Table 1.
Characteristics of the included RCTs
| Study | Location | Design | Diagnosis | Patient number | Mean age (years) | Men (%) | Background therapy | Type and source of stem cells | Amount, delivery methods, and sessions of SCT | Control | Follow-up duration | Definition of CR |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Garcia-Olmo 2009 | Spain | R, OL | CD with complex perianal fistula | 14 | 43.3 | 49 | Standard medical management including immunomodulators and infliximab, antibiotics, and fibrin glue | ADSCs, autologous | 1*10^7 cells, local injection, 1–2 sessions | No additional treatment | 8 weeks | Absence of drainage through the external openings and complete reepithelialization of external openings |
| Molendijk 2015 | The Netherlands | R, DB, PC | CD with refractory perianal fistulas | 21 | 37.8 | 57.1 | Mesalamine and steroids 4 weeks; immunosuppressive drugs 8 weeks; anti-TNFa agents 8 weeks | BM-MSCs, allogeneic | 1*, 3*, or 9* 10^7 cells, local injection, 1 session | Placebo (solution with no cells) | 12 weeks | Reduction in the number of draining fistulas determined by absence of discharge at physical examination and absence of collections of 2 cm directly related to the treated fistula tracts as measured by MRI |
| Melmed 2015 | USA | R, DB, PC | Moderate-to-severe CD with CDAI: 220 ~ 450 | 46 | 35.7 | 47.1 | Stable doses of immunomodulators and/or biologics | Placenta-derived cells, allogeneic | 1.5* or 5* 10^8 cells, IV infusion, 1–2 sessions | Placebo (solution with no cells) | 6 weeks | CDAI < 150 |
| Hawkey 2015 | 11 European centers | R, OL | Medically refractory CD | 45 | 32.4 | 46.7 | Azathioprine/6 mercaptopurine, Methotrexate, and anti-TNFa agents | HSCs, autologous | 9.0*10^6 cells/kg, IV infusion, 1 session | No additional treatment | 52 weeks | CDAI < 150 |
| Panes 2016 | 49 European and Israel centers | R, DB, PC | CD with complex perianal fistula | 212 | 38.3 | 54.8 | Immunomodulators and anti-TNFa agent | Adipose-derived MSCs, allogenic | 12*10^7 cells, local injection, 1–2 sessions | Placebo (solution with no cells) | 24 weeks | Clinical assessment of closure of all treated external openings that were draining at baseline, and the absence of collections larger than 2 cm of the treated perianal fistulas in at least two of three dimensions, confirmed by masked central MRI |
| Zhang 2018 | China | R, OL | Medically refractory CD | 82 | 33.5 | 61 | Glucocorticoids, immunosuppressive agents, and anti-TNFa agent | UC-MSCs, allogenic | 1*10^6 cells/kg, IV infusion, 4 sessions | No additional treatment | 52 weeks | CDAI < 150 |
| Zhou 2020 | China | R, OL | CD with complex perianal fistula | 22 | 24.7 | 95.5 | ASA, probiotics, immunomodulators, antibiotics, glucocorticoids, and anti-TNFa agent | ADSCs, autologous | 1*10^7 cells, local injection, 1 sessions | No additional treatment | 52 weeks | Complete epithelialization of external openings (i.e., no pus outflow from the external openings under any circumstances) and no evidence of fistulas in MRI or ERUS |
| Ascanelli 2021 | Italy | R, OL | CD with complex perianal fistula | 120 | 50.4 | 61.2 | Standard medical treatments (not specified) | ADSCs, autologous | Cells in 16 ml adipose tissue, local injection, 1–2 sessions | No additional treatment | 24 weeks | External opening was closed with no perianal discharge on clinical assessment and MRI |
| Lightner 2022 | USA | R, SB, PC | Refractory CD | 6 | 41.6 | 66.7 | Standard medical treatments (not specified) | BM-MSCs, allogeneic | 15* or 30* 10^7 cells, local injection, 1–2 sessions | Placebo (saline) | 12 weeks | CRp < 2.87 mg/l and CDAI < 150 |
| Lightner 2023a | USA | R, SB, PC | CD with complex perianal fistula | 23 | 33.9 | 47.8 | Glucocorticoids, immunosuppressive agents, and anti-TNFa agent | BM-MSCs, allogeneic | 7.5* 10^7 cells, local injection, 1–2 sessions | Placebo (saline) | 24 weeks | Complete cessation in drainage and the external opening was epithelialized on clinical examination and an absence of a fluid collection ≥ 2 cm in any 2 of 3 dimensions and a lack of edema, inflammation, or sign of active inflammatory response on MRI |
| Lightner 2023b | USA | R, SB, PC | CD with peripouch fistulas | 22 | 41.2 | 31.8 | Glucocorticoids, immunosuppressive agents, and anti-TNFa agent | BM-MSCs, allogeneic | 7.5* 10^7 cells, local injection, 1 session | Placebo (saline) | 24 weeks | External opening was closed with no discharge on clinical assessment and MRI |
| Lightner 2023c | USA | R, SB, PC | CD with rectovaginal fistulizing | 19 | 42.6 | 0 | Glucocorticoids, immunosuppressive agents, and anti-TNFa agent | BM-MSCs, allogeneic | 7.5* 10^7 cells, local injection, 1–2 sessions | Placebo (saline) | 24 weeks | Combined clinical and radiological healing of the rectovaginal fistulizing |
RCTs, randomized controlled trials; SCT, stem cell therapy; CR, clinical remission; R, randomized; OL, open-label; SB, single-blind; DB, double-blind; PC, placebo-controlled; TNFa, tumor necrosis factor alpha; CD, Crohn’s disease; CDAI, Crohn's Disease Activity Index; ADSCs, adipose-derived stem cells; BM-MSCs, bone marrow-derived mesenchymal stem cells; HSCs, hematopoietic stem cells; MSCs, mesenchymal stem cells; UC-MSCs, umbilical cord mesenchymal stem cells; CRP, C-reactive protein; MRI, magnetic resonance imaging;