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

#### **5.1. Surgical treatment of SUI**

**4.2. Conservative treatment of UUI**

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

**4.3. Conservative treatment of FI**

*4.3.1. Sacral nerve stimulation (SNS) therapy*

was found to be very effective in patients with FI [48].

(BoNT‐A) [46].

on animal models.

*4.3.2. Stem cell therapy*

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

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

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

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

#### *5.1.1. Efficacy of slings tested by LPP*

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

#### *5.1.2. Tissue reaction of different sling materials*

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

#### **5.2. Surgical treatment of FI**

Obstetric anal sphincter trauma is the most common cause of fecal incontinence with a severe impact on quality of life. Anal sphincter rupture is reported in about 2.5% of vaginal deliveries in centers that practice mediolateral episiotomy and about 11% in centers that practice mid‐ line episiotomy [54]. The effect of anal sphincter laceration (with repair) at the time of parturi‐ tion after term pregnancy on physiologic function of the external anal sphincter was studied on eighty rats [55]. Overall, anal sphincter laceration at time of delivery results in signifi‐ cantly impaired anal function. Rat anal sphincter neurophysiologic functions were assessed. Recovery of sphincter function was evident as early as three months and maintained at six months after injury. The diagnosis and repair of sphincter tear is very important. Unrepaired or badly repaired sphincter can lead to FI. Several simulator models have been developed to provide surgical training to consultants, midwives and trainees. The early diagnosis of anal sphincter injury is very important for effective surgical outcome. The pig model was intro‐ duced due to its similarity to both internal and external anal sphincters [56]. The model used cadaveric pig perineum with a clear demarcation between internal and external anal sphinc‐ ters simulating human sphincters. Another study showed effective teaching of repair of peri‐ neal tears using goat perineum model (**Figure 2**), which mimics human female anatomy [57]. Both anal sphincter latex/plastic and cadaveric animal sphincter models have been effectively used for hands on training in different workshops.

experiment on humans, it was tried in 16 animals. In experimental animals, anal sphincters were destroyed and artificial sphincter device was implanted. The animals were observed for twenty weeks. The study concluded the safety of implanted sphincter against anal ischemia.

Animal Models of Double Incontinence: "Fecal and Urinary"

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During last decade, investigators have developed and tested animal models of SUI in the female rat, seeking to mimic the symptoms of SUI in female patients. Bilateral pudendal nerve crush injury or transection or sciatic nerve transection has been used to cause SUI in rats. The VD model was used by Lin et al. [28] to simulate the damage that occurs in the pelvic floor during vaginal delivery of children. They demonstrated the feasibility of creating a mouse model of acute SUI by VD. Distention volumes of 0.1–0.3 ml in 20 g female mice of strain C57BL/6 resulted in significant reductions of LP, possibly due to partial urethral denervation. This novel model of SUI in mice could be used in future mechanistic studies of female SUI treatment. The childbirth induced vaginal distension, and SUI can be correlated but women recover out of these transient changes with only few remaining symptomatic for SUI. There is a need to develop specific mouse genetic models for incontinence/SUI induced by VD.

Moreover, animals were continent during 85% of activation times [58].

**6. Animal genetic models developed for incontinence/SUI studies**

Further studies can be performed to know the spontaneous cure of incontinence.

The use of animal models has helped in understanding the pathogenesis and etiology of both urinary and fecal incontinence. Due to ethical issues related to human cadaveric stud‐ ies, animal models are good substitute for research related to surgical innovations for treat‐ ment of double incontinence. Animal models like sheep, goat and pig have been validated for surgical training for perineal tears. The latest use of animal model is related to stud‐ ies on mouse for simulated birth trauma‐induced SUI and stem cell treatment for double

**7. Conclusion**

incontinence.

**List of abbreviations and acronyms**

DI Double incontinence FI Fecal incontinence UI Urinary incontinence SUI Stress urinary incontinence UUI Urgency urinary incontinence

OAB Overactive bladder

**Figure 2.** Multiperous goat. Cut edge of external anal sphincter (E) held by Allis forceps, (I) internal anal sphincter between anal canal (A) and (E) external anal sphincter.

#### *5.2.1. Artificial anal sphincter*

The artificial anal sphincter is used in cases where other treatment modalities fail. It includes an inflatable expander that compresses and flattens the bowel against a pillow. Before its experiment on humans, it was tried in 16 animals. In experimental animals, anal sphincters were destroyed and artificial sphincter device was implanted. The animals were observed for twenty weeks. The study concluded the safety of implanted sphincter against anal ischemia. Moreover, animals were continent during 85% of activation times [58].
