Techniques in Coloproctology

, Volume 21, Issue 5, pp 345–353 | Cite as

Autologous adipose tissue-derived stem cells for the treatment of complex perianal fistulas not associated with Crohn’s disease: a phase II clinical trial for safety and efficacy

  • S. Choi
  • S.-B. Ryoo
  • K. J. ParkEmail author
  • D.-S. Kim
  • K.-H. Song
  • K. H. Kim
  • S. S. Chung
  • E. J. Shin
  • Y. B. Cho
  • S. T. Oh
  • W.-K. Kang
  • M. H. Kim
Original Article



Injection of adipose tissue-derived stem cells (ASCs) is a novel method for the treatment of complex perianal fistulas. We aimed to evaluate the safety and efficacy of ASCs in the treatment of complex anal fistulas not associated with Crohn’s disease.


A phase II clinical trial was performed comparing two different doses of ASCs (group 1: 1 × 107 cells/mL and group 2: 2 × 107 cells/mL). Eligible patients were administered an amount of ASCs proportional to the length of the fistula by injection into the submucosal layer surrounding the internal opening and inside of the fistula tract. ASCs at twice the initial concentration were administered if complete closure was not achieved within 8 weeks. The efficacy endpoint was the complete closure of fistulas 8 weeks after injection. Patients demonstrating complete closure at week 8 were subjected to follow-up for 6 months.


Fifteen patients were injected with ASCs; thirteen completed the study. Complete closure was observed in 69.2% (9/13) of patients at 8 weeks. Three of five patients in group 1, and six of eight in group 2 displayed complete closure; no significant differences were observed between the groups. Six of nine patients who showed complete closure participated in additional follow-up; five (83.3%) showed persistent response at 6 months. No grade 3 or 4 adverse events (AEs) were observed; observed AEs were not related to ASC treatment.


ASCs might be a good option for the treatment of complex perianal fistulas are not healed by conventional operative procedures.


Stem cells Adipose tissue-derived Autologous Perianal fistula Complex 



Sang-ji Choi, and Seung-Bum Ryoo contributed equally to this study. This research was sponsored by the Grant of Clinical Research Institute, Seoul National University Hospital (Grant No: 0620102730), from Anterogen Co., Ltd.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The protocol was approved by the institutional review boards at each of the four study sites for compliance with ethical standards and by the Ministry of Food and Drug Safety (IND number: 10844).

Informed consent

Written informed consent was obtained from all patients.


  1. 1.
    Parks AG, Stitz RW (1976) The treatment of high fistula-in-ano. Dis Colon Rectum 19(6):487–499CrossRefPubMedGoogle Scholar
  2. 2.
    Steele SR, Kumar R, Feingold DL, Rafferty JL, Buie WD, Standards Practice Task Force of the American Society of C, Rectal S (2011) Practice parameters for the management of perianal abscess and fistula-in-ano. Dis Colon Rectum 54(12):1465–1474. doi: 10.1097/DCR.0b013e31823122b3 CrossRefPubMedGoogle Scholar
  3. 3.
    Whiteford MH, Kilkenny J 3rd, Hyman N, Buie WD, Cohen J, Orsay C, Dunn G, Perry WB, Ellis CN, Rakinic J, Gregorcyk S, Shellito P, Nelson R, Tjandra JJ, Newstead G, Standards Practice Task F, American Society of C, Rectal S (2005) Practice parameters for the treatment of perianal abscess and fistula-in-ano (revised). Dis Colon Rectum 48(7):1337–1342. doi: 10.1007/s10350-005-0055-3 CrossRefPubMedGoogle Scholar
  4. 4.
    Cadeddu F, Salis F, Lisi G, Ciangola I, Milito G (2015) Complex anal fistula remains a challenge for colorectal surgeon. Int J Colorectal Dis 30(5):595–603. doi: 10.1007/s00384-014-2104-7 CrossRefPubMedGoogle Scholar
  5. 5.
    Mizuno H, Zuk PA, Zhu M, Lorenz HP, Benhaim P, Hedrick MH (2002) Myogenic differentiation by human processed lipoaspirate cells. Plast Reconstr Surg 109(1):199–209 (discussion 210–191) CrossRefPubMedGoogle Scholar
  6. 6.
    Garcia-Olmo D, Garcia-Arranz M, Herreros D, Pascual I, Peiro C, Rodriguez-Montes JA (2005) A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 48(7):1416–1423. doi: 10.1007/s10350-005-0052-6 CrossRefPubMedGoogle Scholar
  7. 7.
    Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M (2009) Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum 52(1):79–86. doi: 10.1007/DCR.0b013e3181973487 CrossRefPubMedGoogle Scholar
  8. 8.
    Herreros MD, Garcia-Arranz M, Guadalajara H, De-La-Quintana P, Garcia-Olmo D, Group FC (2012) Autologous expanded adipose-derived stem cells for the treatment of complex cryptoglandular perianal fistulas: a phase III randomized clinical trial (FATT 1: fistula Advanced Therapy Trial 1) and long-term evaluation. Dis Colon Rectum 55(7):762–772. doi: 10.1097/DCR.0b013e318255364a CrossRefPubMedGoogle Scholar
  9. 9.
    Cho YB, Park KJ, Yoon SN, Song KH, Kim DS, Jung SH, Kim M, Jeong HY, Yu CS (2015) Long-term results of adipose-derived stem cell therapy for the treatment of Crohn’s fistula. Stem Cells Transl Med 4(5):532–537. doi: 10.5966/sctm.2014-0199 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lee WY, Park KJ, Cho YB, Yoon SN, Song KH, Kim DS, Jung SH, Kim M, Yoo HW, Kim I, Ha H, Yu CS (2013) Autologous adipose tissue-derived stem cells treatment demonstrated favorable and sustainable therapeutic effect for Crohn’s fistula. Stem Cells 31(11):2575–2581. doi: 10.1002/stem.1357 CrossRefPubMedGoogle Scholar
  11. 11.
    Son HJ, Sohn DK, Hong CW, Han KS, Kim BC, Park JW, Choi HS, Chang HJ, Oh JH (2013) Factors associated with complete local excision of small rectal carcinoid tumor. Int J Colorectal Dis 28(1):57–61. doi: 10.1007/s00384-012-1538-z CrossRefPubMedGoogle Scholar
  12. 12.
    Park KJ, Ryoo SB, Kim JS, Kim TI, Baik SH, Kim HJ, Lee KY, Kim M, Kim WH (2016) Allogeneic adipose-derived stem cells for the treatment of perianal fistula in Crohn’s disease: a pilot clinical trial. Colorectal Dis 18(5):468–476. doi: 10.1111/codi.13223 CrossRefPubMedGoogle Scholar
  13. 13.
    Parks AG, Gordon PH, Hardcastle JD (1976) A classification of fistula-in-ano. Br J Surg 63(1):1–12CrossRefPubMedGoogle Scholar
  14. 14.
    Cho YB, Lee WY, Park KJ, Kim M, Yoo HW, Yu CS (2012) Autologous adipose tissue-derived stem cells for the treatment of Crohn’s fistula: a Phase I clinical study. Cell Transplant. doi: 10.3727/096368912x656045 CrossRefPubMedGoogle Scholar
  15. 15.
    Jorge JM, Wexner SD (1993) Etiology and management of fecal incontinence. Dis Colon Rectum 36(1):77–97CrossRefPubMedGoogle Scholar
  16. 16.
    Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47(1):207–214CrossRefPubMedGoogle Scholar
  17. 17.
    Garcia-Olmo D, Garcia-Arranz M, Garcia LG, Cuellar ES, Blanco IF, Prianes LA, Montes JA, Pinto FL, Marcos DH, Garcia-Sancho L (2003) Autologous stem cell transplantation for treatment of rectovaginal fistula in perianal Crohn’s disease: a new cell-based therapy. Int J Colorectal Dis 18(5):451–454. doi: 10.1007/s00384-003-0490-3 CrossRefPubMedGoogle Scholar
  18. 18.
    de la Portilla F, Alba F, Garcia-Olmo D, Herrerias JM, Gonzalez FX, Galindo A (2013) Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis 28(3):313–323. doi: 10.1007/s00384-012-1581-9 CrossRefPubMedGoogle Scholar
  19. 19.
    Garcia-Olmo D, Guadalajara H, Rubio-Perez I, Herreros MD, de-la-Quintana P, Garcia-Arranz M (2015) Recurrent anal fistulae: limited surgery supported by stem cells. World J Gastroenterol 21(11):3330–3336. doi: 10.3748/wjg.v21.i11.3330 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, Lee RJ (2004) Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium. J Am Coll Cardiol 44(3):654–660. doi: 10.1016/j.jacc.2004.04.040 CrossRefPubMedGoogle Scholar
  21. 21.
    Kim YS, Choi YJ, Suh DS, Heo DB, Kim YI, Ryu JS, Koh YG (2015) Mesenchymal stem cell implantation in osteoarthritic knees: is fibrin glue effective as a scaffold? Am J Sports Med 43(1):176–185. doi: 10.1177/0363546514554190 CrossRefPubMedGoogle Scholar
  22. 22.
    Han EC, Ryoo SB, Oh HK, Choe EK, Moon SH, Park KJ (2014) Crohn’s anal fistula: haw bad is it compared to ordinary non-Crohn’s anal fistula? Colorectal Dis 16(suppl. 3):37–105Google Scholar
  23. 23.
    Yagi H, Soto-Gutierrez A, Parekkadan B, Kitagawa Y, Tompkins RG, Kobayashi N, Yarmush ML (2010) Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transplant 19(6):667–679. doi: 10.3727/096368910X508762 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Papadakis KA, Targan SR (2000) The role of chemokines and chemokine receptors in mucosal inflammation. Inflamm Bowel Dis 6(4):303–313CrossRefPubMedGoogle Scholar
  25. 25.
    Le Blanc K (2006) Mesenchymal stromal cells: tissue repair and immune modulation. Cytotherapy 8(6):559–561. doi: 10.1080/14653240601045399 CrossRefPubMedGoogle Scholar
  26. 26.
    Champagne BJ, O’Connor LM, Ferguson M, Orangio GR, Schertzer ME, Armstrong DN (2006) Efficacy of anal fistula plug in closure of cryptoglandular fistulas: long-term follow-up. Dis Colon Rectum 49(12):1817–1821. doi: 10.1007/s10350-006-0755-3 CrossRefPubMedGoogle Scholar
  27. 27.
    Garg P, Song J, Bhatia A, Kalia H, Menon GR (2010) The efficacy of anal fistula plug in fistula-in-ano: a systematic review. Colorectal Dis 12(10):965–970. doi: 10.1111/j.1463-1318.2009.01933.x CrossRefPubMedGoogle Scholar
  28. 28.
    Zmora O, Mizrahi N, Rotholtz N, Pikarsky AJ, Weiss EG, Nogueras JJ, Wexner SD (2003) Fibrin glue sealing in the treatment of perineal fistulas. Dis Colon Rectum 46(5):584–589. doi: 10.1097/01.DCR.0000064697.21308.37 CrossRefPubMedGoogle Scholar
  29. 29.
    Sentovich SM (2003) Fibrin glue for anal fistulas: long-term results. Dis Colon Rectum 46(4):498–502. doi: 10.1097/01.DCR.0000059658.99412.3C CrossRefPubMedGoogle Scholar
  30. 30.
    van der Hagen SJ, Baeten CG, Soeters PB, van Gemert WG (2006) Long-term outcome following mucosal advancement flap for high perianal fistulas and fistulotomy for low perianal fistulas: recurrent perianal fistulas: failure of treatment or recurrent patient disease? Int J Colorectal Dis 21(8):784–790. doi: 10.1007/s00384-005-0072-7 CrossRefPubMedGoogle Scholar
  31. 31.
    Schouten WR, Zimmerman DD, Briel JW (1999) Transanal advancement flap repair of transsphincteric fistulas. Dis Colon Rectum 42(11):1419–1422 (discussion 1422–1413) CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • S. Choi
    • 1
  • S.-B. Ryoo
    • 2
  • K. J. Park
    • 2
    Email author
  • D.-S. Kim
    • 3
  • K.-H. Song
    • 3
  • K. H. Kim
    • 4
  • S. S. Chung
    • 4
  • E. J. Shin
    • 5
  • Y. B. Cho
    • 6
  • S. T. Oh
    • 7
  • W.-K. Kang
    • 7
  • M. H. Kim
    • 8
  1. 1.Kangwon National University HospitalChuncheon-siRepublic of Korea
  2. 2.Department of SurgerySeoul National University HospitalSeoulRepublic of Korea
  3. 3.Daehang HospitalSeoulRepublic of Korea
  4. 4.Ewha Womans University Medical CenterSeoulRepublic of Korea
  5. 5.Soonchunhyang University HospitalBucheon-siRepublic of Korea
  6. 6.Samsung Medical CenterSungkyunkwan University School of MedicineSeoulRepublic of Korea
  7. 7.College of MedicineThe Catholic University of KoreaSeoulRepublic of Korea
  8. 8.Anterogen Co., Ltd.SeoulRepublic of Korea

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