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MRI analysis of femural condyle cartilage before and 48 weeks after AD-MSCs injection. A lateral radiograph indicates enhancement in anterior, posterior, and central area of femoral condyle cartilage. B Medial radiograph revealed increase in the thickness of femoral condyle cartilage in anterior, posterior, and central area. MRI magnetic resonance imaging, FLC Femur lateral central, FLP femur lateral posterior, FLA femur lateral anterior, FMC femur medial central, FMP femur medial posterior, FMA femur medial anterior, AD-MSCs adipose-derived mesenchymal stromal cells
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Abstract Background Intra-articular injection of mesenchymal stromal cells (MSCs) with immunomodulatory features and their paracrine secretion of regenerative factors proposed a noninvasive therapeutic modality for cartilage regeneration in knee osteoarthritis (KOA). Methods Total number of 40 patients with KOA enrolled in two groups. Twenty patien...
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... Notably, adipose tissue yields an MSC volume approximately 500 times greater than bone marrow [42,43]. While some researchers assert that BM-MSC exhibits superior cartilage generation capabilities compared to AD-MSC, others propose that augmenting the stromal vascular fraction derived from AD-MSC with growth factors and cytokines can also enhance cartilage growth [44,45]. Synovium-derived MSCs have been explored for assessing efficacy and functional outcomes in osteoarthritic knees, with several studies suggesting their superior chondrogenesis potential [46,47]. ...
Background
In knee osteoarthritis (KOA), treatments involving knee injections of bone marrow-derived mesenchymal stem cells (BM-MSC), adipose tissue-derived mesenchymal stem cells (AD-MSC), or umbilical cord-derived mesenchymal stem cells (UC-MSC) have shown promise in alleviating symptoms. However, which types of mesenchymal stem cells (MSCs) have the best therapeutic outcomes remain uncertain.
Method
We systematically searched PubMed, OVID, Web of Science, and the Cochrane Library until January 1, 2024. The study evaluated five endpoints: Visual Analog Score (VAS) for Pain, Range of Motion (ROM), Whole-Organ Magnetic Resonance Imaging Score (WORMS), Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), and adverse events (ADs). Standard meta-analysis and network meta-analysis were performed using Stata 16.0.
Results
Fifteen studies involving 585 patients were included in the meta-analysis. Standard meta-analysis revealed significant improvements with MSCs in VAS score (P < 0.001), knee ROM (P < 0.001), and WOMAC (P < 0.016) compared to traditional therapy. In the network meta-analysis, autologous MSCs significantly improved VAS score [SMD = 2.94, 95% CI (1.90, 4.56)] and knee ROM [SMD = 0.26, 95% CI (0.08, 0.82)] compared to traditional therapy. Similarly, BM-MSC significantly improved VAS score [SMD = 0.31, 95% CI (0.11, 0.91)] and knee ROM [SMD = 0.26, 95% CI (0.08, 0.82)] compared to hyaluronic acid. However, compared with traditional therapy, autologous or allogeneic MSCs were associated with more adverse reactions [SMD = 0.11, 95% CI (0.02, 0.59)], [SMD = 0.13, 95% CI (0.002, 0.72)]. Based on the surface under the cumulative ranking results, autologous BM-MSC showed the most improvement in ROM and pain relief in KOA patients, UC-MSC (SUCRA 94.1%) were most effective for positive WORMS, and AD-MSC (SUCRA 70.6%) were most effective for WOMAC-positive patients.
Conclusion
MSCs transplantation effectively treats KOA patients, with autologous BM-MSC potentially offering more excellent benefits.
... Additionally, research on MSCs has come under heavy criticism; several MSC-based clinical trials have failed on primary end points, causing many to question whether these stem cells should continue to be studied (22). Nonetheless, many new studies evaluating the therapeutic effect of MSCs were reported in 2023 (23)(24)(25). Therefore, this review summarizes and updates the results of studies on the use of MSCs for treating OA. ...
... A total of 633 patients were included in the intervention group. Among the cell sources, 3 studies examined allogeneic AD-MSCs (14,25,39), 4 studies examined autologous AD-MSCs (24,32,34,41), 3 studies examined allogeneic BM-MSCs (16,23,40), 5 studies examined autologous BM-MSCs (15,33,(35)(36)(37), and 3 studies examined allogeneic UC-MSCs (38,42,43). In the included studies, the average number of MSCs per injection ranged from 1× 10 6 to 150 × 10 6 . ...
... One study had a follow-up duration of 24 months (14), 13 studies had a follow-up duration of 12 months (15,16,23,25,32,(35)(36)(37)(39)(40)(41)(42)(43), and 4 studies had a follow-up duration of 6 months (24,33,34,38). Seventeen studies were registered, and one study was not registered (35). ...
Introduction
The aim of this meta-analysis was to evaluate the efficacy and safety of mesenchymal stem cells (MSCs) for the treatment of knee osteoarthritis (OA).
Methods
The PubMed, Embase, Cochrane Central Register of Controlled Trials, Scopus and Web of Science databases were searched from inception to May 6, 2024 to identify randomized controlled trials that compared MSCs and placebo or other nonsurgical approaches for treating OA. Two investigators independently searched the literature and extracted data, and conventional meta-analyses were conducted with Review Manager 5.3. The outcomes included pain relief, functional improvement, and risk of adverse events (AEs).
Results
A total of 18 articles were included. Overall, MSCs were superior to placebo in terms of relieving pain and improving function at the 12-month follow-up. However, the differences in treatment-related AEs were not significant.
Conclusion
MSCs may relieving pain and improving function of OA. The limitations of this study include the high heterogeneity of the included studies. Additionally, the follow-up time in the included studies was relatively short, so more clinical trials are needed to predict the long-term efficacy and safety of MSCs.
Systematic review registration
https://doi.org/10.17605/OSF.IO/5BT6E, identifier CRD42022354824.
... It has been proved that ADSC transplantation provides an alternative strategy for OA treatment by anti-inflammation, reducing chondrocyte cell apoptosis and dedifferentiation (Manferdini et al. 2013;Jiang et al. 2016). Recently, the benefic effects of ADSC transplantation have also been confirmed by animal models and clinical trials (Carneiro et al. 2023;Kim et al. 2022Kim et al. , 2023Chen et al. 2021;Sadri et al. 2023). Although ADSC transplantation has achieved promising results for OA treatment, the long-term therapeutic efficiency is still limited due to the low cell survival or retention in the joint (Bhattacharjee et al. 2022). ...
Although adipose tissue-derived mesenchymal stem cell (ADSC) transplantation has been effectively used to treat osteoarthritis (OA), the low cell survival rate induced by the inflammatory and oxidative stress, severely affects the therapeutic efficiency of ADSC transplantation in OA. This study was designed to evaluate whether melatonin pretreatment could improve ADSC survival and its therapeutic efficacy in OA. The papain-induced OA rats were pretreated with melatonin via intra-articular injection and then intra-articular injected with indocyanine green (ICG)-labeled ADSCs (3 × 10⁶/rat). Afterward, ADSC retention was evaluated by NIR-II fluorescence imaging. The tibia and synovial fluid were collected for histopathological examination and ELISA assay, respectively. To confirm the anti-inflammatory effect of melatonin, a TNF-α and IL-1β-induced cell model was used to evaluate the protective effects of melatonin on ADSC viability, cell apoptosis, and migration. Our results showed that melatonin pretreatment enhanced ADSC survival and improved the therapeutic effects of ADSC transplantation on cartilage repair, and anti-inflammation by reducing TNF-α, IL-6, IL-1β, and IL-12 in vivo. In particular, we also found that melatonin promoted ADSC viability and migration, and reduced cell apoptosis in vitro. In conclusion, this study supports that melatonin pretreatment can effectively improve ADSC survival and therapeutic efficiency in OA by reducing inflammatory injuries, which provides a novel strategy for enhancing ADSC therapy.
... The results of 6 months of follow-up showed that MSCs (including bone marrow, fat, and umbilical cord MSCs) and control groups were The network meta-analysis also examined the efficacy of different MSC sources, getting WOMAC total, WOMAC stiffness, and WOMAC function scores for short-term efficacy (6 months) and long-term efficacy (12 months), respectively. [19,20,22,23,26,27,28,29,30,31,32,33,34,35,36] at 6 months of follow-up included 813 patients reporting WOMAC total scores between MSCs of different origins (including bone marrow, fat, and umbilical cord) and the control group (Figure 3(a)). The results of the network meta-analysis, categorized by treatment modality, are presented in Supplementary 2. Although the analysis revealed no significant differences among the treatment modalities, the efficacy of BMMSC was superior to that of ADMSC and UCMSC (BMMSC vs. ...
... The results of the network meta-analysis, categorized by treatment modality, are presented in Supplementary 2. Although the analysis revealed no significant differences among the treatment modalities, the efficacy of BMMSC was superior to that of ADMSC and UCMSC (BMMSC vs. A total of 11 RCTs [19,21,22,23,27,29,30,32,33,34,35] at 12 months of follow-up included 424 patients who reported WOMAC total scores between MSCs of different origins (including bone marrow, fat, and umbilical cord) and the control group (Figure 3(b)). The results of the network meta-analysis, categorized by treatment modality, are presented in Supplementary 2. The results showed that there was no significant difference between MSCS derived from different sources, but BMMSC had advantages over ADMSC and KLⅡ-Ⅲ ...
... VAS Score. A total of 14 RCTs [19,22,23,26,28,29,31,32,33,34,35,37,38,39] at 6 months of follow-up included 858 patients who reported VAS scores between different sources of MSCs (including bone marrow, fat, umbilical cord, placenta) and control subjects (Figure 3(g)). ...
Background. Joint articular injection of mesenchymal stem cells (MSCs) has emerged as a novel treatment approach for osteoarthritis (OA). However, the effectiveness of MSCs derived from different sources in treating OA patients remains unclear. Therefore, this study aimed to explore the differences between the effectiveness and safety of different sources of MSCs. Materials and Methods. For inclusion consideration, we searched trial registries and published databases, including PubMed, Cochrane Library, Embase, and Web of Science databases. Revman (V5.3), STATA (V16.0), and R (V4.0) were utilized for conducting data analysis, while the Cochrane Risk of Bias Tool was employed for assessing the quality of the studies. We derived outcome measures at 6 and 12 months based on the duration of study follow-up, including visual analog scale (VAS) score, WOMAC score, WOMAC pain, WOMAC Functional Limitation, and WOMAC stiffness. The evaluation time for short-term effectiveness is set at 6 months, while 12 months is utilized as the longest follow-up time for most studies to assess long-term effectiveness. Results. The evaluation of literature quality showed that the included studies had excellent methodological quality. A meta-analysis revealed that different sources of MSCs improved knee function and pain more effectively among patients suffering from knee OA (KOA) than controls. The results of the network meta-analysis showed the following: short-term functional improvement (the indexes were evaluated after 6 months of follow-up) (WOMAC total score: bone marrow-derived MSC (BMMSC) vs. adipose-derived MSC (ADMSC) (mean difference (MD) = −20.12, 95% confidence interval (CI) −125.24 to 42.88), umbilical cord-derived MSC (UCMSC) (MD = −7.81, 95% CI −158.13 to 74.99); WOMAC stiffness: BMMSC vs. ADMSC (MD = −0.51, 95% CI −7.27 to 4.29), UCMSC (MD = −0.75, 95% CI −9.74 to 6.63); WOMAC functional limitation: BMMSC vs. ADMSC (MD = −12.22, 95% CI −35.05 to 18.86), UCMSC (MD = −9.31, 95% CI −44.26 to 35.27)). Long-term functional improvement (the indexes were evaluated after 12 months of follow-up) (WOMAC total: BMMSC vs. ADMSC (MD = −176.77, 95% CI −757.1 to 378.25), UCMSC (MD = −181.55, 95% CI −937.83 to 541.13); WOMAC stiffness: BMMSC vs. ADMSC (MD = −0.5, 95% CI −26.05 to 18.61), UCMSC (MD = −1.03, 95% CI −30.44 to 21.69); WOMAC functional limitation: BMMSC vs. ADMSC (MD = −5.18, 95% CI −316.72 to 177.1), UCMSC (MD = −8.33, 95% CI −358.78 to 218.76)). Short-term pain relief (the indexes were evaluated after 6 months of follow-up) (VAS score: UCMSC vs. BMMSC (MD = −10.92, 95% CI −31.79 to 12.03), ADMSC (MD = −14.02, 95% CI −36.01 to 9.81), PLMSC (MD = −17.09, 95% CI −46.31 to 13.17); WOMAC pain relief: BMMSC vs. ADMSC (MD = −11.42, 95% CI −39.52 to 11.77), UCMSC (MD = −6.73, 95% CI −47.36 to 29.15)). Long-term pain relief (the indexes were evaluated after 12 months of follow-up) (VAS score: BMMSC vs. UCMSC (MD = −4.33, 95% CI −36.81 to 27.08), ADMSC (MD = −11.43, 95% CI −37.5 to 13.42); WOMAC pain relief: UCMSC vs. ADMSC (MD = 0.23, 95% CI −37.87 to 38.11), BMMSC (MD = 5.89, 95% CI −25.39 to 51.41)). According to the GRADE scoring system, WOMAC, VAS, and AE scores were of low quality. Conclusion. Meta-analysis suggests MSCs can effectively treat KOA by improving pain and knee function compared to control groups. In terms of functional improvement in KOA patients, both short-term (6-month follow-up) and long-term (12-month follow-up) results indicated that while the differences between most treatments were not statistically significant, bone marrow-derived MSCs may have some advantages over other sources of MSCs. Additionally, BM-MSCs and UC-MSCs may offer certain benefits over ADMSCs in terms of pain relief for KOA patients, although the variances between most studies were not statistically significant. Therefore, this study suggests that BM-MSCs may present clinical advantages over other sources of MSCs.
... Two studies were judged to be at high risk of bias for > 10% missing participant data (Figure 2; Supplementary Table 1). Among included studies, seven trials received funding from industry 41, 44-47, 49, 51 , four trials had no funding statement 36, 38,39,42 , and the remaining studies reported no funding or support from non-profit agencies 35,37,40,43,48,50 . ...
... Recently, mesenchymal stem cells (MSCs) have been explored as a new, potentially disease-modifying treatment for osteoarthritis (OA). Some small clinical studies have reported that intra-articular injection of MSCs could modulate the immune microenvironment and promote cartilage regeneration in a knee with OA [8,23]. MSC paracrine factors such as extracellular vesicles are proposed as the principal mechanism for their regulatory effects [15]. ...
Background
Extracellular vesicles derived from mesenchymal stem cells (MSCs) show great promise in treating osteoarthritis (OA). However, studies from the perspective of clinical feasibility that consider an accessible cell source and a scalable preparation method for MSC-extracellular vesicles are lacking.
Questions/purposes
(1) Does an infrapatellar fat pad obtained from patients undergoing TKA provide a suitable source to provide MSC-extracellular vesicles purified by anion exchange chromatography? Using an in vivo mouse model for OA in the knee, (2) how does injection of the infrapatellar fat pad–derived MSC-extracellular vesicles alter gait, cartilage structure and composition, protein expression (Type II collagen, MMP13, and ADAMTS5), subchondral bone remodeling and osteophytes, and synovial inflammation?
Methods
The infrapatellar fat pad was collected from three patients (all female; 62, 74, 77 years) during TKA for infrapatellar fat pad–derived MSC culturing. Patients with infection, rheumatic arthritis, and age > 80 years were excluded. MSC-extracellular vesicles were purified by anion exchange chromatography. For the animal study, we used 30 male C57BL/6 mice aged 10 weeks, divided into six groups. MSC-extracellular vesicles were injected weekly into the joint of an OA mouse model during ACL transection (ACLT). To answer our first research question, we characterized MSCs based on their proliferative potential, differentiation capacity, and surface antigen expression, and we characterized MSC-extracellular vesicles by size, morphology, protein marker expression, and miRNA profile. To answer our second research question, we evaluated the effects of MSC-extracellular vesicles in the OA mouse model with quantitative gait analysis (mean pressure, footprint area, stride length, and propulsion time), histology (Osteoarthritis Research Society International Score based on histologic analysis [0 = normal to 24 = very severe degeneration]), immunohistochemistry staining of joint sections (protein expression of Type II collagen, MMP13, and ADAMTS5), and micro-CT of subchondral bone (BV/TV and Tb.Pf) and osteophyte formation. We also examined the mechanism of action of MSC-extracellular vesicles by immunofluorescent staining of the synovium membrane (number of M1 and M2 macrophage cells) and by analyzing their influence on the expression of inflammatory factors (relative mRNA level and protein expression of IL-1β, IL-6, and TNF-α) in lipopolysaccharide-induced macrophages.
Results
Infrapatellar fat pads obtained from patients undergoing TKA provide a suitable cell source for producing MSC-extracellular vesicles, and anion exchange chromatography is applicable for isolating MSC-extracellular vesicles. Cultured MSCs were spindle-shaped, proliferative at Passage 4 (doubling time of 42.75 ± 1.35 hours), had trilineage differentiation capacity, positively expressed stem cell surface markers (CD44, CD73, CD90, and CD105), and negatively expressed hematopoietic markers (CD34 and CD45). MSC-extracellular vesicles purified by anion exchange chromatography had diameters between 30 and 200 nm and a typical cup shape, positively expressed exosomal marker proteins (CD63, CD81, CD9, Alix, and TSG101), and carried plentiful miRNA. Compared with the ACLT group, the ACLT + extracellular vesicle group showed alleviation of pain 8 weeks after the injection, indicated by increased area (0.67 ± 0.15 cm ² versus 0.20 ± 0.03 cm ² , -0.05 [95% confidence interval -0.09 to -0.01]; p = 0.01) and stride length (5.08 ± 0.53 cm versus 6.20 ± 0.33 cm, -1.12 [95% CI -1.86 to -0.37]; p = 0.005) and decreased propulsion time (0.22 ± 0.06 s versus 0.11 ± 0.04 s, 0.11 [95% CI 0.03 to 0.19]; p = 0.007) in the affected hindlimb. Compared with the ACLT group, the ACLT + extracellular vesicles group had lower Osteoarthritis Research Society International scores after 4 weeks (8.80 ± 2.28 versus 4.80 ± 2.28, 4.00 [95% CI 0.68 to 7.32]; p = 0.02) and 8 weeks (16.00 ± 3.16 versus 9.60 ± 2.51, 6.40 [95% CI 2.14 to 10.66]; p = 0.005). In the ACLT + extracellular vesicles group, there was more-severe OA at 8 weeks than at 4 weeks (9.60 ± 2.51 versus 4.80 ± 2.28, 4.80 [95% CI 0.82 to 8.78]; p = 0.02), indicating MSC-extracellular vesicles could only delay but not fully suppress OA progression. Compared with the ACLT group, the injection of MSC-extracellular vesicles increased Type II collagen expression, decreased MMP13 expression, and decreased ADAMTS5 expression at 4 and 8 weeks. Compared with the ACLT group, MSC-extracellular vesicle injection alleviated osteophyte formation at 8 weeks and inhibited bone loss at 4 weeks. MSC-extracellular vesicle injection suppressed inflammation; the ACLT + extracellular vesicles group had fewer M1 type macrophages than the ACLT group. Compared with lipopolysaccharide-treated cells, MSC-extracellular vesicles reduced mRNA expression and inhibited IL-1β, IL-6, and TNF-α in cells.
Conclusion
Using an OA mouse model, we found that infrapatellar fat pad–derived MSC-extracellular vesicles could delay OA progression via alleviating pain and suppressing cartilage degeneration, osteophyte formation, and synovial inflammation. The autologous origin of extracellular vesicles and scalable purification method make our strategy potentially viable for clinical translation.
Clinical Relevance
Infrapatellar fat pad–derived MSC-extracellular vesicles isolated by anion exchange chromatography can suppress OA progression in a mouse model. Further studies with large-animal models, larger animal groups, and subsequent clinical trials are necessary to confirm the feasibility of this technique for clinical OA treatment.
... Vast research is underway to enhance MSC potency via preconditioning in bioreactors and combinatorial scaffolds. Standardization of cell processing and dosing is also needed [79][80][81][82][83][84][85][86][87]. ...
Background: Knee osteoarthritis (OA) involves complex interactions between biological and biomechanical factors that drive joint degeneration. Conservative rehabilitation approaches are standard initial management, but have limited long-term efficacy.
Purpose: To review key aspects of knee OA pathophysiology and emerging therapeutic directions.
Main body: Abnormal loading and altered neuromuscular control disrupt knee joint biomechanics in OA. Inflammation, PAR receptor signaling, and impaired chondrocyte mechanobiology promote cartilage catabolism. Subchondral bone and osteophyte changes also occur. While conservative strategies like gait retraining, proprioceptive exercises, bracing, and core strengthening help reduce symptoms and improve function, intrinsic joint damage eventually limits efficacy. Novel approaches using biologics, regenerative cell therapy, tissue engineering constructs, and nanotechnology aim to repair cartilage and modify disease progression, but require further optimization and testing before clinical implementation.
Conclusion: Addressing both the biomechanical and biological factors contributing to knee OA will be key for developing effective therapies able to halt joint degeneration and restore function.
... However, with the MD and LD, we observed a significant reduction of WOMAC pain and function corroborating the results previously observed in the other clinical trials. Consequently, these results demonstrated the relevance of the 44 Moreover, we demonstrated that UC-MSC injection is safe, and our results showed that low doses display lower initial pain with high clinical positive results as compared to baseline, at 6 months follow-up. Additionally, our previous study described a controlled randomized phase I/ II to treat knee OA with our product Cellistem, observing no severe adverse events and a significant reduction of pain and function compared to baseline, at 1-year follow-up. ...
Osteoarthritis (OA) is the most common degenerative joint disease. Mesenchymal stromal cells (MSC) are promising cell-based therapy for OA. However, there is still a need for additional randomized, dose-dependent studies to determine the optimal dose and tissue source of MSC for improved clinical outcomes. Here, we performed a dose-dependant evaluation of umbilical cord (UC)-derived MSC (Celllistem) in a murine model and in knee OA patients. For the preclinical study, a classical dose (200.000 cells) and a lower dose (50.000 cells) of Cellistem were intra-articularly injected into the mice knee joints. The results showed a dose efficacy response effect of Cellistem associated with a decreased inflammatory and degenerative response according to the Pritzker OARSI score. Following the same approach, the dose-escalation phase I clinical trial design included 3 sequential cohorts: low-dose group (2 × 106 cells), medium-dose group (20 × 106), and high-dose group (80 × 106). All the doses were safe, and no serious adverse events were reported. Nonetheless, 100% of the patients injected with the high-dose experienced injection-related swelling in the knee joint. According to WOMAC total outcomes, patients treated with all doses reported significant improvements in pain and function compared with baseline after 3 and 6 months. However, the improvements were higher in patients treated with both medium and low dose as compared to high dose. Therefore, our data demonstrate that the intra-articular injection of different doses of Cellistem is both safe and efficient, making it an interesting therapeutic alternative to treat mild and symptomatic knee OA patients.
Trial registration: ClinicalTrials.gov NCT03810521.
... In another review, 12 articles comprising 539 patients and 576 knees treated with a single intraarticular injection of MSCs for knee OA were analyzed by Kyriakidis et al. (2023) 28 , who reported that MSC injection is a safe and effective treatment for K-L grade I-III knee OA. Interestingly, a triple-blinded, placebo-controlled, randomized trial compared the treatment efficacy of allogeneic MSCs (from adipose tissue) to that of normal saline (control group) and confirmed that allogeneic MSC injection is safe and significantly improves treatment efficacy 29 Some allogeneic MSCs have been successfully developed into "off-the-shelf " MSC products for knee OA and have been approved in some countries as stem cell drugs. A system that contains allogeneic UCBderived MSCs was first approved by the Korean FDA for knee OA treatment. ...
Regenerative medicine-based therapies are considered promising for some chronic diseases, such as osteoarthritis (OA). Because OA is the most common disease in many countries, significant efforts have long been made to develop effective treatments. Current therapies for OA include hyaluronic acid, platelet-rich plasma, bone marrow aspirate concentrates, the stromal vascular fraction from adipose tissue, bone marrow-derived mesenchymal stem cells, and adipose tissue-derived mesenchymal stem cells. Clinical trials testing these agents for OA treatment have been performed for over 10 years. In this review, we summarize and compare the effects of these agents for treating knee OA based on recent meta-analyses.
... However, the various advantages presented hereabove in favor of the implementation of allogeneic cell-based protocols are counterbalanced by the time-and resource-consuming process of obtaining the ad hoc regulatory approvals [50,[91][92][93][94][95][96][97][98][99]. Specifically, extensive riskbased approaches to the transition from autologous to allogeneic investigational medicinal products (IMP) must be followed, along with appropriate (i.e., specific and general) risk analyses (for product quality, purity, efficacy, safety, and stability; see Tables S4-S7) [48]. ...
Cytotherapies are often necessary for the management of symptomatic large knee (osteo)-chondral defects. While autologous chondrocyte implantation (ACI) has been clinically used for 30 years, allogeneic cells (clinical-grade FE002 primary chondroprogenitors) have been investigated in translational settings (Swiss progenitor cell transplantation program). The aim of this study was to comparatively assess autologous and allogeneic approaches (quality, safety, functional attributes) to cell-based knee chondrotherapies developed for clinical use. Protocol benchmarking from a manufacturing process and control viewpoint enabled us to highlight the respective advantages and risks. Safety data (telomerase and soft agarose colony formation assays, high passage cell senescence) and risk analyses were reported for the allogeneic FE002 cellular active substance in preparation for an autologous to allogeneic clinical protocol transposition. Validation results on autologous bioengineered grafts (autologous chondrocyte-bearing Chondro-Gide scaffolds) confirmed significant chondrogenic induction (COL2 and ACAN upregulation, extracellular matrix synthesis) after 2 weeks of co-culture. Allogeneic grafts (bearing FE002 primary chondroprogenitors) displayed comparable endpoint quality and functionality attributes. Parameters of translational relevance (transport medium, finished product suturability) were validated for the allogeneic protocol. Notably, the process-based benchmarking of both approaches highlighted the key advantages of allogeneic FE002 cell-bearing grafts (reduced cellular variability, enhanced process standardization, rationalized logistical and clinical pathways). Overall, this study built on our robust knowledge and local experience with ACI (long-term safety and efficacy), setting an appropriate standard for further clinical investigations into allogeneic progenitor cell-based orthopedic protocols.
