Treatment of perianal fistula in Crohn’s disease with autologous adipose tissue-derived regenerative cells

• Bedzhanyan A.L.
• Eremin I.I.
• Bumbazhay A.A.
• Petrenko К.N.
• Sumbaev A.A.
• Matinyan A.V.
• Ushakov N.S.
• Petrikina A.P.
• Lazareva N.L.
• Butenko A.V.

Abstract

Crohn’s disease (CD) is a chronic transmural inflammation that can affect any part of the gastrointestinal tract, from the oral cavity to the anus. Perianal fistulas are a common complication, occurring in nearly one-third of patients with Crohn’s disease. This condition causes chronic pain, purulent discharge, abscess formation, and episodic fecal incontinence, significantly impairing the quality of life. As a result, perianal involvement represents a serious clinical challenge, despite the availability of a wide range of therapeutic options. Treatment of this condition requires a comprehensive approach, involving both surgical and pharmacological interventions. The goal of treating the perianal manifestations of CD is the surgical resolution of fistulas, improvement of patients’ quality of life, and preservation of anal sphincter function.

Currently, the combination of pharmacological and surgical treatments leads to positive outcomes in 50% of cases. The use of new biological drugs and modern minimally invasive surgical techniques improves remission rates in CD treatment, but the rate of complete healing of perianal fistulas remains low.

A promising alternative treatment involves stimulating the regeneration of affected tissues. The possibility of tissue repair without the need for excision opens new avenues in the treatment of anorectal fistulas associated with Crohn’s disease. Several experimental studies have confirmed the efficacy of this approach. In 2001, a group of researchers demonstrated the presence of multipotent mesenchymal stromal cells in adipose tissue obtained through traditional liposuction. A protocol for isolating the stromal-vascular cellular fraction from lipoaspirate for clinical use was also developed. This discovery opened new possibilities in the field of cell therapy, making it more accessible for practical use in disciplines such as oncology, coloproctology, and reconstructive and plastic surgery.

Autologous stromal-vascular cell fraction (SVF), isolated from adipose tissue, serves as an accessible source of cells with angiogenic, anti-inflammatory, immunomodulatory, and regenerative properties. Cells obtained through enzymatic processing of adipose tissue from the anterior abdominal wall are injected into the fistula tract wall under visual control.

This publication presents a case of treating a female patient with a complex posterior transsphincteric rectal fistula, resistant to therapeutic interventions.

Keywords: Crohn’s disease; Crohn’s disease-related rectal fistulas; perianal manifestations of Crohn’s disease; surgical treatment; conservative treatment; adiposederived stem cells; autologous regenerative adipose tissue cells

References

1.     Ardizzone S., Porro G.B. Perianal Crohn’s disease: overview. Dig Liver Dis. 2007; 39: 957–8.

2.     Marzo M., Felice C., Pugliese D., Andrisani G., Mocci G., Armuzzi A., et al. Management of perianal fistulas in Crohn’s disease: an up-to-date review. World J Gastroenterol. 2015; 21 (5): 1394–403.

3.     Gecse K.B., Bemelman W., Kamm M.A., Stoker J., Khanna R., Ng S.C., et al.; World Gastroenterology Organization; International Organisation for Inflammatory Bowel Diseases IOIBD; European Society of Coloproctology and Robarts Clinical Trials; World Gastroenterology Organization International Organisation for Inflammatory Bowel Diseases IOIBD European Society of Coloproctology and Robarts Clinical Trials. A global consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn’s disease. Gut. 2014; 63 (9): 1381–92. DOI: https://doi.org/10.1136/gutjnl-2013-306709

4.     Kotze P.G., Shen B., Lightner A., Yamamoto T., Spinelli A., Ghosh S., et al. Modern management of perianal fistulas in Crohn’s disease: future directions. Gut. 2018; 67 (6): 1181–94. DOI: https://doi.org/10.1136/gutjnl-2017-314918

5.     Colombel J.F., Sandborn W.J., Reinisch W., Mantzaris G.J., Kornbluth A., Rachmilewitz D., et al.; SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med. 2010; 362 (15): 1383–95. DOI: https://doi.org/10.1056/NEJMoa0904492

6.     Cawthorn W.P., Scheller E.L., Mac Dougald O.A. Adipose tissue stem cells: the great WAT hope. Trends Endocrinol Metab. 2012; 23 (6): 270–7. DOI: https://doi.org/10.1016/j.tem.2012.01.003

7.     Baer P.C., Geiger H. Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells Int. 2012; 2012: 812693. DOI: https://doi.org/10.1155/2012/812693

8.     Gimble J., Guilak F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy. 2003; 5 (5): 362–9. DOI: https://doi.org/10.1080/14653240310003026

9.     Kilroy G.E., Foster S.J., Wu X., Ruiz J., Sherwood S., Heifetz A., et al. Cytokine profile of human adipose-derived stem cells: expression of angiogenic, hematopoietic, and pro-inflammatory factors. J Cell Physiol. 2007; 212 (3): 702–9. DOI: https://doi.org/10.1002/jcp.21068

10. Eremin I.I., Vasil’ev V.S., Zorin V.L. Adipose tissue is a source of cells with regenerative potential. Geny i kletki [Genes and Cells]. 2017; 12 (3): 91–2. (in Russian)

11. Vasil’ev V.S., Vasil’ev S.A., Teryushkova Zh.I., Vasil’ev Yu.S., Vasil’ev I.S., Eremin I.I., et al. Mechanisms of biological action of various products based on autologous lipoaspirate and the possibility of their clinical use. Geny i kletki [Genes and Cells]. 2019; 14 (S): 50. (in Russian)

12. Teryushkova Zh.I., Vasil’ev V.S., Vazhenin A.V., Vasil’ev S.A., Eremin I.I. Lipografting and stromal-vascular fraction of adipose tissue in the treatment of patients with post-radiation rectovaginal fistulas. Onkologicheskaya koloproktologiya [Oncological Coloproctology]. 2019; 9 (1): 34–41. (in Russian).

13. Vasil’ev V.S., Vasil’ev S.A., Teryushkova Zh.I., Vasil’ev Yu.S., Vasil’ev I.S., Eremin I.I. Safety of clinical use of lipografting and local injection of stromal-vascular fraction of adipose tissue in cancer patients. Geny i kletki [Genes and Cells]. 2019; 14 (S): 49. (in Russian)

14. Vasil’ev V.S., Teryushkova Zh.I., Vazhenin A.V., Vasil’ev S.A., Lomakin E.A., Dimov G.P., et al. Safety and effectiveness of injection autotransplantation of adipose tissue and stromal vascular fraction in the treatment of post-radiation rectovaginal fistulas and rectal ulcers. Geny i kletki [Genes and Cells]. 2019; 14 (S): 50–1. (in Russian)

15. Vasil’ev V.S., Vasil’ev S.A., Teryushkova Zh.I., Vasil’ev Yu.S., Vasil’ev I.S., Eremin I.I. Possibility of using products based on autologous lipoaspirate in the correction of scars. Geny i kletki [Genes and Cells]. 2019; 14 (S): 49. (in Russian)

16. Vasil’ev V.S., Vasil’ev S.A., Vasil’ev Yu.S., Vasil’ev I.S., Karpov I.A., Dubrovskaya N.S., et al. The role of injection autotransplantation of adipose tissue in reconstructive breast surgery. Annaly plasticheskoy, rekonstruktivnoy i esteticheskoy khirurgii [Annals of Plastic, Reconstructive and Aesthetic Surgery]. 2018; (2): 37–53. (in Russian).

17. Vasil’ev V.S., Vasil’ev S.A., Karpov I.A., Dimov G.P., Teryushkova Zh.I., Gromov I.A., et al. Possibilities of clinical use of the stromal-vascular fraction of adipose tissue in plastic surgery. Annaly plasticheskoy, rekonstruktivnoy i esteticheskoy khirurgii [Annals of Plastic, Reconstructive and Aesthetic Surgery]. 2017; (2): 82–91. (in Russian)

18. Vasil’ev V.S., Eremin I.I., Vasil’ev S.A., Vazhenin A.V., Teryushkova Zh.I., Vasil’ev Yu.S., et al. Mechanisms of fat graft engraftment and the possibilities of lipografting in reconstructive surgery of various anatomical zones. Geny i kletki [Genes and Cells]. 2017; 12 (3): 57–8. (in Russian)

19. Podluzhny P.S., Presnyakov E.V., Zhemkov N.I., Sorochanu I., Deev R.V. Reparative regeneration of histogenetically different bones. Geny i kletki [Genes and Cells]. 2021; 16 (4): 50–4. URL: https://cyberleninka.ru/article/n/reparativnaya-regeneratsiya-gistogeneticheski-razlichnyh-kostey (date of access October 15, 2024). (in Russian)

20. Bozo I.Ya., Presnyakov E.V., Rochev E.S., Tsertseil V.V., Podluzhny P.S., Mavlikeev M.O., et al. Non-viral gene transfer in hydrogel matrices with octacalcium phosphate microgranules in optimizing reparative osteogenesis. Geny i kletki [Genes and Cells]. 2021; 16 (3): 91–6. URL: https://cyberleninka.ru/article/n/nevirusnyy-gennyy-transfer-v-gidrogelevyh-matriksah-s-mikrogranulami-oktakaltsievogo-fosfata-v-optimizatsii-reparativnogo  (date of access October 15, 2024). (in Russian)

21. Smyshlyaev I.A. The use of stromal vascular fraction for the treatment of degenerative-dystrophic injuries of articular cartilage of the knee joint. Geny i kletki [Genes and Cells]. 2017; 12 (3): 228. DOI: https://doi.org/10.23868/gc121168 (in Russian)

22. Vasil’ev V.S., Vasil’ev S.A., Teryushkova Zh.I., Vasil’ev Y.S., Vasil’ev I.S., Eremin I.I., et al. Mechanisms of biological action of various products based on autologous lipoaspirate and the possibility of their clinical application. Geny i kletki [Genes and Cells]. 2019; 14 (3): 50. DOI: https://doi.org/10.23868/gc122302 (in Russian)

23. Smyshlyaev I., Gil’fanov S., Kryuchkova O., Markina N., Chichva A., Batukhtina E., et al. Efficiency of using stromal-vascular fraction in the treatment of cartilage tissue damage of the knee joint. Interim results. Kremlevskaya meditsina. Klinicheskiy vestnik [Kremlin Medicine. Clinical Bulletin]. 2017; 2 (4): 70–9. (in Russian)

24. Eremin I.I., Vasil’ev V.S., Zorin V.L. Adipose tissue is a source of cells with regulatory understanding. Geny i kletki [Genes and Cells]. 2017; 12 (3): 91–2. DOI: https://doi.org/10.23868/gc120895 (in Russian)

25. Dykstra J.A., Facile T., Patrick R.J., et al. Concise review: fat and furious: harnessing the full potential of adipose-derived stromal vascular fraction. Stem Cells Transl Med. 2017; 6 (4): 1096–108.

26. Cao Y., Su Q., Zhang B., Shen F., Li S. Efficacy of stem cells therapy for Crohn’s fistula: a meta-analysis and systematic review. Stem Cell Res Ther. 2021; 12 (1): 32. DOI: https://doi.org/10.1186/s13287-020-02095-7