Intra-articular Injection Of Mesenchymal Stem Cells Research Articles

Research progress in mesenchymal stem cell-related therapies in the treatment of temporomandibular joint osteoarthritis

Temporomandibular joint osteoarthritis (TMJOA) is a kind of organic disease with synovial inflammation, cartilage degeneration and subchondral bone remodeling as the main pathological changes. The current treatment is mainly to relieve symptoms, but cannot completely stop the progression of the disease. Mesenchymal stem cells (MSC) have multi-lineage differentiation potential and have good prospects in the repair therapy of TMJOA. Intra-articular injection of MSC from bone marrow, adipose, umbilical cord, dental pulp, etc. has been shown to be effective in numerous animal studies. The above exogenous MSCs can also be used as seed cells to participate in tissue engineering and repair more severe defects. Recent studies have shown that exosomes are important mediators of MSC action and have some potential in the treatment of TMJOA. As the mechanisms of TMJOA are further investigated, there is some prospect that endogenous repair capacity can be activated by local injection of relevant drugs targeting the resident stem cells in the joint.

Mesenchymal stem cells for chronic knee pain secondary to osteoarthritis: A systematic review and meta-analysis of randomized trials

ObjectiveTo assess the effectiveness of mesenchymal stem cells (MSCs) for chronic knee pain secondary to osteoarthritis (OA). MethodsWe searched MEDLINE, EMBASE, CINAHL, and Cochrane Central to September 2023 for trials that: (1) enrolled patients with chronic pain associated with knee OA, and (2) randomized them to MSC therapy vs. placebo or usual care. We performed random-effects meta-analysis for all patient-important outcomes and used GRADE to assess the certainty of evidence. ResultsWe included 16 trials (807 participants). At 3-6 months, when restricted to low risk of bias studies, MSC therapy probably results in little to no difference in pain relief (weighted mean difference [WMD] -0.74cm on a 10cm visual analogue scale [VAS], 95%CI -1.16 to -0.33; minimally important difference [MID] 1.5cm) or physical functioning (WMD 2.23 points on 100-point SF-36 physical functioning subscale, 95%CI -0.97 to 5.43; MID 10-points; both moderate certainty). At 12-months, injection of MSCs probably results in little to no difference in pain (WMD -0.73 cm on a 10cm VAS, 95%CI -1.69 to 0.24; moderate certainty, restricted to low risk of bias studies) and may improve physical functioning (WMD 19.36 points on 100-point SF-36 PF subscale, 95%CI -0.19 to 38.9; low certainty). MSC therapy may increase risk of any adverse events (RR 2.67, 95%CI 1.19 to 5.99; low certainty) and pain and swelling of the knee joint (RR 1.58, 95%CI 1.04 to 2.38; low certainty). ConclusionsWhen restricted to moderate certainty evidence, compared to placebo, intra-articular injection of MSCs for chronic knee pain associated with OA probably provides little to no improvement in pain or physical function.

Clinical Trials with Mesenchymal Stem Cell Therapies for Osteoarthritis: Challenges in the Regeneration of Articular Cartilage.

Osteoarthritis (OA) is a whole-joint disease primarily characterized by the deterioration of hyaline cartilage. Current treatments include microfracture and chondrocyte implantation as early surgical strategies that can be combined with scaffolds to repair osteochondral lesions; however, intra-articular (IA) injections or implantations of mesenchymal stem cells (MSCs) are new approaches that have presented encouraging therapeutic results in animal models and humans. We critically reviewed clinical trials with MSC therapies for OA, focusing on their effectiveness, quality, and outcomes in the regeneration of articular cartilage. Several sources of autologous or allogeneic MSCs were used in the clinical trials. Minor adverse events were generally reported, indicating that IA applications of MSCs are potentially safe. The evaluation of articular cartilage regeneration in human clinical trials is challenging, particularly in the inflammatory environment of osteoarthritic joints. Our findings indicate that IA injections of MSCs are efficacious in the treatment of OA and the regeneration of cartilage, but that they may be insufficient for the full repair of articular cartilage defects. The possible interference of clinical and quality variables in the outcomes suggests that robust clinical trials are still necessary for generating reliable evidence with which to support these treatments. We suggest that the administration of just-sufficient doses of viable cells in appropriate regimens is critical to achieve effective and durable effects. In terms of future perspectives, genetic modification, complex products with extracellular vesicles derived from MSCs, cell encapsulation in hydrogels, and 3D bioprinted tissue engineering are promising approaches with which to improve MSC therapies for OA.

Intraarticular Injections of Mesenchymal Stem Cells in Knee Osteoarthritis: A Review of Their Current Molecular Mechanisms of Action and Their Efficacy

More than 10% of the world's population suffers from osteoarthritis (OA) of the knee, with a lifetime risk of 45%. Current treatments for knee OA pain are as follows: weight control; oral pharmacological treatment (non-steroidal anti-inflammatory drugs, paracetamol, opioids); mechanical aids (crutches, walkers, braces, orthotics); therapeutic physical exercise; and intraarticular injections of corticosteroids, hyaluronic acid, and platelet-rich plasma (PRP). The problem is that such treatments usually relieve joint pain for only a short period of time. With respect to intraarticular injections, corticosteroids relieve pain for several weeks, while hyaluronic acid and PRP relieve pain for several months. When the above treatments fail to control knee pain, total knee arthroplasty (TKA) is usually indicated; however, although a very effective surgical technique, it can be associated with medical and postoperative (surgery-related) complications. Therefore, it seems essential to look for safe and effective alternative treatments to TKA. Recently, there has been much research on intraarticular injections of mesenchymal stem cells (MSCs) for the management of OA of the knee joint. This article reviews the latest information on the molecular mechanisms of action of MSCs and their potential therapeutic benefit in clinical practice in patients with painful knee OA. Although most recent publications claim that intraarticular injections of MSCs relieve joint pain in the short term, their efficacy remains controversial given that the existing scientific information on MSCs is indecisive. Before recommending intraarticular MSCs injections routinely in patients with painful knee OA, more studies comparing MSCs with placebo are needed. Furthermore, a standard protocol for intraarticular injections of MSCs in knee OA is needed.

Intra-articular Injection of Mesenchymal Stem Cells After High Tibial Osteotomy: A Systematic Review and Meta-analysis.

Multiple studies have investigated the use of mesenchymal stem cells (MSCs) for patients undergoing high tibial osteotomy (HTO), and the effectiveness thereof remains controversial. To analyze the effectiveness of intra-articular MSC injection in patients who underwent HTO in terms of clinical outcomes, radiological outcomes, and cartilage repair by a meta-analysis of the available literature. Systematic review; Level of evidence, 3. The electronic databases of PubMed, Embase, Web of Science, and the Cochrane Library were searched from their inception to October 30, 2021, for comparative studies between patients who underwent HTO with and without intra-articular injection of MSCs, according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Study quality was assessed by the Coleman Methodology Score (CMS). Data with comparable results were pooled for meta-analysis. The primary outcomes of interest were the Hospital for Special Surgery (HSS), International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), and Lysholm scores, as well as the International Cartilage Regeneration & Joint Preservation Society (ICRS) grade of cartilage repair. Radiological outcomes including femorotibial angle, posterior tibial slope, and hip-knee-ankle (HKA) angle were included as secondary outcomes. A fixed-model effect was used for meta-analyses with low heterogeneity between studies (I 2 < 25%), while the random-model effect was used for medium- to high-heterogeneity analyses (I 2 ≥ 25%). A total of 843 studies were screened, of which 6 studies with 452 patients met the inclusion criteria and were included. The mean CMS was 81.17. Patients with MSC injection had significantly higher Lysholm scores (P = .007) and HSS scores (P = .01) and higher proportions of ICRS grade 1 (P = .03) and grade 2 (P = .02) cartilage repair in the medial femoral condyle and grade 2 cartilage repair in the tibial plateau (P = .04). There were no significant differences between groups in the IKDC score, KOOS Pain and Symptoms subscales, femorotibial angle, posterior tibial slope, or HKA angle. Intra-articular MSC injection may enhance the cartilage repair for patients who undergo HTO. However, evidence of improvement in knee functions remains limited. CRD42021291345 (PROSPERO).

Imaging cartilage characteristics after intra-articular injection of mesenchymal stemcells as treatment of knee osteoarthritis: A literature review

Category: Musculoskeletal

Safety and Efficacy of Injecting Mesenchymal Stem Cells Into a Human Knee Joint To Treat Osteoarthritis: A Systematic Review.

Intraarticular stem cell therapy has become increasingly used to treat knee osteoarthritis (KOA) with minimal high-quality evidence to support its use. This study aims to see how well intra-articular injections of mesenchymal stem cells (MSCs) worked and how safe they were for individuals with KOA. A total of 10 studies were extracted using PubMed, Cochrane Library, and PMC from 2017 to 2021 in the English language. An assessment of the risk of bias was applied via the Cochrane Collaborative Bias Risk Tool and Newcastle-Ottawa Quality. Changes in pain and functional outcomes in patients with KOA were measured by a Knee injury and Osteoarthritis Outcome Score (KOOS) scores, Visual Analogue Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores at baseline, and follow-up evaluation criteria. The magnetic resonance imaging (MRI) was evaluated using the whole-organ magnetic resonance imaging score (WORMS) and cartilage volume changes. A total of six randomized controlled trials (RCTs), three prospective retrospective clinical trials, and one retrospective clinical trial included 723 patients. They were diagnosed with unilateral or bilateral KOA with Kellgren-Lawrence (KL) grade 1-4 KOA and followed up for six, 12, and 24 months. The experimental groups received multipotent MSCs, mesenchymal progenitor cells (MPCs), adipose tissue progenitor stem cells (AD-MPCs), adipose tissue mesenchymal stem cells (AD-MSCs), bone marrow mesenchymal stem cells (BM-MSCs), bone marrow aspiration (BMA), bone marrow aspiration concentration (BMAC), or micro fragmented adipose tissue (MFAT) while the controlled groups received normal saline (NS), hyaluronic acid (HA), placebo, or went through conservative management.In conclusion, significant improvements were noticed in the MSCs groups via different outcome measuring tools like KOOS, VAS, WOMAC, and MRI. Furthermore, no significant adverse events (AEs) have been observed. Therefore, intra-articular injections of MSCs are effective and safe in relieving pain and improving motor function in individuals with KOA in the short term, contrary to earlier research findings.

Conditioned Medium of Mesenchymal Stem Cells Prevents Degenerative Changes in Ankle Osteoarthritis in Rat Models

Category:Ankle; Ankle Arthritis; Basic Sciences/Biologics; TraumaIntroduction/Purpose:Osteoarthritis (OA) is the most common degenerative joint disorder, characterized mainly by progressive articular cartilage degradation, subchondral bone thickening, osteophyte formation, and synovial inflammation. About 80% of ankle OA is believed to be post-traumatic and affects the younger population leading to a higher risk of disabilities during life. Mesenchymal stem cells (MSCs) have shown promising effects in preventing the degenerative process of OA via paracrine effect and great differentiation potential. Recently, using chondrocyte conditioned medium (CCM) that contains all necessary secretomes was shown to enhance MSC differentiation and regeneration of the cartilage tissue. In this study, we aimed to assess the effects of intraarticular injection of MSCs plus CCM on the degenerative process of monoiodoacetate (MIA)-induced ankle OA in rats.Methods:Fifty male rats were randomly divided into 5 groups (n=10): Non-treated control group (C); the group treated with intra-articular Hyaluronic acid (HA). Hyaluronic acid has shown beneficial effects on the degenerative process of OA in different reports. The other treatment groups received intraarticular synovial derived MSCs (5′105), intraarticular CCM, and intraarticular MSCs combined with CCM (MSC+CCM), respectively. Induction of ankle OA was conducted via 1 mg MIA injection in the right tibiotarsal joint for two consecutive days. Three months after starting the treatments, radiological assessments of joint space width (Normal=0, reduced=1, abcent=2) and osteophytes of the tibia and talus (No osteophyte=0, small=1, moderate=2, severe=3) were performed. Ankle specimens were obtained for histopathological examination of the joint surface, matrix, cell distribution, cell viability, subchondral bone, and mineralization; lower scores indicated more severe damages. Scores for each assessment were recorded. Mann-Whitney U test was used for comparisons and p-value<0.05 was considered statistically significant.Results:Our findings showed significant differences between the controls and the treatment groups regarding all pathological scores including joint surface, matrix, cell distribution, cell viability, subchondral bone, and mineralization, that were higher and radiological scores including joint space width and osteophytes of the tibia and talus that were lower in the controls (P<0.05; Figure 1). Among the treatment groups, HA-treated rats showed significantly lower pathological and higher radiological scores compared to CCM, MSC, and MSC+CCM (P<0.05). Among CCM, MSC, and MSC+CCM treated groups, no significant difference was found regarding the pathological and radiological scores (P>0.05). However, although not statistically noticeable, the MSC+CCM group showed slightly better outcomes, both radiologically and histopathologically, compared to the MSC and CCM groups (Figure 1).Conclusion:Our results showed that the combination of CCM can have a similar effect on the degenerative changes in ankle OA. However, the combination of MSC+CCM showed better scores regarding pathological and radiological evaluation. Although further studies with a greater population seem to be needed to validate these outcomes, our study indicates the efficacy of CCM in reducing the degenerative rate of OA. CCM is also known as 'secret factors' since it is still a 'black box' in terms of identifying its content and effects.

Intra-articular Injections of Mesenchymal Stem Cells Without Adjuvant Therapies for Knee Osteoarthritis: A Systematic Review and Meta-analysis

Background: While many reviews have been performed to attempt to provide conclusive evidence regarding the outcomes of mesenchymal stem cells (MSCs) in osteoarthritis treatment, the evidence for MSC treatment in osteoarthritis remains contentious, as these reviews have been limited by the heterogeneous evidence available. Purpose: To pool the results of treatment using intra-articular injections of MSCs without any adjuvant therapies for osteoarthritis. Study Design: Systematic review and meta-analysis. Methods: The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. All clinical trials of level 1 or 2 evidence that reported clinical outcomes of patients with osteoarthritis of the knees treated using intra-articular injections of MSCs without any adjuvant therapies were included. Results: A total of 19 studies with 440 knees were included. All studies reported an improvement in the outcomes after intervention. The standardized mean differences (SMDs) for the visual analog scale (VAS) for pain at rest and upon exertion were –1.48 (95% CI, –1.85 to –1.11) and –2.25 (95% CI, –2.64 to –1.85), respectively. The SMDs for the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and total Knee injury and Osteoarthritis Outcome Score were –1.19 (95% CI, –1.53 to –0.84) and 0.88 (95% CI, 0.66-1.10), respectively. Only the source of MSCs and whether the MSCs were cultured or uncultured were clinically important and statistically significant moderators of the treatment outcome. The use of bone marrow MSCs reduced the VAS for pain by 1.50 (95% CI, 0.04-2.96; P = .04) and reduced the total WOMAC by 23.2 (95% CI, 10.0-36.4; P < .01) as compared with adipose MSCs. The use of cultured MSCs reduced the VAS for pain by 2.19 (95% CI, 0.57-3.81; P < .01) and reduced the total WOMAC by 14.4 (95% CI, 1.21-27.5; P = .03) as compared with uncultured MSCs. Conclusion: Intra-articular injections of MSCs without any adjuvant therapies improves pain and function for osteoarthritis. Significantly better outcomes were obtained with the use of bone marrow MSCs as compared with adipose MSCs and with the use of cultured MSCs as opposed to uncultured MSCs.

Comparative matched-pair cohort analysis of the short-term clinical outcomes of mesenchymal stem cells versus hyaluronic acid treatments through intra-articular injections for knee osteoarthritis

PurposeIntra-articular injection of hyaluronic acid (HA) has shown promises in reducing pain and improving physical function in knee osteoarthritis (OA). Recently, cell-based therapies using mesenchymal stem cells (MSCs) have emerged as potential treatments. However, few studies have compared the treatment outcomes between MSCs and HA. This study aimed to compare the clinical and radiological outcomes of intra-articular injections of MSCs versus HA in patients with knee OA.MethodsA cohort of 209 patients with knee OA were retrospectively screened for those who underwent intra-articular injections using MSCs or HA. Thirty MSC-treated patients (MSC group) were pair-matched with thirty HA-treated patients (HA group) based on gender and age. Clinical outcomes were evaluated using the visual analog scale (VAS), International Knee Documentation Committee (IKDC) rating system, and Lysholm scoring system. Radiological evaluation was assessed using the Kellgren-Lawrence (K-L) grading system.ResultsMSC treatment yielded consistent significant improvements in VAS, IKDC and Lysholm scores. In the HA group, VAS scores significantly decreased at 1 month, slightly increased at 3 months, and increased significantly from 3 months to 1 year after injection. The IKDC and Lysholm scores improved significantly until 3 months, but gradually worsened thereafter. Significantly greater improvements in VAS (P = 0.041), IKDC (P = 0.014), and Lysholm (P = 0.020) scores were observed in the MSC group compared to those in the HA group at 1-year post-treatment. The K-L grade worsened in a few patients, especially those in the HA group, albeit no significant difference.ConclusionsMSC group showed better VAS, IKDC, and Lysholm scores at 1-year post-treatment, compared to the HA group, although earlier clinical improvements were superior in the HA group for the initial 3 months.Level of EvidenceTherapeutic study, Level III.

CORR Synthesis: What Is the Evidence for the Clinical Use of Stem Cell-based Therapy in the Treatment of Osteoarthritis of the Knee?

CORR Synthesis: What Is the Evidence for the Clinical Use of Stem Cell-based Therapy in the Treatment of Osteoarthritis of the Knee?

Timing of Intra-Articular Injection of Synovial Mesenchymal Stem Cells Affects Cartilage Restoration in a Partial Thickness Cartilage Defect Model in Rats

We investigated the effect of administration of intra-articular mesenchymal stem cells (MSCs) on cartilage repair at different timings, and the distribution of MSCs in the knee. A partial thickness cartilage defect (PTCD) was created on the medial femoral condyle in 14-week-old Sprague-Dawley rats. Intra-articular injection of 1 × 106 MSCs was performed at 3 time points, namely at the time of surgery (0w group), at 1 week after surgery (1w group), and at 2 weeks after surgery (2w group). For the control, 50 μL phosphate-buffered saline was injected at the time of surgery. The femoral condyles were collected at 6 weeks after creation of PTCD and assessed histologically. To investigate the distribution of MSCs, fluorescent-labeled MSCs were injected into the knee joint. In the control group, the cartilage lesion was distinguishable from surrounding cartilage. In the 0w group, hypocellularity and a slight decrease in safranin O stainability were observed around the injured area, but cartilage was restored to a nearly normal condition. In contrast, in the 1w and 2w groups, the cartilage surface was irregular and safranin O stainability in the injured and surrounding areas was poor. Histological score in the 0w group was significantly better than in the control, 1w, and 2w groups. At 1 day postinjection, fluorescent-labeled MSCs were mostly distributed in synovium. However, no migration into the PTCD was observed. Early intra-articular injection of MSCs was effective in enhancing cartilage healing in a rat PTCD model. Injected MSCs were distributed in synovium, not in cartilage surrounding the PTCD.

Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model.

Persistent inflammation is well known to promote the progression of arthropathy. mesenchymal stem cells (MSCs) have been shown to possess anti-inflammatory properties and tissue differentiation potency. Although the experience so far with the intraarticular administration of mesenchymal stem cell (MSC) to induce cartilage regeneration has been disappointing, MSC implantation is now being attempted using various surgical techniques. Meanwhile, prevention of osteoarthritis (OA) progression and pain control remain important components of the treatment of early-stage OA. We prepared a shoulder arthritis model by injecting monoiodoacetate (MIA) into a rat shoulder, and then investigated the intraarticular administration of MSC from the aspects of the cartilage protective effect associated with their anti-inflammatory property and inhibitory effect on central sensitization of pain. When MIA was administered in this rat shoulder arthritis model, anti-Calcitonin Gene Related Peptide (CGRP) was expressed in the joint and C5 spinal dorsal horn. Moreover, expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a marker of joint cartilage injury, was similarly elevated following MIA administration. When MSC were injected intraarticularly after MIA, the expression of CGRP in the spinal dorsal horn was significantly deceased, indicating suppression of the central sensitization of pain. The expression of ADAMTS 5 in joint cartilage was also significantly inhibited by MSC administration. In contrast, a significant increase in the expression of TNF-α stimulated gene/protein 6 (TSG-6), an anti-inflammatory and cartilage protective factor shown to be produced and secreted by MSC intraarticularly, was found to extend to the cartilage tissue following MSC administration. In this way, the intraarticular injection of MSC inhibited the central sensitization of pain and increased the expression of the anti-inflammatory and cartilage protective factor TSG-6. As the least invasive conservative strategies possible are desirable in the actual clinical setting, the intraarticular administration of MSC, which appears to be effective for the treatment of pain and cartilage protection in early-stage arthritis, may achieve these aims.

Are We Right to Consider Mesenchymal Stem Cells to Be a New Perspective for Patients with Juvenile Idiopathic Arthritis?

Juvenile idiopathic arthritis (JIA) is the most common cause of chronic arthritis in childhood. Up to 50% of patients are resistant to standard therapy, which includes non-steroid anti-inflammatory drugs, corticosteroids, disease-modifying anti-rheumatic drugs and biologic therapies. Intra-articular injection of mesenchymal stem cells (MSCs) is proposed as a new approach to JIA treatment. MSCs can modulate inflammation via mechanisms of both adaptive and innate immune response. They are able to inhibit T and B cell proliferation, promote regulatory T cells, suppress the maturation of dendritic cells, stimulate macrophage differentiation into M2 phenotype and reduce effectiveness of natural killer cells. They also secrete plethora of soluble factors which influence joint inflammation. Recent clinical studies reviewed in the article provide promising results which may suggest including intra-articular injection of MSCs in therapy of patients with oligoarticular JIA.

Intra-articular Injection of Mesenchymal Stem Cells and Platelet-Rich Plasma to Treat Patellofemoral Osteoarthritis: Preliminary Results of a Long-Term Pilot Study

PurposeTo assess the feasibility and safety of concomitant intra-articular (IA) knee injection of mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) under fluoroscopic guidance to treat patellofemoral osteoarthritis (OA). Materials and MethodsThis prospective study included 19 consecutive patients referred for fluoroscopically guided IA MSC and PRP injection for symptomatic patellofemoral chondropathy in which conservative treatment had failed. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and magnetic resonance (MR) data, including T2 mapping sequence, were prospectively collected before and 6 months after treatment. Clinical data without MR imaging were collected until 12 months after the procedure. ResultsWOMAC scores were significantly lower after IA injection of MSCs and PRP at 6 months and during 12-months follow-up compared with baseline (mean score decreased from 34.3 to 14.2; P < .0018). Patients reported no complications. Concerning MR imaging follow-up, there were no significant differences in grade, surface, or T2 value of the chondral lesions (P > .375). ConclusionsIA injection of MSCs and PRP in early patellofemoral OA appears to allow functional improvement.

Role of Mesenchymal Stem Cells Densities When Injected as Suspension in Joints with Osteochondral Defects.

The aim of this study was to evaluate an intraarticular injection of different doses of autologous mesenchymal stem cells (MSCs) for improving repair of midterm osteochondral defect. At 4 weeks postoperative marrow stimulation model bilaterally (3 mm diameter; 4 mm depth) in the medial femoral condyle, autologous MSCs were injected into knee joint. Twenty-four Japanese rabbits aged 6 months were divided randomly into 4 groups ( n = 6 per group): the control group and and MSC groups including 0.125, 1.25, and 6.25 million MSCs. Repaired tissue was assessed macroscopically and histologically at 4 and 12 weeks after intraarticular injection of MSCs. At 12 weeks, there was no repair tissue in the control group. The gross appearance of the 1.25 and 6.25 million MSC groups revealed complete repair of the defect with white to pink tissue at 12 weeks. An osteochondral repair was histologically significantly better in the 1.25 and 6.25 million MSC groups than in the control and 0.125 million MSC groups at 4 and 12 weeks, due to presence of hyaline-like tissue in the deep layer at 4 weeks, and at 12 weeks hyaline cartilage formation at the periphery and fibrous tissue containing some chondrocytes in the deep layer of the center of the defect. Subchondral bone was restructured in the 1.25 and 6.25 million MSC groups, although it did not resemble the normal bone. An intraarticular injection of 1.25 or 6.25 million MSCs could promote the repair of subchondral bone, even in the case of midterm osteochondral defect.

Pre-Treatment of Human Mesenchymal Stem Cells With Inflammatory Factors or Hypoxia Does Not Influence Migration to Osteoarthritic Cartilage and Synovium

Background: Mesenchymal stem cells (MSCs) are promising candidates as a cell-based therapy for osteoarthritis (OA), although current results are modest. Pre-treatment of MSCs before application might improve their therapeutic efficacy. Hypothesis: Pre-treatment of MSCs with inflammatory factors or hypoxia will improve their migration and adhesion capacities toward OA-affected tissues. Study Design: Controlled laboratory study. Methods: We used real-time polymerase chain reaction to determine the effects of different fetal calf serum (FCS) batches, platelet lysate (PL), hypoxia, inflammatory factors, factors secreted by OA tissues, and OA synovial fluid (SF) on the expression of 12 genes encoding chemokine or adhesion receptors. Migration of MSCs toward factors secreted by OA tissues was studied in vitro, and attachment of injected MSCs was evaluated in vivo in healthy and OA knees of male Wistar rats. Results: Different FCS batches, PL, or hypoxia did not influence the expression of the migration and adhesion receptor genes. Exposure to inflammatory factors altered the expression of CCR1, CCR4, CD44, PDGFRα, and PDGFRβ. MSCs migrated toward factors secreted by OA tissues in vitro. Neither pre-treatment with inflammatory factors nor the presence of OA influenced MSC migration in vitro or adhesion in vivo. Conclusion: Factors secreted by OA tissues increase MSC migration in vitro. In vivo, no difference in MSC adhesion was found between OA and healthy knees. Pre-treatment with inflammatory factors influenced the expression of migration and adhesion receptors of MSCs but not their migration in vitro or adhesion in vivo. Clinical Relevance: To improve the therapeutic capacity of intra-articular injection of MSCs, they need to remain intra-articular for a longer period of time. Pre-treatment of MSCs with hypoxia or inflammatory factors did not increase the migration or adhesion capacity of MSCs and will therefore not likely prolong their intra-articular longevity. Alternative approaches to prolong the intra-articular presence of MSCs should be developed to increase the therapeutic effect of MSCs in OA.

Intra-articular Implantation of Mesenchymal Stem Cells, Part 2: A Review of the Literature for Meniscal Regeneration.

Knee osteoarthritis (OA) after partial or total meniscectomy is a prevalent issue that patients must face. Various methods of replacing meniscal tissue have been studied to avoid this progression, including meniscal allograft transplantation, meniscal scaffolds, and synthetic meniscus replacement. Studies have shown that meniscal scaffolds may improve symptoms but have not been shown to prevent progression of OA. Recently, mesenchymal stem cells (MSCs) have been proposed as a possible biological therapy for meniscal regeneration. Several animal studies and 1 human study have evaluated the effect of transplanting MSCs into the knee joint after partial meniscectomy. The purpose of this review was to assess the outcomes of intra-articular transplantation of MSCs on meniscal regeneration in animals and humans after partial meniscectomy. Limited results from animal studies suggest that there is some potential for intra-articular injection of MSCs for the regeneration of meniscal tissue. However, further studies are necessary to determine the quality of regenerated meniscal tissue through histological and biomechanical testing.

Regenerative potential of the cartilaginous tissue in mesenchymal stem cells: update, limitations, and challenges

Advances in the studies with adult mesenchymal stem cells (MSCs) have turned tissue regenerative therapy into a promising tool in many areas of medicine. In orthopedics, one of the main challenges has been the regeneration of cartilage tissue, mainly in diarthroses. In the induction of the MSCs, in addition to cytodifferentiation, the microenvironmental context of the tissue to be regenerated and an appropriate spatial arrangement are extremely important factors. Furthermore, it is known that MSC differentiation is fundamentally determined by mechanisms such as cell proliferation (mitosis), biochemical-molecular interactions, movement, cell adhesion, and apoptosis. Although the use of MSCs for cartilage regeneration remains at a research level, there are important questions to be resolved in order to make this therapy efficient and safe. It is known, for instance, that the expansion of chondrocytes in cultivation, needed to increase the number of cells, could end up producing fibrocartilage instead of hyaline cartilage. However, the latest results are promising. In 2014, the first stage I/II clinical trial to evaluate the efficacy and safety of the intra-articular injection of MSCs in femorotibial cartilage regeneration was published, indicating a decrease in injured areas. One issue to be explored is how many modifications in the articulate inflammatory environment could induce differentiation of MSCs already allocated in that region. Such issue arose from studies that suggested that the suppression of the inflammation may increase the efficiency of tissue regeneration. Considering the complexity of the events related to the chondrogenesis and cartilage repair, it can be concluded that the road ahead is still long, and that further studies are needed.

Intra-articular Injection of platelet-rich fibrin releasates in combination with bone marrow-derived mesenchymal stem cells in the treatment of articular cartilage defects: An in vivo study in rabbits.

The use of mesenchymal stem cells (MSCs), which can be differentiated into chondrocytes under specific conditions, has been proposed for the treatment of cartilage defects. Blood-derived platelet-rich fibrin releasate (PRFr), which is rich in growth factors and cytokines, may improve cartilage regeneration. In this study, the therapeutic effects of PRFr in combination with bone marrow-derived MSCs for articular cartilage regeneration were evaluated in a rabbit model. Critical osteochondral defects were surgically created in the femoral condyle of the rabbits, and 3 × 106 of MSCs, 0.8 mL of PRFr, or a combination of MSCs and PRFr were injected intra-articularly and one week after first administration. The animals were sacrificed 12 weeks postoperatively, and the regenerated cartilages were assessed by gross inspection and histological examination. No treatment-related adverse events were noted in any of the rabbits. The size of the defect decreased and the volume of regenerated cartilage increased in the medial femoral condyles of the MSCs + PRFr group. Relative to the MSCs or PRFr group, histological examination demonstrated that the MSCs + PRFr group had thicker hyaline-like cartilaginous tissue with normal glycosaminoglycan production. Grading scores revealed that MSCs + PRFr injection had better matrix, cell distribution, and surface indices than other groups. The results showed that intra-articular injections of MSCs + PRFr into the knee can reduce cartilage defects by regenerating hyaline-like cartilage without adverse events. This approach may provide an alternative method of autologous chondrocyte implantation to repair cartilage defects with an unlimited source of cells and releasate. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1536-1543, 2017.