Review of stem cells as promising therapy for perianal disease in inflammatory bowel disease

Table 1 Summary of studies utilizing stem cell therapy in perianal Crohn’s disease

Ref.	Study year	Stem cell therapy type	Type of study	Type of perianal disease	Method and amount of administration	Concurrent therapies	Outcome
[8]	2003	Autologous Adipose Stem Cell Studies	Case Report	Complex recurrent rectovaginal CD fistula	Local injection of 9 × 106 MSCs	Olsalazine (previously failed immunomodulators and biologics)	Healed 7 d after injection; no serious adverse events from MSC therapy were observed
[9]	2005	Autologous Adipose Stem Cell Studies	Phase I Clinical Trial	Complex refractory CD fistulas, refractory to medical therapy and failing surgical therapy at least twice	Local injection of 3 × 106 MSCs	Immunosuppression without infliximab	Tissue repair in 75% (3 of 4) patients at 8 wk, no AE at 1 and 2 yr follow up; no serious adverse events from MSC therapy were observed
[10]	2009	Autologous Adipose Stem Cell Studies	Phase IIb Clinical Trial	Complex perianal cryptoglandular and CD fistulas, refractory to medical and surgical therapy (including at least one induction with anti-TNF)	Local injection of 2 × 106 MSCs plus fibrin glue vs fibrin glue alone; second local injection of 4 × 106 MSCs if no healing seen at 8 wk	Immunosuppression without infliximab, cyclosporine, or tacrolimus	71% (5 of 7) with fistula healing at 12 mo vs 14% healing in control group; higher quality of life in those with stem cell treatment; 1 serious adverse event from therapy (anal abscess)
[11]	2013	Autologous Adipose Stem Cell Studies	Dose-escalation Phase I Clinical Trial	Perianal CD fistula, with CD confirmed by biopsy; 5 patients with previously unsuccessful surgical therapy	Local injection of 1 × 107, 2 × 107, 4 × 107 MSC, based on fistula size (total of 3-40 × 107 MSC)	Immunosuppression including infliximab	30% (3 of 10) patients with complete healing at two months and then continued eight month follow up; no serious adverse events from MSC therapy were observed
[12]	2013	Autologous Adipose Stem Cell Studies	Dose-proportional Phase II Clinical Trial	Perianal CD fistula, less than 2cm in length	Local injection of 3 × 107 or 6 × 107 MSC, per 1 cm of fistula length; average 15.8 × 107 MSC, followed by second injection of 1.5 × previous (average 19 × 107 MSC) if incomplete closure at 8 wk	Immunosuppression including infliximab, but no infliximab within three months prior to MSC therapy	82% (27 of 33) patients with healing at 2 mo and continued healing of 88% these individuals (23 of 26) at 12 mo; of the 6/33 patients with incomplete closure, 5 had > 50% closure; no serious adverse events from MSC therapy were observed
[13]	2015	Autologous Adipose Stem Cell Studies	Phase II Clinical Trial	Perianal CD fistulas	Local injection of 3 × 107 MSC, per 1 cm of fistula length; if second dose needed, 1.5 × previous dose administered	Immunosuppression including biologics	80.8% (21 of 26) patients with complete healing at 12 and 24 mo; recurrence in 11.5% at 12 mo and 16.7% at 24 mo; no serious adverse events from MSC therapy were observed
[14]	2017	Autologous Adipose Stem Cell Studies	Phase I Clinical Trial	Refractory Perianal Fistulas in CD	Intra-operative placement of fistula plug, consisting of 20 × 106 MSC per plug attached to a bioabsorbable matrix	Biologic therapies (patients had failure to immunomodulators)	Healing in 83% (10 of 12) of patients at 6 mo; no serious adverse events from MSC therapy were observed
[15]	2011	Autologous Bone Marrow Stem Cell Studies	Phase II Clinical Trial	Active complex perianal CD fistulas, refractory to medical and surgical therapies (including biologics)	Local injection of 1.5-3 × 107 MSC every 3 wk until improvement or until no longer available (2-5 injections total)	All patients took mesalamine and azathioprine, except for 2 taking prednisone with mesalamine and 2 on mesalamine monotherapy	Complete closure 67% (6 of 9) patients at 2 mo with continued closure at 12 mo; no serious adverse events from MSC therapy were observed
[16]	2017	Allogeneic Adipose Stem Cell Studies	Phase III Randomized Clinical Trial	Refractory complex perianal CD fistulas; maximum of 2 internal and 3 external openings; draining for at least 6 wk	Local injection of 120 million C × 601 MSC or placebo; second injection of	Biologic therapies, immunomodulators, antibiotics	Closure at 24 wk in 50% (53 of 107) patients compared to placebo 34% (36 of 105) patients; shorter time to remission in treatment group vs placebo: 6.7 wk vs 14.6 wk; serious adverse events occurred in 6.8% of treatment subjects (7 of 103) and 6.9% of placebo subjects (7 of 102)-in both groups, the most common serious events were anal abscess/fistula and proctalgia
[17]	2015	Allogeneic Bone Marrow Stem Cell Studies	Phase IIa Randomized Clinical Trial	Refractory perianal CD fistulas to medical and surgical therapies, including all patients refractory to anti-TNF therapy	Local injections of 1 × 107 MSC for 5 patients; 3 × 107 MSC for 5 patients; 9 × 107 MSC for 5 patients; placebo for 6 patients	Stable doses of concurrent therapies, including mesalamine and steroids > 4 wk, immunomodulators > 8 wk, and anti-TNF > 8 wk	Healing in 47% (7 of 15) patients with MSC therapy vs 33% (2 of 6) with placebo at 12 wk; no serious adverse events from MSC therapy were observed

AE: Adverse events; MSC: Mesenchymal stem cell; CD: Crohn’s disease; TNF: Tumor necrosis factor.