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Abstract

Osteoarthritis (OA) is the prevailing manifestation of degenerative arthritis and is primarily characterized by the erosion of articular cartilage and its association with subchondral bone. This condition poses a significant burden on healthcare systems globally. Mesenchymal stem cells (MSCs), which originate from the mesoderm, have the capacity to differentiate into cells of mesodermal lineage tissues, suggesting their potential for treating ailments such as OA. MSCs can modulate immune responses and positively impact the microenvironment of diseased tissues by interacting directly with cells or secreting various factors. These actions can trigger inherent regenerative processes within the OA joint. The utilization of targeted gene-modified MSC-based therapy, facilitated by engineered constructs from cell-seeded scaffolds, holds promise for augmenting cartilage regeneration in OA. Nevertheless, the administration of intra-articular MSC transplantation sans scaffolds has emerged as a more promising option for OA treatment. This paper consolidates the present understanding of MSC-based therapy for OA prevention or treatment, particularly focusing on direct intra-articular MSC injection for OA management. MSCs possess distinctive immunomodulatory and regenerative attributes, rendering them an appealing therapeutic avenue for alleviating cartilage damage and mitigating pain. The objective of this review is to provide a comprehensive overview of the current advancements and prospective avenues in MSC therapy for knee OA.

Keywords

Osteoarthritis, Mesenchymal stem cells (MSCs), Gene-modified MSCs, Intra-articular injection.

Introduction

Osteoarthritis is typified by the progressive deterioration of the cartilage enveloping the knee joints, along with the surfaces of subchondral bone and synovium. This process is accompanied by pain, reduced mobility, muscle stiffness, and diminished function, impacting the ability to perform daily activities. The joints most commonly affected are those in the fingers, neck, base of the thumbs, lower back, and hips. With the global population experiencing a rapid increase in the number of elderly individuals, osteoarthritis has emerged as a significant public health challenge. As the aging population grows, osteoarthritis is receiving increasing attention as a pressing health concern. A considerable portion of people over the age of 60 will experience some form of osteoarthritis. In response to this challenge, a variety of pharmacological agents have been developed to either prevent or alleviate short-term pain and decelerate the progression of physical deterioration associated with osteoarthritis. Recent progress in pharmaceutical drug discovery has unveiled new chemical entities that hold promise as disease-modifying osteoarthritis drugs. However, securing regulatory approval for such medications necessitates fulfilling specific clinical development criteria outlined by both European and US regulatory frameworks. To qualify as a disease-modifying osteoarthritis drug, a new chemical entity must demonstrate its capacity to impede the physical progression of the disease, as assessed by joint space narrowing (JSN) via plain X-ray assessments. Obesity is a major risk factor for osteoarthritis. Individuals who are overweight, have legs of different lengths, or engage in certain occupations face a greater risk of developing osteoarthritis due to increased stress on their joints. Managing and averting the onset of osteoarthritis hinges significantly on addressing these risk factors [1].

Osteoarthritis can be broadly classified into two main categories:

Primary Osteoarthritis: This type of osteoarthritis is also referred to as idiopathic osteoarthritis. It is the most common form and often occurs without any specific underlying cause. Primary osteoarthritis typically affects multiple joints, including the fingers, thumbs, spine, hips, knees, and toes. It can also manifest in a generalized manner, affecting various joints throughout the body.

Secondary Osteoarthritis: This type occurs as a consequence of preexisting joint abnormalities or underlying conditions. Various factors can lead to secondary osteoarthritis, such as joint injuries, trauma, or repetitive stress on the joints, often related to sports or occupation. Inflammatory conditions such as psoriatic arthritis, rheumatoid arthritis, and gout can also contribute to the development of secondary osteoarthritis. Other factors include joint infections and genetic joint disorders [1].

Pathophysiology of Osteoarthritis

Articular Cartilage Degeneration: Articular cartilage coats the ends of bones within joints, furnishing a sleek surface that facilitates smooth, frictionless movement. In OA, mechanical stresses and wear and tear cause disruptions to the delicate structure of the cartilage. Chondrocytes, specialized cells within cartilage, are crucial for maintaining cartilage health. However, in OA, these cells undergo functional changes. These cells secrete increased levels of enzymes such as matrix metalloproteinases (MMPs) and aggrecanases, which participate in the degradation of the extracellular matrix, a complex mixture of collagen fibers and proteoglycans. This degradation undermines the structural integrity of the cartilage, resulting in fissures, roughness, and eventual loss of protective cushioning [2].

Synovial Inflammation: The synovium, a delicate tissue layer lining the joint capsule, is important for maintaining joint health. In osteoarthritis (OA), inflammation occurs within the synovium owing to the release of proinflammatory molecules, including cytokines such as interleukin-1? and tumor necrosis factor-?. These molecules provoke an immune response, drawing immune cells such as macrophages and lymphocytes into the joint space. The influx of these cells exacerbates the inflammatory environment, leading to the secretion of more inflammatory mediators. This ongoing inflammation contributes to the degradation of cartilage and further compromises joint function [3].

Subchondral Bone Changes: Below the cartilage lies the subchondral bone, which serves to provide structural support to the joint. In OA, the subchondral bone undergoes alterations due to the increased mechanical load placed on the joint and microfractures that occur over time. The bone responds by attempting to repair these microfractures, leading to changes in bone density and the formation of osteophytes (bone spurs) at the joint's edges. These osteophytes can further irritate surrounding tissues, contributing to pain and inflammation. Additionally, altered bone remodelling releases growth factors that can stimulate synovial inflammation and accelerate the cartilage degradation process [4].

       
            Fig. 1 Synovial Joint.png
       
 Fig. 1 Synovial Joint

The pathophysiology of osteoarthritis involves a multifaceted interplay of articular cartilage degeneration, synovial inflammation, and alterations in subchondral bone. Mechanical stresses, genetic predispositions, and various other factors collectively contribute to the onset and progression of this condition. Grasping the underlying mechanisms offers valuable insights into potential targets for therapeutic intervention, with the objective of mitigating pain, decelerating disease progression, and enhancing the quality of life for individuals affected by osteoarthritis.

Mesenchymal stem cell (MSC) therapy

Mesenchymal stem cell (MSC) therapy has garnered substantial attention in recent years. These adaptable cells can be sourced from various locations, with bone marrow being the primary source for their extraction. In addition to bone marrow, MSCs have been identified in numerous other tissues, including the periosteum, trabecular bone, adipose tissue, synovium, skeletal muscle, tendon, lung, and deciduous teeth. [5-6].

One area of interest in MSC research is the investigation of their relationship with pericytes, as they exhibit parallel behaviour and potential both in vivo and in vitro [7-8]. Studies have suggested the existence of a perivascular niche for MSCs [9-10], and in vitro studies have established that pericytes in human tissues express MSC markers [9]. However, Kurth et al. [11] reported distinct phenotypic and functional differences between MSCs isolated from the synovium and pericytes in vivo. Overall, MSCs indeed hold immense promise for therapeutic applications owing to their abundance and versatile potential across various tissues. Understanding their relationship with pericytes and exploring the perivascular niche further can provide valuable insights for enhancing MSC-based therapies.

Isolation and characterization of MSCs

The isolation and characterization of mesenchymal stem cells (MSCs) represent significant milestones in the field of regenerative medicine. The pioneering work in this area was conducted by Alexander Friedenstein and his colleagues [12-13]. Researchers have successfully isolated fibroblastic cells from the stromal compartment of the bone marrow, demonstrating their ability to differentiate into bone tissue and bone marrow stroma in vivo. Initially, termed stromal progenitor cells, these fibroblastic cells were subsequently referred to as stromal stem cells [12-13]. After this ground-breaking discovery, MSCs were subsequently isolated from various other tissues [14]. These include adipose tissue [15], skeletal muscle, umbilical cord blood [16], and Wharton's jelly [17]. As progenitors of the mesoderm lineage, MSCs demonstrate remarkable multilineage differentiation potential, enabling them to differentiate into bone, fat, cartilage, and muscle cells in vitro [14]. To establish standardized criteria for MSC classification, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy has proposed specific guidelines [18]. These criteria encompass the following features: fibroblast-like morphology; plastic adherence under standard culture conditions; in vitro differentiation potential into osteoblasts, adipocytes, and chondroblasts; expression of surface markers such as CD105, CD73, and CD90; and the absence of expression of markers such as CD45, CD34, CD14 or CD11b, CD79a or CD19, and the human leukocyte antigen DR.

Differentiation potential of MSCs

The remarkable differentiation potential of these cells allows them to give rise to various lineages of mesodermal tissues. The differentiation capacities of MSCs include bone, cartilage, fat, muscle, tendon/ligament, bone marrow stroma, dermis, and other connective tissues. Osteogenic differentiation of MSCs typically involves the addition of specific factors such as ?-glycerophosphate, ascorbic acid-2-phosphate, dexamethasone, and fetal bovine serum. Successful osteogenic differentiation can be assessed by the upregulation of alkaline phosphatase activity and the deposition of a calcium-rich mineralized extracellular matrix, which can be detected using staining methods such as alizarin red. Adipogenic differentiation of MSCs requires the involvement of various factors, including nuclear receptors, transcription factors (e.g., peroxisome proliferator-activated receptor-g), and fatty acid synthetase. The resulting adipocytes can be identified by their distinct morphology characterized by large lipid-filled vacuoles and staining with oil red O. MSCs can also differentiate into other cell types, such as myocytes and neurons. Immunocytochemistry using specific antibodies against cell type-specific antigens is typically employed to identify these differentiated cells [19-20]. Chondrogenic differentiation of MSCs occurs when they are cultured in serum-free nutrient medium under three-dimensional culture conditions supplemented with a member of the transforming growth factor (TGF)-? superfamily. Chondrogenically differentiated cells exhibit characteristic markers specific to cartilage, including collagen type II, aggrecan, and sulphated proteoglycans. Previous studies on MSC chondrogenesis have utilized high-density micro mass cultures or pellet cultures to promote cellular condensation [21-22]. A method developed by Caplan and colleagues involves pellet or aggregate culture for chondrogenic differentiation of both animal and human MSCs [23-24]. Subsequent studies have indicated that human marrow-derived MSCs can form chondrocytes with the addition of TGF-? to the growth medium, whereas human adipose-derived MSCs require TGF-? and bone morphogenetic protein for efficient chondrogenesis [25-26].  The potential of MSCs to differentiate into these various lineages holds significant promise for regenerative medicine and tissue engineering applications, as they provide a valuable source of cells for repairing and regenerating damaged or diseased tissues.

       
            Differentiation of mesenchymal stem cells.png
       
   Fig. 2 Differentiation of mesenchymal stem cells

Characteristics and properties of mesenchymal stem cells (MSCs)

Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, can be isolated from various adult or neonatal tissues, with bone marrow, fat tissue, dental pulp, placenta, and umbilical cord being common sources. They are characterized by their fibroblastic shape and specific immunophenotype, which includes the expression of markers such as CD73, CD90, and CD105 but lack the expression of markers such as CD11b, CD14, CD34, CD45, and HLA-DR. MSCs possess remarkable trilineage differentiation potential, as they can differentiate into bone, cartilage, and adipose tissue [27]. In the bone marrow, endogenous MSCs have been suggested to reside in a perisinusoidal location and may be marked by a nest-in or leptin receptor in mice, while CD146 has been identified as a marker for human MSCs. However, it should be noted that perisinusoidal cells do not fully exhibit all the properties of MSCs, indicating the potential existence of another skeletal stem cell population. Recent studies have identified endogenous mouse skeletal stem cells (SSCs), such as osteochondral reticular stem cells, based on Gremlin 1 expression and a subpopulation of stem cells capable of generating bone, cartilage, and stromal tissue [28-33]. MSCs exert their functions through the secretion of various factors. These cells produce growth factors such as transforming growth factor (TGF)-?, hepatocyte growth factor (HGF), basic fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF), which stimulate proliferation and angiogenesis in different cell types, including fibroblasts, epithelial cells, and endothelial cells. MSCs also possess the ability to rescue cells from apoptosis induced by trauma, oxidative stress, radiation, or chemical injury. Key proteins such as insulin-like growth factor (IGF)-1, interleukin (IL)-6, stanniocalcin-1, VEGF, HGF, and TGF-?1 have been implicated in the reversal of fibroblast apoptosis and protection of endothelial cells from apoptosis [34-35]. MSCs have demonstrated antifibrotic effects in vitro and in various preclinical models of fibrosis. While some discussions have raised the possibility that MSCs exert profibrotic effects, there is currently no evidence in the literature showing that MSC transplantation induces fibrosis in either developing or established diseases. Furthermore, MSCs have been shown to have a protective effect on scar tissue formation [27]. These characteristics and properties of MSCs highlight their potential therapeutic applications, as they can promote tissue regeneration, angiogenesis, and antifibrotic effects. Further research is needed to fully understand the mechanisms underlying these functions and to optimize their clinical utilization.

The molecular mechanisms associated with the therapeutic effect of MSCs in OA

The therapeutic efficacy of mesenchymal stem cells (MSCs) in osteoarthritis (OA) involves multiple molecular mechanisms that aid in cartilage repair and preservation. The use of MSCs in stem cell therapies for cartilage regeneration has been extensively studied [28,29,30]. MSCs are commonly employed in tissue engineering strategies, where they can be combined with a scaffold and implanted into cartilage lesions. Clinical evidence indicates that MSCs are effective at treating traumatic injuries in chondral and osteochondral cartilage defects. Nonetheless, there is a paucity of research on the application of MSC-based tissue engineering approaches in the OA [31]. In this study, focusing on knee OA patients, comparable clinical outcomes were observed between patients receiving MSCs and those receiving cell-free scaffolds. However, the group receiving MSCs demonstrated better arthroscopic and histological scores [29]. Nevertheless, further evidence is needed to establish whether MSCs are superior to chondrocytes. Alternatively, a simpler and more direct approach could involve the injection of MSCs without the use of a scaffold [36-37]. MSCs have also been investigated as cell therapy products that release paracrine factors upon local or systemic injection [28]. Through the secretion of these factors, MSCs can potentially stimulate endogenous regeneration and proliferation of tissue progenitors, counteract apoptosis, and protect cartilage. Several studies have highlighted the stimulatory impact of MSCs on chondrocyte proliferation. Coculturing bone marrow- or synovium-derived MSCs with chondrocytes has been demonstrated to enhance chondrocyte proliferation [38-39]. In a coculture model utilizing human osteoarthritis (OA) chondrocytes and adipose-derived MSCs (ASCs), a decrease in the expression of hypertrophic, fibrotic, and inflammatory markers was observed [40]. The antifibrotic effect was predominantly linked to the secretion of hepatocyte growth factor (HGF) by ASCs [41]. Additionally, ASCs exhibited minimal levels of proinflammatory cytokines and chemokines, yet they notably diminished the secretion of interleukin (IL)-6, IL-8, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1? by both chondrocytes and synoviocytes. [42].

These findings suggest that MSCs exert their therapeutic effects on OA through paracrine signalling and modulation of the local inflammatory environment. The secretion of factors such as HGF by MSCs can promote chondrocyte proliferation and reduce the expression of hypertrophic, fibrotic, and inflammatory markers. Furthermore, MSCs can inhibit the secretion of proinflammatory cytokines and chemokines by chondrocytes and synoviocytes. These molecular mechanisms contribute to cartilage repair, protection, and overall improvement in OA pathology.

Gene-modified mesenchymal stem cells for cartilage repair in osteoarthritis

The application of gene-modified mesenchymal stem cells (MSCs) holds promise for cartilage repair in osteoarthritis (OA) patients. By transducing MSCs with genes that encode specific therapeutic proteins, it is possible to address some of the major pathologies associated with OA [43]. Genetically modified MSCs can be delivered as a cell suspension to affected joints, where they can counteract inflammation and matrix degradation processes. These transduced MSCs can then release therapeutic proteins that interact with injured cartilage tissue, promoting repair [42]. Furthermore, MSCs can also modulate the local environment and activate endogenous progenitor cells, contributing to tissue repair [45].

Several studies have investigated the use of intra-articular injections of genetically modified MSCs for cartilage repair in OA. Three relevant examples are as follows:

  • In a sheep model of OA, retrovirally modified bone marrow-derived MSCs were transplanted, leading to the retardation of cartilage destruction. However, transfection was used to trace the implanted MSCs rather than for therapeutic purposes [46-47].
  • Injection of bone marrow-derived MSCs transfected with Bcl-xL, an antiapoptotic protein, enhanced the regeneration of cartilage defects in rabbits. Bcl-xL expression improved the survival and implantation efficiency of MSCs [48-49].
  • In an immunodeficient rat model of osteoarthritis (OA), intra-articular injection of murine muscle-derived MSCs expressing bone morphogenetic protein (BMP)-4 in conjunction with MSCs expressing the vascular endothelial growth factor antagonist soluble Flt-1 (sFlt-1) led to enhancements in the quality and longevity of regenerated articular cartilage [50-53].

Additionally, the transduction of differentiated cells to produce therapeutic factors such as transforming growth factor (TGF)-? and interleukin-1 receptor antagonists has shown promising results in patients affected by cartilage disorders [54-55]. These studies demonstrate the potential of using gene-modified MSCs for cartilage repair in OA. By delivering specific therapeutic genes to MSCs, it is possible to enhance their regenerative capabilities and provide targeted treatment for the pathologies associated with OA. However, further research and clinical studies are necessary to fully explore the safety and efficacy of this approach in human patients.

Use of MSCs seeded on scaffolds for articular cartilage repair

Mesenchymal stem cells (MSCs) seeded onto three-dimensional (3D) scaffolds have shown promise for articular cartilage repair. MSCs can serve as progenitors or regenerative cells for cartilage and can be differentiated into chondrocytes in vitro, resembling the characteristics of hyaline cartilage. However, there are challenges associated with MSC differentiation, including differences in differentiation capacity depending on the cell source, the potential for hypertrophy during differentiation, and difficulties in maintaining the phenotypic stability of mature chondrocytes [56-60]. Connective tissue growth is crucial for cartilage repair, and MSC-seeded scaffolds have been used to repair small-area cartilage defects. However, these methods have limitations in addressing larger cartilage defects associated with osteoarthritis (OA). Various scaffolds, such as polylactic-co-glycolic acid, polyethylene glycol, polylactic acid, polyglycolic acid, collagen, gelatin, hyaluronic acid (HA), and fibrin, have been investigated for use in articular cartilage implantation [61-65]. Although studies have demonstrated the safety and efficacy of MSC-based tissue engineering approaches, these methods have not yet become routine treatments in clinical practice. One challenge in utilizing scaffolds is the bidirectional effects of growth factors on chondrogenic and osteogenic differentiation. Different levels of growth factors can influence the promotion of both chondrogenic and osteogenic differentiation. Therefore, finding ways to minimize osteogenic differentiation in the newly formed cartilage area while maximizing chondrogenic differentiation ability is important. The effectiveness of MSC-seeded scaffolds in larger groups of OA patients before they can be implemented on a larger scale in clinical practice. Continued research and optimization of scaffold materials, growth factor formulations, and differentiation protocols are required to enhance the efficacy and long-term stability of MSC-based tissue engineering approaches for articular cartilage repair in OA patients.

       
            Implanting host cells into biomaterial scaffolds.png
       
Fig. No. 3 Implanting host cells into biomaterial scaffolds

The therapeutic MSC exosomes

In recent years, researchers have recognized the potential therapeutic role of exosomes secreted by mesenchymal stem cells (MSCs) in the treatment of osteoarthritis (OA) [66-71]. Exosomes are small vesicles involved in intercellular communication that are capable of transferring lipids, nucleic acids (mRNAs and microRNAs), and proteins between cells, thereby eliciting biological responses in recipient cells [72-75]. MSC exosomes are rich in microRNAs, which can specifically bind to the transcribed mRNAs of target genes, leading to the silencing of these genes or the formation of a signalling network involving multiple targets [71-73]. MicroRNAs are believed to play a crucial role in mediating the therapeutic efficacy of MSC-derived exosomes in the treatment of OA [76].

Studies have shown that exosomes derived from human synovial MSCs overexpressing microRNA-140-5p can promote cartilage regeneration and suppress OA in rat models, indicating the protective role of microRNA-140 in OA pathogenesis. MicroRNA-140 can upregulate the expression of SOX9 and aggrecan (ACAN), maintaining cartilage homeostasis and preventing and alleviating OA [77]. MSC exosomes also contain extracellular matrix (ECM) proteins and enzymes, which play a role in regulating and restoring the ECM balance. The activity of these enzymes is correlated with the loss of normal equilibrium. Exosome-associated enzymes promote tissue repair and regeneration by restoring homeostasis during injury and disease. Once homeostasis is restored and injury subsides, the activity of exosome enzymes ceases [78-80].

MSC-derived exosomes have great potential for the treatment of OA due to their tolerance, minimal risk of immunogenicity, and toxicity. However, there are challenges that need to be addressed. These include the large-scale purification of exosomes, improving their utilization efficiency, exploring their biosafety, and enhancing their therapeutic efficacy.

Local intra-articular injection of MSCs and mixed injections

In recent years, the local intra-articular injection of mesenchymal stem cells (MSCs) has emerged as a promising approach for promoting cartilage tissue regeneration and alleviating degeneration associated with osteoarthritis (OA). MSCs exert their therapeutic effects by improving the local microenvironment, regulating the immune response, and exerting anti-inflammatory effects through the secretion of various bioactive molecules, including exosomes, growth factors, cytokines, and anti-inflammatory factors. This method has become increasingly recognized as a simple and convenient approach for OA treatment [67-68]. For instance, Zhou et al. demonstrated that local intra-articular injection of adipose-derived MSCs (AD-MSCs) effectively alleviated OA in a rat model by inducing autophagy, which led to a reduction in the secretion of proinflammatory cytokines [81]. Another study by Toghraie et al. utilized a rabbit model of OA induced by anterior cruciate ligament resection. In this study, the combination of hyaluronic acid (HA) with MSCs effectively repaired damaged cartilage. The mechanism underlying this therapeutic effect may involve the suppression of the inflammatory response and chondrocyte apoptosis [82]. These studies highlight the potential of local intra-articular injection of MSCs for the treatment of OA. MSCs can modulate the local microenvironment, reduce inflammation, and promote cartilage repair. When combined with substances such as HA, they can enhance therapeutic outcomes by providing additional benefits, such as suppressing inflammation and supporting chondrocyte survival. Further research is needed to optimize the treatment protocols, determine the optimal dosage and frequency of MSC injections, and evaluate the long-term efficacy and safety of this approach. However, local intra-articular injection of MSCs holds promise as a relatively simple and minimally invasive strategy for OA treatment, offering potential benefits to patients in terms of cartilage regeneration and pain relief.

Preclinical studies on MSC therapy for knee OA

Overview of Animal Models Used in Preclinical Studies

Preclinical studies on mesenchymal stem cell (MSC) therapy for knee osteoarthritis (OA) often utilize animal models to investigate the potential efficacy and safety of this regenerative approach. Various animal models have been used to mimic the pathological features of human knee OA and assess the therapeutic effects of MSCs. Commonly used animal models include [83].

Surgically Induced OA Models: These models involve surgical interventions, such as destabilization of the medial meniscus (DMM) or anterior cruciate ligament transection (ACLT), to induce joint instability and cartilage degeneration, similar to human OA.

Chemical-Induced OA Models: In these models, chemical agents, such as monosodium iodoacetate (MIA) or papain, are injected into the joint to induce cartilage degradation and OA-like changes.

Spontaneous OA models: Certain animal strains, such as STR/ort mice and Dunkin Hartley guinea pigs, naturally develop OA-like changes with age and are used to study the progression of OA and the potential therapeutic effects of MSCs. Summary of Key Findings from Preclinical Research Preclinical studies investigating MSC therapy for knee OA have reported promising results. The key findings include:

Cartilage Repair and Regeneration: MSC therapy has demonstrated the potential to promote cartilage repair and regeneration in animal models of knee OA. MSCs have been shown to differentiate into chondrocyte-like cells, contributing to the formation of new cartilage tissue and improving overall joint structure.

Anti-Inflammatory Effects: MSCs exert potent anti-inflammatory effects in preclinical models of knee OA. They can modulate the immune response, leading to reduced inflammation in the joint microenvironment. This anti-inflammatory action helps mitigate the progressive destruction of cartilage in OA.

Pain reduction: Preclinical studies have suggested that MSC therapy can alleviate pain associated with knee OA. The anti-inflammatory properties of MSCs, along with their ability to promote tissue repair, contribute to pain relief in OA animal models.

Joint function improvement: MSC therapy has been associated with improvements in joint function and mobility in preclinical studies. The regeneration of damaged cartilage and the suppression of inflammation contribute to the restoration of joint functionality [82].

Evaluation of the efficacy and safety of MSC therapy in preclinical settings

The efficacy and safety of MSC therapy in preclinical settings are crucial aspects to consider before these findings can be translated to clinical trials. Preclinical studies have provided evidence of the potential therapeutic benefits of MSCs for treating knee OA, but several considerations must be addressed:

Long-Term Effects: Assessing the long-term effects of MSC therapy in animal models is essential for determining the durability and sustainability of the observed therapeutic benefits. Immune Response: Understanding the immune response to MSCs in preclinical models is vital to ensure that the treatment does not elicit adverse reactions, such as immune rejection. Dosage and Administration: Optimizing the dosage and route of MSC administration is critical for achieving the desired therapeutic effects while minimizing potential risks.

Safety Monitoring: Rigorous safety monitoring in preclinical studies is necessary to identify any potential adverse effects associated with MSC therapy [83-84]. Preclinical studies on MSC therapy for knee OA have shown promising results, with evidence of cartilage repair, pain reduction, and improved joint function. However, further research is needed to fully understand the mechanisms involved and to address safety considerations before advancing to human clinical trials.

Clinical Trials Evaluating MSC Therapy for Knee OA

Overview of Clinical Trial Design and Methodology

Clinical trials evaluating mesenchymal stem cell (MSC) therapy for knee osteoarthritis (OA) follow a structured design and methodology to assess the safety and efficacy of the treatment. The design of such trials typically includes the following components:

Study Population: Participants were recruited based on specific inclusion and exclusion criteria, ensuring that they met the necessary demographic and clinical characteristics. Randomization: Patients were randomly assigned to treatment and control groups to minimize bias and confounding factors.

Intervention: The treatment group received MSC therapy, while the control group usually received a placebo or standard-of-care treatment.

Follow-up Duration: Clinical trials have predefined follow-up periods during which participants are regularly assessed for outcomes and adverse events.

Outcome Measures: Clinical trials employ various outcome measures, such as pain scores (e.g., visual analog scale), functional assessments (e.g., Western Ontario and McMaster Universities Osteoarthritis Index), and imaging (e.g., MRI), to evaluate treatment effectiveness. Safety Assessment: Adverse events and potential risks associated with MSC therapy were closely monitored and reported.

Several clinical trials have investigated the use of MSC therapy for knee OA. Some notable trials include:

Table 1: Clinical Trials Investigating MSC Therapy for Knee OA

 

S. No.

Author’s Name

Clinical Trial

References

 

1.

Centeno et al. (2014)

This trial assessed the safety and efficacy of intra-articular injection of autologous adipose-derived MSCs in patients with knee OA. The study reported improved knee function and reduced pain in the treatment group, with no significant adverse events observed.

87

2.

Emadedin et al. (2015)

In this trial, patients with knee OA received intra-articular injection of allogeneic bone marrow-derived MSCs. The treatment group demonstrated significant pain relief and improved joint function compared to the control group, with no severe adverse events reported.

88

3.

Vega et al. (2015)

This randomized controlled trial evaluated the efficacy of intra-articular injection of allogeneic bone marrow-derived MSCs in knee OA patients. The MSC-treated group showed significant reductions in pain and improved knee function, along with MRI evidence of cartilage regeneration.

89

Clinical trials evaluating MSC therapy for knee OA have shown promising results, with significant pain relief, functional improvement, and evidence of cartilage regeneration. These outcomes support the potential of MSC therapy as a safe and effective regenerative approach for managing knee OA.

Challenges and Limitations of MSC Therapy for Knee OA Despite the promising results of mesenchymal stem cell (MSC) therapy for knee osteoarthritis (OA), several challenges and limitations must be acknowledged: [90-91]

Heterogeneity of MSCs: MSCs obtained from different tissue sources or donors may exhibit variability in their regenerative potential and immunomodulatory properties, making it essential to standardize cell processing and characterization.

Intra-articular Delivery: The optimal delivery method for MSCs into the joint remains an area of investigation. Ensuring efficient and targeted delivery to the affected area without rapid clearance is crucial for maximizing therapeutic benefits.

Age and Health Status of Donors: The age and health status of MSC donors can influence the quality and functionality of the cells, potentially affecting treatment outcomes.

Disease severity and duration: The effectiveness of MSC therapy may vary depending on the stage of OA and the extent of cartilage damage. Advanced OA may present greater challenges for regeneration.

Immune Response and Immunogenicity: Despite their immunomodulatory properties, MSCs can still trigger immune responses in some cases, leading to potential graft rejection or complications.

Future Directions and Emerging Strategies Introduction of Novel Approaches and Advances in MSC Therapy for Knee OA

The future of mesenchymal stem cell (MSC) therapy for knee osteoarthritis (OA) holds exciting prospects with the introduction of novel approaches and advancements. Some promising directions include the following:

Gene Editing Techniques: Utilizing gene editing technologies, such as CRISPR-Cas9, to modify MSCs can enhance their regenerative potential and tailor them for specific functions, such as increased chondrogenesis or improved immunomodulation.

Preconditioning of MSCs: Preconditioning MSCs with specific growth factors or environmental stimuli before transplantation may enhance their therapeutic properties and survival in the OA joint.

Exosome Therapy: The use of MSC-derived exosomes, which contain a range of bioactive molecules, has emerged as a potential therapeutic approach. Exosomes can mimic the regenerative effects of MSCs without the need for cell transplantation, thereby avoiding potential risks associated with living cell therapy.

Nanotechnology-based Delivery: Nanoparticles can serve as carriers to efficiently deliver MSC-secreted factors or other therapeutic agents to the OA-affected joint, enhancing the therapeutic effects of MSC therapy. The future of MSC therapy for knee OA is promising, with novel approaches, combination therapies, and tissue engineering strategies showing potential to further improve treatment outcomes. Harnessing the full potential of MSCs and integrating them with cutting-edge regenerative medicine techniques will pave the way for more effective and personalized treatments for knee OA [92].

Regulatory considerations and commercialization

Overview of the Regulatory Landscape and Approval Processes for MSC Therapy The regulatory landscape for mesenchymal stem cell (MSC) therapy is subject to strict oversight to ensure patient safety and treatment efficacy. The approval process typically involves several stages:

Preclinical Studies: Preclinical studies in animal models are conducted to assess the safety and efficacy of MSC therapy, providing essential data for advancing to human clinical trials.

Phase I Clinical Trial: Phase I trials involving a small group of healthy volunteers or patients with knee OA are needed to evaluate the safety and dosage of MSC treatment.

Phase II Clinical Trial: Phase II trials expand the patient cohort to further assess safety and efficacy. This stage aims to determine the optimal dosing and treatment parameters.

Phase III Clinical Trial: Phase III trials involving large-scale randomized controlled studies to confirm the effectiveness and safety of MSC therapy compared to standard-of-care treatments or placebos.

Regulatory Approval: After successful completion of clinical trials, regulatory authorities, such as the FDA in the United States or the EMA in the European Union, review the data for potential approval [93-95].

Challenges and Requirements for Commercialization

Several challenges and requirements must be met for the successful commercialization of MSC therapy for knee OA:

Manufacturing Standardization: Establishing standardized protocols for MSC isolation, expansion, and characterization is essential for ensuring consistent and reproducible product quality.

GMP Compliance: MSC manufacturing facilities must comply with good manufacturing practice (GMP) guidelines to ensure product safety and quality.

Scalability: Developing scalable manufacturing processes is crucial for meeting potential commercial demands while maintaining product quality.

Regulatory Compliance: Meeting regulatory requirements for marketing authorization is a critical step in commercialization. Compliance with safety and efficacy standards is paramount.

Intellectual Property: Protecting intellectual property rights is essential for ensuring market exclusivity and preventing unauthorized use of MSC therapies. The commercialization of MSC therapy for knee OA involves navigating regulatory approval processes, addressing manufacturing challenges, and ensuring cost-effectiveness and reimbursement considerations. Successful commercialization will rely on meeting regulatory standards, demonstrating product efficacy, and navigating the complexities of healthcare reimbursement systems [96].

DISCUSSION

Summary of Current Insights into MSC Therapy for Knee OA

Mesenchymal stem cell (MSC) therapy has emerged as a promising regenerative approach for treating knee osteoarthritis (OA). Current insights from preclinical and clinical studies indicate that MSCs can contribute to cartilage repair, reduce inflammation, and improve joint function. MSC immunomodulatory properties and paracrine signaling have been shown to play a crucial role in mediating these regenerative effects. Clinical trials have demonstrated significant pain relief, functional improvement, and cartilage regeneration in knee OA patients treated with MSCs. Despite these promising results, challenges related to cell heterogeneity, optimal delivery methods, and variable treatment responses remain.

Identification of Gaps in Knowledge and Areas for Further Research

Despite the progress made in understanding the potential of MSC therapy for knee OA, several gaps in knowledge and areas for further research exist:

Mechanisms of Action: Further studies are needed to elucidate the precise mechanisms underlying MSC therapy for knee OA. Understanding the interactions between MSCs and the joint microenvironment will help optimize treatment approaches.

Long-Term Efficacy and Safety: Long-term follow-up data from clinical trials are essential for assessing the durability of the effects of MSC therapy and identifying potential late adverse events.

Patient Selection and Personalization: Identifying patient-specific factors that influence treatment responses will allow for personalized and targeted MSC therapy.

Comparison to Standard-of-Care: More head-to-head comparisons between MSC therapy and standard-of-care treatments are needed to establish the relative effectiveness of this therapy.

Combination therapies: Exploring the synergistic effects of MSCs combined with other regenerative approaches or therapies can improve treatment outcomes.

Potential of MSC Therapy as a Future Treatment Option for Knee OA

MSC therapy for knee OA holds immense potential as a future treatment option. The regenerative properties of MSCs, along with their immunomodulatory effects, offer a unique and promising approach to address the underlying pathology of OA. While challenges and limitations exist, ongoing research and advancements in cell biology, tissue engineering, and gene editing techniques are continuously refining MSC therapy. As we bridge the gaps in knowledge and gain a deeper understanding of MSC therapy mechanisms and long-term effects, it is increasingly clear that MSCs have the potential to revolutionize knee OA management. In addition to favourable reimbursement policies, successful commercialization will ensure broader patient access to this cutting-edge treatment.

CONCLUSION

The article discusses various approaches to MSC therapy, with a particular focus on intra-articular injection. This method appears more promising than scaffold-based gene-modified MSC therapies for treating OA. Directly injecting MSCs into the joint aims to capitalize on their regenerative capabilities without the complexities associated with engineered constructs. Future directions in MSC therapy research emphasize the necessity for additional clinical trials and technological innovations. Key areas of interest include optimizing treatment protocols, exploring combination therapies, and refining MSC delivery methods to maximize therapeutic outcomes. MSC therapy for knee OA shows considerable promise; ongoing research and clinical validation are crucial to fully exploit its potential. The review underscores the importance of advancing our understanding and application of MSCs in clinical settings, aiming for improved patient outcomes and potentially transformative treatments for osteoarthritis.

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Sanjita Das
Corresponding author

Department of Pharmacy, SMAS, Galgotias University, Greater Noida, UP203201

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Neha Singh
Co-author

Department of Pharmacy, SMAS, Galgotias University, Greater Noida, UP203201

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Prem Mishra
Co-author

Department of Pharmacy, SMAS, Galgotias University, Greater Noida, UP203201

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Ritika Singh
Co-author

Department of Pharmacy, SMAS, Galgotias University, Greater Noida, UP203201

Neha Singh, Sanjita Das*, Prem Mishra, Ritika Singh, Current Insights and Future Directions of Mesenchymal Stem Cell Therapy for Knee Osteoarthritis, Int. J. of Pharm. Sci., 2024, Vol 2, Issue 12, 2694-2713. https://doi.org/10.5281/zenodo.14539436

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