background: Lumbar facet joint arthropathy (LFJA) is a major cause of low back pain (LBP), with current treatments offering limited long-term benefits. Bone marrow–derived mesenchymal stem cells (BM-MSCs) show promise due to their immunomodulatory and trophic effects, potentially addressing underlying degenerative processes in LFJA. Objectives: This initial report describes the outcomes of the first treated patient in an ongoing mutidisciplinary phase 1 clinical trial evaluating the safety and feasibility of intra-articular allogeneic BM-MSCs for painful LFJA. Methods: Following enrollment in our IRB-approved protocol, symptomatic LFJA was confirmed through double blocks on L4 and L5 medial branches. Two 1-mL syringes, each containing 10 million BM-MSCs, were prepared in the cGMP facility and administered bilaterally to the patient’s L4-L5 lumbar facet joints. The patient underwent standardized follow-ups, including clinical examinations and functional and imaging assessments for 2 years, utilizing patient-reported outcomes measurement information system—computer adaptive tests (PROMIS CATs), visual analogue scale, Oswestry disability index, work functional status and opioid pain medication use, and MR imaging Fenton–Czervionke score. Results: The patient tolerated the procedure well, with no drug-related adverse events during the study period. Pain, spine function, and work functional status improved at multiple follow-ups. This patient also reported improvements in mental and social health, along with a notable improvement in the grade of facet synovitis observed at the one-year follow-up MRI evaluation. Conclusions: This case report suggests the safety and feasibility of administering intra-articular allogeneic BM-MSCs, offering therapeutic benefits for pain management and functional activities.

AbstractKnee osteoarthritis (KOA) significantly contributes to the global disability burden, with its incidence expected to escalate by 74.9% by 2050. The urgency to comprehend and tackle this condition is critical, necessitating an updated and thorough review of KOA. A systematic review up to February 26, 2024, has elucidated the principal aspects of KOA's pathogenesis, risk factors, clinical manifestations, and contemporary management paradigms. The origins of KOA are intricately linked to mechanical, inflammatory, and metabolic disturbances that impair joint function. Notable risk factors include age, obesity, and previous knee injuries. Diagnosis predominantly relies on clinical assessment, with radiographic evaluation reserved conditionally. The significance of rehabilitation assessments, informed by the International Classification of Functioning, Disability, and Health framework, is highlighted. Treatment strategies are diverse, prioritizing nonpharmacological measures such as patient education, exercise, and weight management, with pharmacological interventions considered adjuncts. Intra‐articular injections and surgical options are contemplated for instances where conventional management is inadequate. KOA stands as a predominant disability cause globally, characterized by a complex etiology and profound effects on individuals’ quality of life. Early, proactive management focusing on nonpharmacological interventions forms the cornerstone of treatment, aiming to alleviate symptoms and enhance joint function. This comprehensive review underscores the need for early diagnosis, individualized treatment plans, and the integration of rehabilitation assessments to optimize patient outcomes. Further research is needed to refine prevention strategies and improve management outcomes for KOA patients.

Back pain with radicular symptoms is associated with detrimental physical and emotional functioning and economic burden. Conservative treatments including physical, pharmacologic and injection therapy may not provide clinically significant or long-standing relief. Regenerative medicine research including Platelet rich plasma (PRP), Platelet lysate (PL) or Plasma rich in growth factors (PRGF) continues to develop, however evidence appraisal for treatment of radicular pain remains lacking. Thus, we performed a systematic review to evaluate the effectiveness of epidural steroid injections containing PRP or related products to treat radicular pain. Embase, PubMed/MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar databases were queried. Twelve studies were included in qualitative analysis, consisting of three randomized controlled trials and nine observational studies. The primary outcome was pain intensity, and secondary outcomes included functional improvement, anatomical changes on advanced imaging, and adverse events. All studies identified improved pain intensity and functional outcomes after epidural injection of PRP, PRGF and/or PL. Similar or longer lasting pain relief was noted in the PRP cohort compared to the cohort receiving epidural steroid injections with effects lasting up to 12–24 months. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis revealed a very-low certainty of evidence due to risk of bias, indirectness, and imprecision.

Abstract MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I 2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I 2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.

Abstract Background Neuropathic pain is a complex condition that can be refractory to conventional management and can cause persistent suffering in patients. Current pharmacologic treatments can provide temporary symptomatic relief; however, the mechanism of these therapies does not address the underlying cause of neuropathic pain. The use of injectable biologics for neuropathic pain has multiple proposed mechanisms for analgesia including attenuation of inflammatory mediated processes, arrest or delay of the degenerative process, inhibition of apoptotic pathways, and augmentation of the survival and recovery of injured and uninjured nerves. Study Design A systematic review of human studies involving the use of injectable biologics for neuropathic pain. Methods A comprehensive search of several data bases including Ovid MEDLINE ® and Epub Ahead of Print, In Process & Other Non-Indexed Citations and Daily, and Ovid Embase from inception to November 24, 2020. Results The initial search yielded 3,450 studies with an additional 6 studies identified through other resources. Twenty-seven studies were included after independent review by two of the investigators. The included studies assessed the efficacy of injectable biologics for the treatment of neuropathic pain defined as pain reduction. Secondary outcome measures included functional improvement as well as safety of the procedures. A qualitative assessment of the literature without meta-analysis was performed due to the heterogeneity of the data. Conclusion According to the GRADE criteria, there is very low certainty of evidence in support of the efficacy of injectable biologics for treatment of neuropathic pain. Future efforts should focus on creating a standardized methodology and study design with respect to preparation, dosage and route of administration of biologics. This will serve as a catalyst for higher quality randomized trials with generation of more useful data to help drive informed clinical decision making.

Currently, large numbers of clinical trials are performed to investigate different forms of experimental therapy for patients suffering from chronic spinal cord injury (SCI). However, for the enrollment process, there are different views on how the time period between injury and interventions should be determined. Herein, we sought to evaluate the impact of time-to-enrollment in chronic SCI clinical trials. A data set comprising 957 clinical studies from clinicalTrials.gov was downloaded and analyzed focusing on the eligibility criteria for post-injury time-to-enrollment. We also aggregated individual patient data from nine clinical trials of regenerative interventions for chronic SCI selected by a systematic literature search from 1990 to 2018. Characteristics of the studies were assessed and compared by dividing into three groups based on time-to-enrollment (group 1 ≤ 12 months, group 2 = 12–23 months and group 3 ≥ 24 months). In ClinicalTrials.gov registry, 445 trials were identified for chronic SCI where 87% (385) were unrestricted in the maximum post-injury time for trial eligibility. From systematic literature search, nine studies and 156 patients (group 1 = 30, group 2 = 55 and group 3 = 71) were included. The range of time-to-enrollment was 0.5 to 321 months in those studies. We also observed various degrees of motor and sensory improvement in between three time-to-enrollment groups. Our results indicate that enrolling wide ranges of time-to-enrollment in a group may present imprecise outcomes. Clinical trial designs should consider appropriate post-injury time frames to evaluate therapeutic benefit.

AbstractSevere cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO2/FiO2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources.Significance statement The potential benefits of mesenchymal stromal cell (MSC) therapy for patients with COVID-19 acute respiratory distress syndrome support the rapid commencement of clinical trials, as well as the compassionate use of MSCs that already have documented safety profiles from FDA-approved studies.

Abstract Objective To evaluate the association between hypovitaminosis D and outcomes of symptom severity, mood disorders, fatigue, and quality of life in fibromyalgia (FM) patients. Methods Five hundred ninety-three FM patients were surveyed from May 2012 to November 2013. Patients with serum vitamin D <25 ng/mL were considered to have hypovitaminosis D. The primary outcome was FM symptom severity (FIQ-R questionnaire). Secondary outcomes included quality of life (SF-36), fatigue (MFI-20), anxiety (GAD-7), and depression (PHQ-9). Independent t tests and chi-square tests were performed for continuous and categorical variables, respectively. Regression analysis was performed adjusting for age, gender, body mass index, ethnicity, and season. A post hoc analysis examined for correlation between outcomes and serum vitamin D (ng/mL) as a continuous variable. Results One hundred twenty-two patients (20.6%) had hypovitaminosis D. In our adjusted regression analysis, the total FIQ-R score in patients with hypovitaminosis D was higher compared with control patients with adequate serum vitamin D (57.85 ± 18.09 vs 62.79 ± 18.10, P = 0.04). Adjusted regression analysis revealed higher total GAD-7 (P = 0.01) and higher total PHQ-9 scores (P = 0.04) in patients with hypovitaminosis D compared with control patients. There were no differences based on severity of depression or anxiety. No differences in fatigue or quality of life were identified. Unadjusted post hoc analysis revealed that as serum vitamin D increased, there was an association with lower total FIQ-R (β coefficient = –0.11, P = 0.02) and lower SF-36 subscale scores of role-physical (β coefficient = –0.10, P = 0.03). Adjusted post hoc analysis revealed no significant associations. Conclusions Hypovitaminosis D may be a risk factor for worse symptom severity, anxiety, and depression in FM patients.

ObjectiveTo assess the biologic effects of lidocaine on the viability, proliferation, and function of human adipose tissue–derived mesenchymal stromal/stem cells (MSCs) in vitro.MethodsAdipose‐derived MSCs from three donors were exposed to lidocaine at various dilutions (2 mg/mL to 8 mg/mL) and exposure times (0.5 to 4 hours). Cell number and viability, mitochondrial activity, and real‐time reverse‐transcriptase quantitative polymerase chain reaction (RT‐qPCR) were analyzed at 0 (immediate effects) or 24 and 48 hours (recovery effects) after treatment with lidocaine.ResultsTrypan blue staining showed that increasing concentrations of lidocaine decreased the number of observable viable cells. 3‐[4,5,dimethylthiazol‐2‐yl]‐5‐[3‐carboxymethoxy‐phenyl]‐2‐[4‐sulfophenyl]‐2H‐tetrazolium (MTS) assays revealed a concentration‐ and time‐ dependent decline of mitochondrial activity and proliferative ability. Gene expression analysis by RT‐qPCR revealed that adipose‐derived MSCs exposed to lidocaine express robust levels of stress response/cytoprotective genes. However, higher concentrations of lidocaine caused a significant downregulation of these genes. No significant differences were observed in expression of extracellular matrix (ECM) markers COL1A1 and DCN except for COL3A1 (P < .05). Levels of messenger RNA (mRNA) for proliferation markers (CCNB2, HIST2H4A, P < .001) and MKI67 (P < .001) increased at 24 and 48 hours. Expression levels of several transcription factors— including SP1, PRRX1, and ATF1—were modulated in the same manner. MSC surface markers CD44 and CD105 demonstrated decreased expression immediately after treatment, but at 24 and 48 hours postexposure, the MSC markers showed no significant difference among groups.ConclusionLidocaine is toxic to MSCs in a dose‐ and time‐ dependent manner. MSC exposure to high (4‐8 mg/mL) concentrations of lidocaine for prolonged periods can affect their biologic functions. Although the exposure time in vivo is short, it is essential to choose safe concentrations when applying lidocaine along with MSCs to avoid compromising the viability and potency of the stem cell therapy.