Futuristic Concept in Management of Female SUI: Permanent Repair Without Permanent Material

Stress urinary incontinence (SUI) is defined as the complaint of involuntary leakage of urine on exertion or on sneezing or coughing (Abrams et al, 2002). Female SUI is a common distressing health problem, affecting large number of women worldwide, with prevalence rates ranging from 12.8% to 46.0% (Botlero et al, 2008). SUI is considered the most common type of urinary incontinence among women and presents about 50 % of these populations, while mixed urinary incontinence presents 36 % and only 14 % are due to urge urinary incontinence (Hannestad et al, 2000). SUI has a negative impact on women quality of life specially their social, physical, occupational, psychological, and sexual aspects of life.


Introduction
Stress urinary incontinence (SUI) is defined as the complaint of involuntary leakage of urine on exertion or on sneezing or coughing (Abrams et al, 2002).Female SUI is a common distressing health problem, affecting large number of women worldwide, with prevalence rates ranging from 12.8% to 46.0% (Botlero et al, 2008).SUI is considered the most common type of urinary incontinence among women and presents about 50 % of these populations, while mixed urinary incontinence presents 36 % and only 14 % are due to urge urinary incontinence (Hannestad et al, 2000).SUI has a negative impact on women quality of life specially their social, physical, occupational, psychological, and sexual aspects of life.SUI arises when the bladder pressure exceeds the urethral pressure, in the setting of sudden increases of intra-abdominal pressure (coughing, sneezing …etc).Most researchers now identify two main etiologic mechanisms for the development of SUI: urethral hypermobility due to loss of urethral support -the hammock-like supportive layer described by DeLancey (DeLancey, 1994 ), and intrinsic sphincter deficiency (ISD), with most patients having elements of both disorders (Table 1).
There are several options for treatment of female SUI.Conservative treatment (pelvic floor muscle exercise) is usually advocated as a 1st line therapy since it carries minimal risks and studies have shown up to 70% improvement in symptoms of SUI following appropriately performed pelvic floor exercise (Price, Dawood and Jackson, 2010).Conservative management strategies include: 1. Life style changes (weight reduction, smoking cessation, ↓ fluid intake, treatment of constipation …. etc).2. Pelvic floor muscle training ± biofeedback.3. Vaginal cones and electrical stimulation.
Regarding pharmacotherapy, no drug till now has been approved to be used by the Food and Drug Administration (FDA) for the treatment of female SUI.Duloxetine is a serotoninnorepinephrine reuptake inhibitor (SNRI) has been investigated, it can significantly improve the quality of life of patients with SUI, but it is unclear whether or not benefits are sustainable in addition it has a common side-effects (Mariappan et al, 2007).
Table 1.Show various etiological factors involved in the pathophysiology of SUI.
Surgical treatment for SUI should be undertaken for women with SUI who have failed conservative treatment strategies or if the patient wants definitive treatment from the start.
Over the past years, many surgical procedures have been used for the treatment of female SUI with varying degrees of success.Recently, a number of new minimally invasive surgical techniques have been developed for treatment of female SUI that aimed to decrease the morbidity, improved safety and improvement of the surgical outcomes, while maintaining the efficacy of traditional open incontinence surgery.The Tension free vaginal tape (TVT) procedure was first described and evaluated by Ulmsten et al in Sweden in 1996(Ulmsten et al, 1996), then the Transobturator tape (TOT) procedure was developed in 2001 by DeLorme to avoid the retropubic space (DeLorme E, 2001).Midurethral slings (TVT and TOT) have the following advantages: 1.The ability to be performed under local anaesthesia in patients who are unfit for major surgery.2. Better for young aged women due to better cosmetic appearance since there is now open wound such the old traditional surgical methods.3. Lower costs, shorter hospital stay, early recovery time and less postoperative pain.
Further improvement in surgical procedures towards less invasive sling technique has led to the innovation of a mini-sling e.g.TVT Secur system, which is a surgical device requiring only a single suburethral incision to be inserted (Neuman and Shaare-Zedek, 2007).Mini-slings have the following advantages over the ordinary midurethral slings (TVT and TOT): 1.The complications associated with suprapubic and groin incisions will be eliminated.2. Cystoscopy will not be necessary.3. Operative time will be shorter than with other midurethral sling techniques.

Surgical principle of midurethral slings
Petros and Ulmsten proposed the integral or midurethral theory of the female pelvic floor and urethral closure mechanism (Petros and Ulmsten, 1993), which has been the basis upon which many of the newer treatments for SUI have been developed.The idea that a loss of mid-urethral support is a causative factor in female SUI led to the use of synthetic midurethral tapes which became popular because of ease of placement and excellent outcomes.After their introduction by Ulmsten and Delorme, TVT and TOT gained a great popularity and rapid widespread and become now the gold standard treatment minimally invasive treatment of female SUI.Both techniques (TVT and TOT) aimed to recreating urethral support using a polypropylene mesh placed at midurethral without tension to create an artificial collagenous neoligament, using the foreign body reaction induced by the host defense mechanism.TVT acts as a pubourethral neoligament anchored suprapubically, which tightens around the urethra in the setting of increased intra-abdominal pressure.TOT had the following advantage over TVT by avoiding the blind trocar passage in the retropubic space by passing the trocar through the obturator muscles and membrane, thus decreasing the risk of major bladder, bowel perforation and vascular injury also decreasing the need for cystoscopy use after tape placement (figure 1 and 2).TVT has undergone the most rigorous testing all over the years, and now it is considered the gold standard treatment option for female SUI.To date it is estimated that more than 1 million cases have been performed worldwide (Deng et al, 2007).There are now many prospective studies in literature with a long-term follow-up showing great success of TVT for the treatment of female SUI with cure rate > 80 % as seen in (table 2) denoting the long term durability of this procedure.In 2008, Nilsson et al reported the longest follow-up (11 years) of TVT operation and demonstrated that (90% objective cure rate) of women treated without any significant late-onset adverse effects (Nilsson et al, 2008).In another study with follow-up for 10 years.TVT showed satisfactory objective (84%) and subjective (57%) cure rates with (23%) improvement (Aigmueller et al, 2011).TVT has replaced the old gold standard Burch colposuspension.In a randomized control trial (RCT) conducted by Ward and Hilton who compared TVT with the open colposuspension on they reported equal efficacy with subjective cure rate 81% and 80% in TVT and Burch group respectively.The duration of hospitalization, operative time and the time taken to return to normal activity seem to be shorter in the TVT group.The authors concluded that the TVT procedure is as effective as the Burch colposuspension in urodynamically proven patients with SUI at a 2-year follow-up (Ward and Hilton, 2004).

Number of patients
The same authors have published their 5-year out comes in this study where they reported subjective cure in 81% in the TVT group and 90% in the colposuspension group.They stated that the effect of both procedures on cure and improvement in quality of life has been maintained for long time (Ward and Hilton, 2008).

TOT surgical outcomes
Short-term data regarding the efficacy of the TOT suggest that this procedure perform as well as the TVT and may perhaps cause fewer complications.TOT has shown to be of equal

TVT versus TOT outcomes
TVT and TOT since their introduction in the treatment of female SUI have gained a great popularity and wide spread use in a large number of studies.Both techniques showed nearly equal efficacy with more than 80% cure rate in the majority of studies as mentioned before (Table 2, table 3).Novara et al, in a large systematic review and meta-analysis showed that patients treated with TVT had slightly higher objective cure rates (OR: 0.8;CI: 0.65-0.99;p = 0.04) than those treated with TOT; however, subjective cure rates were similar in both technique (Novara et al, 2010).In a long term follow-up after 5 years both TVT and TVT-O procedures were safe, with equivalent results (72.9% and 71% of patients objectively cured after TVT-O and TVT, respectively) (Angioli et al, 2010).

Material used for midurethral slings
Over the past years there was a great evolution in the use of biological and synthetic materials in the treatment of different reconstructive pelvic surgery e.g.SUI and pelvic organ prolapse (POP) in an effort to improve surgical outcomes.However, the potential benefits of using grafts need to be carefully balanced against the risks of using foreign materials to the patient's body.Amid in 1997 published a classification for synthetic mesh used in abdominal hernia surgery based on the pore size (macroporous, microporous, submicro-porous) and fiber type (monofilaments or multifilament) of the synthetic mesh (Amid, 1997).Synthetic grafts may be non-absorbable, absorbable, or a mixture of the two.The non-absorbable polypropylene mesh is the most common type used in reconstructive pelvic surgery.Synthetic tapes available in the market for urogynecological practice see (table 4).
The pore size and interstices distance between the fibers (figure 3) are important mesh characteristics that determine whether host inflammatory cell and fibroblasts can penetrate the mesh or not.The ideal synthetic tapes used for the treatment of SUI should have the following characters: made of polypropylene, low weight, macroporous, monofilament mesh, with an elasticity between 20 and 35%, as these tapes have a lower incidence of infection and tissue erosion (  Type I macroporous mesh with (pore size >75 μm) allowing easier penetration of inflammatory cells such as leukocytes (9-15 μm), macrophages (16-20 μm), fibroblast and blood vessels into the graft to phagocytose bacteria (<1 μm) lowering the risk of infection, in addition host tissue in growth and incorporation is promoted resulting in good support.On the other hand, multifilament meshes have interstices that are <10 μm and bacteria (<1 μm) can replicate within these interstices.However, access to macrophages and ability to fight bacterial colonisation within the interstices is impaired (Winters et al, 2006).Monofilament mesh does not have small interstices and the risk of mesh infection and erosion is reduced with its use.

Complications of synthetic midurethral slings
Although midurethral slings are minimally invasive procedures with high efficacy, however they result in bothersome complications which should not be minimized.The reported complication rates for midurethral slings ranged from 4.3% to 75.1% for TVT and 10.5% to 31.3% for TOT (Daneshgari et al, 2008).Awareness of these complications should encourage improvements in patient counseling as well as further investigation of the underlying mechanisms.Summary of the complications of midurethral sling procedures (table 6):
-Groin and thigh pain.
-Dyspareunia.A new terminology and classification system has been developed by the International Urogynecological Association (IUGA) and the International Continence Society (ICS) for full description of all possible physical complications related directly to the insertion of prostheses (meshes, implants, tapes) & grafts in female pelvic floor surgery (figure 4).A key advantage of a standardized classification is that all parties involved in female pelvic floor surgery including surgeons, physicians, nurses, allied health professionals and industry will be referring to the same clinical issue.It is anticipated that a category (C), time (T), and site (S) -(CTS) codified table of complications will be a necessary part of reports of surgical procedures relevant to this document.With a standardized classification in place, quicker assessment of adverse events will be achieved together with uniform reporting of prosthetic-related complications (Haylen et al, 2011).

Intraoperative and early postoperative complications
Bladder perforation: occur during trocar passage in the retropubic space, it is a common intraoperative complication with reported rates of 0.7% to 24%.Genitourinary erosion: it is the most frequent and distressing complication after synthetic midurethral sling operations.Costantini and colleagues reported erosion rates after midurethral sling operations based on ranges as reported in the literatures a range from 0.7% -33%, 2.7% -33% and 0.5% -0.6% for vaginal, urethra and urinary bladder erosion respectively (Costantini et al, 2007).
The etiology of the erosion is multifactorial and includes inadequate closure of vaginal wall incision, extensive or incorrect plane of dissection, wound infection, mesh rejection, early sexual activity, tape rolling and abnormal vaginal epithelium i.e. atrophic, scarred or otherwise compromised vaginal mucosa as in post-menopausal women or after previous vaginal surgery and unrecognized vaginal laceration injury during trocar passage.The sling material also plays an important role in this complication.
Patients with genitourinary erosion may be asymptomatic discovered on routine follow-up or presented with a group of symptoms which raise the suspicion of its diagnosis such as pain, dyspareunia, dysuria, discharge and/or bleeding from the urethra or vagina or tape palpable to the patient or partner.Hammad et al, reported that 35% of vaginal erosions were asymptomatic and erosion was discovered on routine follow-up (Hammad et al, 2005).Kobashi et al seemed to confirm these data.In > 90 women who received a polypropylene mesh for the treatment of SUI, 3 developed vaginal erosion, but only 1 had symptoms such as pain, discomfort during sexual activity, and vaginal discharge and erosion was discovered during a routine check-up (Kobashi et al, 2003).Most cases occur in the first few months after surgery but they can also happen much later.
Mesh erosion may be treated with conservative measures or surgically treated depends on the erosion site and size, mesh material, and local tissue condition.Surgical approach ranges from partial simple excision of the exposed mesh to surgical exploration for total graft removal and tissue reconstruction with a Martius flap.
Conservative management with observation might be a viable option if erosion is limited to the vagina and the sling were made of autologous, allograft and new, loosely woven polypropylene material because the latter provides large interstices, which favour tissue ingrowth and healing With the new classification system of IUGA and ICS the description of the complications related to midurethral slings especially genitourinary erosion now become standardized and easy as shown in some the following reported cases of complication related to the use of midurethral tapes (figures 5, 6, 7)

Introduction
The perfect implant material currently is not available yet, but in general surgery there is now a consensus, that low weight, large pore (macroporus), monofilament synthetic materials are preferable.However, still serious local complications (e.g.erosion and infection) may occur and related to an increased foreign body reaction.Subsequently, biologic implants were introduced in an effort to reduce the local complications associated with synthetic materials without compromising the surgical results.
Biological xenograft is a mammalian extracellular matrix (ECM) composed of laminin, fibrinectin, elastin, and collagen.Tissue sources from which xenografts are chosen include: porcine (small intestine, dermis), bovine (pericardium, fetal, dermis) and equine.Collagen based implants can either be cross-linked or not.Cross-linking protects the implant against degradation by collagenases, so that they remain intact very long, if not ever.At present, most xenogenic materials are from porcine source and it is the most commonly used, as bovine material became less acceptable.Production is strictly controlled by Food and Drug Administration (FDA) guidelines, which include knowledge of the animal herd, vaccination status, feed source, abattoir approval and bovine spongiform encephalopathy clearance (Deprest et al, 2006).
We will discuss below the role of Small intestinal submucosal (SIS) graft as a futuristic biodegradable implant to substitute synthetic slings in the treatment of female SUI.

Small intestinal submucosal (SIS) graft
SIS xenograft is an acellular, nonimmunogenic, biodegradable, biocompatible, collagen matrix manufactured from porcine small intestinal submucosa, which could induce native tissue regeneration in various organs.

Clinical applications of SIS
SIS graft has gained popularity in the field of urogynecology and reconstructive surgery.
Promising results have been reported with the use of SIS as a bladder and urethral substitute material in animals (Kropp, 1998a; Kropp et al, 1998b; Chen, Yoo and Atala, 1999).Also, SIS has been used in humans undergoing urogenital procedures such as cystoplasties, ureteral reconstructions, penile chordee, and even urethral reconstruction for hypospadias and strictures

Graft biocompatibility
SIS is made by a way that all cells responsible for an eventual immune response are removed, but the ECM and natural growth factors are left intact.It contains collagen, growth factors TGF-beta and FGF-2 (Wiedemann and Otto, 2004).Many clinical trials and histopathological studies support the fact that the SIS graft has excellent biocompatibility as evidenced by lack of significant immunological reaction, foreign body reaction, and chronic inflammatory reaction (figure 8).In addition, the SIS sling is well known for its strength,

Biomechanical properties
SIS is degraded in 4 to 12 weeks by a "constructive" remodeling process that replaces the graft gradually by host connective tissue (Clarke et al, 1996;Prevel et al, 1995).Tensiometric strength initially decreases down to 45% 10 days after implantation, but by 1 month it is identical to that of the native tissue (Badylak et al, 2001).The task of the SIS sling is mainly to act as a scaffold that allows in-growth and structural organization of the native host tissue.The implant actively supports connective and epithelial tissue ingrowth and differentiation, as well as deposition, organization, and maturation of ECM components that characterize site-specific tissue remodeling.This phenomenon has been called smart tissue remodeling (Badylak, 1993) and it is important to note that the balance between implant degradation and host incorporation results in a dynamic implant strength response.The strength of the SIS sling is expected to be the net result between SIS degradation and tissue regeneration.Degradation rates that are too rapid or reconstruction rates that are too slow can result in transient minimum strengths that are below the critical threshold.Supposedly, this carries increased risk of recurrence of incontinence symptoms after an initial successful anti-incontinence surgery (Jankowski et al, 2004).

Outcome of the SIS Sling
The suitability of the SIS sling is better reflected by the clinical outcome.In terms of clinical efficacy in correction of SUI, the results of different studies showed that SIS was able to provide a strong suburethral support and durable clinical results (table 7).
Rutner et al, reported in their work utilizing SIS as a pubovaginal slings in the treatment of female SUI that all patients had minimal local reactions and pelvic pain; no cases of erosion or extrusion were noted.The authors also performed a biopsy for cases which required reoperation for correction of incontinence.They observed absence of the implanted graft on gross examination.Microscopically, only a few remnants of the SIS (< 0.4 mm) could be found (Rutner et al, 2003).Farahat et al, reported also using SIS as TVT (figure 9) in the treatment of female SUI that the SIS sling was accepted nicely by the tissue after 12 months.No erosion, extrusion, or severe inflammatory reactions were noted.Most reactions were mild and usually observed as early as 10 days or as late as 45 days after the procedure.No study till now compared the 1-ply, 4-ply, and 8-ply SIS grafts in humans.The SIS graft material is well accepted by the host tissue, and considered safe and effective with lower incidence of erosion and infection than the synthetic midurethral slings.
However, Long period of follow up are still required to support the durability of these preliminary results.

Introduction
Stem cells therapy for the regenerative repair of the deficient rhabdosphincter has been the most recent advance in incontinence research.The ultimate goal has been to achieve a permanent cure for SUI by restoration of the intrinsic and extrinsic urethral sphincter and the surrounding connective tissue, including peripheral nerves and blood vessels.Overall, the aim of stem cell therapy is to replace, repair, or enhance the biological function of damaged tissue or organs.

Cell source
There are two general types of stem cells potentially useful for therapeutic treatment, embryonic stem cells (ESCs) and adult stem cells

Transurethral ultrasound (TUUS) guided injection of stem cell
At the beginning of the cell injection, the TUUS probe (8 Ch, 15-20 MHz) was carefully inserted into the urethra.The urethral wall and the rhabdosphincter were visualized.A specially designed patent-pending injection device was used for precisely adjusted injection of several small portions.First, 15-18 portions of the myoblast suspension were injected directly into the omega-shaped rhabdosphincter at two different levels.Then, 25-30 depots of the fibroblast/collagen suspension were injected into the submucosa circumferentially at three levels (Figure 13).After implantation of the cells the patients were instructed to perform PFT and FES for 4 wk postoperatively to support integration of the cells and to improve formation of new muscle tissue (Strasser et al, 2007).

Clinical results of stem cell therapy
Few human trials have been conducted using autologous derived stem cells in the treatment of female SUI, which mainly involved the use of MDSCs.Stem cell therapy, shows an early encouraging results and these results suggest the ability of pure cellular therapy to treat female SUI (Table 8).In general, stem cell injection therapy into the middle urethra may restore the contractile response of the striated muscle and rhabdosphincter.Early results were encouraging with no reported serious side effects.Autologous MDSCs and ADSC pure injection therapy may be a promising treatment to restore urethral sphincter function.These promising early clinical results warrant further evaluation to validate results, determine durability and focus on safety and possible adverse reactions.

Fig. 3 .
Fig. 3. Terminology used to classify synthetic implants.Magnified view of a part of a polypropylene tape as used for TVT procedure (Gynaecare, Johnson and Johnson) with identification of filament type, interstitium, and pore size (Deprest et al, 2006).Biological implants have many sources; they may be an autologous graft (derived from the patient's own body tissue), allograft (derived from post-mortem tissue banks) or xenograft (derived from animals)(Dwyer, 2006).Types of biologic implants available in the market that can be used in urogynecology practice (table 5):

Futuristic
Fig. 4. A classification by category (C), time (T), and site (S) of complications directly related to the insertion of prostheses (meshes, implants, tapes) or grafts in female pelvic floor surgery (Haylen et al, 2011).

Fig. 5 .
Fig. 5. 52 year old female underwent a transobturator tape.At 6 weeks, she was cured of her USI and reported no vaginal discharge.Vaginal examination revealed a smaller mesh exposure away from vaginal suture line.Classification: 2A T2 S2 (Haylen et al, 2011)

(
Dedecker et al, 2005; Atala et al, 1999; Le Roux, 2005; Kassaby et al, 2003; Sharma and Secrest, 2003; Liatsikos et al, 2001).In the field of urinary incontinence, SIS has been used with encouraging results in treatment of postprostatectomy incontinence (Jones et al, 2005a), neuropathic incontinence (Misseri et al, 2005), and SUI (Wiedemann and Otto, 2004; Rutner et al, 2003; Jones et al, 2005b; Farahat et al, 2009).Practical concerns regarding the use of the SIS implant in clinical practice: The first practical concern is related to the graft biocompatibility and how the tissue would react to the implant.The second practical concern is related to the biomechanical properties of the SIS sling and its suitability for curing SUI (Farahat et al, 2009).

Fig. 10 .
Fig. 10.CT shows inflammation of subcutaneous tissue (A) and along arms of the SIS sling (Ho et al, 2004).

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also may improve neurogenic bladder dysfunction in animal models by reconstitution of damaged peripheral nerve cells (eg, Schwann cells, perineum) and vascular cells (eg, vascular smooth muscle cells, pericytes, endothelial cells) (Nitta et al, 2010).For the treatment of SUI myoblasts have been injected to the striated urinary sphincter of a pig model.The animals have shown an increase in urethral pressure profile and muscular myofibrils (Mitterberger et al, 2008).Advantages of MDSCs injection therapy over conventional treatments for SUI: 1. MDSCs that are derived from the incontinent patient (autologous cell transplantation) will not cause an immunogenic or allergic reaction (Yokoyama et al, 2001a; Lee et al, 2004).2. MDSCs are uniquely different from fibroblasts and smooth muscle cells since MDSCs will fuse to form post-mitotic multinucleated myotubes.This limits persistent expansion and risk of obstruction that may occur with other cell sources such as fibroblasts (Kwon et al, 2006).3. MDSCs form contractile myotubes and myofibers that become innervated into the host muscle by activating the intrinsic nerve regeneration and formation of neuromuscular junctions.Therefore, they can not only serve as a bulking agent, but they are also physiologically capable of improving urethral sphincter function (Chancellor et al, 2000; Yokoyama et al, 2001b; Huard et al, 2002; Hoshi et al, 2008).4.3 Isolation of muscle-derived stem cells in humans Mitterberger M et al. and Strasser H et al. reported biopsy in the right or left upper limb (biceps muscle) to obtain 0.32 to 2 cm3 of muscle tissue (figure 11).At the same time, 250 mL of blood were drawn for autologous serum (Mitterberger et al, 2008; Strasser et al, 2007b).

Fig. 11 .
Fig. 11.Diagram showing autologous stem cell injection therapy for SUI.Autologous stem cells are obtained with a biopsy of tissue, the cells are dissociated and expanded in culture, and the expanded cells are implanted into the same host.MDSCs = muscle derived stem cells (Jankowski et al, 2008)

Fig. 12 .
Fig. 12. Characterisation of cells: (A) Immunohistochemical image of human myoblasts stained with antidesmin antibodies.(B) Immunofl uorescence image of human fibroblasts stained with antivimetin antibodies.(C) Fluorescent antibody cell sorter (FACS) analysis of myoblast cell culture showing that 97% of the myoblasts are positive for CD56 antibodies.(D) Phase-contrast microscope image of multinucleated myotubes (marked with arrows) that have formed after fusion of mononucleated myoblasts in diff erentiation medium (Strasser et al, 2007b).

Fig. 13 .
Fig. 13.Cross-sectional ultrasonography images of the urethra and the rhabdosphincter (A) The tip of the needle (marked with an arrow) is positioned at the inner aspect of the rhabdosphincter (RS) for injection of myoblasts.(B) The tip of the needle is placed at the outer aspect of the submucosa (SM) for injection of fibroblasts (Strasser et al, 2007b).

Table 2 .
Long term results of TVT.

Table 3 .
Results of TOT.

Type IV: Submicronic pore size (pore size of <1 μm)
PTFE:Polytetrafluoroethylene a Collagen coated macroporous polypropylene materials.b Several kinds of Surgipro (Tyco) materials are marketed under the same name and have different constructs.

Table 4
. Classification and characteristics of synthetic implant materials marketed for urogynecologic indications (Deprest et al, 2006).

Table 6 .
Summary of the complications of midurethral sling procedures.
With regard to complications, most of the complications reported were intraoperative minor ones, with little or no disabling effects provided they are recognized and treated intraoperatively.A very limited number of major complications (e.g.bowel, vascular, and nerve injuries, necrotizing fasciitis, ischiorectal abscess, urethrovaginal fistulas, sepsis, and patient deaths) have been reported after placement of midurethral slings.Deng et al reported on the prevalence of major complications in the US Food and Drug Administration's Manufacturer and User Facility Device Experience database, identifying 32 cases of vascular injuries, 33 bowel injuries, and 8 patient deaths after TVT placement (

(Laurikainen et al, 2007; Andonian et al, 2005).
Incidence of perforation increases with poor surgeon experience with the procedure or in recurrent cases.Bladder perforation is suspected intraoperatively by observation of hematuria after trocar passage and diagnosed by cystoscopy.Perforation is easily treated by correct reinsertion of the trocar and catheter drainage for 2-4 days.TOT avoids the needle passage in the retropubic space, and hence bladder perforation is much lower than that of TVT. and in majority of cases minor bleeding occur during vaginal dissection and easily controlled.Sometimes excessive bleeding may lead to retropubic hematoma formation usually arises from pelvic floor veins, epigastric, external iliac or obturator vessels injury due to inadvertent trocar passage if laterally directed or externally rotated during the course of insertion.Hematomas size < 100 ml usually asymptomatic, between 100 -200 ml cause moderate pain, while those >300 ml associated with severe pain and require surgical evacuation of Retzius space (

Flock et al, 2004
(Costantini et al, 2007)a et al, 2004)mmon complication in TOT procedures, with reported rate 0% to 2%(Barber et al, 2006;Costa et al, 2004).Bowel perforation: a very rare (< 0.007%) (Costantini et al, 2007) but serious complication and may be fatal.A recent review revealed 7 deaths that occurred after TVT placement of which 6 were associated with bowel injury (Nygaard and Heit, 2004).Bowel perforation is not reported with TOT procedures.Risk factors for bowel injury include previous pelvic and abdominal surgery due to presence of adhesions in the retropubic space.2.4.2Late postoperative complicationsDe novo urgency: The rate of de novo urgency after midurethral slings placement as reported in literature ranges from 7.2% to 25%(Costantini et al, 2007).The mechanisms of de novo urgency after midurethral slings procedures are poorly understood.Combined outlet obstruction and urethral irritation by the sling has commonly been used as an explanation.TOT procedure is usually associated with a lower rate of de novo urgency than TVT (

Juanos et al, 2011). Meanwhile
, such complication usually does not improve by time.Holmgren et al reported 14.5% of de novo urgency after long term follow-up of 5.2 years after TVT (

Holmgren et al, 2007). Groin and thigh pain:
On the other hand, TOT procedure has a significant risk of postoperative groin and thigh pain.This pain was observed with range of 5% to 26%. (

Meschia et al, 2007; Dobson et al, 2007).
However, the pain is usually transient and resolves spontaneously within a few months in most of cases.The exact etiology of this pain remains unknown but it may be related to the tape's presence in the adductor muscles or the foreign body reaction to the tape lying in proximity to peripheral obturator nerve branches or secondary to the trauma to the obturator membrane and muscles during the procedure.Postoperative obstruction is another challenging complication after a mid urethral sling procedure which varies from urinary retention (temporary or permanent), difficulty emptying or a weak urinary stream.Obstruction usually arises from excessive tension placed over the midurethra by the tape.The reported rates of postoperative obstruction after TVT range from 1.9% to 19.7% (

Fischer et al, 2005; Delorme et al, 2004).
Although urine retention and voiding dysfunction are thought to be less common after TOT approach, a recent multicenter randomized trial did not reveal significant differences in postoperative urinary retention between the TVT and TOT (6% and 3%, respectively) (Barber et al, 2008).Early postoperative transient urinary retention could be treated with intermittent sterile self-catheterisation or indwelling catheter and usually resolve spontaneously within 12 wk with restoration of complete bladder emptying in the majority of cases.If no improvement occur, early simple sling lysis should be considered or suburethral tape transaction.

Clemens et al, 2000; Duckett and Constantine
If conservative management is unsuccessful or the erosion is (1 cm), the exposed mesh may be excised with the patient under local anesthesia with vaginal closure after the edges have been freshened.Erosions with copious vaginal discharge or if local tissue appears to be infected may require more extensive resection of the mesh.Surgery is recommended when erosion involves the lower urinary tract (bladder or urethra), independently of sling materials ( (Karram et al, 2003)a-analysis of polypropylene midurethral slings revealed a possible trend toward increased erosion rates after TOT approach (OR 1.5, 95% CI 0.51-4.4)(Lattheetal,2007).Although rare, erosion of mesh into the urethra can occur.A recent large retrospective series of TVT revealed urethral erosion in 0.3% of cases(Karram et al, 2003).

Table 7 .
Most reactions were well tolerated and resolved spontaneously (Farahat et al, 2009).Treatment outcome of SIS graft.

Novara and Artibani, 2007).
(Edwards, 2007)se of ESCs has ethical limitations inherent to cell harvesting from fetal tissue and histocompatibility problems.(Edwards,2007).In contrast, adult stem cells have no significant ethical issues related to their use and have more limited differentiation potential which makes them safer.Tissues engineering therapies are based on autologous multipotent stem cells, of which bone marrow stromal cells are most often used.Drost et al. in a pilot study transplanted autologous BMSCs into injured rat urethral sphincter.The cultured BMSCs were injected periurethrally 1 week after the urethral injury.Both histological and immunohistochemistry evaluation showed that transplanted BMSCs survived and differentiated into peripheral nerve cells and striated muscle cells compared to the cell-free group (

Drost et al, 2009). 4.2.2 Adipose-derived stem cells
Adipose derived stem cells (ADSCs), is a pluripotent cells which have the ability to differentiate into cells of the same and of another germ layer, such as adipogenic, chondrogenic, neurogenic, myogenic and osteogenic cells (Roche et al, 2010).In the field of urinary incontinence ADSCs are of special interest for mesodermal and neuronal regeneration and to promote revascularization.Bacou et al, reported that transplantation of ADSCs increases mass and functional capacity of damaged skeletal muscle.

Lin et al, 2010).
Fu et al.injected predifferentiated ADSCs with 5-azacitidine periurethrally into incontinent rats.A significant difference in bladder capacity and leak point pressure was observed after 3 months of follow-up between the control group and the pretreated group.Also increased number of myoblasts under the mucosa and expression of α-smooth muscle actin was observed 3 months after implantation (

Carr et al, 2008; Herschorn et al, 2010).
Strasser et al. conductedthe first clinical experiments in women with SUI.42 women suffering from SUI were recruited and subsequently treated with transurethral ultrasonography-guided injections of autologous myoblasts and fibroblasts obtained from skeletal muscle biopsies.After a follow-up of 12 months incontinence was cured in 39 women (Strasser et al, 2007a).In another trial 42 women were randomly assigned to receive transurethral ultrasonography guided injections of autologous myoblasts and fibroblasts, at 12-months' follow-up, 38 of the 42 women injected with autologous cells were completely continent (Strasser et al, 2007b).Mitterbarger et al. studied 20 female patients suffering from SUI after TUUS guidance injection of autologous myoblasts and fibroblasts.At 1 year follow-up 18 patients were cured and 2 patients improved.At 2 years after therapy 16 of the 18 patients presented as cured, 2 others were improved, and 2 were lost to follow-up (Mitterbarger et al, 2008a).Other studies have been reported early good results for stem cell injection in female with SUI (Not only stem cell injection therapy is limited to the field of female SUI, however its usage has been extended to treat males with post-prostatectomy incontinence (

Table 8 .
Results of the first clinical studies have recently become available.