Osteoarthritis - Clinical research overview

Abstract Purpose Implantation of mesenchymal stem cells (MSCs) is a potential non‐surgical option for cartilage repair. Currently, its clinical use largely focuses on focal cartilage defect repair and intra‐articular injections in knee osteoarthritis (OA). Most studies have looked at the efficacy of MSCs from autologous sources, which can be limited by inter‐patient variability of age, diseases, sites and methods of harvest. This systematic review aims to evaluate studies that focus on allogeneic MSCs implantation versus placebo in patients with knee OA to summarise the efficacy and safety of allogeneic MSCs in knee OA. Methods A systematic search following PRISMA guidelines was performed in PubMed, Scopus and EMBASE. Original studies investigating the outcomes of allogeneic MSC implantations in patients with knee OA were included. Data on clinical outcomes, such as subjective scores such as VAS and WOMAC, radiological outcomes, such as cartilage thickness, and histological outcomes, such as ICRSII score, were extracted. Results Seven studies were included in this review. There was 30.4 points improvement in Visual Analogue Scale scores and 40.0 points of improvement in Western Ontario and McMaster Universities Osteoarthritis Index scores at 12 months. Improved cartilage thickness and decreased poor cartilage quality as measured by T2 relaxation. Measurements at the lesion site were observed in three studies as assessed by postoperative magnetic resonance imaging and this was correlated clinically. One study also showed histological improvement with overall ICRSII scores significantly improving from 32.0 ± 21.6 at baseline to 55.9 ± 23.2 at 6 months ( p < 0.05). No major complications or tumorigenesis occurred. Conclusion Allogeneic MSC implantation in patients with knee osteoarthritis provides sustained clinical improvement and satisfactory cartilage restoration, up to 12 months follow‐up. These results are supported by both imaging and histological studies. The safety profile of allogeneic MSCs is excellent, with minimal adverse events mainly limited to local reaction to injection and no long‐term adverse effects. Level of Evidence Level II.

Osteoarthritis (OA) is a degenerative multifactorial disease with concomitant structural, inflammatory, and metabolic changes that fluctuate in a temporal and patient-specific manner. This complexity has contributed to refractory responses to various treatments. MSCs have shown promise as multimodal therapeutics in mitigating OA symptoms and disease progression. Here, we evaluated 15 randomized controlled clinical trials (RCTs) and 11 nonrandomized RCTs using culture-expanded MSCs in the treatment of knee OA, and we found net positive effects of MSCs on mitigating pain and symptoms (improving function in 12/15 RCTs relative to baseline and in 11/15 RCTs relative to control groups at study endpoints) and on cartilage protection and/or repair (18/21 clinical studies). We examined MSC dose, tissue of origin, and autologous vs. allogeneic origins as well as patient clinical phenotype, endotype, age, sex and level of OA severity as key parameters in parsing MSC clinical effectiveness. The relatively small sample size of 610 patients limited the drawing of definitive conclusions. Nonetheless, we noted trends toward moderate to higher doses of MSCs in select OA patient clinical phenotypes mitigating pain and leading to structural improvements or cartilage preservation. Evidence from preclinical studies is supportive of MSC anti-inflammatory and immunomodulatory effects, but additional investigations on immunomodulatory, chondroprotective and other clinical mechanisms of action are needed. We hypothesize that MSC basal immunomodulatory "fitness" correlates with OA treatment efficacy, but this hypothesis needs to be validated in future studies. We conclude with a roadmap articulating the need to match an OA patient subset defined by molecular endotype and clinical phenotype with basally immunomodulatory "fit" or engineered-to-be-fit-for-OA MSCs in well-designed, data-intensive clinical trials to advance the field.

Mesenchymal stromal cells (MSCs) have gained significant attention in regenerative medicine for their potential in treating a variety of diseases even intractable ones, due to their ability to differentiate into various cell types and promote tissue repair. In addition to their regenerative properties, MSCs possess potent immunomodulatory effects, which make them particularly promising for treating orthopedic conditions and musculoskeletal disorders complicated by chronic inflammation, infection, or other comorbidities. This review explores the immunomodulatory mechanisms of MSCs and their role in facilitating bone and cartilage repair in conditions such as fractures, osteoarthritis, and tendon injuries. We examine the key mechanisms by which MSCs regulate the immune responses, including the paracrine activity by secreting cytokines, growth factors and extracellular vesicles on one hand, and modulation of immune cell activities through direct cell-cell contact. Furthermore, this review examines how comorbidities impact MSC function and quality and explores the potential of MSCs in treating orthopedic conditions complicated by diabetes, obesity, smoking, and infections, which can hinder the healing process. The challenges of translating MSC-based therapies into orthopaedic clinical practice are also discussed, particularly concerning MSC source selection, optimal dosing strategies and long-term safety and efficacy. Finally, we highlight emerging strategies aimed at enhancing the immunomodulatory effects of MSCs, such as preconditioning, genetic modifications, biomaterial-based delivery systems and combination therapies. A profound understanding of MSC immunomodulatory mechanisms can pave the way toward optimizing their application in orthopedic cell therapy and tissue engineering and enhancing clinical outcomes for patients with complex healing conditions.

Osteoarthritis is the most prevalent joint disease and a frequent cause of joint pain, functional loss, and disability. Osteoarthritis often becomes chronic, and conventional treatments have demonstrated only modest clinical benefits without lesion reversal. Cell-based therapies have shown encouraging results in both animal studies and a few human case reports. We designed a pilot study to assess the feasibility and safety of osteoarthritis treatment with mesenchymal stromal cells (MSCs) in humans and to obtain early efficacy information for this treatment.

Osteoarthritis is the most prevalent joint disease and a common cause of joint pain, functional loss, and disability. Conventional treatments demonstrate only modest clinical benefits without lesion reversal. Autologous mesenchymal stromal cell (MSC) treatments have shown feasibility, safety, and strong indications for clinical efficacy. We performed a randomized, active control trial to assess the feasibility and safety of treating osteoarthritis with allogeneic MSCs, and we obtain information regarding the efficacy of this treatment.

The aim of this study was to assess whether allogeneic cultured, pooled, bone marrow derived mesenchymal stromal cells (BMMSCs), has potential to impact progression of osteoarthritis (OA). Randomized, double blind, multicentric, placebo-controlled trial to assess efficacy and safety of BMMSCs in Grade 2 and 3 OA of knee. 146 patients were randomized, 73 patients each received either BMMSCs (25 million cells) or placebo followed by 20 mg HA. The primary end point was evaluation of WOMAC Composite Index and secondary end points were WOMAC sub-scores, VAS, magnetic resonance (MR) assessment (T2 mapping and cartilage volume). 58 patients from BMMSC arm and 60 patients from placebo arm completed 24 months follow-up. At 24 months follow up, WOMAC composite index and WOMAC sub scores showed significant improvements in cell arm as compared to placebo (p < 0.0001); T2 mapping showed there is no worsening of the cartilage in the medial femoral tibial compartment in BMMSC arm whereas placebo arm shows gradual worsening (p < 0.0001). Cartilage volume increased in BMMSC arm. At Day 90 & 730, Urinary C - terminal cross linked telopeptide of type II collagen significantly decreased in the cell arm and increased in the placebo arm (p-value<0.0001). 5 AEs were possibly related to the study drug and were local site administration effects. By 24 months follow-up, 4 patients in the placebo group underwent TKR versus 1 patient in the BMMSC arm. This study demonstrates that BMMSC's is safe and effective for the treatment of grade 2 & 3 OA of knee. CTRI/2018/09/015785 [Registered on: September 20, 2018].

Patients with late-stage Kellgren-Lawrence knee osteoarthritis received a single intra-articular injection of 1, 10, or 50 million bone marrow mesenchymal stromal cells (BM-MSCs) in a phase I/IIa trial to assess safety and efficacy using a broad toolset of analytical methods. Besides safety, outcomes included patient-reported outcome measures (PROMs): Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); contrast-enhanced magnetic resonance imaging (MRI) for cartilage morphology (Whole Organ MRI Scores [WORMS]), collagen content (T2 scores), and synovitis; and inflammation and cartilage turnover biomarkers, all over 12 months. BM-MSCs were characterized by a panel of anti-inflammatory markers to predict clinical efficacy. There were no serious adverse events, although four patients had minor, transient adverse events. There were significant overall improvements in KOOS pain, symptoms, quality of life, and WOMAC stiffness relative to baseline; the 50 million dose achieved clinically relevant improvements across most PROMs. WORMS and T2 scores did not change relative to baseline. However, cartilage catabolic biomarkers and MRI synovitis were significantly lower at higher doses. Pro-inflammatory monocytes/macrophages and interleukin 12 levels decreased in the synovial fluid after MSC injection. The panel of BM-MSC anti-inflammatory markers was strongly predictive of PROMs over 12 months. Autologous BM-MSCs are safe and result in significant improvements in PROMs at 12 months. Our analytical tools provide important insights into BM-MSC dosing and BM-MSC reduction of synovial inflammation and cartilage degradation and provide a highly predictive donor selection criterion that will be critical in translating MSC therapy for osteoarthritis. Stem Cells Translational Medicine 2019;8:746&757.

To assess the impact of a single intra-articular (IA) injection of bone marrow–derived mesenchymal stem cells (BM-MSCs) in patients with knee osteoarthritis (OA), a randomized, double-blind, placebo-controlled study was conducted. The study included 24 patients with knee OA who were randomly assigned to receive either a single IA injection of BM-MSCs or normal saline. Changes in the visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Knee Injury and Osteoarthritis Outcome Score (KOOS) after IA injection were assessed at 3, 6, 9, and 12 months. Magnetic resonance imaging (MRI) with T2 mapping sequences was conducted for knee cartilage assessment at baseline and at 3 and 12 months. The MSC group showed between-group improvement in WOMAC (–5.0 ± 3.6 vs. –0.1 ± 5.5, P = 0.02) and KOOS (23.9 ± 18.3 vs. 7.2 ± 15.9, P = 0.028) scores at 9 months compared with the control group. The MSC group exhibited a less sharp increase in the mean T2 value of the medial compartment than the control group at 12 months, with no serious adverse events observed during follow-up. A single IA injection of allogeneic BM-MSCs provided satisfactory pain relief for patients with knee OA compared with the control group at 9 months. Quantitative T2 MRI mapping of the cartilage showed that IA BM-MSCs could have a preventive effect on OA progression for 12 months. Our findings suggest the potential of allogeneic BM-MSCs IA injection as a pain-relieving and disease-modifying treatment for patients with knee OA in the outpatient setting.

AbstractIntra-articular injection of adipose-derived mesenchymal stem cell (ADMSC) after medial open-wedge high tibial osteotomy (MOWHTO) would be a promising disease-modifying treatment by correcting biomechanical and biochemical environment for arthritic knee with varus malalignment. However, there is a paucity of clinical evidence of the treatment. This randomized controlled trial (RCT) was aimed to assess regeneration of cartilage defect, functional improvement, and safety of intra-articular injection of ADMSCs after MOWHTO compared with MOWHTO alone for osteoarthritic knee with varus malalignment. This RCT allocated 26 patients into the MOWHTO with ADMSC-injection group (n = 13) and control (MOWHTO-alone) group (n = 13). The primary outcome was the serial changes of cartilage defect on periodic magnetic resonance imaging (MRI) evaluation using valid measurements until postoperative 24 months. Secondary outcomes were the 2-stage arthroscopic evaluation for macroscopic cartilage status and the postoperative functional improvements of patient-reported outcome measures until the latest follow-up. Furthermore, safety profiles after the treatment were evaluated. Cartilage regeneration on serial MRIs showed significantly better in the ADMSC group than in the control group. The arthroscopic assessment revealed that total cartilage regeneration was significantly better in the ADMSC group. Although it was not significant, functional improvements after the treatment showed a tendency to be greater in the ADMSC group than in the control group from 18 months after the treatment. No treatment-related adverse events, serious adverse events, and postoperative complications occurred in all cases. Concomitant intra-articular injection of ADMSCs with MOWHTO had advantages over MOWHTO alone in terms of cartilage regeneration with safety at 2-year follow-up, suggesting potential disease-modifying treatment for knee OA with varus malalignment.

This study aimed to evaluate the safety and therapeutic potential of autologous human adipose-derived mesenchymal stem cells (haMSCs) in patients with osteoarthritis.

Background: Intra-articular injection of autologous culture-expanded adipose-derived mesenchymal stem cells (ADMSCs) has introduced a promising treatment option for knee osteoarthritis. Although the clinical efficacy and safety of ADMSCs have been reported, the treatment remains controversial owing to the small sample sizes and heterogeneous osteoarthritis grades in previous studies. Purpose: To assess the efficacy and safety of intra-articular injection of ADMSCs as compared with placebo in alleviating pain and improving functional capacity in a large sample of patients with knee osteoarthritis of Kellgren-Lawrence (K-L) grade 3. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: This phase III multicenter clinical trial was a double-blind randomized controlled study that included 261 patients with K-L grade 3 symptomatic knee osteoarthritis who were administered a single injection of autologous culture-expanded ADMSCs or placebo. Clinical data were assessed at baseline and at 3 and 6 months after the injection. The primary endpoints were improvements in 100-mm visual analog scale (VAS) for pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for function at 6 months after the injection. The secondary endpoints included clinical and radiologic examinations and safety after injection. The changes in cartilage defects after injection were assessed by magnetic resonance imaging at 6 months. Results: The ADMSC and control groups included 125 and 127 patients available for follow-up, respectively. At 6 months, the ADMSC group showed significantly better improvements in 100-mm VAS (ADMSC vs control, 25.2 vs 15.5; P = .004) and total WOMAC score (21.7 vs 14.3; P = .002) as compared with the control group. The linear mixed model analysis indicated significantly better improvements in all clinical outcomes in the ADMSC group after 6 months. At 6 months, the ADMSC group achieved significantly higher proportions of patients above the minimal clinically important difference in 100-mm VAS and WOMAC score. Radiologic outcomes and adverse events did not demonstrate significant differences between the groups. No serious treatment-related adverse events were observed. Magnetic resonance imaging revealed no significant difference in change of cartilage defects between the groups at 6 months. Conclusion: Intra-articular injection of autologous culture-expanded ADMSCs provided significant pain relief and functional improvements in patients with K-L grade 3 osteoarthritis. Long-term results are needed to determine the disease-modifying effects of ADMSCs, such as structural changes, and the duration of effect of intra-articular injection of ADMSCs in knee osteoarthritis. Registration: NCT03990805 (ClinicalTrials.gov identifier).