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International Urogynecology Journal

Published in:

01-03-2017 | Review Article

Regenerative medicine provides alternative strategies for the treatment of anal incontinence

Authors: Søren Gräs, Cæcilie Krogsgaard Tolstrup, Gunnar Lose

Published in: International Urogynecology Journal | Issue 3/2017

Abstract

Introduction and hypothesis

Anal incontinence is a common disorder but current treatment modalities are not ideal and the development of new treatments is needed. The aim of this review was to identify the existing knowledge of regenerative medicine strategies in the form of cellular therapies or bioengineering as a treatment for anal incontinence caused by anal sphincter defects.

Methods

PubMed was searched for preclinical and clinical studies in English published from January 2005 to January 2016.

Results

Animal studies have demonstrated that cellular therapy in the form of local injections of culture-expanded skeletal myogenic cells stimulates repair of both acute and 2 – 4-week-old anal sphincter injuries. The results from a small clinical trial with ten patients and a case report support the preclinical findings. Animal studies have also demonstrated that local injections of mesenchymal stem cells stimulate repair of sphincter injuries, and a complex bioengineering strategy for creation and implantation of an intrinsically innervated internal anal sphincter construct has been successfully developed in a series of animal studies.

Conclusion

Cellular therapies with myogenic cells and mesenchymal stem cells and the use of bioengineering technology to create an anal sphincter are new potential strategies to treat anal incontinence caused by anal sphincter defects, but the clinical evidence is extremely limited. The use of culture-expanded autologous skeletal myogenic cells has been most intensively investigated and several clinical trials were ongoing at the time of this report. The cost-effectiveness of such a therapy is an issue and muscle fragmentation is suggested as a simple alternative.

Bharucha AE, Dunivan G, Goode PS, Lukacz ES, Markland AD, Matthews CA, Mott L, Rogers RG, Zinsmeister AR, Whitehead WE, Rao SS, Hamilton FA (2015) Epidemiology, pathophysiology, and classification of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Workshop. Am J Gastroenterol 110:127–136CrossRefPubMed

Koelbl H, Igawa T, Salvatore S, Laterza RM, Lowry A, Siewert K-D, Sultan AH (2013) Pathophysiology of urinary incontinence, faecal incontinence and pelvic organ prolapse. In: Abrams P, Cardozo L, Khoury S, Wein A (eds) Incontinence, 5th edn. International Consultation on Urological Diseases, Bristol, pp 261–359

Madoff RD, Laurberg S, Lehur P, Matzel KE, Mellgren AF, Mimura T, O’Connell PR, Varma MG (2013) Surgery for faecal incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A (eds) Incontinence, 5th edn. International Consultation on Urological Diseases, Bristol, pp 1487–1527

Whitehead WE, Rao SS, Lowry A, Nagle D, Varma M, Bitar KN, Bharucha AE, Hamilton FA (2015) Treatment of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases workshop. Am J Gastroenterol 110:138–146CrossRefPubMed

Orlando G, Wood KJ, De Coppi P, Baptista P, Binder K, Bitar KN, Breuer C, Burnett L, Christ G, Farney A, Figliuzzi M, Holmes J, Koch K, Macchiarini P, Sani M, Opara E, Remuzzi A, Rogers J, Saul J, Seliktar D, Sharpira-Schweitzer K, Smith T, Solomon D, van Dyke M, Yoo JJ, Zhang Y, Atala A, Stratta RJ, Soker S (2012) Regenerative medicine as applied to general surgery. Ann Surg 255:867–880CrossRefPubMedPubMedCentral

Parmar N, Kumar L, Emmanuel A, Day RM (2014) Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regen Med 9:831–840CrossRefPubMed

Kang SB, Lee HN, Lee JY, Park JS, Lee HS, Lee JY (2008) Sphincter contractility after muscle-derived stem cells autograft into the cryoinjured anal sphincters of rats. Dis Colon Rectum 51:1367–1373CrossRefPubMedPubMedCentral

White AB, Keller PW, Acevedo JF, Word RA, Wai CY (2010) Effect of myogenic stem cells on contractile properties of the repaired and unrepaired transected external anal sphincter in an animal model. Obstet Gynecol 115:815–823CrossRefPubMed

Craig J, Lane F, Nistor G, Motakef S, Pham Q-A, Keirstead H (2010) Allogenic myoblast transplantation in the rat anal sphincter. Female Pelvic Med Reconstr Surg 16:205–208CrossRefPubMed

10.

Kajbafzadeh AM, Elmi A, Talab SS, Esfahani SA, Tourchi A (2010) Functional external anal sphincter reconstruction for treatment of anal incontinence using muscle progenitor cell auto grafting. Dis Colon Rectum 53:1415–1421CrossRefPubMed

11.

Kang SB, Lee HS, Lim JY, Oh SH, Kim SJ, Hong SM, Jang JH, Cho JE, Lee SM, Lee JH (2013) Injection of porous polycaprolactone beads containing autologous myoblasts in a dog model of fecal incontinence. J Korean Surg Soc 84:216–224CrossRefPubMedPubMedCentral

12.

Lane F, Jacobs S, Craig J, Nistor G, Markle D, Noblett K, Osann K, Keirstead H (2013) In vivo recovery of the injured anal sphincter after repair and injection of myogenic stem cells: an experimental model. Dis Colon Rectum 56:1290–1297CrossRefPubMed

13.

Jacobs S, Lane F, Pham Q-A, Nistor G, Robles R, Chua C, Boubion B, Osann K, Keirstead H (2013) Safety assessment of myogenic stem cell transplantation and resulting tumor formation. Female Pelvic Med Reconstr Surg 19:362–368CrossRefPubMed

14.

Elmi A, Kajbafzadeh AM, Oghabian MA, Talab SS, Tourchi A, Khoei S, Rafie B, Esfahani SA (2014) Anal sphincter repair with muscle progenitor cell transplantation: serial assessment with iron oxide-enhanced MRI. AJR Am J Roentgenol 202:619–625CrossRefPubMed

15.

Bisson A, Fréret M, Drouot L, Jean L, Le Corre S, Gourcerol G, Doucet C, Michot F, Boyer O, Lamacz M (2015) Restoration of anal sphincter function after myoblast cell therapy in incontinent rats. Cell Transplant 24:277–286CrossRefPubMed

16.

Fitzwater J, Grande K, Sailors J, Acevedo J, Word RA, Wai C (2015) Effect of myogenic stem cells on the integrity and histomorphology of repaired transected external anal sphincter. Int Urogynecol J 26:251–256CrossRefPubMed

17.

Montoya TI, Acevedo J, Smith B, Keller P, Sailors J, Tang L, Word RA, Wai C (2015) Myogenic stem cell-laden hydrogel scaffold in wound healing of the disrupted external anal sphincter. Int Urogynecol J 26:893–904CrossRefPubMed

18.

Oh HK, Lee H, Lee J, Oh S, Lim JY, Ahn S, Kang SB (2015) Coadministration of basic fibroblast growth factor-loaded polycaprolactone beads and autologous myoblasts in a dog model of fecal incontinence. Int J Colorectal Dis 30:549–557CrossRefPubMed

19.

Oh HK, Lee HS, Lee JH, Oh SH, Lim JY, Ahn S, Hwang JY, Kang SB (2015) Functional and histological evidence for the targeted therapy using biocompatible polycaprolactone beads and autologous myoblasts in a dog model of fecal incontinence. Dis Colon Rectum 58:517–525CrossRefPubMed

20.

Lorenzi B, Pessina F, Lorenzoni P, Urbani S, Vernillo R, Sgaragli G, Gerli R, Mazzanti B, Bosi A, Saccardi R, Lorenzi M (2008) Treatment of experimental injury of anal sphincters with primary surgical repair and injection of bone marrow-derived mesenchymal stem cells. Dis Colon Rectum 51:411–420CrossRefPubMed

21.

Aghae-afshar M, Rezazadehkermani M, Asadi A, Malekpour-afshar R, Shahesmaeli A, Nematollahi-mahani S (2009) Potential of human umbilical cord matrix and rabbit bone marrow-derived mesenchymal stem cells in repair of surgically incised rabbit external anal sphincter. Dis Colon Rectum 52:1753–1761CrossRef

22.

Pathi SD, Acevedo JF, Keller PW, Kishore AH, Miller RT, Wai CY, Word RA (2012) Recovery of the injured external anal sphincter after injection of local or intravenous mesenchymal stem cells. Obstet Gynecol 119:134–144CrossRefPubMed

23.

Salcedo L, Mayorga M, Damaser M, Balog B, Butler R, Penn M, Zutshi M (2013) Mesenchymal stem cells can improve anal pressures after anal sphincter injury. Stem Cell Res 10:95–102CrossRefPubMed

24.

Salcedo L, Penn M, Damaser M, Balog B, Zutshi M (2014) Functional outcome after anal sphincter injury and treatment with mesenchymal stem cells. Stem Cells Transl Med 3:760–767CrossRefPubMedPubMedCentral

25.

Hecker L, Baar K, Dennis RG, Bitar KN (2005) Development of a three-dimensional physiological model of the internal anal sphincter bioengineered in vitro from isolated smooth muscle cells. Am J Physiol Gastrointest Liver Physiol 289:G188–G196CrossRefPubMed

26.

Hashish M, Raghavan S, Somara S, Gilmont RR, Miyasaka E, Bitar KN, Teitelbaum DH (2010) Surgical implantation of a bioengineered internal anal sphincter. J Pediatr Surg 45:52–58CrossRefPubMedPubMedCentral

27.

Raghavan S, Miyasaka EA, Hashish M, Somara S, Gilmont RR, Teitelbaum DH, Bitar KN (2010) Successful implantation of physiologically functional bioengineered mouse internal anal sphincter. Am J Physiol Gastrointest Liver Physiol 299:G430–G439CrossRefPubMedPubMedCentral

28.

Raghavan S, Gilmont RR, Miyasaka EA, Somara S, Srinivasan S, Teitelbaum DH, Bitar KN (2011) Successful implantation of bioengineered, intrinsically innervated, human internal anal sphincter. Gastroenterology 141:310–319CrossRefPubMedPubMedCentral

29.

Miyasaka E, Raghavan S, Gilmont R, Mittal K, Somara S, Bitar K, Teitelbaum D (2011) In vivo growth of a bioengineered internal anal sphincter: comparison of growth factors for optimization of growth and survival. Pediatr Surg Int 27:137–143CrossRefPubMedPubMedCentral

30.

Gilmont RR, Raghavan S, Somara S, Bitar KN (2014) Bioengineering of physiologically functional intrinsically innervated human internal anal sphincter constructs. Tissue Eng Part A 20:1603–1611CrossRefPubMedPubMedCentral

31.

Raghavan S, Miyasaka EA, Gilmont RR, Somara S, Teitelbaum DH, Bitar KN (2014) Perianal implantation of bioengineered human internal anal sphincter constructs intrinsically innervated with human neural progenitor cells. Surgery 155:668–674CrossRefPubMed

32.

Frudinger A, Kolle D, Schwaiger W, Pfeifer J, Paede J, Halligan S (2010) Muscle-derived cell injection to treat anal incontinence due to obstetric trauma: pilot study with 1 year follow-up. Gut 59:55–61CrossRefPubMed

33.

Frudinger A, Pfeifer J, Paede J, Kolovetsiou-Kreiner V, Marksteiner R, Halligan S (2015) Autologous skeletal muscle-derived cell injection for anal incontinence due to obstetric trauma: a five-year follow-up of an initial study of ten patients. Colorectal Dis 17:794–801CrossRefPubMed

34.

Romaniszyn M, Rozwadowska N, Nowak M, Malcher A, Kolanowski T, Walega P, Richter P, Kurpisz M (2013) Successful implantation of autologous muscle-derived stem cells in treatment of faecal incontinence due to external sphincter rupture. Int J Colorectal Dis 28:1035–1036CrossRefPubMed

35.

Gras S, Lose G (2011) The clinical relevance of cell-based therapy for the treatment of stress urinary incontinence. Acta Obstet Gynecol Scand 90:815–824CrossRefPubMed

36.

Gräs S, Klarskov N, Lose G (2014) Intraurethral injection of autologous minced skeletal muscle: a simple surgical treatment for stress urinary incontinence. J Urol 192:850–855CrossRefPubMed

37.

Peters KM, Dmochowski RR, Carr LK, Robert M, Kaufman MR, Sirls LT, Herschorn S, Birch C, Kultgen PL, Chancellor MB (2014) Autologous muscle derived cells for treatment of stress urinary incontinence in women. J Urol 192:469–476CrossRefPubMed

38.

Raya-Rivera A, Esquiliano DR, Yoo JJ, Lopez-Bayghen E, Soker S, Atala A (2011) Tissue-engineered autologous urethras for patients who need reconstruction: an observational study. Lancet 377:1175–1182CrossRefPubMedPubMedCentral

39.

Raya-Rivera AM, Esquiliano D, Fierro-Pastrana R, Lo¦pez-Bayghen E, Valencia P, Ordorica-Flores R, Soker S, Yoo JJ, Atala A (2014) Tissue-engineered autologous vaginal organs in patients: a pilot cohort study. Lancet 384:329–336CrossRefPubMed

40.

Bharucha AE (2006) Pelvic floor: anatomy and function. Neurogastroenterol Motil 18:507–519CrossRefPubMed

41.

Bitar KN, Raghavan S, Zakhem E (2014) Tissue engineering in the gut: developments in neuromusculature. Gastroenterology 146:1614–1624CrossRefPubMedPubMedCentral

42.

Yin H, Price F, Rudnicki MA (2013) Satellite cells and the muscle stem cell niche. Physiol Rev 93:23–67CrossRefPubMedPubMedCentral

43.

De Francesco F, Ricci G, D’Andrea F, Nicoletti GF, Ferraro GA (2015) Human adipose stem cells: from bench to bed-side. Tissue Eng Part B Rev 21:572–584CrossRefPubMed

44.

Heilbrun ME, Nygaard IE, Lockhart ME, Richter HE, Brown MB, Kenton KS, Rahn DD, Thomas JV, Weidner AC, Nager CW, Delancey JO (2010) Correlation between levator ani muscle injuries on magnetic resonance imaging and fecal incontinence, pelvic organ prolapse, and urinary incontinence in primiparous women. Am J Obstet Gynecol 202:488.e1–488.e6CrossRef

45.

Bitar KN, Bohl J, Fortunato JE, Somara S, Raghavan S, Zakhem E, Rego SL, Koch KL (2015) In situ implantation of autologous Biosphincter re-instates continence in a large animal model of passive fecal incontinence. Gastroenterology 148:S-117CrossRef

46.

Zakhem E, Rego SL, Raghavan S, Bitar KN (2015) The appendix as a viable source of neural progenitor cells to functionally innervate bioengineered gastrointestinal smooth muscle tissues. Stem Cells Transl Med 4:548–554CrossRefPubMedPubMedCentral

47.

Davies BM, Rikabi S, French A, Pinedo-Villanueva R, Morrey ME, Wartolowska K, Judge A, MacLaren RE, Mathur A, Williams DJ, Wall I, Birchall M, Reeve B, Atala A, Barker RW, Cui Z, Furniss D, Bure K, Snyder EY, Karp JM, Price A, Carr A, Brindley DA (2014) Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: a pilot study. J Tissue Eng 5:2041731414551764CrossRefPubMedPubMedCentral

48.

Montarras D, Morgan J, Collins C, Relaix F, Zaffran S, Cumano A, Partridge T, Buckingham M (2005) Direct isolation of satellite cells for skeletal muscle regeneration. Science 309:2064–2067CrossRefPubMed

49.

Sacco A, Doyonnas R, Kraft P, Vitorovic S, Blau HM (2008) Self-renewal and expansion of single transplanted muscle stem cells. Nature 456:502–506CrossRefPubMedPubMedCentral

50.

Nicolai JP (1980) Earliest free muscle graft? Br J Plast Surg 33:350–352CrossRefPubMed

51.

Hakelius L, Olsen L (1991) Free autogenous muscle transplantation in children. Long-term results. Eur J Pediatr Surg 6:353–357CrossRef

52.

Danielson J, Karlbom U, Graf W, Wester T (2010) Long-term outcome after free autogenous muscle transplantation for anal incontinence in children with anorectal malformations. J Pediatr Surg 45:2036–2040CrossRefPubMed

53.

Studitsky AN (1964) Free auto- and homografts of muscle tissue in experiments on animals. Ann N Y Acad Sci 120:789–801CrossRefPubMed

54.

Carlson B (1972) The regeneration of minced muscle. Monogr Dev Biol 4:1–128PubMed

55.

Lecoeur C, Swieb S, Zini L, Rivière C, Combrisson H, Ghérardi R, Abbou C, Yiou R (2007) Intraurethral transfer of satellite cells by myofiber implants results in the formation of innervated myotubes exerting tonic contractions. J Urol 178:332–337CrossRefPubMed

56.

Biérinx AS, Sebille A (2008) Mouse sectioned muscle regenerates following auto-grafting with muscle fragments: a new muscle precursor cells transfer? Neurosci Lett 431:211–214CrossRefPubMed

57.

Hall JK, Banks GB, Chamberlain JS, Olwin BB (2010) Prevention of muscle aging by myofiber-associated satellite cell transplantation. Sci Transl Med 2:57ra83CrossRefPubMedPubMedCentral

58.

Boennelycke M, Christensen L, Nielsen LF, Gras S, Lose G (2011) Fresh muscle fiber fragments on a scaffold in rats – a new concept in urogynecology? Am J Obstet Gynecol 205:235e10–235e14CrossRef

59.

Corona BT, Garg K, Ward CL, McDaniel JS, Walters TJ, Rathbone CR (2013) Autologous minced muscle grafts: a tissue engineering therapy for the volumetric loss of skeletal muscle. Am J Physiol Cell Physiol 305:C761–C775CrossRefPubMed

Title: Regenerative medicine provides alternative strategies for the treatment of anal incontinence
Authors: Søren Gräs
Cæcilie Krogsgaard Tolstrup
Gunnar Lose
Publication date: 01-03-2017
Publisher: Springer London
Published in: International Urogynecology Journal / Issue 3/2017
Print ISSN: 0937-3462
Electronic ISSN: 1433-3023
DOI: https://doi.org/10.1007/s00192-016-3064-y

ACC 2024 Congress

Springer Medicine

Regenerative medicine provides alternative strategies for the treatment of anal incontinence

Abstract

Introduction and hypothesis

Methods

Results

Conclusion

ACC 2024 Congress

Springer Medicine

Abstract

Introduction and hypothesis

Methods

Results

Conclusion

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