Introduction
Overview on injective mesenchymal stem cell-based treatments
Aim of the review
References | Cell donor | Patients | Study design | Study results | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Number of patients | Knee OA grading | Age range | Type of study (ClinicalTrials.gov Identifier if applies) | Experimental group(s) | Cell dosage | Treatment comparator | Final follow-up | Measurements | Main outcomes | ||
Davatchi [19] | Autologous | 4 | KL II–III | 54–65 years | Phase I single-arm, open label (NCT00550524) | BMSC injection | 8–9 × 106 BMSCs | – | 12 months | VAS Knee motion range Algofunctional assessments Patellae crepitus X-ray | Treatment safety ↓ Pain ↑ Knee function
Note: no statistical analysis on average data available
|
Emadedin [20] | Autologous | 6 | KL IV | 40–64 years | Case series | BMSC injection | 20–24 × 106 BMSCs | – | 12 months | VAS WOMAC OA Index Knee flection Walking distance MRI | Treatment safety ↓ Pain ↑ Knee function ↑ Walking distance ↑ Cartilage thickness |
Orozco [21] | Autologous | 12 | KL II–IV | 29–75 years | Open-label, single-arm clinical trial (NCT01183728) | BMSC injection | 40 × 106 BMSCs | – | 12 months | VAS WOMAC OA Index Lequesne Functional Index SF-36 quality-of-life questionnaire MRI | ↓ Pain ↑ Knee function ↑ Cartilage quality |
Orozco [22] | Autologous | 12 | KL II–IV | 29–75 years | Phase I/II single-arm, open-label clinical trial (NCT01183728) | BMSC injection | 40 × 106 BMSCs | – | 24 months | VAS WOMAC OA index Lequesne functional index SF-36 quality-of-life questionnaire MRI | Maintenance of the improvements achieved at 12 months and reported in [Orozco 2013] |
Emadedin [23] | Autologous | 6 | KL III–IV | 18–65 years | Case series | BMSC injection | 0.5 × 106 BMSCs/kg | – | 30 months | VAS WOMAC OA index Walking distance MRI | Long-term safety ↓ Pain ↑knee function ↑ Walking distance ↑Cartilage quality |
Vega [24] | Allogeneic (from single donors) | 30 (15/treatment 15/control) | KL II–IV | 36–73 years | Phase I/II multicenter, prospective, randomized, double-blind, comparator-controlled clinical trial (NCT01586312) | HA combined with BMSCs | 40 × 106 BMSCs | HA injection (control) | 12 months | VAS WOMAC OA index Lequesne functional index SF-12 quality-of-life questionnaire MRI | In the experimental group (HA + BMSCs) ↓ Pain ↑ Knee function ↑ Cartilage quality No significant changes in the control group (HA) |
Soler [25] | Autologous | 15 | KL II–III | 33–63 years | Phase I/II prospective, open-label, single-dose, single-arm clinical trial (NCT01183728) | BMSC injection | 40 × 106 BMSCs | – | 12 months Yearly VAS assessment for 4 years | VAS WOMAC OA index Lequesne functional index SF-36 quality-of-life questionnaire MRI | ↓ Pain ↑ Knee function
Note: further reduction of VAS value at 4 year follow-up
|
Davatchi [26] | Autologous | 4 | KL II–III | 54–65 years | Phase I single-arm, open label (NCT00550524) | BMSC injection | 8–9 × 106 BMSCs | – | 60 months | VAS Knee motion range Algofunctional assessments Patellae crepitus X-ray | Progressive loss of some of the improvements measured at 12 months [Davatchi 2011]
Note: no statistical analysis on average data available
|
Lamo-Espinosa [27] | Autologous | 30 (10/group 10/control) | KL II–IV | 50–80 years | Phase I/II multicenter, randomized, comparator-controlled, open-label clinical trial (NCT02123368) | HA combined with two different BMSC doses | 10 × 106 BMSCs 100 × 106 BMSCs | HA injection (control) | 12 months | VAS WOMAC OA index Knee motion range MRI X-ray | In both HA + BMSCs groups ↓ Pain Only in HA + BMSCs (high dose) ↑ Knee function ↑ Cartilage quality No significant changes at 12 months in the control group (HA) |
Gupta [28] | Allogeneic (pooled from multiple donors) | 60 (10/group 20 placebo) | KL II–III | 40–70 years | Phase II multicenter randomized, placebo-controlled, double-blind, clinical trial (NCT01453738) | HA combined with four different BMSC doses | 25 × 106 BMSCs 50 × 106 BMSCs 75 × 106 BMSCs 150 × 106 BMSCs | Placebo | 12 months | VAS WOMAC OA index Intermittent and constant OA pain MRI | Adverse events predominant for relevant BMSC doses (≥ 50 × 106) Despite some improvements in the low-dose group, no significant changes compared to baseline or placebo |
Al-Najar [29] | Autologous | 13 | KL II–III | 34–63 | Phase I prospective, open-label, clinical trial (NCT02118519) | Two BMSC doses injected 1-month apart from each other | 1st dose: 30.8 × 106 BMSCs 2nd dose: 30.4 × 106 BMSCs | – | 24 months | Knee injury and OA outcome score MRI | Treatment safety ↓ Pain ↑ Knee function Improvements in pain and knee function maintained from 6 to 24 months ↑ Cartilage thickness at 12 months |
References | Cell donor | Patients | Study design | Study results | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Number of patients | Knee OA grading | Age range | Type of study (ClinicalTrials.gov Identifier if applies) | Experimental group(s) | Cell dosage | Treatment comparator | Follow-up | Measurements | Main outcomes | ||
Kim [30] | Autologous | 41 (75 knees) | KL I–IV | 53–80 years | N/A | BMAC injected in combination with adipose tissue | N/A | – | 12 months | VAS International knee documentation committee scale SF-36 quality-of-life questionnaire Knee injury and OA outcome score Lysholm score | ↓ Pain ↑ Knee function Poorer outcomes in patients with KL IV compared to patients with OA at an earlier stage |
Centeno [31] | Autologous | 681 (840 knees) | KL I–IV | N/A Mean age reported for the two groups 54.3 years 59.9 years | Report based on registry data | BMAC injected in combination with PRP BMAC injected in combination with adipose graft and PRP | N/A | – | 12 months | Numeric pain scale Lower extremity functional scale Improvement rating score | ↓ Pain ↑ Knee function No difference between BMAC injection with and without adipose graft |
Centeno [32] | Autologous | 373 (424 knees) | KL I–IV | N/A Mean age reported for the two groups 54.5 years 50.2 years | Report based on registry data | BMAC with low cell content combined with PRP and platelet lysate BMAC with high cell content combined with PRP and platelet lysate | -> 4 × 108 cells -≤ 4 × 108 cells | – | 12 months | Numeric pain scale Lower extremity functional scale International knee documentation committee scale Improvement rating score | ↓ Pain ↑ Knee function Significantly higher pain reduction in patients treated with BMAC with high mononuclear cell content |
Sampson [33] | Autologous | 27 (bilateral knee OA) 46 (unilateral knee OA) | KL III–IV | 23–79 years | Retrospective case series | BMAC injection followed by PRP injection (8 weeks later) | N/A | – | 5 months | VAS Global patient satisfaction survey | ↓ Pain High levels of patient satisfaction |
Shapiro [34] | Autologous | 25 (bilateral knee OA) | KL I–III | 42–68 years | Prospective, randomized single-blind, placebo-controlled trial (NCT01931007) | Injection of BMAC combined with platelet-poor plasma | N/A | Placebo (contralateral knee) | 6 months | VAS Intermittent and constant OA pain questionnaire | ↓ Pain No significant difference in pain relief between knees treated with BMAC and with saline solution |
References | Cell donor | Patients | Study design | Study results | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Number of patients | Knee OA grading | Age range | Type of study (ClinicalTrials.gov Identifier if applies) | Experimental group(s) | Cell dosage | Treatment comparator | Final follow-up | Measurements | Main outcomes | ||
Jo [35] | Autologous | Phase I: 9 (3/group) Phase II: 9 | KL II–IV | 18–75 years | Proof-of-concept clinical trial | Phase I: injection with three different ASC doses Phase II injection with the highest ASC dose | Phase I: 10 × 106 ASCs 50 × 106 ASCs 100 × 106 ASCs Phase II: 100 × 106 ASCs | – | 6 months | Safety VAS WOMAC OA index Second-look arthroscopy Histology MRI | Treatment safe for all the tested ASC doses ↓ Pain and ↑ knee function only in the high-dose group |
Pers [36] | Autologous | 18 (6/group) | KL III–IV | 50–75 years | Phase I multicentric, prospective, single-arm, open-label, dose escalating clinical trial (NCT01585857) | Injection with three different ASC doses | 2 × 106 ASCs 10 × 106 ASCs 50 × 106 ASCs | – | 6 months | VAS WOMAC OA index Patient global assessment Knee injury and OA outcome score Short arthritis assessment scale SF-36 quality-of-life questionnaire | ↓ Pain and ↑ knee function only in the low-dose group |
Jo [37] | Autologous | Phase I: 9 (3/group) Phase II: 9 | KL II–IV | 18–75 years | 2-year follow-up of the trial described in [35] | Phase I: injection with three different ASC doses Phase II injection with the highest ASC dose | Phase I: 10 × 106 ASCs 50 × 106 ASCs 100 × 106 ASCs Phase II: 100 × 106 ASCs | – | 24 months | VAS WOMAC OA index Knee society clinical rating system Knee injury and OA outcome score MRI | At 1 year, significant improvements mainly in the high-dose group Only in the high-dose group, improvements maintained at 2 years |
Song [38] | Autologous | Phase I: 18 (6/group) Phase II: 14 (the same patients treated in Phase I) | KL II–IV | 40–70 years | Phase I/II randomized, double-blind clinical trial (NCT01809769) | Injection with three different ASC doses. Two injections at 3 and 6 weeks after liposuction A third ASC injection was provided after 48 weeks | Phase I: 10 × 106 ASCs 20 × 106 ASCs 50 × 106 ASCs Phase II: third injection with 50 × 106 ASCs | – | 24 months | WOMAC OA index Numerical pain rating scale SF-36 quality-of-life questionnaire MRI | Treatment safe for all the tested ASC doses ↓ Pain, ↑ knee function, ↑ cartilage volume more relevant and long-lasting in the high-dose group The third injection increased the improvement rate, especially in patients previously treated with the low and middle ASC dose |
References | Cell donor | Patients | Study design | Study results | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Number of patients | Knee OA grading | Age range | Type of study (ClinicalTrials.gov Identifier if applies) | Experimental group(s) | Cell dosage | Treatment comparator | Final follow-up | Measurements | Main outcomes | ||
Pak [39] | Autologous | 2 | N/A | 70–79 years | Case series | Injection of SVF combined with PRP and dexamethasone, followed by weekly PRP injections for 1 month | N/A | – | 3 months | VAS Knee motion range Functional rating index MRI | ↓ Pain ↑ Knee function Note: no statistical analysis on average data available |
Gibbs [40] | Autologous | 4 | N/A | 23–50 years | Case series | Injection of SVF combined with PRP followed by monthly PRP injections for 4 months | 11.5 × 106 − 50 × 106 cells | – | 12 months | Knee injury and OA outcome score Physical function test | ↓ Pain ↑ Knee function Note: no statistical analysis on average data available |
Pak [41] | Autologous | 3 | KL III | 60–87 years | Case series | Injection of SVF combined with HA + PRP followed by weekly HA + PRP injections for 3 weeks | N/A | – | 5 months | VAS Knee motion range Functional rating index MRI | ↓ Pain ↑ Knee function Note: no statistical analysis on average data available |
Fodor [42] | Autologous | 6 (8 knees) | KL I–III | 51–69 years | Phase I open-label single-arm clinical trial (NCT02357485) | Injection of SVF | 14.1 × 106 cells | – | 12 months | VAS WOMAC OA index Knee motion range MRI | ↓ Pain ↑ Knee function Improvements at 3 months maintained at 12 months |
Bansal [43] | Autologous | 10 (13 knees) | KL I–II | ≥ 50 years | Phase I open-label single-arm clinical trial (NCT03089762) | Injection of SVF combined with PRP | N/A | – | 24 months | WOMAC OA index 6-min walk distance MRI | ↓ Pain ↑ Knee function ↑ Walking distance Improvements maintained at 24 months |
Hudetz [44] | Autologous | 17 (32 knees) | KL II–IV | 40–85 years | Prospective, open-label single-arm, clinical trial | Injection of micro-fragmented adipose tissue | N/A | – | 12 months | VAS X-rays dGEMRIC MRI IgG glycome composition in blood plasma and synovial fluid | Treatment safety ↓ Pain ↑ Knee function ↑ Glycosaminoglycan content in residual areas of cartilage |