Building rings with spheres: a cell therapy approach to incontinence

Cell & Gene Therapy Insights 2023; 9(10), 1293–1306

DOI: 10.18609/cgti.2023.167

Published: 7 December 2023
Commentary
M Gilbert, S Čaputová, D Poli et al.

Fecal incontinence is a prevalent condition, that remains vastly underreported. The condition impacts the patients’ quality of life and has negative socio-economic and environmental impact on the society. Current patient management guidelines recommend a stepwise approach to treating fecal incontinence, from conservative treatment options, through minimally invasive surgical options, all the way to first- and second-line surgical options. Unfortunately, the conservative treatments remain ineffective, and, in many cases, the surgical options are either not desirable or not suitable. Regenerative medicine, and specifically, cell therapy, has the potential to offer a curative treatment that is less invasive, more effective and efficient. Cell therapy technologies, while still under development, can improve the current state-of-play in the realm of fecal incontinence at the clinical, patient, and socio-economic level. The aim of this article is twofold. Firstly, it is to raise awareness about the silent affliction that fecal incontinence is and about the impact that it has on patients and society. Secondly, it is to position cell therapy, relative to the current treatment approaches, including, for example, sacral nerve stimulation and sphincteroplasty, as to emphasize its potential to provide a suitable treatment alternative. 


The problem: Fecal incontinence is a prevalent condition that is currently lacking appropriate treatment options

Fecal incontinence: a brief introduction to the condition

Fecal incontinence (FI) is a condition in which control of bowel movement is impaired, leading to leakage of feces. According to the symptomatic profile, FI is classified in three categories [1]Shah R, Herrero JAV. Fecal Incontinence. 2022; StatPearls.:

  1. Passive incontinence;
  2. Urge incontinence;
  3. Fecal seepage.

In case of passive incontinence, patients are unaware of the discharge that involuntarily arises due to overflow of the full rectum [2]Knol ME, Snijders HS, Heyden JT, Baeten CI. Fecal incontinence: the importance of a structured pathophysiological model. J. Anus Rectum Colon 2022; 6, 58.. Passive incontinence indicates the malfunctioning of the anal sphincter, anorectal reflexes, or a neurological disease. As opposed to passive incontinence, urge incontinence occurs when patients consciously defecate while being unable to control sudden bowel movements [3]Rao SSC. Pathophysiology of adult fecal incontinence. Gastroenterology 2004; 126, S14–22. . Urge incontinence suggests impairment of the anal sphincter or the rectum to prevent discharge. Lastly, fecal seepage is the complication of involuntary discharge after the occurrence of normal continence and bowel movement [4]Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. . The disruption of the anal organs, notably to the sphincter muscle that creates a ring structure around the anal canal, can be structural or functional, respectively meaning that FI has occurred after injury, trauma, or childbirth, or naturally due to neurological disorders [1]Shah R, Herrero JAV. Fecal Incontinence. 2022; StatPearls..

While underreported, FI is a prevalent condition, most common in parous women, frail older patients and patients with neurological disorders

Although an estimation of European adults affected by FI is recognized, its precise and worldwide prevalence is unknown, as the lack of patients reporting their FI-related symptoms and diagnosis discrepant symptoms thus leads to a potentially underestimated prevalence of patients suffering from FI [5]Whitehead WE, C Rao SS, Lowry A, et al. Treatment of fecal incontinence: state of the science summary for the National Institute of Diabetes and Digestive and Kidney Diseases Workshop 2014. Am. J. Gastroenterol. 2015; 110(1), 138–146.. Despite lacking precise data, it is estimated that in Europe approximately 57 million adults are affected with FI [6]Assmann SL, Keszthelyi D, Kleijnen J, et al. Guideline for the diagnosis and treatment of faecal incontinence-A UEG/ESCP/ESNM/ESPCG collaboration 2022. United European Gastroenterol. J. 2022; 10(3), 251–286.. Specifically, FI occurs in up to 15% of the Western population. Both men and women of all ages worldwide are affected by FI (Figure 1Overall prevalence of FI by age group analysed by the US National Health and Nutrition Examination survey (US data) <b>[7]</b>.), and although FI in men has received little attention in the past, it is still as much of a problem in men as it is in women [7]Ditah I, Devaki P, Luma HN, et al. Prevalence, trends, and risk factors for fecal incontinence in United States adults, 2005–2010. Clin. Gastroenterol. Hepatol. 2014; 12, 636-643.e2. .

Groups with the highest incidence rates of FI are parous women with sphincter muscle damage or dysfunction, frail older patients, and patients with neurological or spinal disease/injury. These groups are described below, respectively.

Parous women may suffer from sphincter injury as a result of pregnancy and childbirth

It has been reported that 11% of postpartum women globally have sustained sphincter muscle injury [8]Dudding TC, Lee EM, Faiz O, et al. Economic evaluation of sacral nerve stimulation for faecal incontinence. Br. J. Surgery 2008; 95, 1155–1163. Dudding TC, Lee EM, Faiz O, et al. Economic evaluation of sacral nerve stimulation for faecal incontinence. Br. J. Surgery 2008; 95, 1155–1163. . While the prevalence is primarily studied in high-income countries [9]Swain D, Parida SP, Jena SK, Das M, Das H. Obstetric fistula: a challenge to public health. Indian J. Public Health 2019; 63, 3–8. , it is apparent that women from low- and middle-income countries (LMICs) are at a high risk of developing FI, too. Specifically, women that develop uncommon communication between the gastrointestinal tract, the urinary tract and/or the genital tract, so-called obstetric fistulas (OF), during labor are at a higher risk of developing FI [9]Swain D, Parida SP, Jena SK, Das M, Das H. Obstetric fistula: a challenge to public health. Indian J. Public Health 2019; 63, 3–8.  [10]Ndoye M, Greenwell T. Obstetric fistula. Urinary Fistula 2016, 197–228. . The majority of these OF cases are in sub-­Saharan Africa and South Asia, followed by Latin America and the Caribbean [11]Semere L, Nour NM. Obstetric fistula: living with incontinence and shame. Rev. Obstet. Gynecol. 2008; 1, 193–197.Semere L, Nour NM. Obstetric fistula: living with incontinence and shame. Rev. Obstet. Gynecol. 2008; 1, 193–197.. Those affected by OF in low- and middle-income countries (LMICs) are young, primiparous, impoverished women that have little, or no access to health care [11]Semere L, Nour NM. Obstetric fistula: living with incontinence and shame. Rev. Obstet. Gynecol. 2008; 1, 193–197.Semere L, Nour NM. Obstetric fistula: living with incontinence and shame. Rev. Obstet. Gynecol. 2008; 1, 193–197.. Pregnancy and childbirth are risk factors for transient postpartum FI. Studies have shown that during pregnancy and childbirth, women encounter issues such as pelvic floor injury and stretching or tearing of the nerves, muscles, and supporting tissues [12]Subki H, Fakeeh M, Hindi M, et al. Fecal and urinary incontinence associated with pregnancy and childbirth. Mater. Sociomed. 2019; 31, 202–206. . Vacuum or forceps-assisted vaginal delivery is seen as a risk factor for developing FI as these methods increase the risk of anal sphincter ruptures [13]van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. . There are studies that suggest that caesarean section protects against developing sphincter injury, specifically fecal incontinence beyond the postpartum period [14]Rørtveit G, Hannestad YS. Association between mode of delivery and pelvic floor dysfunction 1848–52. Tidsskr. Nor. Legeforen. Nr. 2014; 19, 1848–1852.. Of the 11% of women with sphincter muscle injury, between one-third and two-thirds will suffer from FI [8]Dudding TC, Lee EM, Faiz O, et al. Economic evaluation of sacral nerve stimulation for faecal incontinence. Br. J. Surgery 2008; 95, 1155–1163. Dudding TC, Lee EM, Faiz O, et al. Economic evaluation of sacral nerve stimulation for faecal incontinence. Br. J. Surgery 2008; 95, 1155–1163. . To illustrate the impact of this, of the 4.09 million women who gave birth in Europe in 2021 [15]Eurostat. How many children were born in the EU in 2021? Products Eurostat News; Eurostat 2023 (accessed Aug 2, 2023)., 449,900 are likely to have a sphincter muscle injury, of which 150,000 to 300,000 will be affected by FI. The type of birth and delivery method also plays a role in the prevalence of FI in parous women [13]van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. . In some cases, postpartum FI is only temporary and neuromuscular injury sometimes improves during the first year after giving birth [13]van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. van Meegdenburg MM, Trzpis M, Broens PMA. Fecal incontinence and parity in the Dutch population: a cross-sectional analysis. United European Gastroenterol. J. 2018; 6, 781–790. , while in others the condition gets progressively worse due to the confounding effect of aging and the menopause.

Frail older patients have a high risk of bowel disturbances

FI in older patients can be a challenging and stigmatizing condition to deal with alone. Patients often do not seek help for their condition. The main risk factors for FI in the elderly include bowel disturbances such as diarrhea and irritable bowel syndrome (IBS) [4]Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. . Bowel disturbances are more amenable to therapeutic intervention as they are often easier to correct than neuromuscular injuries to the pelvic floor [4]Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. . Several causes have been reported for the onset of FI in frail older patients, of which examples include living a sedentary lifestyle or having a decreased fiber intake. No differences between sexes have been analyzed in older patients, as opposed to lower age groups that suffer from FI [16]Abrams P, Andersson K-E, Apostolidis A, et al. Evaluation and treatment of urinary incontinence, pelvic organ prolapse and faecal incontinence. Neurourol. Urodynamics 2018; 37(7), 2271–2272.. There are certain comorbidities associated with FI, such as diabetes mellitus, stroke, and neurological disorders [4]Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. Pasricha T, Staller K. Fecal incontinence in the elderly. Clin. Geriatr. Med. 2021; 37, 71–83. . Prevalence rates of FI increases in patients over the age of 50, among hospitalized patients and in patients that are institutionalized. According to a systematic review of older patients in care homes in Europe, approximately 50% of older people living in care homes are affected by FI, compared to an estimated 18% of the general population [17]Musa MK, Saga S, Blekken LE, Harris R, Goodman C, Norton C. The prevalence, incidence, and correlates of fecal incontinence among older people residing in care homes: a systematic review. J .Am. Med. Dir. Assoc. 2019; 20, 956–962.e8. .

Patients with neurological injury or disorder suffer from disruption of nerves that control storage and excretion of waste

Other examples of patients suffering from FI include those with neurological disorders, metabolic disorders or other types of disorders that affect the functioning of the sphincter muscle. Individuals with a neurological disease have a higher risk of FI than the general population [18]Coggrave M, Norton C, Cody JD. Management of faecal incontinence and constipation in adults with central neurological diseases. Cochrane Database Syst. Rev. 2014; 13(1), CD002115.. The nervous system controls storage and excretion of fecal waste, hence the disruption to the nerves enhances the likelihood to develop FI [19]Mawer S, Alhawaj AF. Physiology, Defecation. 2022; StatPearls.. For example, the incidence of FI is higher in patients with multiple sclerosis, spinal cord injuries, cerebrovascular diseases, and Alzheimer’s disease [19]Mawer S, Alhawaj AF. Physiology, Defecation. 2022; StatPearls. [20]Russell B, Buswell M, Norton C, et al. Supporting people living with dementia and faecal incontinence. Br. J. CommunityNurs. 2017; 22, 110–114. . Patients with dementia are prone to FI due to use of medication, dietary intolerance, or the decreased cortical control over stool release [21]Goodman C, Malone JR, Norton C, et al. Reducing and managing faecal incontinence in people with advanced dementia who are resident in care homes: protocol for a realist synthesis. BMJ Open 2015; 5(7), e007728..

Current treatment options for treating FI are often either not effective, or not desirable and/or suitable

Current patient management guidelines recommend a stepwise approach to treating FI—from conservative treatment options, through minimally invasive surgical options, all the way to first- and second-line surgical options (Figure 2Stepwise treatment approach for patients with FI.). Conservative treatments designed to minimize symptoms are typically used in first-line therapy, especially in those with mild symptoms. Such treatment options include dietary modifications, patient education, bowel management exercises, biofeedback and anti-diarrheal or antimotility medication [22]Rao SSC. Current and emerging treatment options for fecal incontinence. J. Clin. Gastroenterol. 2014; 48(9), 752–764.. If conservative treatments do not have the desired effect (estimated to fail in 40–75% of the cases), patients will be treated with minimally invasive options including injections of bulking agents, balloon devices, posterior tibial nerve stimulation, transanal irrigation and radiofrequency therapy [6]Assmann SL, Keszthelyi D, Kleijnen J, et al. Guideline for the diagnosis and treatment of faecal incontinence-A UEG/ESCP/ESNM/ESPCG collaboration 2022. United European Gastroenterol. J. 2022; 10(3), 251–286. [23]Adil E, Bharucha A, Satish S, Rao M, Shin A. Surgical interventions and the use of device-aided therapy for the treatment of fecal incontinence and defecatory disorders. Physiol. Behav. 2018; 176, 139–148.. In case of ineffective treatment by means of non-surgical options, first-line and second-line surgical options are proposed. In first-line surgical treatment, the sacral nerve is stimulated or sphincteroplasty is performed to strengthen weakened muscle areas [24]Fecal incontinence - Diagnosis and treatment. Mayo Clinic 2022 (accessed Aug 2023).. Of the patients recommended for first-line surgical treatment, approximately 80–90% receive SNS and 10–20% undergo sphincteroplasty. The success rate of these treatment options is approximately 60% and 80%, respectively, with potential declining effect over time [25]Leo CA, Thomas GP, Bradshaw E, et al. Long-term outcome of sacral nerve stimulation for faecal incontinence. Colorectal Disease 2020; 22, 2191–2198.  [26]Berg MR, Gregussen H, Sahlin Y. Long-term outcome of sphincteroplasty with separate suturing of the internal and the external anal sphincter. Tech. Coloproctol. 2019; 23, 1163–1172. . The efficiency of sphincteroplasty can be enhanced by magnetic sphincter augmentation [27]Pakravan F, Helmes C, Alldinger I. Magnetic sphincter augmentation in patients with fecal incontinence after failure of an implanted artificial bowel sphincter. Coloproctology 2018; 40, 127–129. . The last resort is second-line surgical treatment, to create a colostomy, where stool into a collection bag is diverted through an opening in the abdomen.

The effectiveness of different treatment options for FI depends on the severity of the condition and the patient group. The treatment considerations differ for the three patient groups: parous women, frail older patients, and patients with neurological disorders. The most suitable stepwise approach for parous women is to first attempt conservative treatment (electrical stimulation of the pelvic floor muscles, physiotherapy, dietary management, etc.), and then minimally invasive and first-line surgical treatments (SNS). In frailty, patients are prescribed dietary modification or referred for the minimally invasive and first-line surgical treatments (SNS). For patients with neurological disorders, treatment depends on the symptoms but most often starts with conservative treatment options, such as bowel management programs. Unfortunately, conservative treatment options are generally ineffective and the patient undergoes surgical treatment. However, many patients do not wish to, or are unsuitable for undergoing surgery.

FI impacts patients’ quality of life and has socio-economic and environmental implications on the society

FI poses emotional & mental stress on patients’ lives

FI heavily affects the quality of life (QoL) of affected individuals. Lifestyle, social interaction, coping behavior, depression or self-perception, and level of embarrassment are aspects of the QoL of FI patients that are influenced by several FI severity factors (i.e., frequency of soiling, quantity and type of fecal loss, and urgency) to different degrees [28]Bartlett L, Nowak M, Ho L, Bartlett Y-H, Chiarioni G. Impact of fecal incontinence on quality of life. World J. Gastroenterol. 2009; 15, 3276–3282. Bartlett L, Nowak M, Ho L, Bartlett Y-H, Chiarioni G. Impact of fecal incontinence on quality of life. World J. Gastroenterol. 2009; 15, 3276–3282. . Due to the associated social stigma of FI, it is often deemed as the ‘silent affliction’ [29]Gallagher DL, Thompson DL. Identifying and managing fecal incontinence. J. Wound. Ostomy Continence Nurs. 2012; 39, 95–97.  or the ‘unvoiced symptom’ [30]Leigh RJ, Turnberg LA. Faecal incontinence: the unvoiced symptom. Lancet 1982; 319, 1349–1351.. Topics that breach social norms about bodily functions are often regarded as something that should be discussed in private. The fact that patients are aware of the public stigma makes them develop self-stigma, i.e., they internalize the public’s negative reactions and interpret the stereotypes as true and accurate. This can lead to the avoidance of help-seeking [31]Devendorf AR, Bradley SE, Barks L, Klanchar A, Orozco T, Cowan L. Stigma among veterans with urinary and fecal incontinence. Stigma Health 2021; 6, 335–343. . Those with mild symptoms may be unwilling to realize that they are experiencing FI symptoms; and those that eventually come to terms with a diagnosis are reluctant to share it with others and seek further help from health care professionals [32]Norton C, Whitehead W, Bliss D, Harari D, Lang J. Conservative and pharmacological management of faecal incontinence in adults. Neurourol. Urodyn. 2010; 29(1), 199-206.. Approximately 70% of patients with FI do not reach out for medical help [28]Bartlett L, Nowak M, Ho L, Bartlett Y-H, Chiarioni G. Impact of fecal incontinence on quality of life. World J. Gastroenterol. 2009; 15, 3276–3282. Bartlett L, Nowak M, Ho L, Bartlett Y-H, Chiarioni G. Impact of fecal incontinence on quality of life. World J. Gastroenterol. 2009; 15, 3276–3282. . Moreover, FI can lead to social isolation and has an impact on intimate relationships and self-esteem [33]Meyer I, Richter HE. Impact of fecal incontinence and its treatment on quality of life in women. Womens Health 2015; 11, 225–238. Meyer I, Richter HE. Impact of fecal incontinence and its treatment on quality of life in women. Womens Health 2015; 11, 225–238. . For example, despite the partners and spouses being generally supportive of their partners’ diagnosis, they have also reported avoiding intimate and sexual activities with the affected individual [33]Meyer I, Richter HE. Impact of fecal incontinence and its treatment on quality of life in women. Womens Health 2015; 11, 225–238. Meyer I, Richter HE. Impact of fecal incontinence and its treatment on quality of life in women. Womens Health 2015; 11, 225–238. .

FI imposes significant costs both for patients and society

Patients suffering from FI have substantial medical costs. Firstly, this includes expenditure for incontinence products, medications, and other healthcare products [34]de Miguel Valencia MJ, Margallo Lana A, Pérez Sola MÁ, et al. Economic burden of long-term treatment of severe fecal incontinence. Cir. Esp. 2022; 100, 422–430. ; secondly, costs are incurred due to greater frequency of health care practitioner visits, which includes costs of transportation, costs of the consultations [33]Meyer I, Richter HE. Impact of fecal incontinence and its treatment on quality of life in women. Womens Health 2015; 11, 225–238. . Patients with FI have on average 4.21 more healthcare visits per year than patients without FI [35]Dunivan GC, Heymen S, Palsson OS, et al. Fecal incontinence in primary care: prevalence, diagnosis, and healthcare utilization. Am. J. Obstet. Gynecol. 2010; 202(5), 493.E1–493.E6.Dunivan GC, Heymen S, Palsson OS, et al. Fecal incontinence in primary care: prevalence, diagnosis, and healthcare utilization. Am. J. Obstet. Gynecol. 2010; 202(5), 493.E1–493.E6.. Moreover, FI patients need support in their day-to-day activities, in particular, frail older patients that need nursing support. While more recent statistics are not available, in 2012, the average annual cost per person was €4,110, including direct medical and non-medical costs and indirect costs for productivity loss [36]Meyer I, Richter HE. Impact of fecal incontinence and its treatment on quality of life in women. Womens Health (Lond.) 2015; 11(2), 225–238.. This causes an overall economic burden, as the money could otherwise be invested elsewhere [35]Dunivan GC, Heymen S, Palsson OS, et al. Fecal incontinence in primary care: prevalence, diagnosis, and healthcare utilization. Am. J. Obstet. Gynecol. 2010; 202(5), 493.E1–493.E6.Dunivan GC, Heymen S, Palsson OS, et al. Fecal incontinence in primary care: prevalence, diagnosis, and healthcare utilization. Am. J. Obstet. Gynecol. 2010; 202(5), 493.E1–493.E6.. Regarding the financial impact to society, affected individuals become less active through increased days off, loss of productivity, and higher rates of unemployment and absenteeism [37]Xu X, Menees SB, Zochowski MK, Fenner DE. Economic cost of fecal incontinence. Dis. Colon Rectum 2012; 55, 586–598.Xu X, Menees SB, Zochowski MK, Fenner DE. Economic cost of fecal incontinence. Dis. Colon Rectum 2012; 55, 586–598.. Considering the EU as the relevant population for this article, patients with large-volume FI report missing an average of 50 days from work or school annually, relative to those individuals without FI symptoms [37]Xu X, Menees SB, Zochowski MK, Fenner DE. Economic cost of fecal incontinence. Dis. Colon Rectum 2012; 55, 586–598.Xu X, Menees SB, Zochowski MK, Fenner DE. Economic cost of fecal incontinence. Dis. Colon Rectum 2012; 55, 586–598..

FI imposes environmental costs due to the increasing use of medication and products

Patients with FI use a wide range of medications and hygienic products. In Europe, the contamination of groundwater is enhanced due to the increasing use of medication [38]Bunting SY, Lapworth DJ, Crane EJ, et al. Emerging organic compounds in European groundwater. Environmental Pollution 2021; 269, 115945., with anti-diarrheal medication reportedly being found in groundwater [39]Baltic Marine Environment Protection Commission. Vieno N, Hallgren P, Wallberg P. International Initiative on Water Quality. Pharmaceuticals in the aquatic environment of the Baltic Sea region. A status report 2017.. With the rising need for incontinence products (e.g., pads or diapers), the energy consumption and carbon emissions increase [40]Gu X, Sun M, Long X, Deng H, Wang Y. Environmental impact of adult incontinence products in China in the context of population aging. Sci. Total Environ. 2023; 875, 162596.. Similarly, as the products often contain non-biodegradable material, the environmental pollution increases too [41]Muthu SS, Ng FSF, Li Y, Hui PCL, Guo Y. Carbon and eco-footprints of adult incontinence products. Fibers and Polymers 2013; 14, 1776–1781..

Overall, without effective treatments, parous women, frail older patients and patients with neurological disorders suffering from FI will continue experiencing a decreased QoL and the condition has significant economic and environmental impacts on society.

The solution: A curative treatment decreasing the burden on patients’ lives & on society

Conservative treatment options are generally ineffective and patients are often referred to undergo different kinds of surgical treatments. While surgical sphincter repair is the most successful improvement of continence, it does not always persist in the long-term [42]Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.. Hence, regenerative medicine approaches have been under investigation as a novel alternative approach due to their success in the treatment of other indications (e.g., hematological, cardiovascular, neurological, digestive, traumatic, endocrine, renal, and metabolic conditions) [42]Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105..

Regenerative medicine products

Regenerative medicine aims to restore tissue that is impaired due to injury, aging or disease [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . Treating fecal incontinence with regenerative medicine is at its infancy, there is a lot more within the field to be explored and developed. While the development of regenerative medicine in the relatively new realm of FI is rather fast, it is still lagging relative to other indications [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . Among else, this is due to the stigma associated with FI, resulting in patients’ reluctance to openly discuss the condition [31]Devendorf AR, Bradley SE, Barks L, Klanchar A, Orozco T, Cowan L. Stigma among veterans with urinary and fecal incontinence. Stigma Health 2021; 6, 335–343. . Consequently, the potential of patient recruitment for clinical trials is limited. Moreover, in the context of sphincter defects, it remains difficult to understand the choice of suitable biomaterial, the cell behavior following implantation and other technological aspects [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . The most common approaches in the field of regenerative medicine include injection of biomaterials, tissue engineering, cell therapy, and a combination of the therapies [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . The focus of this article has been narrowed down to, specifically, cell therapy, due to the vast potential that the approach shows in treating FI. While cell therapies for treating FI are still under development, the plethora of ongoing studies shows a clear positive signal regarding their potential as an alternative FI treatment. While the rest of the article focuses specifically on cell therapy, for the sake of completeness, the section below presents an overview of the four different regenerative medicine approaches.

Biomaterials can be used for injection into the anal sphincter to promote the restoration. Biomaterials include materials such as polymer, ceramics, metal, and composite materials [44]Han F, Wang J, Ding L, et al. Tissue engineering and regenerative medicine: achievements, future, and sustainability in Asia. Front. Bioeng. Biotechnol. 2020; 8, 495216. . Bulking agents are one type of biomaterial and can be inserted into the individual under local, regional, or general anesthesia. The injection depends very much on the type of clinical indication as well as the substance used. Bulking agents are intended to expand the tissue in the anal canal and prevent fecal leakage [45]Mellgren A, Matzel KE, Pollack J, et al. Long-term efficacy of NASHA Dx injection therapy for treatment of fecal incontinence. Neurogastroenterol. Motil. 2014; 26, 1087–1094.Mellgren A, Matzel KE, Pollack J, et al. Long-term efficacy of NASHA Dx injection therapy for treatment of fecal incontinence. Neurogastroenterol. Motil. 2014; 26, 1087–1094.. They can be performed in an outpatient setting with a low risk of morbidity, therefore increasing in popularity [45]Mellgren A, Matzel KE, Pollack J, et al. Long-term efficacy of NASHA Dx injection therapy for treatment of fecal incontinence. Neurogastroenterol. Motil. 2014; 26, 1087–1094.Mellgren A, Matzel KE, Pollack J, et al. Long-term efficacy of NASHA Dx injection therapy for treatment of fecal incontinence. Neurogastroenterol. Motil. 2014; 26, 1087–1094.. The use of bulking agents results in less frequent episodes of fecal incontinence over time as they can guide the healing process [46]Camilleri-Brennan J. Anal injectable and implantable bulking agents for faecal incontinenceIn: Current Topics in Faecal Incontinence (Editor: Camilleri-Brennan J). 2020. IntechOpen.. Some examples of bulking agents include the silicon biomaterial (PTQ), carbon-coated microsphere (Durasphere®), and the dextranomer in stabilized hyaluronic acid, also known as NASHA Dx [47]Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.. Among those that are currently utilized, the NASHA Dx is the bulking agent that has shown to be most successful. This agent is approved for use in the USA and was trialed in Europe and in the USA in 2011. The result of the bulking agent was a >50% reduction in incontinence episodes, a 50% or greater reduction in incontinence episodes in 52% of the therapeutic treatment group compared to 31% in the placebo group at a 6-month interval [47]Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.. Follow-up at 12 months presented a 50% or more reduction in FI episodes in 69% of patients in the therapeutic group, whilst the placebo group were not measured at 12 months [47]Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.. In 2013, the efficacy of all injectable bulking agents was measured, and it was concluded that the NASHA Dx injectable demonstrated a significant improvement in continence [47]Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7.Price AD, Paquette IM. Best conservative options for fecal incontinence. Ann. Laparosc. Endosc. Surg. 2022; 7..

Tissue engineering is an approach that evolved from the field of biomaterials which involves the growth of functional organs in vitro that are then implanted into the body [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . The goal of tissue engineering is to restore, maintain or improve damaged tissue and organs. Further research should enlighten upon the clinical application of tissue engineering in patients with fecal incontinence. So far, the vascularization and integration of the engineered tissue are challenges that yet need to be overcome before patients can be treated by means of tissue engineering [48]Williams DF. Challenges with the development of biomaterials for sustainable tissue engineering. Front. Bioeng. Biotechnol. 2019; 7, 456529. . Although it is stated that the cells’ environment and thus cell differentiation can be carefully regulated [49]Brown PT, Handorf AM, Jeon WB, Li W-J. Stem cell-based tissue engineering approaches for musculoskeletal regeneration. Curr. Pharm. Des. 2013; 19, 3429. , some of the disadvantages of tissue engineering include the risk of tumorigenicity, immunogenicity, graft rejection and cell migration [50]Seppänen-Kaijansinkko R. Tissue engineering—pros and cons. Int. J. Oral Maxillofac. Surg. 2017; 46, 50. . Additionally, vascularization of the site of implantation is potentially limited and the formation of the implantation requires time [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . Autologous tissue repair showed to be an effective surgery. The advantages of autologous tissue repair include a minimal to moderate inflammatory response as well as a good integration with host tissues, however a disadvantage includes a high recurrence rate [51]Lin M, Lu Y, Chen J. Tissue-engineered repair material for pelvic floor dysfunction. Front. Bioeng. Biotechnol. 2022; 10, 968482. .

Cell therapy is a relatively novel, long-lasting, and effective regenerative therapy that uses stem cells for the purpose of tissue regeneration. This makes it a very interesting option to identify potentially curative treatments for FI when linked to damage sphincter muscles. In the context of FI, there are no approved cell therapies yet, but the ones under development use autologous cells (i.e. patient’s own cells) and relocate them to the site of damage to repair the sphincter muscle. Cell therapy uses a variety of stem cell types, most commonly mesenchymal stem cells that can be obtained from a variety of tissues, often bone marrow, adipose or muscle tissue [52]Li P-C, Ding D-C. Stem-cell therapy in stress urinary incontinence: a review. Tzu Chi Med. J. 2023; 35, 111.  [53]Kim M, Oh BY, Lee JS, Yoon D, Chun W, Son IT. A systematic review of translation and experimental studies on internal anal sphincter for fecal incontinence. Ann. Coloproctol. 2022; 38, 183–196. . Autologous skeletal muscle derived cells (ASMDCs) are the most common cell types, these are obtained from the isolation of satellite cells from skeletal muscle biopsies that after processing can become myogenic progenitor cells [54]Frudinger A, Marksteiner R, Pfeifer J, Margreiter E, Paede J, Thurner M. Skeletal muscle-derived cell implantation for the treatment of sphincter-related faecal incontinence. Stem. Cell Res. Ther. 2018; 9, 1–20. . These ASMDC can regenerate skeletal muscle cells to repair the external anal sphincter muscle. The current cell therapies under development for FI could be of benefit to patients with urinary incontinence [55]Despite high prevalence, urinary incontinence is still very much a taboo. Uroweb 2021 (accessed Aug 3, 2023). [56]Sam P, Jiang J, LaGrange CA. Anatomy, Abdomen and Pelvis, Sphincter Urethrae. In: StatPearls (Editors: Sam P, Jiang J, Leslie SW, et al.) 2022, StatPearls Publishing., but also patients with joint or other muscle injuries [52]Li P-C, Ding D-C. Stem-cell therapy in stress urinary incontinence: a review. Tzu Chi Med. J. 2023; 35, 111.  [57]Seval MM, Koyuncu K. Current status of stem cell treatments and innovative approaches for stress urinary –incontinence. Front. Med. (Lausanne) 2022; 9, 1073758. . A study showed that patients with limited FI duration and high incontinence episode frequency (IEF) are most responsive to cells [58]Frudinger A, Gauruder-Burmester A, Graf W, et al. Skeletal muscle–derived cell implantation for the treatment of fecal incontinence: a randomized, placebo-controlled study. Clin. Gastroenterol. Hepatol. 2023; 21, 476–486.e8. . Unfortunately, the survival rate of cultured cells is influenced due to the altered immunogenicity occurring during the ex vivo culturing period [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . In addition, it is evident that routine use of cell therapy involves high costs [59]Luca M De, Cossu G. Cost and availability of novel cell and gene therapies: can we avoid a catastrophic second valley of death? EMBO Rep. 2023; 24. . A more cost-effective method for cell transplantation for anal sphincter regeneration has been proposed. Rather than expanding cells into injured anal sphincters, fragmented muscle fibers could be injected [60]Balaphas A, Meyer J, Meier RPH, et al. Cell therapy for anal sphincter incontinence: where do we stand? Cells 2021; 10, 2086. .

Cell therapy can be combined with biomaterials that provide a scaffold structure that can protect cells and then increase the chances of engraftment to form functional tissue [43]Parmar N, Kumar L, Emmanuel A, Day RM. Prospective regenerative medicine therapies for obstetric trauma-induced fecal incontinence. Regenerative Med. 2014; 9, 831–840. . When they are isolated from the patient, the cells are cultured in vitro and, in the case of FI, can be injected in combination with stimulating biomaterials to facilitate the functionality and attachment of the ASMDCs to the damaged site of the anal sphincter. Hence, the microenvironment is of upmost importance to sustain the quality of the ASMDCs. Without a sustaining environment, the ASMDCs are more likely to undergo apoptosis or reduced viability leading to decreased effect of the therapy. Presence of a scaffold has proven beneficial for the proliferation and myogenic ability of satellite cells [61]Jiang Y, Torun T, Maffioletti SM, Serio A, Tedesco FS. Bioengineering human skeletal muscle models: recent advances, current challenges and future perspectives. Exp. Cell Res. 2022; 416, 113133. Jiang Y, Torun T, Maffioletti SM, Serio A, Tedesco FS. Bioengineering human skeletal muscle models: recent advances, current challenges and future perspectives. Exp. Cell Res. 2022; 416, 113133. . Since ASMDC are at a more advanced differentiation stage than satellite cells, the importance of scaffold could be greater for this cell type [61]Jiang Y, Torun T, Maffioletti SM, Serio A, Tedesco FS. Bioengineering human skeletal muscle models: recent advances, current challenges and future perspectives. Exp. Cell Res. 2022; 416, 113133. Jiang Y, Torun T, Maffioletti SM, Serio A, Tedesco FS. Bioengineering human skeletal muscle models: recent advances, current challenges and future perspectives. Exp. Cell Res. 2022; 416, 113133. . Studies researching cell therapy in combination with biomaterials have proved promising results, due to the ability of the created microenvironment to sustain the implanted cells. Although it is difficult to maintain a promotive microenvironment to sustain the quality of the ASMDCs, many technologies are emerging with the aim to improve the conditions of patients with FI [62]Zhao X, Li Q, Guo Z, Li Z. Constructing a cell microenvironment with biomaterial scaffolds for stem cell therapy. Stem Cell Res. Ther. 2021; 12, 1–13.. In the following section we report on the competitive landscape of cell therapies in the field of FI as these therapies have been gaining more popularity over the past few years.

Competitive landscape within cell therapy

By December 2022, the US Food and Drug Administration (FDA) had approved a total of 27 cell and gene therapies [63]Viscomi S. What’s Holding Cell Therapies Back? A Look Into The Evolution And Future Of Stem Cell Tech 2023 (accessed Aug 3, 2023).Viscomi S. What’s Holding Cell Therapies Back? A Look Into The Evolution And Future Of Stem Cell Tech 2023 (accessed Aug 3, 2023).. The FDA anticipate approving another 10–20 therapies each year by 2025 [63]Viscomi S. What’s Holding Cell Therapies Back? A Look Into The Evolution And Future Of Stem Cell Tech 2023 (accessed Aug 3, 2023).Viscomi S. What’s Holding Cell Therapies Back? A Look Into The Evolution And Future Of Stem Cell Tech 2023 (accessed Aug 3, 2023).. Worldwide, the UK has the third largest cluster for cell and gene therapy production. In 2021, there were a total of 168 ongoing trials which made up around 9% of all global trials [64]Osborne A. Catapult’s Cell and Gene Therapies Vision for the UK - Phacilitate 2022 (accessed Aug 3, 2023).Osborne A. Catapult’s Cell and Gene Therapies Vision for the UK - Phacilitate 2022 (accessed Aug 3, 2023).. As of 2021, there have been a total of 16 new approvals of cell and gene therapies by the European Medicines Agency (EMA), of which 12 have been granted marketing authorization by the Medicines and Healthcare products Regulatory Agency (MHRA) [64]Osborne A. Catapult’s Cell and Gene Therapies Vision for the UK - Phacilitate 2022 (accessed Aug 3, 2023).Osborne A. Catapult’s Cell and Gene Therapies Vision for the UK - Phacilitate 2022 (accessed Aug 3, 2023).. Among the emerging technologies intended for FI cell therapy, a few have explored the use of microcarriers alongside different cell types. A comparison of the existing technologies based on stage of development, presence of the scaffold and intellectual property (IP) protection of the technologies is presented in Table 1 [65]Oh HK, Lee HS, Lee JH, et al. Coadministration of basic fibroblast growth factor-loaded polycaprolactone beads and autologous myoblasts in a dog model of fecal incontinence. Int. J. Colorectal Dis. 2015; 30, 549–557.  [66]Montoya TI, Acevedo JF, Smith B, et al. Myogenic stem cell-laden hydrogel scaffold in wound healing of the disrupted external anal sphincter. Int. Urogynecol. J. 2015; 26, 893–904.  [67]Kuismanen K, Juntunen M, Girish N, et al. Functional outcome of human adipose stem cell injections in rat anal sphincter acute injury model. Stem Cells Transl. Med. 2018; 7, 295–304. . Notably, the most advanced therapies currently in phase 3 clinical trials are cell therapy approaches that do not use scaffold technologies. Conversely, the published studies on FI cell therapy with the use of scaffolds are relatively outdated and seem to have paused at the ical stage. The emerging technology with the most competitive advantage is the one developed by Innovacell, an Austrian start-up that has a broad IP coverage and a product at an advanced clinical development phase (phase 3 trials). Emerging evidence suggests that several cell therapies are seen as safe, however their therapeutic application and effectiveness remains a challenge [68]Ntege EH, Sunami H, Shimizu Y. Advances in regenerative therapy: a review of the literature and future directions. Regen. Ther. 2020; 14, 136–153. .

Table 1. Comparisons of key players in the field of cell therapy for FI.
Entity
Cell type
Scaffold
Development phase
Patents
Reference
AMELIE
Autologous skeletal muscle derived cells
Poly DL-lactide-co-glycolide
Preclinical
1 European,
1 international
Amelie-project.eu
Seoul National University College of Medicine
Autologous myoblasts
bFGF-loaded
polycaprolactone beads
Preclinical (dog)
Not found
[65]
University of Texas Southwestern Medical Center
Myogenic stem cells
Polyethylene glycol-based hydrogel matrix scaffold
Preclinical (rat)
Not found
[66]
University of Tampere
Human adipose stem cell
Bulkamid, a non-degradable viscoelastic water-based polymer
Preclinical (rat)
Not found
[67]
Yonsei University
Allogenic-adipose-derived mesenchymal stem cells
None, but in one patent they use chitin and ligament stem cells to promote collagen formulation
Phase 1 completed
2 Korean,
1 international
(NCT02384499)
Innovacell AG
Autologous skeletal muscle-derived cell
None
Phase 3 ongoing
6 European,
6 international
(NCT04976153)
Cook MyoSite
Itamocel auto-logous muscle-derived stem cell therapy
None
Phase 3 ongoing
Not found
(NCT05776277)
Andalusian
Initiative for
Advanced Therapies
Autologous mesenchymal stem cells from adipose tissue
None
Phase 2 completed
Not found
(NCT02292628)
Cellf Bio LLC
Smooth muscle cells and neural stem cells
None
Phase 1 ongoing
Not found
(NCT05616208)
Wake Forest University Health Sciences
Muscle fiber fragments that contain muscle precursor cells (MPCs)
None
N/A (procedural)
6 European,
11 international
(NCT05396456)
University
Hospital, Rouen
Autologous muscle-derived progenitor cell injection
None
Phase 3 completed
3 European,
2 international
(NCT01523522)
Sources: desk research, Wheesbee, and clinicaltrials.gov. Query for clinicaltrials.gov: (regenerative medicine) OR (tissue regeneration) OR (regenerative therapy) OR (cell therapy) | faecal incontinence; Selected status: Not yet recruiting, Recruiting, Enrolling by invitation, and Active not recruiting.

Impact: Introduction of new cell therapy technologies will improve the current state-of-play in FI at the clinical, patient, & socio-economic level

Clinical level: expansion of available treatment options

Cell therapy technologies have the potential to significantly alter the paradigm of treatment for patients with sphincter damage and for elderly patients. The conservative treatment options are generally not effective enough and the patient is referred further to undergo the different kinds of surgical treatments [46]Camilleri-Brennan J. Anal injectable and implantable bulking agents for faecal incontinenceIn: Current Topics in Faecal Incontinence (Editor: Camilleri-Brennan J). 2020. IntechOpen. [69]Demirci S, Gallas S, Bertot-Sassigneux P, Michot F, Denis P, Leroi AM. Anal incontinence: the role of medical management. Gastroenterol. Clin. Biol. 2006; 30, 954–60. , which are often unsuitable or undesirable. Treatment using regenerative medicine products need to be entirely safe to differentiate them from other surgical interventions. For instance, surgical sphincter repair carries a high risk of wound breakdown and infection [70]Okeahialam NA, Wong KW, Thakar R, Sultan AH. The incidence of wound complications following primary repair of obstetric anal sphincter injury: a systematic review and meta-analysis. Am. J. Obstet. Gynecol. 2022; 227, 182–191.  and can result in permanent stoma in some patients [71]Van Koughnett JAM, Wexner SD. Current management of fecal incontinence: choosing amongst treatment options to optimize outcomes. World J. Gastroenterol. 2013; 19, 9216–9230. . SNS has the downside of initial cost and necessity for ongoing (lifelong) therapy maintenance (with further cost e.g., for battery replacements) [72]Thaha MA, Abukar AA, Thin NN, Ramsanahie A, Knowles CH. Sacral nerve stimulation for faecal incontinence and constipation in adults. Cochrane Database Syst. Rev. 2015; 8, CD004464.. Cell therapy could be an effective alternative for these patient groups. Due to its lower invasiveness and associated risk of adverse events, it is seen as a breakthrough therapeutical option for these patient groups.

Patient level: improvement of QoL for patients

Cell therapy products have the potential to significantly improve the patients’ QoL. Quality of patients’ lives is shown to increase after a clinically successful treatment [73]Deutekom M, Terra MP, Dobben AC, et al. Impact of faecal incontinence severity on health domains. Colorectal Disease 2005; 7, 263–269. Deutekom M, Terra MP, Dobben AC, et al. Impact of faecal incontinence severity on health domains. Colorectal Disease 2005; 7, 263–269. . Cell therapy products will provide an alternative treatment option for those patients with severe FI that are not responding to conservative therapies, as described in more detail in the section above. These products have the potential advantage over other surgical interventions and conservative treatment methods. As such, they will be a better alternative for several patient groups. An effective clinical treatment would spare patients from risks and inconveniences, ultimately leading to a higher QoL [73]Deutekom M, Terra MP, Dobben AC, et al. Impact of faecal incontinence severity on health domains. Colorectal Disease 2005; 7, 263–269. Deutekom M, Terra MP, Dobben AC, et al. Impact of faecal incontinence severity on health domains. Colorectal Disease 2005; 7, 263–269. .

Socio-economic level: reduction of the negative impact of FI on the economy

Treatment of FI with cell therapies would have the potential to create considerable savings for the EU and would increase the productivity of patients. An effective clinical treatment would allow patients to substantially reduce the medical costs associated with the condition, as well as enable FI patients to be economically contributing members in society. Considering the above-mentioned assumption of 2–5% market penetration, these are the predicted socio-economic impacts of cell therapy products targeting FI:

  • The new treatments could save EU citizens between approximately €11.74 and €29.34 million per year for women affected by FI arising from obstetric sphincter injury and between approximately €65.90 and €164.75 million per year saved for all patients with FI in the EU; and
  • The new treatments could save between 222,650–556,000 working days per year for women affected by FI arising from obstetric sphincter injury and 1.25–3.125 million working days per year saved for all patients with FI in the EU.

Recommendations & conclusion

Where current therapies against FI often are not as effective as required, regenerative medicine often offer less invasive treatments and can be applied to a broad range of patients. Amongst regenerative medicine, new cell therapies are under development, reflecting positive signals for the field of FI. Exploring some of the recommendations below might further support the endeavors within the field of regenerative medicine, especially in the context of FI.

Technological improvements

Among the key obstacles in regenerative medicine therapies based on skeletal muscle-derived cells are insufficient cell count at delivery/survival and recapitulating the features of adult cells [42]Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.. Both these hurdles could be tackled by integrating a biocompatible scaffold, potentially also releasing stimulatory molecules (e.g., growth factors and cytokines) to facilitate both delivery and functionality of the cells [42]Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.. Additionally, most studies for the use of stem cell therapy for FI so far lacked potential for clinical translation [53]Kim M, Oh BY, Lee JS, Yoon D, Chun W, Son IT. A systematic review of translation and experimental studies on internal anal sphincter for fecal incontinence. Ann. Coloproctol. 2022; 38, 183–196. . This is thought to potentially be a consequence of the general focus on the external sphincter muscle regeneration and the lack of understanding of role of the internal sphincter muscle. This could potentially go as far as stimulating vascularization to ensure successful survival and regeneration [42]Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105. [61]Jiang Y, Torun T, Maffioletti SM, Serio A, Tedesco FS. Bioengineering human skeletal muscle models: recent advances, current challenges and future perspectives. Exp. Cell Res. 2022; 416, 113133. . Safety of the cell therapy approaches should be confirmed, as the replicative property of stem cells is associated with the risk of carcinogenicity. Results from ongoing long-term studies using the cell type of choice, ASMDCs for FI in most cases, should be carefully monitored [42]Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.Trébol J, García-Arranz M. Stem cell therapy for faecal incontinence: current state and future perspectives World J. Stem Cells 2018; 10(7), 82–105.. Finally, cellular therapy is costly, so once the technology is improved, their commercialization will depend on efficiently scaling up production of the therapy, potentially through the use of allogeneic cells (i.e. from healthy donors) [74]Chan AML, Ng AMH, Yunus MH, et al. Safety study of allogeneic mesenchymal stem cell therapy in animal model. Regen. Ther. 2022; 19, 158–165. .

Educating patients about different treatment options

Alongside the development of cell therapies that potentially offer a curative treatment for patients with FI, patients’ families and the society should be made aware of the arising treatment options. Few patients are informed of the different therapies that are available to treat incontinence. Clinicians should be involved not only in the development of new potentially curative cell therapy treatments, but also in the education of the patients regarding the available options. A more effective treatment will eventually contribute to the reduction of the stigma associated with FI.

Providing safe platform for discussion and raising awareness

While the charities and patient groups active in the field of FI exist to provide the much-needed support to patients with FI, it still remains true that the disease is highly stigmatized and its prevalence underreported. A community-based approach providing a safe platform for discussion and sharing, combined with an educative element as described above, needs to be in place. Public information campaigns should emphasize that the condition is relatively common, especially among the groups that are at risk, for the lack of conversation around FI contributes to the public under-estimation of is prevalence, making the experiences feel more alone and perpetuating the cycle of stigma further. Similarly, public-facing campaigns could include information on prophylactic actions that doctors might provide to patients in a clinical setting. It is crucial that there is a unified effort across the EU, or at least that such charitable efforts take place in all countries, so that the inequality among countries does not further exacerbate the negative effect on FI on patients. With an increased awareness and decreased stigma, patients may feel motivated not only to share with fellow patients and thus raise awareness further, but they might also feel more comfortable in participating in the clinical development of alternative treatments.

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Affiliations

Martha Gilbert
ttopstart, Rijswijk, The Netherlands

Simona Čaputová
ttopstart, Rijswijk, The Netherlands

Delielena Poli
ttopstart, Rijswijk, The Netherlands

Manou Kooy
ttopstart, Rijswijk, The Netherlands

Georgia Sturt
Bowel Research UK, London, UK

Josephine Parker
Comprehensive Clinical Trials Unit, University College London,
London, UK

Richard M Day
Centre for Precision Healthcare,
University College London, London, UK

Authorship & Conflict of Interest

Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given his approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: Richard Day is a Director and shareholder of Luna Therapeutics Ltd.

Funding declaration: ttopstart operates as a beneficiary within the Anchored Muscle cELls for Incontinence (AMELIE) project, receiving funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No 874807. Bowel Research UK operates as a beneficiary within the Anchored Muscle cELls for IncontinencE (AMELIE) project, receiving funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No 874807. UCL operates as a coordinator within the Anchored Muscle cELls for Incontinence (AMELIE) project, receiving funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No 874807.

Article & copyright information

Copyright: Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2023 Gilbert M, Čaputová S, Poli D, Kooy M, Sturt G, Parker J & Day RM. Published by Cell & Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited; externally peer reviewed.

Submitted for peer review: Aug 9, 2023; Revised manuscript received: Oct 5, 2023; Publication date: Dec 7,2023.