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Surgery Today

, Volume 46, Issue 7, pp 835–842 | Cite as

A clinical trial of autologous adipose-derived regenerative cell transplantation for a postoperative enterocutaneous fistula

  • Tsunekazu MizushimaEmail author
  • Hidekazu Takahashi
  • Hiroshi Takeyama
  • Atsushi Naito
  • Naotsugu Haraguchi
  • Mamoru Uemura
  • Junichi Nishimura
  • Taishi Hata
  • Ichiro Takemasa
  • Hirofumi Yamamoto
  • Yuichiro Doki
  • Masaki Mori
Original Article

Abstract

Purpose

Adipose-derived stem cell (ADSC) transplantation is expected to be a minimally invasive, but effective, treatment for postoperative enterocutaneous fistulas associated with poor blood flow and chronic inflammation. The aim of this study was to assess the safety and efficacy of a novel ADSC therapy for this condition.

Methods

We conducted an open-label, single-arm exploratory phase I study to assess the safety and efficacy of a novel ADSC therapy. Using the Celution system, we isolated adipose-derived regenerative cells (ADRCs) containing abundant ADSCs from liposuction-obtained gluteal adipose tissue. A mixture of ADRCs and fibrin glue was subsequently transplanted into the fistula, and ADRCs were percutaneously and endoscopically injected around the fistula. We evaluated the safety and feasibility of ADRC transplantation and fistula closure in six patients (UMIN000007316).

Results

ADRC transplantation was completed in all patients. The fistula closure rates were 83.3 % at 4 and 12 weeks and 100 % at 24 weeks. All patients had grade 1 pain and subcutaneous hemorrhage at the liposuction sites, but no serious adverse events related to this procedure were observed.

Conclusions

Transplantation of autologous ADRCs is safe, feasible and advantageous, as it can secure a sufficient cell count without culture or multiple passages, and will likely be effective for a postoperative enterocutaneous fistula.

Keywords

Adipose-derived regenerative cells Adipose-derived stem cells Cell therapy Enterocutaneous fistula 

Notes

Acknowledgments

We thank Dr. Ezoe and the members of the Medical Center for Translational Research, Osaka University Hospital for helpful suggestions and discussions. We also thank Ms. Maruyama and Ms. Shimamoto for help with the data collection. This work was supported by a Grant-in-Aid for Scientific Research (C), the Takeda Science Foundation, and the Japanese Society for Advancement of Surgical Techniques.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Golub R, Golub RW, Cantu R Jr, Stein HD. A multivariate analysis of factors contributing to leakage of intestinal anastomoses. J Am Coll Surg. 1997;184:364–72.PubMedGoogle Scholar
  2. 2.
    Watanabe A, Kohnoe S, Shimabukuro R, Yamanaka T, Iso Y, Baba H, Higashi H, Orita H, Emi Y, Takahashi I, Korenaga D, Maehara Y. Risk factors associated with surgical site infection in upper and lower gastrointestinal surgery. Surg Today. 2008;38:404–12.CrossRefPubMedGoogle Scholar
  3. 3.
    Daams F, Wu Z, Lahaye MJ, Jeekel J, Lange JF. Prediction and diagnosis of colorectal anastomotic leakage: a systematic review of literature. World J Gastrointest Surg. 2014;6:14–26.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of fistulizing Crohn’s disease in Olmsted County, Minnesota. Gastroenterology. 2002;122:875–80.CrossRefPubMedGoogle Scholar
  5. 5.
    Fazio VW, Tekkis PP, Remzi F, Lavery IC, Manilich E, Connor J, Preen M, Delaney CP. Quantification of risk for pouch failure after ileal pouch anal anastomosis surgery. Ann Surg. 2003;238:605–14 (discussion 614–7).Google Scholar
  6. 6.
    Sagar PM, Pemberton JH. Intraoperative, postoperative and reoperative problems with ileoanal pouches. Br J Surg. 2012;99:454–68.CrossRefPubMedGoogle Scholar
  7. 7.
    Oomen JW, Spauwen PH, Bleichrodt RP, van Goor H. Guideline proposal to reconstructive surgery for complex perineal sinus or rectal fistula. Int J Colorectal Dis. 2007;22:225–30.CrossRefPubMedGoogle Scholar
  8. 8.
    Girotto JA, Ko MJ, Redett R, Muehlberger T, Talamini M, Chang B. Closure of chronic abdominal wall defects: a long-term evaluation of the components separation method. Ann Plast Surg. 1999;42:385–94 (discussion 394–5).Google Scholar
  9. 9.
    Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, Fujii T, Uematsu M, Ohgushi H, Yamagishi M, Tokudome T, Mori H, Miyatake K, Kitamura S. Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation. 2005;112:1128–35.CrossRefPubMedGoogle Scholar
  10. 10.
    Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.CrossRefPubMedGoogle Scholar
  11. 11.
    Fraser JK, Wulur I, Alfonso Z, Hedrick MH. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. 2006;24:150–4.CrossRefPubMedGoogle Scholar
  12. 12.
    Safford KM, Hicok KC, Safford SD, Halvorsen YD, Wilkison WO, Gimble JM, Rice HE. Neurogenic differentiation of murine and human adipose-derived stromal cells. Biochem Biophys Res Commun. 2002;294:371–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Rangappa S, Fen C, Lee EH, Bongso A, Sim EK. Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes. Ann Thorac Surg. 2003;75:775–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, Pell CL, Johnstone BH, Considine RV, March KL. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109:1292–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Puissant B, Barreau C, Bourin P, Clavel C, Corre J, Bousquet C, Taureau C, Cousin B, Abbal M, Laharrague P, Penicaud L, Casteilla L, Blancher A. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005;129:118–29.CrossRefPubMedGoogle Scholar
  16. 16.
    Takahashi H, Haraguchi N, Nishikawa S, Miyazaki S, Suzuki Y, Mizushima T, Nishimura J, Takemasa I, Yamamoto H, Mimori K, Ishii H, Doki Y, Mori M. Biological and clinical availability of adipose-derived stem cells for pelvic dead space repair. Stem Cells Transl Med. 2012;1:803–10.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Rullier E, Laurent C, Garrelon JL, Michel P, Saric J, Parneix M. Risk factors for anastomotic leakage after resection of rectal cancer. Br J Surg. 1998;85:355–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Pryor KO, Fahey TJ 3rd, Lien CA, Goldstein PA. Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population—a randomized controlled trial. JAMA. 2004;291:79–87.CrossRefPubMedGoogle Scholar
  19. 19.
    Yeh CY, Changchien CR, Wang JY, Chen JS, Chen HH, Chiang JM, Tang R. Pelvic drainage and other risk factors for leakage after elective anterior resection in rectal cancer patients: a prospective study of 978 patients. Ann Surg. 2005;241:9–13.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Itani KM, Wilson SE, Awad SS, Jensen EH, Finn TS, Abramson MA. Ertapenem versus cefotetan prophylaxis in elective colorectal surgery. N Engl J Med. 2006;355:2640–51.CrossRefPubMedGoogle Scholar
  21. 21.
    El-Gazzaz G, Geisler D, Hull T. Risk of clinical leak after laparoscopic versus open bowel anastomosis. Surg Endosc. 2010;24:1898–903.CrossRefPubMedGoogle Scholar
  22. 22.
    Fujita F, Torashima Y, Kuroki T, Eguchi S. The risk factors and predictive factors for anastomotic leakage after resection for colorectal cancer: reappraisal of the literature. Surg Today. 2014;44:1595–602.CrossRefPubMedGoogle Scholar
  23. 23.
    Chambers WM, Mortensen NJ. Postoperative leakage and abscess formation after colorectal surgery. Best Pract Res Clin Gastroenterol. 2004;18:865–80.CrossRefPubMedGoogle Scholar
  24. 24.
    Keighley MR, Eastwood D, Ambrose NS, Allan RN, Burdon DW. Incidence and microbiology of abdominal and pelvic abscess in Crohn’s disease. Gastroenterology. 1982;83:1271–5.PubMedGoogle Scholar
  25. 25.
    Elton C, Makin G, Hitos K, Cohen CR. Mortality, morbidity and functional outcome after ileorectal anastomosis. Br J Surg. 2003;90:59–65.CrossRefPubMedGoogle Scholar
  26. 26.
    Setti-Carraro P, Ritchie JK, Wilkinson KH, Nicholls RJ, Hawley PR. The first 10 years’ experience of restorative proctocolectomy for ulcerative colitis. Gut. 1994;35:1070–5.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Araki T, Okita Y, Uchino M, Ikeuchi H, Sasaki I, Funayama Y, Fukushima K, Futami K, Maeda K, Iiai T, Itabashi M, Hase K, Motoya S, Kitano A, Mizushima T, Maeda K, Kobayashi M, Mohri Y, Kusunoki M. Risk factors for surgical site infection in Japanese patients with ulcerative colitis: a multicenter prospective study. Surg Today. 2014;44:1072–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Yoshimura K, Shigeura T, Matsumoto D, Sato T, Takaki Y, Aiba-Kojima E, Sato K, Inoue K, Nagase T, Koshima I, Gonda K. Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates. J Cell Physiol. 2006;208:64–76.CrossRefPubMedGoogle Scholar
  29. 29.
    Mareschi K, Ferrero I, Rustichelli D, Aschero S, Gammaitoni L, Aglietta M, Madon E, Fagioli F. Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J Cell Biochem. 2006;97:744–54.CrossRefPubMedGoogle Scholar
  30. 30.
    Ohgushi H, Caplan AI. Stem cell technology and bioceramics: from cell to gene engineering. J Biomed Mater Res. 1999;48:913–27.CrossRefPubMedGoogle Scholar
  31. 31.
    Garcia-Olmo D, Herreros D, Pascual I, Pascual JA, Del-Valle E, Zorrilla J, De-La-Quintana P, Garcia-Arranz M, Pascual M. Expanded adipose-derived stem cells for the treatment of complex perianal fistula: a phase II clinical trial. Dis Colon Rectum. 2009;52:79–86.CrossRefPubMedGoogle Scholar
  32. 32.
    Herreros MD, Garcia-Arranz M, Guadalajara H, De-La-Quintana P, Garcia-Olmo D, FATT Collaborative Group. 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. 2012;55:762–72.CrossRefPubMedGoogle Scholar
  33. 33.
    Houtgraaf JH, den Dekker WK, van Dalen BM, Springeling T, de Jong R, van Geuns RJ, Geleijnse ML, Fernandez-Aviles F, Zijlsta F, Serruys PW, Duckers HJ. First experience in humans using adipose tissue-derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59:539–40.CrossRefPubMedGoogle Scholar
  34. 34.
    Marino G, Moraci M, Armenia E, Orabona C, Sergio R, De Sena G, Capuozzo V, Barbarisi M, Rosso F, Giordano G, Iovino F, Barbarisi A. Therapy with autologous adipose-derived regenerative cells for the care of chronic ulcer of lower limbs in patients with peripheral arterial disease. J Surg Res. 2013;185:36–44.CrossRefPubMedGoogle Scholar
  35. 35.
    Kølle SF, Fischer-Nielsen A, Mathiasen AB, Elberg JJ, Oliveri RS, Glovinski PV, Kastrup J, Kirchhoff M, Rasmussen BS, Talman ML, Thomsen C, Dickmeiss E, Drzewiecki KT. Enrichment of autologous fat grafts with ex vivo expanded adipose tissue-derived stem cells for graft survival: a randomised placebo-controlled trial. Lancet. 2013;382:1113–20.CrossRefPubMedGoogle Scholar
  36. 36.
    Gotoh M, Yamamoto T, Kato M, Majima T, Toriyama K, Kamei Y, Matsukawa Y, Hirakawa A, Funahashi Y. Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose-derived regenerative cells: 1-year outcomes in 11 patients. Int J Urol. 2014;21:294–300.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  • Tsunekazu Mizushima
    • 1
    Email author
  • Hidekazu Takahashi
    • 1
  • Hiroshi Takeyama
    • 1
  • Atsushi Naito
    • 1
  • Naotsugu Haraguchi
    • 1
  • Mamoru Uemura
    • 1
  • Junichi Nishimura
    • 1
  • Taishi Hata
    • 1
  • Ichiro Takemasa
    • 1
  • Hirofumi Yamamoto
    • 1
  • Yuichiro Doki
    • 1
  • Masaki Mori
    • 1
  1. 1.Department of SurgeryOsaka University Graduate School of MedicineSuitaJapan

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