**4. Use of animal model in conservative treatment of incontinence**

Since conservative management involves the use of medicine with many side effects, labora‐ tory animals are used in preclinical drug trials. Several animal models have been used to evaluate the best possible conservative remedies for treating both urinary and fecal incon‐ tinence. Animal models were to test midurethral slings for surgical treatment of SUI which currently provides the best surgical cure. An outline of conservative management of double incontinence is shown in **Figure 1**.

#### **4.1. Conservative management of SUI**

Conservative treatment of SUI includes lifestyle interventions, pelvic floor muscle training, electrical stimulation, vaginal cones, urethral plugs and the drug duloxetine. Medical treat‐ ment has been tried and tested on animal models to assess their safety and effects on nervous system in improving SUI.

**Figure 1.** Conservative management of double incontinence.

#### *4.1.1. Selective norepinephrine reuptake inhibitor*

inflation was performed, mimicking the pressure effects of child birth on the pelvic side wall and pelvic floor. Both groups of rats showed signs of EAS muscle atrophy and denervation, leading to FI. However, EMG signs of re‐innervation were seen in both groups and recovery of

Since conservative management involves the use of medicine with many side effects, labora‐ tory animals are used in preclinical drug trials. Several animal models have been used to evaluate the best possible conservative remedies for treating both urinary and fecal incon‐ tinence. Animal models were to test midurethral slings for surgical treatment of SUI which currently provides the best surgical cure. An outline of conservative management of double

Conservative treatment of SUI includes lifestyle interventions, pelvic floor muscle training, electrical stimulation, vaginal cones, urethral plugs and the drug duloxetine. Medical treat‐ ment has been tried and tested on animal models to assess their safety and effects on nervous

muscle mass at 4 weeks, mimicking human pathophysiology of fecal incontinence.

130 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

**4. Use of animal model in conservative treatment of incontinence**

incontinence is shown in **Figure 1**.

system in improving SUI.

**4.1. Conservative management of SUI**

**Figure 1.** Conservative management of double incontinence.

Venlafaxine is a selective norepinephrine (NE) reuptake inhibitor, and it significantly decreases the contraction of bladder muscle and increases urethral resistance. This was ini‐ tially tested on rabbits and rodents. Bladder and proximal urethral muscle strips were electri‐ cally stimulated, and their contractile responses were measured both pre‐ and posttreatment with venlafaxine. It was observed that it significantly increased the contraction of urethral strips (*P* = 0.008) tested by urethral pressure profilometry (UPP) [39].

#### *4.1.2. Norepinephrine (NE) and serotonin (5‐HT) reuptake inhibitor*

Duloxetine, a norepinephrine (NE) and serotonin (5‐HT) reuptake inhibitor, can prevent SUI by facilitating noradrenergic and serotonergic systems in the spinal cord at S3 level (nucleus of Onuf) to enhance the sneeze‐induced active urethral closure mechanism. Based on this mechanism, duloxetine is currently being used in humans for conservative manage‐ ment of SUI. Before the human trials, it was tested on cat sphincter [40] and in rat models. Duloxetine caused urethral closing contractions and increased the urethral resistance (leak point pressure) measured using a microtip transducer catheter in the middle urethra of rat models [41].

#### *4.1.3. Stem cell therapy*

One of the SUI causes includes urethral sphincter deficiency which is called type III SUI or intrinsic sphincter deficiency (ISD). This occurs usually due to inherent defects in the collagen and elastin of urethral sphincter. Many preclinical trials have investigated whether trans‐ plantation of patient's own skeletal muscle‐derived cells (SkMDCs) can restore the sphincter musculature. The specific cell type of SkMDCs is myoblasts, satellite cells, muscle progenitor cells, or muscle‐derived stem cells. The other stem cell (SC) types used for urethral defects include those from the bone marrow, umbilical cord blood and adipose tissue. These cells are injected as periurethral injections. Herrera‐Imbroda et al. used rat models for SC injection, and rats were assessed by LPP testing for therapeutic efficacy of SC treatment [42]. The study also used histological assessment, which revealed the sphincter muscle content, existence of transplanted SCs and possible differentiation of these SCs.

Rodents were also used to explore the feasibility, safety and efficacy of cellular regi‐ men to treat SUI. SUI was induced by vaginal dilatation (VD), and cystoscopic urethral injections of bone marrow or adipose tissue‐derived mesenchymal stromal cells (BMSC/ ADSC) were given to rats. It was observed that MSCs restored the continence mecha‐ nism by improving vascular and connective tissue status of urethral tissues after VD [43]. In another study, human mesenchymal stromal cells were isolated, expanded and char‐ acterized. These cells were injected trans‐urethrally in immune‐suppressed Göttingen Minipigs. The study found this cellular sphincter therapy in Göttingen Minipigs as very safe and effective against SUI [44]. Some animal studies employed dogs with induced SUI and injected SCs therapy to test safety and efficacy for SUI treatment and found similar results [45].

#### **4.2. Conservative treatment of UUI**

Clinical observations as well as results from recent studies on murine showed that iatrogenic bladder outlet obstruction leads to a rise in detrusor pressure, mimicking leak in humans secondary to detrusor overactivity (DO) in cases of UUI. Murines were induced DO and then treated by the use of botulinum toxin A (BoNT‐A). The therapeutic effects of intramural injections of botulinum toxin A (BoNT‐A) into the bladder wall resulted in suppression of detrusor overactivity in murine as seen in human bladder, and the refrac‐ tory cases of UUI secondary to DO have shown same results with botulinum toxin A (BoNT‐A) [46].

or muscle‐dominant sphincter structure in all animals receiving rBM and fibrous‐dominant

Animal Models of Double Incontinence: "Fecal and Urinary"

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There are a variety of surgical treatment options for SUI. The two most effective procedures are Burch colposuspension and miduretheral slings (MUS), which are available in different synthetic material. Each material has been tested for its efficacy and safety. There are many

Surgical management including the suburethral sling is one of the most common treatment options for SUI, with an overall objective cure rate of 82% [49]. Suburethral sling therapy provides stability to the supporting layer under the urethra and helps in leak of urine against the rise in abdominal pressure. The urethra remains compressed against the suburethral sling, and continence is maintained. While a sling procedure offers the highest success rate, it also results in the highest morbidity and complication rate among all anti‐incontinence procedures. In the last several years, a number of modifications to the sling procedure have been proposed to improve its safety and efficacy while decreasing morbidity. SUI in rats was induced by pudendal nerve transaction (PNT), they were treated by polypropylene subure‐

Tension‐free vaginal tape (TVT) with polypropylene was first introduced by Ulmsten for surgical treatment of SUI and has shown good success rate [51]. The tensile properties of polypropylene used in TVT were studied in rats and found to be significantly greater than cadaveric fascia lata [52]. There have been many other sling procedures using same mate‐ rial with different surgical approaches. Another study on white rabbits has evaluated tissue reactions to five sling materials used in five different procedures like tension‐free vaginal tape (TVT), intravaginal slingplasty (IVS) for SUI surgery and polypropylene mesh for hernia repair. The other two procedures to cure SUI included suprapubic approach using subure‐ thral polypropylene tape and cadaveric fascia lata. Rabbit abdominal skin was incised, and a patch of all five sling material was attached with absorbable suture. Study compared the mesh‐to‐tissue attachment strength of four sling mesh materials on days 2, 7, 15 and 30 after implantation by electron microscopic studies. All five synthetic sling materials produced similar tissue reactions beginning soon after implantation. Cadaveric fascia lata persisted in tissue with remarkable perifascial fibrosis at day 30. When comparing the four polypropylene mesh materials, the attachment capacity of TVT was superior and that of IVS was the least of the four. TVT was statistically better than IVS at all data points. Suprapublic approach with

sphincter structure in most animals receiving hUCM cells [8].

animal studies regarding the use of mesh before its use in human.

thral sling and the efficacy of sling was assessed by an increase in LPP [50].

polypropylene and hernia mesh provided results similar to those of TVT [53].

**5.1. Surgical treatment of SUI**

*5.1.1. Efficacy of slings tested by LPP*

*5.1.2. Tissue reaction of different sling materials*

**5. The role of animal studies in surgical management of DI**

#### **4.3. Conservative treatment of FI**

Modifying irregular bowel habits is often the first step to manage FI. Pelvic floor exer‐ cises with and without biofeedback therapy, reusable bodyworn products and antidiar‐ rheal treatment all play some role in treatment of FI. Sacral nerve stimulation (SNS) and stem cell therapy for improving contractile function of anal sphincter have been studied on animal models.

#### *4.3.1. Sacral nerve stimulation (SNS) therapy*

Fecal incontinence is multifactorial in origin. Most of the human studies have focused on anal sphincter functions and its restoration for treatment of FI. There have been numerous animal studies which investigated direct effects of SNS on the muscles of continence. In one study, ten dogs received electrical stimulation of the sacral plexus. Histochemical analysis of the striated external anal sphincter following chronic electrical stimulation demonstrated hyper‐ trophy of stimulated muscle fibers. However, these changes reverted to pre‐stimulation level 3 months after the stimulation. Anal tone and reflexes were measured before and during acute stimulation and demonstrated that SNS did not have any significant effect on internal anal sphincter or external anal sphincter force, the recto‐anal inhibitory or recto‐anal excitatory reflexes, internal anal sphincter slow wave frequency or wave amplitude [47]. The mechanism of action of SNS with the use of surgically implanted interstim is not very clear; however, it was found to be very effective in patients with FI [48].

#### *4.3.2. Stem cell therapy*

Stem cell injection at the site of injury can enhance contractile function of the anal sphincter without surgical repair. Human umbilical cord matrix (hUCM) cells have been described as having the characteristics of myofibroblasts, which play a role in healing by producing a wide range of cytokines, growth factors, chemokines and inflammatory mediators. Rabbit bone marrow (rBM) cells are known to secrete many growth factors which contribute to cell propagation and differentiation. Harvested hUCM and rBM stem cells from rabbit femurs and tibias were injected in surgically incised external anal sphincter of the white New Zealand rabbits. Electromyography showed significant improvement in sphincter function 2 weeks after local injection of rBM stem cells, and histopathologic evaluation showed normal or muscle‐dominant sphincter structure in all animals receiving rBM and fibrous‐dominant sphincter structure in most animals receiving hUCM cells [8].
