Introduction
Endogenous | Exogenous |
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Age | Previous joint injuries |
Incidence rates increase linearly in the 50–80 age range | |
Sex | Body mass |
Females have been reported to have a greater incidence rate compared to males | Overweight and obese people are significantly associated with higher KOA risk The risk increases by 35% with every 5 kg/m2 increase in BMI |
Heredity | Excessive joint stress and increased mechanical forces |
Genetics | Repetitive loading (kneeling and squatting) |
Joint laxity | Occupation |
Physical work activities (kneeling/squatting/lifting and climbing) contribute to the occurrence/progression of KOA | |
Ethnic origin | Resective joint surgery |
More common in individuals of European descent | |
Post-menopausal changes | Muscle weakness |
Malalignment | Lifestyle factors (alcohol, tobacco use) |
Methods
Results
Discussion
BM-MSCs for stimulating regeneration in knee osteoarthritis
Classification of MSCs |
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Fibroblastic-like (spindle-shaped) morphology |
Plastic-adherent property under standard culture conditions |
Differentiation potential into osteoblasts, adipocytes, and chondroblasts in vitro |
Expression of surface markers including CD105; CD73 and; CD90 |
Lack of expression of: CD45; CD34; CD14; or CD11b; CD79α or CD19 and; HLA-DR |
References | Animal model | Cell donor | Sample size | Severity of knee OA | BM-MSC dosage | Outcomes |
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Al Faqeh et al. [29] | Sheep | Autologous (chondrogenic-induced) | n = 51 | Surgically induced (monitored for 24 h) 3-weeks post: Sheep ran 100 m on hard surface daily for 3 weeks | 1 Injection: 2 × 106 suspended in 10% foetal bovine serum | Meniscal regeneration and retardation of the progression of OA |
Diekman et al. [28] | Mouse | Autologous (purified) | n = 11 | Surgically induced: closed tibial plateau fracture | 1 Injection: Experimental group: 1 × 105 cells in 6 µl saline Control group: sterile saline solution | Efficacy in preventing OA |
Murphy et al. [32] | Goat | Autologous | n = 24 | Surgically induced: 3-weeks post: Sheep ran on 90 m hard surface daily for 3 weeks | 1 Injection: Experimental group: 10 × 106 suspended in 10% foetal bovine serum Control group: injection of hyaluronan acid (HA) | Meniscal regeneration and retardation of progressive destruction |
Lee et al. [31] | Pig | Autologous | n = 27 | Surgically induced | 1 Injection: Group 1: MSCs with HA Group 2: HA Group 3: Saline solution | Cartilage repair |
Gupta et al. [30] | Rat | Xenogeneic (human) | n = 74 | Monoiodoacetate (MIA)-induced model of OA | 1 Injection: Group 1: sham control received 60 μl of Plasmalyte A Group 2: vehicle control received 60 μl of Plasmalyte A Group 3: 30 μl of HA and 30 μl of vehicle 2 Injections: Group 4: 6 × 105 of Stempeucel® and 30 μl of HA Group 5: 1.3 × 106 of Stempeucel® and 30 μl of HA | Elicited pain reduction and cartilage regeneration |
Suhaeb et al. [33] | Rat | Allogenic | n = 36 | MIA injection | 1 Injection: Control: No treatment Experimental group 1: 25 μl of HA Experimental group 2: 3–5 × 106 cells Experimental group 3: 3–5 × 106 cells + 25 μl of HA | Effective reduction of OA progression alone, compared with combined use of HA and BM-MSCs |
Chiang et al. [27] | Rabbit | Allogenic | n = 2 | ACLT | 1 Injection: Group 1: OA induction without treatment Group 2: Sham operation Group 3: 0.4 mL of HA Group 4: 1 × 106 and 0.4 mL of HA | Reduced OA progression |
References | Cell donor | Sample size/control | OA severity | BM-MSC dosage | Follow-up | Significant findings |
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Case reports | ||||||
Centeno et al. [35] | Autologous | n = 1 Male 56 years No control | OA causing significant on-going pain and disability (ungraded) | 1 Injection: 22.4 × 106 cells suspended in PBS Dexamethasone injection administered following BM-MSC injection | Baseline, 1 and 3 months | No adverse events reported MRI: ↑ cartilage and meniscus growth |
Emadedin et al. [38] | Autologous | n = 6 Female Mean age: 54 years No control | Grade 4 | 1 Injection: 20–24 × 106 cells suspended at a density of 5 × 106 | Baseline, 6 and 12 months | No local or systemic adverse events WOMAC: ↓ at 6 and 12 months Mean walking distance: ↑ at 6 months No local or systemic adverse events Mean walking distance: ↑ at 6 and 30 months after treatment WOMAC: ↓ at 6, 12 and 30 months compared with baseline. ↓ in WOMAC physical function sub scores at 6 and 12 months |
Emadedin et al. [39] Long term-follow up | Autologous | n = 6 Female Mean age: 54 years No control | Grade 4 | 1 Injection: 20–24 × 106 cells suspended at a density of 5 × 106 | Baseline, 6, 12 and 30 months | |
Mehrabani et al. [67] | Autologous | n = 1 Female 47 years No control | Grade 4 Unresponsive to NSAIDs | 1 Injection: 36 × 106 cells provided and transferred in 2 ml of media | 3, 6 and 12 months | No local or systemic adverse events MRI: ↑ thickness of cartilage on distal condyle of femur and proximal tibia at 6 and 12 months |
Preliminary reports | ||||||
Davatchi et al. [36] | Autologous | n = 4 2 Females: 57 and 54 years 2 Males: 55 and 65 years | Grade 2–3 | 1 Injection: 8–9 × 106 in a mean volume of 5.5 mL | Baseline, 1 week, then every month up to 1 year | No adverse events reported |
Davatchi et al. [37] 5-year follow-up | Autologous | n = 3 No control | Grade 2–3 | 1 Injection: 8–9 × 106 in a mean volume of 5.5 mL | 5 years | No adverse events reported |
Pilot studies | ||||||
Orozco et al. [40] | Autologous (according to Good Manufacturing Processes: GMP) | n = 12 6 Females 6 Males Mean age: 49 ± 5 No control | Grade 2 to 4 Unresponsive to conservative treatment for 6 months | 1 Injection: 40 × 106 cells suspended in ringer-lactate at 5 × 106 | Baseline, 3, 6 and 12 months | Mild adverse events: the first 1–6 days and occurred frequently (50% of patients) = controlled by ibuprofen VAS: Pain ↓ at 3 months with progressive improvement during the subsequent 9 months (statistically significant at all time points compared with basal pain level) WOMAC: All subscales ↓ at 12 months compared to baseline Lequesne algofunctional index: Correlation between improvement and the initial score (p < 0.01) MRI: Mean PCI ↓ from 19.5 to 15.4 during first 6 months and further ↓ to 14.3 at 12 months (11 out of 12 patients) Correlation between VAS and PCI |
Orozco et al. [40] Two-year follow up | Autologous (GMP) | n = 12 6 Females 6 Males Mean age: 49 ± 5 No control | Grade 2 to 4 Unresponsive to conservative treatment for 6 months | 1 Injection: 40 × 106 cells suspended in ringer-lactate at 5 × 106 | 2 years | Results of the follow-up reaffirm the conclusions for the first-year results regarding feasibility and safety |
Phase I/II studies | ||||||
Rich et al. [41] Clinical trial-Phase I/II | Autologous (ex-vivo) | n = 50 20 Females 30 Males Mean age: 57.8 ± 14.1 No control | Grade 2–4 | 1 Injection: 40 × 106 suspended in ringer-lactate at 5 × 106 | Day 8, 3, 6 and 12 months | No local or systemic adverse events VAS: ↓ at 6 and 12 months The pattern of 1-year improvement was parallel for VAS, WOMAC and Lequesne algofunctional index MRI: Mean PCI ↓ from 25 to 5 at 12 months post-injection |
Soler et al. [42] Prospective, open-label, single-dose, single-arm clinical trial-Phase I/II final results | Autologous (ex-vivo)-Infusion of XCEL-M-Alpha | n = 15 9 Females 6 Males Mean age: 52 No control | Grade 2 (n = 9) Grade 3 (n = 6) | 1 Injection: 40 × 106 ± 10 × 106 XCEL-M-ALPHA was infused within 6 h from delivery | Day 8, 3, 6- and 12-months | Mild adverse events (local discomfort and back pain from bone marrow extraction) VAS: Pain ↓ and daily activity ↑ at 8 days until the end of the study period HAQ (questionnaire): Over time ↓ from baseline across whole population at 12 months WOMAC: ↓ at 12 months Lequesne algofunctional index: ↓ at 6 and 12 months |
Al Najar et al. [34] Prospective open-label study-Phase I/II | Autologous | n = 13 7 Females 6 Males Mean age: 50 years No control | Grade 2–4 | 2 Injections (1 month apart): 30.5 × 106 cells suspended in 09% normal saline | Adverse events: day 1, 7, 14, 28, 60 and then every 6 months until month 24 Normalised KOOS: baseline, 1, 2, 4, 6, 12 and 24 months after first injection MRI: baseline, 6 and 12 months | 2 local adverse events within 2 h of injection, 1 6 h after injection (all resolved with ice/mild analgesia in 48 h) Normalised KOOS: Symptoms and pain ↓, daily life activity, sport and QoL ↑ at 6, 12 and 24 months MRI: ↑ Mean tibial and femoral plate thickness (mm) at 12 months (1 female deteriorated by MRI despite of KOOS improvement) |
Randomised clinical trails (RCT) | ||||||
Vangsness et al. [43] Double-blinded, randomised, controlled clinical study | Allogenic (GMP) Obtained from donors (screened and tested according to the US FDA) | n = 55 63% were male Group A = 18 Group B = 18 Control = 19 Mean age: 46 years | All underwent subtotal meniscectomies-any previous knee ligament reconstruction needed to have had a stable result | Group A: 50 × 106 cells suspended in 2 mL of HA, human serum albumin and PlasmaLyte A to a volume of 5 ml Group B: 150 × 106 suspended in 2 mL of HA, human serum albumin and PlasmaLyte A to a volume of 5 ml Control: A vehicle control compromised the same HA solution without BM-MSCs | Baseline, 6 weeks, 6 months, 1 year and 2 years post-operatively | 427 adverse events among 55 patients. 272 were mild, 28 sever and 1 life-threatening 1-year post VAS: Knee pain ↓ for all patient’s compared with baselines in all groups. Significant differences were observed at 2 years for group A, and at 1 and 2 years for B Lysholm knee scale: Total scores relative to baseline ↓ at all follow-ups Meniscus volume > 15%: At 12 months, both the control compared with group A and overall comparison were significant (> 15%) and at 2 years the overall group comparison was significant |
Vega et al. [44] Randomised controlled, comparator multi-centre-Phase I/II study | Allogenic (GMP) | n = 30 17 Females 13 Males Mean age: 57 ± 9 Experimental group = 15 Control = 15 | Grade 2–4 Unresponsive to conventional treatments for at least 6 months prior to recruitment | 1 Injection: Experimental group: 40 × 106 cells from a 5 × 106 cell/mL suspension Control: 60 mg of HA in 3 mL | Baseline, day 8, 3, 6 and 12 months | Minor adverse events during first 7 days in both groups = 53–60% of patients AS: ↓ in experimental group at 6 and 12 months. Control group ↓ at 12 months WOMAC: Pain and general WOMAC ↓ at 6 and 12 months for experimental group Lequesne algofunctional index: ↓ at 6 and 12 months in experimental group MRI: Poor Cartilage Index (PCI) ↓ at 12 months in experimental group |
Vangsness et al. [43] Double-blinded, randomised, controlled clinical study | Allogenic (GMP) (screened and tested according to the US FDA) | n = 55 63% were male Group A = 18 Group B = 18 Control = 19 Mean age: 46 years | All underwent subtotal meniscectomies-any previous knee ligament reconstruction needed to have had a stable result | Group A: 50 × 106 cells suspended in 2 mL of HA, human serum albumin and PlasmaLyte A to a volume of 5 ml Group B: 150 × 106 suspended in 2 mL of HA, human serum albumin and PlasmaLyte A to a volume of 5 ml Control: A vehicle control compromised the same HA solution without BM-MSCs | Baseline, 6 weeks, 6 months, 1 year and 2 years postoperatively | 427 adverse events among 55 patients. 272 were mild, 28 sever and 1 life-threatening 1-year post VAS: Knee pain ↓ for all patient’s compared with baselines in all groups. Significant differences were observed at 2 years for group A, and at 1 and 2 years for B Lysholm knee scale: Total scores relative to baseline ↓ at all follow-ups Meniscus volume > 15%: At 12 months, both the control compared with group A and overall comparison were significant (> 15%) and at 2 years the overall group comparison was significant |
Vega et al. [44] Randomised controlled, comparator multi-centre- Phase I/II study | Allogenic (GMP) Obtained from three healthy donors | n = 30 17 Females 13 Males Mean age: 57 ± 9 Experimental group = 15 Control = 15 | Grade 2–4 Unresponsive to conventional treatments for at least 6 months prior to recruitment | 1 Injection: Experimental group: 40 × 106 cells from a 5 × 106 cell/mL suspension Control: 60 mg of HA in 3 mL | Baseline, day 8, 3, 6 and 12 months | Minor adverse events during first 7 days in both groups = 53–60% of patients VAS: ↓ in experimental group at 6 and 12 months. Control group ↓ at 12 months WOMAC: Pain and general WOMAC ↓ at 6 and 12 months for experimental group Lequesne algofunctional index: ↓ at 6 and 12 months in experimental group MRI: Poor Cartilage Index (PCI) ↓ at 12 months in experimental group |
Gupta et al. [30] Randomised, double-blind multicentre placebo-controlled phase II study | Allogenic (GMP ex-vivo) Stempeucel® | n = 60 15 in each dose group (4 groups) Randomised into two groups within the 4 main groups (2:1) for Stempeucel® and placebo (control) | Grade 2–3 | 1 Injection: Group 1: 25 × 106 of Stempeucel® Group 2: 50 × 106 of Stempeucel® Group 3: 75 × 106 of Stempeucel® Group 4: 150 × 106 of Stempeucel® Each group control: PlasmaLyte placebo | Baseline, 1 week, 1, 3 and 6 months Clinical data unblinded after 6 months but followed-up until 12 months | Adverse events: 97 mild to moderate adverse events were reported in 40 subjects |
Espinosa et al. [49] Randomised clinical trial Phase I/II | Autologous (GMP) co-administered with HA | n = 30 Control group:10 Low dose:10 High dose:10 Active control | Inclusion of ≥ 2 Range: 2–4 | 1 Injection: Control: 60 mg HA (in a volume of 4 ml) Low BM-MSC dose: 10 × 106 cells in 1.5 ml ringer’s lactate solution + 4 ml of HA injection High BM-MSCs dose: 100 × 106 cells in 3 ml ringer’s lactate solution + 4 ml of HA injection | Baseline, 3, 6 and 12 months | Articular pain requiring anti-inflammatory treatment at 24 h post-injection in 1, 3 and 6 patients in the control, low-dose and high-dose groups respectively Range of motion: ↑ in BM-MSCs treated groups (effect seen earlier in higher dose) VAS score ↓ in low and high dosage groups at all follow-up times WOMAC: Control: Pain ↓ at 3 and 6 months, and function ↑ at 3 and 6 months Low dose: Stiffness ↓ at 6 and 12 months High dose: All WOMAC sub-scores improved significantly at 12 months X-ray: Knee joint space ↓ in control group at 12 months |