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Table 1 Characteristics of clinical studies included

From: Efficacy of stem cells therapy for Crohn’s fistula: a meta-analysis and systematic review

Author Year of publication Phase Age (M ± SD) Sex (M:F) Number of case included Source of cell Type of cell Dose of cell injected Donor Follow-up* Outcomes
Both of CD and un-CD fistula
 Garcia-Olmo et al. [43] 2009 II 43.33 ± 9.9 24:25 CD, 14 (ASC, 7; FG, 7); unCD, 35 (ASC, 17; FG, 18) AT, Cx401 ADSC 1 × 107 cells/ml NR 7 M FH, SF-12, SAE
 Guadalajara et al. [44] 2012 II 42.6 ± 10.9 24:25 CD, 20 (ASC+FG, 17; FG, 3); unCD, 29 (ASC+FG, 7; FG, 22) Liposuction, NR ADSC NR Autologous 5 Y FH, MRI, SAE
 Garcia-Olmo et al. [53] 2015 I–II–III 49 8:2 CD, 3; un-CD, 7 AT, homemade ADSC/SVF 1–3 × 107 Autologous/allogeneic 1 Y FH, Wexner scores, SAE
 Herreros et al. [54] 2019 NR 45 24:21 CD, 18; un-CD, 24 NR, homemade ASC/SVF 2 × 106 cells/ml Autologous/allogeneic 1 Y FH, AE, SAE
Only un-CD fistula
 Herreros et al. [45] 2012 III 49.78 NR ASC, 64; ASC+FG, 60; FG, 59 AT, homemade ADSC First, 2 × 107 cells/ml; second, 4 × 107 cells/ml Autologous 1 Y SF-36Q, Wexner score 22, FCS, SAE
 Choi et al. [55] 2017 II 37.9 13:0 1 × 107 cells/mL, 5; 2 × 107 cells/mL, 8 AT, homemade ADSC 2 × 107 or 4 × 107 cells/ml Autologous 6 M FH, Wexner scale, SAEs
 Dozois et al. [56] 2019 I 39.8 7:8 15 AT, homemade AD-MSC NR Autologous 6 M FH, MRI, SAE
 Topal et al. [57] 2019 NR 47 ± 13.1 8:2 10 AT, homemade ADSC NR Autologous 9 M PE, SAE
 Garcia-Arranz et al. [46] 2020 III 50 ± 10 30:14 10 × 107 ASC+FG, 23; FG, 21 NR, NR ADSC 10 × 107 cells/ml Autologous 2 Y PE, MRI, SF-12, Wexner incontinence score, SAE
Only CD fistula
 García-Olmo et al. [37] 2005 I 35.1 ± 2.4 2:3 5 AT, homemade AD-MSC 1–3 × 107 cells/ml Autologous 30 M FH, MRI, SAE
 Ciccocioppo et al. [58] 2011 NR 32 8:4 12 BM, homemade BM-MSC NR Autologous 1 Y CDAI; PDAI; MRI; endoscopy; FoxP3; T cell; IL-2, 5, 10, and 12; IFN; TNF-a; SAE
 Cho et al. [59] 2013 II 26. ± 6.0 4:6 1 × 107 cells/ml, 3; 2 × 107 cells/ml, 4; 4 × 107 cells/ml, 3 AT, homemade ADSC 1/2/4 × 107 cells/ml Autologous 8 M FH, CD4/CD8 ratio, SAE
 de la Portilla et al. [60] 2013 I/IIa 36 ± 9.0 11:13 2 × 107 cells/ml, 9; 6 × 107 cells/ml, 15 AT, homemade ADSC First, 2 × 107 cells/ml; second, 4 × 107 cells/ml Autologous 6 M MRI, PDAI, CDAI, SAE
 Lee et al. [61] 2013 II 26.2 ± 5.4 30:13 42 AT, homemade ADSC First, 15.8 × 107; second, 19.1 × 107 Autologous 1 Y FH, SAE
 Molendijk et al. [47] 2015 NR 37.3 12:9 1 × 107 cells/ml, 5; 3 × 107 cells/ml, 5; 9 × 107 cells/ml, 5; placebo, 6 BM, homemade ADSC 1/3/9 × 107 cells/ml Autologous 2 Y FH, MRI, PDAI, CDAI, IBDQ, CDEIS, SES-CD, SF-36, CRP, IL-8, IL-1β, IL-6 and 10, TNF, IL-12p70, SAE
 Ciccocioppo et al. [62] 2015 NR 39.25 ± 14.32 5:3 8 BM, homemade BM-MSC NR Autologous 6 Y MRI, CDAI, PDAI, SAE
 Cho et al. [63] 2015 II 26.2 ± 5.5 28:13 41 AT, homemade ADSC 3 × 107 cells/ml Autologous 2 Y FH, AE, SAE
 Park et al. [67] 2016 NR 32.17 ± 7.96 4:2 1 × 107 cells/ml, 3; 3 × 107 cells/ml, 3 AT, homemade ADSC 1 × 107 cells/ml, 3 × 107 cells/ml Allogeneic 6 M FH, MRI, CD4/CD8 ratio, SAE
 Panés et al. [48] 2016 III 38 116:96 ASC, 107; placebo, 105 AT, alofisel AD-MSC 12 × 107 cells Allogeneic 6 M MRI, PDAI, CDAI, IBDQ, van Assche score, IgG AE, SAE
 García-Arranz et al. [68] 2016 I–IIa 35 NR 10 AT, homemade ADSC First, 2 × 107 cells; second, 4 × 107 cells Allogeneic 4.5 M QoL, SF-36, fecal incontinence, severity index
 Dietz et al. [64] 2017 I 35 ± 14.21 6:6 12 BM, homemade MSC 2 × 107 cells/ml Autologous 6 M MRI, Van Assche score, SAE
 Scott [69] 2018 III 38 NR 24 AT, alofisel ADSC 12 × 107 cells Allogeneic 13 M IL-6, 12, and 10; TNF-α; TGF-β; PDAI; CDAI; SAE
 Panés et al. [49] 2018 III 38.3 114:98 12 × 107 cells, 107; placebo, 105 AT, alofisel ADSC 12 × 107 cells Allogeneic 13 M IBDQ, PDAI, CDAI, TNF, MRI, TEAE
 Wainstein et al. [70] 2018 NR 36 2:7 9 AT, homemade ADSC NR Autologous 37 M IBDQ, PDAI, SAE
 Avivar-Valderas et al. [52] 2019 NR NR NR ASC 58; placebo 42 AT, Alofisel AD-MSC NR Allogeneic 13 M DSA; HLA-I; CRPs; CD55, 46, and 59; AE; SAE
 Dige et al. [66] 2019 NR NR 6:15 21 AT, homemade AT NR Autologous 6 M FH, complications
 Zhou et al. [50] 2020 NR 28.86 ± 10.13 21:1 ADSC, 11; placebo, 11 AT, homemade ADSC 5 × 106 cells/ml NR 1 Y FH, MRI, ultrasonography, CDAI, PDAI, IBDQ, VAS, Wexner score, CRP, ESR, FC, SAE
 Barnhoorn et al. [51] 2020 NR 42 8:6 1 × 107 cells/ml, 5; 3 × 107 cells/ml, 5; 9 × 107 cells/ml, 5; placebo, 6 BM homemade BM-MSC 1/3/9 × 107 cells/ml Allogeneic 4 Y FH, HLA, MRI, rectoscopy, PDAI, CDAI, Vaizey, QoL, SF36, IBDQ, SAE
 Lightner et al. [65] 2020 NR 49 0:5 5 BM, homemade MSC NR Autologous 6 M FH, MRI, AE, SAE
  1. *Y = years and M = months
  2. Abbreviations: NR not report, FG fibrin glue, AT adipose tissue, BM bone marrow, ADSC adipose-derived stem cells, SVF stromal vascular fraction, MSC mesenchymal stem cell, BM-MSC bone marrow-derived mesenchymal stromal cells, FH fistula healing, PE physical examination, QoF quality of life, MRI magnetic resonance imaging, FCS fistula complexity score, CDAI Crohn’s disease activity index, PDAI perianal disease activity index, CDEIS Crohn’s disease endoscopic index of severity, SES-CD simplified endoscopic activity score, CRP C-reactive protein, TGF-β transforming growth factor-β, DSA donor-specific antibodies, VSA pain scores with visual analog score, ESR erythrocyte sedimentation rate, FC fecal calprotectin, GF growth factor, BLI bioluminescence, TEAEs treatment-emergent adverse events