Table 1.
Summary of included studies
| Author | Subject population | KL grade | Treatment | Donor | Outcomes | Follow-up | Funding |
|---|---|---|---|---|---|---|---|
| Single-arm, prospective follow-up studies | |||||||
| Bui 201420 (Vietnam) | N = 21 | II–III | SVF injection + PRP | Auto | Lysholm score, VAS pain, MRI | 1, 3, 6 M | X |
| Centeno 2008a21 (Unites states) | N = 1 (age: 36 y; M) | – | BD-MSC injection (4.56 × 107 cells) | Auto | VAS pain, MRI (cartilage and meniscus volumes) | 1, 3 M | – |
| Centeno 2008b22 (Unites states) | N = 1 (46 y; M) | – | BD-MSC injection (2.24 × 107 cells) | Auto | VAS pain, functional rating index, ROM, MRI evaluation (cartilage and meniscus volumes) | 1, 3, 6 M | – |
| Davatchi 201123 (Iran) | N = 4 (age: 57.8 ± 5.0 y; 50% F) | II–III | BD-MSC injection (8–9 × 106 cells) | Auto | VAS pain, ROM | 6 M | X |
| Davatchi 201624 (Iran) | N = 4 (age: 57.8 ± 5.0 y; 50% F) | II–III | BD-MSC injection (8–9 × 106 cells) | Auto | VAS pain, ROM | 60 M | X |
| Emadedin 201225 (Iran) | N = 6 (age: 53.8 ± 8.9 y; 100% F) | IV | BD-MSC injection (2.0–2.4 × 107 cells) | Auto | VAS pain, WOMAC, ROM, MRI evaluation | 2 W; 1, 2, 6, 12 M | X |
| Emadedin 201526 (Iran) | N = 6 (age: 53.8 ± 8.9 y; 100% F) | IV | BD-MSC injection (2.0–2.4 × 107 cells) | Auto | VAS pain, WOMAC, MRI evaluation | 2, 6, 12, 30 M | X |
| Fodor 201627 (Unites states) | N = 6 patients 8 knees (age: 59.0 ± 7.3 y; 83.3% F) | I (N = 2) II (N = 2) III (N = 4) | SVF injection | Auto | VAS pain, WOMAC, ROM, TUG, MRI evaluation | 3, 12 M | X |
| Kim 2015c28 (Korea) | N = 49 patients, 55 knees (age: 58.1 ± 8.9 y; 52.7% F) | I–II | AD-MSC implantation (4.3 × 106 cells) + AD | Auto | IKDC, Tegner activity scale | 26.7 M | – |
| Kim 201629 (Korea) | N = 20 patients, 24 knees (age: 57.9 ± 5.9 y; 45.0% F) | I–II | AD-MSC implantation (4.4 × 106 cells) + AD | Auto | IKDC, Tegner activity scale, MRI evaluation (MOCART and MOAKS) | 27.9 M | – |
| Koh 201332 (Korea) | N = 18 (age: 54.6 ± 7.8 y; 66.7% F) | III–IV | AD-MSC injection (1.18 × 106 cells) + PRP | Auto | WOMAC, Lysholm score, VAS pain, MRI evaluation (WORMS) | 24.3 M | – |
| Koh 2014a30 (Korea) | N = 35 patients, 37 knees (age: 57.4 ± 5.7 y; 60.0% F) | I–II | AD-MSC implantation (3.8 × 106 cells) + AD | Auto | IKDC, Tegner activity scale, arthroscopic evaluation (ICRS grade) | 26.5 M | – |
| Koh 201531 (Korea) | N = 30 (age: 70.3 [65–80] y; 83.3% F) | II–III | AD-SVF (4.2 × 107 cells) injection + PRP + AD | Auto | Lysholm, KOOS, VAS pain, K/L grade, arthroscopic evaluation | 3, 12, 24 M | – |
| Michalek 201533 (Czech Republic) | N = 1114 (age: 62.0 [19–94] y; 47.8% F) | II–IV | AD-SVF injection (1.6 × 106 cells) + PRP | Auto | Modified KOOS, X-ray, MRI evaluation | 17.2 M | X |
| Orozco 201334 (Spain) | N = 12 (age: 49.0 ± 17.3 y; 50.0% F) | II (N = 4) III (N = 3) IV (N = 5) | BD-MSC injection (4.0 × 107 cells) | Auto | VAS pain, Lequesne index, WOMAC, PCI, SF-36 | 3, 6, 12 M | – |
| Orozco 201435 (Spain) | N = 12 (age: 49.0 ± 17.3 y: 50.0% F) | II–IV | BD-MSC injection (4.0 × 107 cells) | Auto | VAS pain score, Lequesne index, WOMAC, PCI | 3, 6, 12, 24 M | – |
| Pak 201136 (Korea) | N = 2 (age: 74.5 ± 6.4 y; 100% F) | – | AD-MSC injection + HA + PRP + CaCl2 + dexamethasone | Auto | VAS pain, ROM, MRI evaluation | 3 M | – |
| Sampson 201637 (Unites states) | N = 125 (age: 57.0 [23–79] y; 100% F) | III–IV | BMC injection + PRP | Auto | VAS, global patients satisfaction survey | 4.8 M | – |
| Soler Rich 201539 (Spain) | N = 50 (age: 57.8 ± 14.1 y; 40.0%F) | II–IV | BD-MSC injectio (4.0 × 107 cells) | Auto | VAS, Lequesne score, WOMAC, MRI evaluation T2 mapping, PCI) | 0, 6, 12 M | – |
| Soler 201638 (Spain) | N = 15 (age: 51.1 ± 10.3 y; 60.0% F) | II (N = 9) III (N = 6) | BD-MSC injection (4.1 × 107 cells) | Auto | VAS, Lequesne score, WOMAC, SF-36, MRI evaluation (T2 mapping) | 1 W; 3, 6, 12, 48 M | X |
| Trajune 201340 (Thailand) | N = 5 (age: 57.2 ± 1.92 y; 80.0% F) | II | AAPBSC injection + GFAP concentrate + HA + MCS | Auto | WOMAC, KOOS | 1, 6 M | X |
| Quasi-experimental studies | |||||||
| Centeno 201441 (Unites states) | I: N = 518 (age 54.3 ± 14.1 y) C: N = 163 (age 59.9 ± 10.3 y) | I: I (N = 223) II (N = 145) III/IV (N = 102) C: I (N = 69) II (N = 58) III/IV (N = 39) | I: BMC injection + PRP with adipose fat graft C: BMC injection + PRP | Auto | Improvement rating scale, LEFS, NPS | 1, 3, 6, 12 M | – |
| Jo 201442 (Korea) | I-a: Low dose, N = 3 (age: 63.0 ± 8.6 y; 66.7% F) I-b: Mid dose, N = 3 (age: 65.0 ± 6.6 y; 100% F) I-c: High dose, N = 12 (age: 61.0 ± 6.2 y; 83.3% F) | I-a: III (N = 2) IV (N = 1) I-b: III (N = 2) IV (N = 1) I-c: III (N = 8) IV (N = 4) | AD-MSC injection (I-a: 1.0 × 107, I-b: 5.0 × 107, I-c: 1.0 × 108 cells) | Auto | WOMAC, VAS pain, KSS, MRI evaluation (defect size and cartilage volume), arthroscopic evaluation (defect size and ICRS grade), biopsy | 1, 2, 3, 6 M | X |
| Kim 2015a43 (Korea) | I: N = 17 patients, 17 knees (age: 57.7 ± 5.8 y; 52.9% F) C: N = 37 patients, 39 knees (age: 57.5 ± 5.9 y; 62.2% F) | I–II | I: AD-MSC implantation with fibrin glue (3.9 × 106 cells) + AD C: AD-MSC implantation (3.9 × 106 cells) + AD | Auto | IKDC, Tegner activity scale, arthroscopic evaluation (ICRS grade) | 28.6 M | – |
| Kim 2015b44 (Korea) | I: N = 20 (age: 59.1 ± 3.5 y; 65.0% F) C: N = 20 (age: 59.4 ± 3.1 y; 65.0% F) | I–II | I: AD-MSC implantation (4.0 × 106 cells) + AD C: AD-MSC injection (4.0 × 106 cells) + PRP | Auto | IKDC, Tegner activity scale, arthroscopic evaluation (ICRS grade) | 28.6 M | – |
| Koh 201245 (Korea) | I: N = 25 (age: 54.2 ± 9.3 y; 68.0% F) C: N = 25 (age: 54.4 ± 11.3 y; 68.0% F) | I: 3.3 ± 0.8 C: 2.7 ± 0.7 | I: AD-MSC injection (1.89 × 106 cells) + PRP C: PRP | Auto | Lysholm, Tegner activity scale, VAS pain | 3, 16.4 M | – |
| Nguyen 201746 (Vietnam) | I: N = 15 (age: 58.6 ± 6.5 y; 80.0% F) C: N = 15 (age: 58.2 ± 5.7 y; 80.0% F) | I: II (N = 4) III/IV (N = 11) C: II (N = 5) III/IV (N = 10) | I: AD-SVF injection (1.89 × 106 cells) + AM + PRP C: AM + PRP | Auto | WOMAC, modified VAS pain, Lysholm, MRI | 1, 6, 12, 18 M | X |
| Pers 20166 (France) | I-a: Low dose, N = 6 (age: 63.2 ± 4.1 y; 50.0% F) I-b: Mid dose, N = 6 (age: 65.5 ± 8.1 y; 50.0% F) I-c: High dose, N = 6 (age: 65.2 ± 2.3 y; 66.7% F) | I-a: III (N = 2) IV (N = 41) I-b III (N = 1) IV (N = 5) I-c III (N = 0) IV (N = 6) | AD-SVF injection (I-a: 2 × 106, I-b: 10 × 106, I-c: 50 × 106 cells) | Auto | WOMAC, Global knee pain, PGA, KOOS, SAS, SF-36, MRI evaluation | 1 W; 3, 6 M | X |
| Randomized controlled trials | |||||||
| Gupta 201647 (India) | Cohort 1: I-a (Low dose): N = 10 (age: 58.1 ± 8.2 y; 70.0% F) I-b (Mid dose): N = 10 (age: 57.3 ± 9.5 y; 80.0% F) C-a: N = 10 (age: 54.9 ± 8.3 y; 100.0% F) Cohort 2: I-c (High dose): N = 10 (age: 55.0 ± 6.7 y; 80.0% F) I-d (Very high dose): N = 10 (age: 54.0 ± 6.7 y; 50.0% F) C-b: N = 10 (age: 56.7 ± 5.2 y; 70.0% F) | I-a: II (N = 4) III (N = 6) I-b: II (N = 1) III (N = 9) C-a: II (N = 3) III (N = 7) I-c: II (N = 1) III (N = 9) I-d: II (N = 3) III (N = 7) C-b: II (N = 2) III (N = 8) | I: BD-MSC injection (I-a: 25 × 106, I-b: 50 × 106, I-c: 75 × 106 cells, I-d: 150 × 106 cells) + HA C: HA | Allo | VAS, WOMAC, ICOAP, X-ray, MRI (WORMS) | 12 M | X |
| Koh 2014b48 (Korea) | I: N = 21 (age: 54.2 ± 2.9 y; 76.2% F) C: N = 23 (age: 52.3 ± 4.9 y; 73.9% F) | I: II (N = 0) III (N = 9) IV (N = 12) C: II (N = 1) III (N = 11) IV (N = 11) | I: HTO + AD-MSC implantation + PRP C: HTO + PRP | Auto | Lysholm, KOOS, VAS pain, FTA, arthroscopic evaluation (Kanamiya grade) | 24.4 M | – |
| Lamo-Espinosa 20165 (Spain) | I-a (Low dose): N = 10 (age: 65.9 [IQR: 59.5, 70.6] y; 60.0% F) I-b (High dose): N = 10 (age: 57.8 [IQR: 55.0, 60.8] y; 20.0% F) C: N = 10 (age: 60.3 [IQR: 55.1, 61.1] y; 30.0% F) | I-a: II (N = 1) III (N = 2) IV (N = 7) I-b: II (N = 3) III (N = 3) IV (N = 4) C: II (N = 4) III (N = 2) IV (N = 4) | I: BD-MSC injection (Low dose: 1 × 107 cells; High dose: 1 × 108 cells) + HA C: HA | Auto | VAS, WOMAC, ROM, X-ray, MRI (WORMS) | 3, 6, 12 M | X |
| Varma 201049 (India) | I: N = 25 (age: 50.7 ± 5.4 y) C: N = 25 (age: 48.2 ± 5.1 y) | – | I: BMC injection + AD C: AD | Auto | VAS pain, OAOS | 1, 2, 3, 6 M | – |
| Vega 201550 (Spain) | I: N = 15 (age: 56.6 ± 9.6 y; 60.0% F) C: N = 23 (age: 57.3 ± 9.4 y; 66.7% F) | I: II (N = 6) III (N = 6) IV (N = 3) C: II (N = 7) III (N = 5) IV (N = 3) | I: BD-MSC injection (4.0 × 107 cells) C: HA | Allo | VAS pain, WOMAC, Lequesne algofunctional indices, SF-12, MRI evaluation (T2 mapping, PCI) | 1 W; 3, 6, 12 M | – |
| Wakitani 200251 (Japan) | N = 24 (I: N = 12; C: N = 12) (age: 63.0 [49–70] y; 62.5% F) | – | I: HTO + BD-MSC implantation (1.0 × 107 cells) C: HTO + cell free collagen gel-sheet implantation | Auto | Hospital for special surgery knee-rating scale, arthroscopic and histological assessment | 16 M | – |
| Wong 201352 (Singapore) | I: N = 28 (age: 53.0 [36–54] y; 54.0% F) C: N = 28 (age: 49.0 [24–54] y; 50.0% F) | – | I: HTO + BD-MSC implantation (1.5 × 107 cells) C: HTO | Auto | IKDC, Lysholm, Tegner activity scale, MRI evaluation (MOCART) | 6, 12, 24 M | – |
AAPBSC autologous activated peripheral blood stem cells, AD arthroscopic debridement, AD-MSC adipose tissue derived mesenchymal stem (stromal) cells, AD-SVF adipose tissue derived stromal vascular fraction, AM arthroscopic microfracture, BD-MSC bone marrow derived mesenchymal stem (stromal) cell, BMC bone marrow concentrate, FTA femorotibial angle, GFAP growth factor addition/preservation, HA hyaluronic acid, HTO high tibial osteotomy, ICOAP intermittent and constant osteoarthritis pain, ICRS international cartilage repair society, IKDC international knee documentation committee, IQR interquartile range, K/L grade Kellgren/Lawrence grade, KOOS knee osteoarthritis outcome score, KSS knee society score, LEFS lower extremity functional questionnaire, MCS microdrilling mesenchymal cell stimulation, MOAKS MRI osteoarthritis knee score, MOCART magnetic resonance observation of cartilage repair tissue, MRI magnetic resonance image, NPS numeric pain scale, OAOS osteoarthritis outcome score, PCI poor cartilage index, PGA patient global assessment, PRP platelet-rich plasma, ROM range of motion, SAS short arthritis assessment scale, SF-12 short form-12 health survey, SF-36 short form-36 health survey, SVF stromal vascular fraction, TUG timed up and go, VAS visual analog scale, WOMAC Western Ontario and McMaster Universities Osteoarthritis Index, WORMS whole-organ magnetic resonance imaging score. X indicates presence of funding.