Advances in the methods for discovering novel painful bladder syndrome therapies.

Review

Expert Opin. Drug Discov. Downloaded from informahealthcare.com by Washington University Library on 12/25/14 For personal use only.

Advances in the methods for discovering novel painful bladder syndrome therapies 1.

Introduction

2.

Current treatment

3.

Tissue engineering

4.

Conclusion

5.

Expert opinion

Ling-Hong Tseng University of Chang Gung, Chang Gung Memorial Hospital, School of Medicine, Lin-Kou Branch, Department of Obstetrics and Gynecology, Tao-Yuan, Taiwan

Introduction: Advances in the treatment of interstitial cystitis or bladder pain syndrome (IC/BPS) depend on a good understanding of its pathogenesis. Presently, oral medicine and intravesical drug instillations may be the most popular therapies in daily practice. To improve the efficacy of intravesical drug delivery, the system requires modulation through coupling them to novel carriers. Numerous investigators have attempted alternative reconstructive procedures for bladder replacement/repair using scaffolds. These scaffolds include acellular extracellular matrix grafts or tissue-derived cell-seeded extracellular matrix grafts as well as the transplantation of mesenchymal progenitor cells into the damaged bladder. Areas covered: This review focuses on the current available IC/BPS treatments and the different strategies employing nanotechnology or tissue engineering in the discovery of novel IC/BPS therapies. Expert opinion: Current studies in the discovery of novel IC/BPS therapies are still imperfect, with novel approaches that use biocompatible nanomaterials or tissue engineering still ongoing. These nanoformulations give the benefit of protecting easily degradable molecules and enhance targeted delivery. Tissue engineering holds the promise of regenerating damaged tissues and organs by replacing damaged tissue and/or by stimulating the body’s own repair mechanisms to heal previously irreparable tissues and organs. For these reasons, nanotechnology and tissue engineering could play key roles in the discovery of novel painful bladder syndrome therapies. Keywords: interstitial cystitis or bladder pain syndrome, intravesical drug delivery, nanoparticles, tissue engineering Expert Opin. Drug Discov. (2014) 9(4):423-432

1.

Introduction

Historic aspect Research into interstitial cystitis or bladder pain syndrome (also IC/BPS) has a very long history. It was first documented by Parrish in 1836, and then characterized by Skene in 1887 as the presence of an inflammation that destroys the urinary bladder mucous membrane, partly or wholly, and extends to muscular parietes [1,2]. In 1915, Hunner popularized IC with the description of a characteristic bladder wall ulcer [3]. Hand made the first epidemiological description of IC as the widespread, small, submucosa bladder hemorrhage and substantial shrinkage in the bladder in 1947 [4]. Messing and Stamey recognized glomerulation as an indicator of IC [5]. Thus far, basic science research into the pathogenesis of IC has been very limited, and it has been acknowledged by the American Urological Association (AUA) as a most challenging disease. 1.1

10.1517/17460441.2014.894975 © 2014 Informa UK, Ltd. ISSN 1746-0441, e-ISSN 1746-045X All rights reserved: reproduction in whole or in part not permitted

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The underlying cause of IC/BPS is currently still unknown, with no consensus on the precise mechanism. Currently, the most acceptable theory is injury or dysfunction of the GAG layer. Oral medicine and intravesical drug instillation are considered the most popular therapies in daily practice along with behavioral/physical therapy, sometimes in combination. Intravesical drug delivery skips the drawback of oral medicine but requires modulation of the release and absorption of the instilled drugs through coupling them to novel carriers. Recent advances in nanomedicine and tissue engineering have improved the efficacy of intravesical drug delivery and provided the possibility of trying to explore the real underlying pathogenesis of IC/BPS in the future. Mucoadhesive drug delivery systems and the use of polymeric hydrogels that make intravesical drug delivery more effective are promising and showing hopes of progress in the forthcoming years.

This box summarizes key points contained in the article.

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Pathophysiology The underlying cause of IC/BPS is currently still unknown, with no consensus agreement on the precise mechanism [15]. This disease might contain some complex pathogenesis and may be more complex than we thought before. Currently, there are several hypotheses that are discussed below: 1.4

Definition changing Currently, the term IC was reserved for those patients with typical cystoscopic findings, such as glomerulations or the classic bladder wall Hunner’s ulcer [3] and histological features. IC was first defined by the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) criteria [6]. This definition, proposed in 1987, was recommended for research purposes and identified a relatively homogeneous patient population. However, it proved to be impractical when applied in the clinical setting. Therefore, in 2002, the International Continence Society developed a new definition of the bladder pain syndrome and it has been referred to as the BPS since the 2010 BPS Committee of the International Consultation on Incontinence. Following further research into the condition, the European Society for the Study of IC/BPS provided a definition, which was more descriptive of the clinical syndrome and the underlying pathology. It was agreed to name the disease the BPS, which described all patients with chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder [7]. The diagnosis of BPS, the presence of pain related to the urinary bladder and accompanied by at least one other urinary symptom, with the exclusion of other diseases, was thus introduced. Cystoscopy with hydrodistension and biopsy should be performed if indicated. In summary, the most important impact of the definition change observed for IC in the past decade was the subsummation of the IC under pain syndrome. With the hope that looking at psychological, physical and organspecific parameters of afflicted patients will aid in proper selection of treatments and may also improve the results of research on etiology, prognosis and new therapeutic agents. 1.2

Association with other conditions IC/BPS may be associated with urgency, frequency, nocturia and sterile urine cultures [8,9]. Some patients with IC/BPS suffer from other conditions that may have the same etiology as IC/BPS. These include irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, endometriosis [10] vulvodynia, chemical sensitivities [11], allergies, Sjogren’s syndrome, systemic lupus erythematosus and anxiety disorder [12]. Recognizing that more overlap exists between IC/BPS and these associated conditions in symptoms and prevalence, the NIDDK actually has initiated a research to try to better understand the relationship [13]. In addition, experts in IC/BPS, as well as from related conditions fields, discussed a new approach to the condition that was ‘based on relationships with other pain syndromes’ [14]. This change in approach emphasizes the fact that recommended management of the condition may shift as more becomes known about IC/BPS and its co-morbid conditions. 1.3

Article highlights.

. Studies related to IC/BPS patients who underwent

bladder biopsy have documented that patients with IC/ BPS have urothelial abnormalities. In addition, it is not known whether these urothelial abnormalities are primary or are secondary to another process. Urothelial abnormalities in patients with IC/BPS include: * Altered bladder epithelial expression of HLA Class I and II antigens [15]. * Decreased expression of uroplakin and chondroitin sulfate proteoglycans [16,17]. * Altered cytokeratin profile, and altered integrity of the glycosaminoglycan (GAG) layer [18]. * A defect in Tamm-Horsfall protein has been found in some patients [19]. * The GAG layer of the bladder normally coats the urothelial surface and renders it impermeable to solutes, and therefore, defects in this layer may allow urinary irritants to penetrate the urothelium and activate the underlying nerve and muscle tissue [20]. This process may promote further tissue damage, pain and hypersensitivity. Bladder mast cells may also play a role in the propagation of ongoing bladder damage after an initial insult [21-23]. . Antiproliferative factor (APF) may also have a pathogenetic role in the generation of IC/BPS symptoms. APF is a lipoglycopeptide that is produced by the urothelium of IC/BPS patients, but not by patients without IC/ BPS [24]. APF may affect urothelial activity through

Expert Opin. Drug Discov. (2014) 9(4)


Advances in the methods for discovering novel painful bladder syndrome therapies

altered production of growth factors and other proteins involved in urothelial growth and function [25]. . Neurologic upregulation of pain sensation likely plays a role in IC/BPS. Central sensitization and increased activation of bladder sensory neurons during normal bladder filling may result in bladder pain [26,27]. This increased sensitivity may be present in the bladder itself or may be due to increased activity and new pathways within the CNS. Animal models suggest that hypersensitivity in the bowel and other pelvic organs may be responsible for sensitization of the bladder [28]. It is also possible that the increase in visceral (bladder) sensitivity is secondary to a primary somatic injury that has sensitized central pathways that overlap with afferents from the bladder. Elbadawi and Light proposed neurogenic inflammation as a trigger that cascades events taking place in this disease [29]. It has been noted that afferent nerves release transmitters like substance P, which could activate immune cells or vasoactive intestinal polypeptide. A prominent increase of tyrosine hydroxylase immunoreactivity was found in bladder tissue of patients with PBS [30]. This could be interpreted as a sign of increased sympathetic outflow that supports a possible neurogenic etiology. . Enhanced urothelial expressions of human chorionic gonadotropin b were found in IC/BPS patients and this might indicate that hCG might gain therapeutical relevance in the future [31]. Currently, the most acceptable theory is injury or dysfunction of the GAG layer that covers the urothelium [11,20], as demonstrated by the increase in the levels of APF in BPS patients [32]. This injury can be caused by bacterial cystitis, pelvic surgery or urological instrumentation. Abnormal diffusion of toxins from the urine to the submucosa leads to sensory nerve activation, neurogenic inflammation, pain and fibrosis. Some genetic subtypes, at gene map locus 13q22-q32 [33], in some patients, have been linked to the disorder and are associated with a constellation of disorders (a ‘pleiotropic syndrome’) including IC/BPS and other bladder and kidney problems, thyroid diseases, serious headaches/migraines, panic disorder and mitral valve prolapse [33].

2.

Current treatment

The decision of treatment should be case-by-case and based on intensity and type of symptoms, patient capableness, bladder capacity, ability to self-catheterize and comorbidity. First-line treatment is recommended for all patients and includes education about normal bladder function and selfcare practices/behavioral modifications that can improve symptoms. However, oral medicine and intravesical drug instillation should be the most commonly used therapies in

daily practice [35] except for behavior/physical therapy, sometimes in combination. Oral medicine Analgesics: Gabapentin, introduced as an anti-convulsant, has been found to be effective in neuropathic pain disorders. Sasaki et al. [36] showed subjective improvement of pain in refractory genitourinary pain. Antidepressants: amitriptyline is a tricyclic antidepressant that blocks H1-histaminergic receptors. It stabilises mast cells and inhibits mediator-stimulated vascular leakage. It inhibits synaptic reuptake of serotonin and nor-epinephrine, thus inhibiting painful nociception from the bladder at the level of the CNS [37]. It was found to be beneficial in a well-controlled trial with long-term follow-up using a stepwise dose escalation [38], and is probably one of the treatments of choice [39]. Recently, Foster et al. studied the effect of amitriptyline on symptoms in treatment-naive patients with IC. They found that it could be beneficial for patients who can tolerate a daily dose of 50 mg or greater [40]. Antihistamines: cimetidine, an H2 receptor antagonist has been investigated for the treatment of PBS. Lewi [41] studied 31 patients who had cimetidine 200 mg three times a day. He reported symptomatic relief in 71% of patients, with 45% of them being pain-free. This effect was further confirmed in a small RCT [41,42]. Sodium pentosan polysulphate is as a synthetic sulphatedpolysaccharide, 3 -- 6% of which is excreted into the urine, and theoretically, it replenishes the damaged GAG layer. It is believed that it works by coating the bladder lining and by reducing potassium leakage into the bladder muscle. It seems to be a well-tolerated medication with no common CNS side effects, and appears to be beneficial with regard to improving the pain in IC. The reported overall response rate varied between 15 and 67% at the 300-mg dose recommended by the FDA. In addition, the NIDDK-supported trial by the IC Clinical Trials Group failed to demonstrate the superiority of pentosan polysulfate over placebo, although the study was underpowered [43,44]. 2.1

Intravesical therapy Based on the most current acceptable theory for IC/BPS is injury or dysfunction of the GAG layer then we might think the rational choice for intravesical drug delivery [45,46] because oral therapy not only require large dose and only a small portion is actually absorbed and reach the bladder. Current available popular intravesical therapies include: 2.2

. Dimethyl sulphoxide (DMSO): it seemed to reduce

inflammation, relax the detrusor muscle and eliminate pain, but the real mechanism is still unknown. Around 80% improvement has been reported in prior studies [47,48]. The instillation is performed once or twice per week for 6 -- 8 weeks. After an initial course,


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treatment can be prolonged and depends on the patient’s response. . Heparin: intravesical heparin may restore bladder surface barrier function and various dosage regimens of heparin (20,000 -- 50,000 units) alone or with alkalinized lidocaine (1 -- 4%) have been used. The AUA guidelines reviewed 3 observational studies evaluating the use of intravesical heparin (10,000 -- 25,000 units 2 -- 3 times a week) in the management of IC with efficacy rates ranging from 56 -- 73%. The frequency of instillation is similar to the DMSO [49]. . Hyaluronic acid: GAG replacement therapies are becoming popular, although most studies are case series with small numbers [50,51]. Most of published papers reported significant improvement in their quality of life and without any significant adverse events. However, one recent study did not support its use as monotherapy for this condition and suggested we should have better strategies for selecting patients with a bladder-specific clinical phenotype might improve the overall response to this type of intravesical therapy [52]. . Lidocaine: as a local anesthetic agent, lidocaine relieves pain by blocking sensory nerves in the bladder. There are several studies that have reported its efficacy [53,54]. In a recent study by Nickel et al. they designed a continuous lidocaine-releasing intravesical system and it was to be retained in the bladder and release therapeutic amounts of the drug into urine over a period of 2 weeks. The device was tested in healthy volunteers and IC/BPS patients and was found to be well tolerated in both subject groups because of its small size and freedom of movement within the bladder. Safety, efficacy, cystoscopic appearance of the bladder and limited pharmacokinetic data were collected. Global response assessment showed an overall responder rate of 64% at day 14 and a sustained overall responder rate of 64% 2 weeks later. Extended follow-up suggests that the reduction in pain was maintained for several months after the device was removed [55]. Though the urothelium is the tightest and most impermeable barrier in the body [56], this is not the case in IC/BPS. Here, the urothelium shows massive defects, and is in part, denuded in later stages of the disease, which might make the intravesical drug delivery more easy, with even the need to modulate the release and absorption of the instilled drugs through coupling them to some novel carriers attributed to the use of nanoparticles, such as liposomes, polymeric nanoparticles, magnetic nanoparticles and dendrimers and others. Liposomes A liposome is an artificially-prepared vesicle composed of a lipid bilayer and can be used as a vehicle for pharmaceutical drugs [57]. Fraser et al. examine the effect of intravesical administration of liposomes on chemically-induced bladder 2.2.1

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hyperactivity in rats. Their data showed that liposomes might enhance the barrier properties of a dysfunctional uroepithelium and increase resistance to irritant penetration, and they thought that intravesical liposomes administration could be a novel treatment for patients with IC [58]. In human study, Chuang et al. recently published information on the clinical safety and efficacy of liposomes in IC/BPS patients. He conducted an open-label prospective study of 24 IC/BPS patients, and the effect of intravesical liposomes (80 mg/40 cc distilled water) once weekly was compared with oral pentosan polysulfate sodium (100 mg) three times daily for 4 weeks each. Their data showed promising results that liposome intravesical instillation is safe for IC/BPS with potential improvement after 1 course of therapy for up to 8 weeks. Intravesical liposomes achieved efficacy similar to that of oral pentosan polysulfate sodium [59]. Later, Lee et al. reported that intravesical liposome twice weekly has a better effect than once weekly [60]. An animal study carried out by Chuang et al. [61] evaluated the feasibility of intravesical botulinum toxin A delivery using liposomes and evaluated the urodynamic and immunohistochemical effects on acetic acid-induced bladder hyperactivity in rats. They proposed that liposomes can co-opt the native vesicular traffic ongoing in the bladder, which might provide a favorable environment for drug delivery. Formulation of botulinum toxin with liposomes in a rat model, protected it from urinary degradation without compromising the efficacy, thus indicating that liposomes can restrict botulinum toxin delivery to the detrusor muscle, and help avoid the risk of retention and incomplete bladder emptying. Nanoparticles Nanoparticles come in various forms including polymeric nanoparticles, liposomes and magnetic nanoparticles. They allow the loading of substances within the particle itself to ensure that the nanoparticle reaches the target site, which can be surface-modified with targeting moieties, such as antibodies, ligands or specific peptides that have strong affinities to unique features on target cells, such as receptors or proteins only expressed on the target. Biodegradable polymeric nanoparticles have been used frequently as drug delivery vehicles due to its grand bioavailability, better encapsulation, control release and less toxic properties [62]. Basically, two common methods for nanoparticles synthesis and surface features [63] are the ‘bottom-up’ and ‘top-down’ approaches. The bottom-up approach process includes: 2.2.2

1) self-assembly of individual small molecules into larger supramolecular structures; 2) peptide-amphiphile assembly into nanofiber, with b-sheet forming blocks; 3) segregation of polymer segments into nanoscale domains; 4) surface printing of nanoscale features.



In the ‘top-down’ design, however, there is:


1) lithographic patterning of bulk surfaces; 2) selective chemical etching to produce nanoscale features; intermediate methods of bulk confinement; 3) template-assisted patterning; 4) electrospinning of micro- and nano-fiber scaffolds. Electrospinning has recently gained popularity among researchers attempting to develop improved scaffolds for bladder tissue engineering and it has obvious advantages in tissue engineering in that it offers an inexpensive and simplistic means to create nanoscale fibers from a large array of natural and synthetic polymers [64]. Han et al. have evaluated the use of electrospinning to create a scaffold modeled after bladder extracellular matrix [65]. Scanning electron micrographs of bladder extracellular matrix demonstrated a tri-layered architecture and the authors were able to modify the electrospinning process to create a cellulose acetate scaffold with remarkably similar physical characteristics. Recent advances of nanoparticles in urologic applications, for example: Chang et al. [66] studied the poly(ethyl-2cyanoacrylate) (PECA) epirubicin-loaded nanoparticles (EPI-NP) against bladder cancer cell lines in pig urothelium. The nanoparticles greatly improved the penetration of epirubicin into the bladder wall and their data showed the successful development of urothelium adhesive and penetrative PECA EPI-NPs. This might have potential for the in vivo application of EPI-NP for intravesical instillation in bladder cancer therapy. Nanoparticles developed using magnetic compounds have potential as targeted drug carriers and for diagnostic imaging. [67]. Magnetic nanoparticles can be used as contrast agents to visualize diseased regions of the body by targeting specific regions of the body utilizing a magnetic field to localize drug-loaded magnetic particles [68]. In an animal study, Leakakos et al. [69] used magnetictargeted carriers to deliver the anticancer drug, doxorubicin, into the bladder wall and their data showed that magnetictargeted carriers delivery may allow greater exposure and specific deposition of drug at a defined site over intravesical administration of doxorubicin alone. They thought the feasibility of this novel method of drug delivery might support further study for its potential use in treating bladder cancer. These same ideas might offer future direction of painful bladder syndrome therapies. Dendrimers Dendrimers are repetitively branched molecules [70]. A dendrimer is typically symmetric around the core and often adopts a spherical three-dimensional morphology. Applications of dendrimers typically involve conjugating other chemical species to the dendrimer surface that can function as detecting agents, affinity ligands, targeting components, radioligands, imaging agents, or as our topic, pharmaceutically active 2.2.3

compounds. Dendrimers have been explored for the encapsulation of hydrophobic compounds and for the delivery of anticancer drugs. The physical characteristics of dendrimers, including their monodispersity, water solubility, encapsulation ability and large number of functionalizable peripheral groups, make these macromolecules appropriate candidates for evaluation as drug delivery vehicles. There are three methods for using dendrimers in drug delivery: first, the drug is covalently attached to the periphery of the dendrimer to form dendrimer prodrugs; second, the drug is coordinated to the outer functional groups via ionic interactions; or, third, the dendrimer acts as a unimolecular micelle by encapsulating a pharmaceutical through the formation of a dendrimer-drug supramolecular assembly [71]. The use of dendrimers as drug carriers by encapsulating hydrophobic drugs is a potential method for delivering highly active pharmaceutical compounds that may not be in clinical use due to their limited water solubility and resulting suboptimal pharmacokinetics. The encapsulation increases with dendrimer generation and this method may be useful to entrap drugs with a relatively high therapeutic dose. Studies based on this dendritic polymer also open up new avenues of research into the further development of drug-dendrimer complexes specific for a cancer and/or targeted organ system. These encouraging results provide further impetus to design, synthesize and evaluate dendritic polymers for use in basic drug delivery studies, and eventually, in the clinic [72]. 3.

Tissue engineering

Currently, the final therapy option for IC/BPS is the cystectomy; however, this therapy might not successfully treat chronic pelvic pain syndrome [73]. This may be due to the development of chronic neuropathic pain from lesions to the peripheral nervous system or CNS related to ongoing tissue damage of the bladder [74]. Tissue engineering is the use of a combination of cells, engineering and suitable materials and methods to improve or replace biological functions. A commonly applied definition of tissue engineering, as stated by Langer and Vacanti, is ‘an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain or improve tissue function or a whole organ’ [75]. Numerous investigators have attempted alternative reconstructive procedures for bladder replacement or repair using scaffolds such as acellular extracellular matrix grafts or tissuederived cell-seeded extracellular matrix grafts [76-79]. Transplantation of mesenchymal progenitor cells into the damaged bladder has also been attempted, and the importance of scaffolds as a microenviroment has been emphasized [80]. In a study of the clinical application of regenerative medicine in humans, Atala et al. reported a small pilot series of seven patients who underwent bladder reconstruction using either a collagen scaffold seeded with autologous detrusor muscle cells with or without omental coverage or a combined polyglycolic acid/collagen


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scaffold seeded with cells and omental coverage. The engineered bladder tissues used in the reconstruction showed increased compliance, decreased filling detrusor pressures, increased capacity and longer dry periods [81]. In contrast, the possibility of composite cystoplasty, which entails the use of combined autologous urothelial cell sheets and de-epithelialized smooth muscle segments from organs, such as the uterus or intestine, has been explored [82,83]. In a pilot study of a surgical minipig model created using autologous cultured urothelial cells combined with vascularized uterine smooth muscle cells, the alternative bladders retained increased capacity and supported normal bladder function for at least 3 months. Potential drawbacks of this technique of composite cystoplasty include the consistent use of autologous urothelium, which increases the risk of cancer formation or insufficient growth of urothelial cells in patients with bladder cancer or neuropathic bladder. Another problem is the possible inherited pathological alteration of the cells in addition to proper re-innervation and functional gain. Therefore, new trial studies of tissue engineering using multipotent stem cells are forthcoming [84-86]. Chung et al. performed augmentation of the rat bladder by introducing porcine small intestinal submucosa seeded with mesenchymal stem cells (MSC) from rat bone marrow. After 3 months, the histological examination showed normal bladder structure in the implanted tissue, with fully differentiated urothelial and smooth muscle cells. Although a three-layered cellular architecture was also observed in control experiments using unseeded small intestinal submucosa, only the stem cell-seeded biohybrid exhibited gene expression levels similar to those of sham-operated animals [87]. Ringde´n et al. investigated the effects of allogeneic hematopoietic stem cell transplantation in seven patients with hemorrhagic cystitis. MSC were taken from human donors and given intravenously to the patients. In 5 patients, the severe hemorrhagic cystitis cleared after MSC infusion and gross hematuria disappeared after a median of 1 -- 14 days. In one advanced case, the perforation healed. In another patient, MSC reduced the need for further transfusions. Although MSC could not be detected, their DNA was found in the host bladder. These results suggest that MSC have the ability to heal the damaged bladder tissue and that this therapeutic approach could be of great benefit in the future therapy for tissue toxicity [88]. Tian et al. reported that MSC from bone marrow can be successfully differentiated into smooth muscle cells when seeded on a highly porous poly-l-lactic acid scaffold and treated with platelet-derived growth factor BB plus TGF b1 [89]. Currently, the ideal protocol for bladder tissue engineering has yet to be identified. All existing protocols rely on either natural or synthetic scaffolds as basis for tissue regeneration. The advances of nanotechnology just offer a chance to realize or improve interaction between these scaffolds and the newly developing tissue. Hoping these techniques or the improved understanding of cell-substrate interactions will be a part of the relevant bladder engineering protocols in the future. 428

4.

Conclusion

Regarding the development of new IC/BPS treatments, targeted therapy is one of the most important features to be considered. However, difficulties exist because the underlying cause of IC/BPS is still unknown and it is usually associated with other conditions. Current treatments include pain management, patient education, physiotherapy, quality of life modification and medication (oral medicine or intravesical drug instillation). However, most of the treatments were unsatisfactory and carried some side effects. Only by restoring the pathways that are disrupted in IC/BPS mechanism can the treatment plans be answers. Based on the most current acceptable theory for IC/BPS is injury or dysfunction of the GAG layer then we might think the rational choice for intravesical drug delivery because oral therapy not only require large dose and only a small portion is actually absorbed and reach the bladder. To overcome the unique characteristics of the urothelium (the tightest junction and impermeable barrier), the intravesical drug delivery needs to modulate the release and absorption of the instilled drugs by coupling them to some novel carriers. Thanks to the advancement of nanotechnology and tissue engineering, we now have the chance to develop new strategies to improve the efficacy of IC/BPS treatment, or more, realize the underlying pathogenesis. Here, we have reviewed the current available modality and new advances in the methods for discovering novel IC/BPS therapies. 5.

Expert opinion

It is a long journey for physicians in the research into IC/BPS and there seems no available effective long-term treatment right now. The underlying cause of IC/BPS is still unknown and it is usually associated with other conditions, and the most currently acceptable theory is injury or dysfunction of the GAG layer. Everything we do right now probably helps us see only part of the disease entity, and only by restoring the pathways that are disrupted in the IC/BPS mechanism can any real solutions be offered. Nanomedicine is the medical application of nanotechnology and has already been tested in mice, in addition, is waiting for human trials to help diagnose and treat cancer. A benefit of doing this for medical technologies is that smaller devices are less invasive and can possibly be implanted inside the body. In addition, going by the advances in nanotechnology, maybe we can try to mimic cell-cell interaction by comparing patients with and without IC/BPS and then exploring the real underlying pathogenesis. We just cannot forget that for discovering novel BPS therapies, regenerative medicine is also the key element besides nanotechnology. Regenerative medicine is the ‘process of replacing or regenerating human cells, tissues or organs to restore or establish normal function’. This field holds the promise of regenerating damaged tissues



Table 1. Current and future therapies for painful bladder syndrome.


Behavioral modification/physical therapy/dietary modifications Oral medication Intravesical drugs Cystoscopy under general anesthesia with hydrodistension Nanocarriers/mucoadhesive carriers/polymeric hydrogels for intravesical drug deliver Gene therapy Stem cells and tissue engineering

and organs in the body by replacing damaged tissue and/or by stimulating the body’s own repair mechanisms to heal previously irreparable tissues or organs. Regenerative medicine refers to a group of biomedical approaches to clinical therapies that may involve the use of stem cells or progenitor cells; and transplantation of in vitro grown organs and tissues (tissue engineering). For patients with IC/BPS, the main goal of bladder regeneration is hoping to obtain a fully functional bladder. The methods we used in today’s clinical practice in urology are unsatisfactory. Tissue engineering may raise the possibility of creating more effective treatments. Our understanding of the underlying mechanisms involved in tissue regeneration is still insufficient. Although some current results are promising, most of our knowledge is based on experimental studies, without verification in clinical work. So far, the use of stem cells has shown only partial results in the regeneration of the urinary bladder. The most examined stem cells are MSC, but the other multipotent stem cells isolated from adipose tissue, amniotic fluid, hair follicles, and urine were shown to have the ability to transform into different types of urinary bladder cells. What we need is to make further efforts to master the differentiation of these cells and to maintain control over them after transplantation. The combination of stem cells with synthetic or natural scaffolds, with the use of appropriate growth factors, should be further examined in order to regenerate the fully functional urinary bladder.

Therefore, development of a regenerative therapy for urogenital tissues is greatly anticipated. However, various obstacles, such as ethical issues or guidelines regarding stem cell therapy, must be resolved in order to transform experimental findings into clinical application. I think two things are promising and showing hope of progress in the coming years. They are the mucoadhesive drug delivery system [90] and the use of polymeric hydrogels. Recently, the mucoadhesive drug delivery system made the intravesical drug delivery more effective. Mucoadhesive materials are mostly hydrophilic macromolecules that can form a large number of hydrogen bonds with the mucin layer, thus allowing the applied agent to wet the mucous layer more effectively and remain bound for long durations. A number of biomolecules, such as chitosan, carbomers and cellulose derivatives, have been identified as having mucoadhesive properties. In addition, another major advancement in intravesical drug delivery is the use of hydrogels to serve as drug depots on the bladder wall. This may improve the need for repeated infusions of drugs, in which the drug is mostly washed out during urination. Most hydrogel formulations are biodegradable and the rate of degradation of the gel needs to be optimized so that it can allow drug delivery into the diseased tissues for the desired time interval. IC/BPS is not a life-threatening event, but it has great impact on a patient’s quality of life. Table 1 lists current and future therapies for IC/BPS, and therefore, it deserves further investigation, but based on the relatively small numbers of population, physicians should be open-minded through global cooperation plus team work with chemists and engineers whose primary interests are in nanomaterial design and tissue engineering. Only then can the real pathogenesis of IC/BPS be disclosed and solutions given.

Declaration of interest The author states no conflict of interest and has received no payment in preparation of this manuscript.


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Christmas TJ. Historical aspects of interstitial cystitis. In: Sant GR, editor, Interstitial cystitis. Lippincott-Raven, Philadelphia; 1997. p. 108; chapter 1 Teichman JM, Thompson IM, Taichman NS. Joseph Parrish, tic doloureux of the bladder and interstitialcystitis. J Urol 2000;164:1473-5

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Hunner GL. A rare type of bladder ulcer in women; report of cases. Boston Med Surg J 1915;172:660-4

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Hand JR. Interstitial cystitis: report of 223 cases (204 women and 19 men). J Urol 1949;61:291-310

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Messing EM, Stamey TA. Interstitial cystitis: early diagnosis, pathology, and treatment. Urology 1978;12:381-92

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Hanno P, Lin A, Nordling J, et al. Bladder pain syndrome committee of the international consultation on incontinence. Neurourol Urodyn 2010;29:191-8

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Gillenwater JY, Wein AJ. Summary of the national institute of arthritis, diabetes, digestive and kidney diseases workshop on interstitial cystitis, national institutes of health, bethesda, maryland. J Urol 1998;140:203-6 Van de Merwe JP, Nordling J, Bouchelouche P, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol 2008;53:60-7 Vij M, Srikrishna S, Cardozo L. Interstitial cystitis: diagnosis and management. Eur J Obstet Gynecol Reprod Biol 2012;161:1-7

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Persu C, Cauni V, Gutue S, et al. From interstitial cystitis to chronic pelvic pain. J Med Life 2010;3:167-74

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Butrick CW. Patients with chronic pelvic pain: endometriosis or interstitial cystitis/ painful bladder syndrome? JSLS 2007;11:182-9

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Moutzouris DA, Falagas ME. Interstitial cystitis:an unsolved enigma. Clin J Am Soc Nephrol 2009;4:1844-57

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National Institute of Diabetes and Digestive and Kidney Diseases. Multi-disciplinary approach to the study

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Slobodov G, Feloney M, Gran C, et al. Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis. J Urol 2004;171:1554-8

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Hurst RE, Roy JB, Min KW, et al. A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology 1996;48:817-21

18.

Graham E, Chai TC. Dysfunction of bladder urothelium and bladder urothelial cells in interstitial cystitis. Curr Urol Rep 2006;7:440-6

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Hurst RE, Moldwin RM, Mulholland SG. Bladder defense molecules, urothelial differentiation, urinary biomarkers, and interstitial cystitis. Urology 2007;69:17-23

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Parsons CL, Stein P, Zupkas P, et al. Defective tamm-horsfall protein in patients with interstitial cystitis. J Urol 2007;178:2665-70

21.

Parsons CL. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 2007;69:9-16

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Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 2001;57:47-55

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Sant GR, Kempuraj D, Marchand JE, Theoharides TC. The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis. Urology 2007;69:34-40



women. Taiwan J Obstet Gynecol 2012;51:526-32


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Sasaki K, Smith CO, Chuang YC, et al. Oral gabapentin treatment of refractory genitourinary tract pain. Tech Urol 2001;7:47-9

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Tura B, Tura SM. The analgesic effect of tricyclic antidepressants. Brain Res 1992;518:19-22

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Van Ophoven A, Hertle L. Long term results of amitriptyline treatment of interstitial cystitis. Urology 2005;174:1837-40

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Hanno PM, Burks DA, Clemens Q, et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome. American Urological Association Guidelines Department, Linthicum, MD, USA: 2011 Foster HE, Hanno PM, Nickel JC, et al. Effect of amitriptyline on symptoms in treatment naı¨ve patients with interstitial cystitis/painful bladder syndrome. J Urol 2010;183:1853-8

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Lewi HJ. Medical therapy in interstitial cystitis: the essex experience. Urology 2001;57:120

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Thilagarajah R, Witherow RO, Walker MM. Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, double-blind placebo-controlled trial. BJU Int 2001;87:207-12

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Dimitrakov J, Kroenke K, Steers WD, et al. Pharmacologic management of painful bladder syndrome/interstitial cystitis: a systematic review. Arch Intern Med 2007;167(18):1922-9

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Seth A, Teichman JM. What’s new in the diagnosis and management of painful bladder syndrome/interstitial cystitis? Curr Urol Rep 2008;9(5):349-57

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Colaco MA, Evans RJ. Current recommendations for bladder instillation therapy in the treatment of interstitial cystitis/bladder pain syndrome. Curr Urol Rep 2013;14:442-7

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Neuhaus J, Schwalenberg T. Intravesical treatments of bladder pain syndrome/ interstitial cystitis. Nat Rev Urol 2012;9:707-20 Fowler JE Jr. Prospective study of intravesical dimethyl sulfoxide in treatment of suspected early interstitial cystitis. Urology 1981;18:21-6

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Ghoniem GM, McBride D, Sood OP, Lewis V. Clinical experience with multiagent intravesical therapy in interstitial cystitis patients unresponsive to single agent therapy. World J Urol 1993;11:178-82 Generali JA, Cada DJ. Intravesical heparin: interstitial cystitis (painful bladder syndrome). Hosp Pharm 2013;48:822-4 Engelhardt PF, Morakis N, Daha LK, et al. Long-term results of intravesical hyaluronan therapy in bladder pain syndrome/interstitial cystitis. Int Urogynecol J 2011;22:401-5 Van Agt S, Gobet F, Sibert L, et al. Treatment of interstitial cystitis by intravesical instillation of hyaluronic acid: a prospective study on 31 patients. Prog Urol 2011;21:218-25 Nickel JC, Hanno P, Kumar K, Thomas H. Second multicenter, randomized, double-blind, parallel-group evaluation of effectiveness and safety of intravesical sodium chondroitin sulfate compared with inactive vehicle control in subjects with interstitial cystitis/bladder pain syndrome. Urology 2012;79:1220-4 Nickel JC, Moldwin R, Lee S, et al. Intravesical alkalinized lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful bladder syndrome. BJU Int 2009;103:910-18 Taneja R. Intravesical lignocaine in the diagnosis of bladder pain syndrome. Int Urogynecol J 2010;21:321-4 Nickel JC, Jain P, Shore N, et al. Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device. Sci Transl Med 2012;4:143 GuhaSarkar S, Banerjee R. Intravesical drug delivery: challenges, current status, opportunities and novel strategies. J Control Release 2010;148:147-59 Comphrehensive review about intravesical therapy.

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Torchilin VP. Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov 2005;4:145-60

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Torchilin VP. Multifunctional nanocarriers. Adv Drug Deliv Rev 2006;58:1532-55

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Fraser MO, Chuang YC, Tyagi P, et al. Intravesical liposome administration -- a


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novel treatment for hyperactive bladder in the rat. Urology 2003;61:656-63 Early research performed on intravesical liposome administration. Chuang YC, Lee WC, Chiang PH. Intravesical liposome versus oral pentosan polysulfate for interstitial cystitis/painful bladder syndrome. J Urol 2009;182:1393-400 Research compared intravesical liposome administration with oral medication.

61.

Lee WC, Chuang YC, Lee WC, Chiang WC. Safety and dose flexibility clinical evaluation of intravesical liposome in patients with interstitial cystitis/painful bladder syndrome. Kaohsiung J Med Sci 2011;27:437-40

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Chuang YC, Tyagi P, Huang CC, et al. Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin a delivery using liposomes. J Urol 2009;182:786-92 Research performed on intravesical liposome administration with urodynamic and immunohistochemical evaluation.

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Harrington DA, Sharma AK, Erickson BA, Cheng EY. Bladder tissue engineering through nanotechnology. World J Urol 2008;26:315-22

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Pham QP, Sharma U, Mikos AG. Electrospinning of polymeric nanofibers for tissue engineering applications. Tissue Eng 2006;12:1197-211

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Han D, Gouma PI. Electrospun bioscaffolds that mimic the topology of extracellular matrix. Nanomedicine 2006;2:37-41

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Kumari A, Yadav SK, Yadav SC. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 2010;75:1-18

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Chang LC, Wu SC, Tsai JW, et al. Optimization of epirubicin nanoparticles using experimental design for enhanced intravesical drug delivery. Int J Pharm 2009;376:195-203

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Gommersall L, Shergill IS, Ahmed HU, et al. Nanotechnology and its relevance to the urologist. Eur Urol 2007;52:368-75 Comphrehensive review about nanotechnology and clinical applications of nanomedicine in the field of urology.

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Chertok B, Moffat BA, David AE, et al. Iron oxide nanoparticles as a drug delivery vehicle for MRI monitored magnetic targeting of brain tumors. Biomaterials 2008;29:487-96 Leakakos T, Ji C, Lawson G, et al. Intravesical administration of doxorubicin to swine bladder using magnetically targeted carriers. Cancer Chemother Pharmacol 2003;51:445-50 Astruc D, Boisselier E, Ornelas C. Dendrimers designed for functions: from physical, photophysical, and supramolecular properties to applications in sensing, catalysis, molecular electronics, and nanomedicine. Chem Rev 2010;110:1857-959 Tekade RK, Tathagata D, Virendra G, Narendra KJ. Exploring dendrimer towards dual drug delivery. J Microencapsul 2009;26:287-96 Andersen AV, Granlund P, Schultz A, et al. Long-term experience with surgical treatment of selected patients with bladder pain syndrome/interstitial cystitis. Scand J Urol Nephrol 2012;46:284-9

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Fall M, Baranowski AP, Elneil S, et al. EAU guidelines on chronic pelvic pain. Eur Urol 2010;57:35-48 Gurocak S, Nuininga J, Ure I, et al. Bladder augmentation: review of the literature and recent advances. Indian J Urol 2007;23:452-7 Langer R, Vacanti JP. Tissue engineering. Science 1993;260:920-6

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Probst M, Dahiya R, Carrier S, Tanagho EA. Reproduction of functional smooth muscle tissue and partial bladder replacement. Br J Urol 1997;79:505-15

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Piechota HJ, Dahms SE, Nunes LS, et al. In vitro functional properties of the rat bladder regenerated by the bladder acellular matrix graft. J Urol 1998;159:1717-24

Tian H, Bharadwaj S, Liu Y, et al. Myogenic differentiation of human bone marrow mesenchymal stem cells on a 3D nano fibrous scaffold for bladder tissue engineering. Biomaterials 2010;31:870-7

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Oberpenning FO, Meng J, Yoo J, Atala A. De novo reconstitution of a functional urinary bladder by tissue engineering. Nat Biotechnol 1999;17:149-55

Kinebuchi Y, Johkura K, Sasaki K, et al. Direct induction of layered tissues from mouse embryonic stem cells: potential for differentiation into urinary tract tissue. Cell Tissue Res 2008;331:605-15

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Chung SY, Krivorov NP, Rausei V, et al. Bladder reconstitution with bone marrow derived stem cells seeded on small intestinal submucosa improves morphological and molecular composition. J Urol 2005;174:353-9 Early research performed on bone marrow derived stem cells for bladder reconstitution.

Imamura T, Yamamoto T, Ishizuka O, et al. The microenvironment of freeze-injured mouse urinary bladders enables successful tissue engineering. Tissue Eng Part A 2009;15:3367-75 Atala A, Bauer SB, Soker S, et al. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 2006;367:1241-6 Early research performed on tissue-engineered autologous bladder. Fraser M, Thomas DF, Pitt E, et al. A surgical model of composite cystoplasty with cultured urothelial cells: a controlled study of gross outcome and urothelial phenotype. BJU Int 2004;93:609-16 Turner A, Subramanian R, Thomas DF, et al. Transplantation of autologous differentiated urothelium in an experimental model of composite cystoplasty. Eur Urol 2011;59:447-54 Rodriguez LV, Alfonso Z, Zhang R, et al. Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells. Proc Natl Acad Sci USA 2006;103:12167-72


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Ringde´n O, Uzunel M, Sundberg B, et al. Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007;21:2271-6 Early research performed on allogeneic mesenchymal stem cells for hemorrhagic cystitis. Shaikh R, Raj Singh TR, Garland MJ, et al. Mucoadhesive drug delivery systems. J Pharm Bioallied Sci 2011;3:89-100

Affiliation Ling-Hong Tseng MD University of Chang Gung, Chang Gung Memorial Hospital, School of Medicine, Lin-Kou Branch, Department of Obstetrics and Gynecology, 5 Fu-Hsing Street, Kwei-Shan, Tao-Yuan 333, Taiwan Tel: +886 3328 1200 ext.8258; Fax: +886 3328 8252; E-mail: [email protected]

Advances in the development of novel antioxidant therapies as an approach for fetal alcohol syndrome prevention.

painful bladder syndrome.

Intravesical heparin: interstitial cystitis (painful bladder syndrome).

Amitriptyline: interstitial cystitis (painful bladder syndrome).

painful bladder syndrome.

Cost-effectiveness of novel therapies for overactive bladder.

interstitial cystitis.

Mathematical Modelling and Tuberculosis: Advances in Diagnostics and Novel Therapies.

Advances in the Study of the Antiatherogenic Function and Novel Therapies for HDL.

Novel nutraceutic therapies for the treatment of metabolic syndrome.

The pain of painful bladder.

Painful bladder: Case studies.

Radiotherapy for painful heel syndrome.

painful bladder syndrome.

Behçet syndrome: from pathogenesis to novel therapies.

Evaluation of Percutaneous Tibial Nerve Stimulation for Treatment of Refractory Painful Bladder Syndrome.

interstitial cystitis?

painful bladder syndrome.

Radiotherapy for painful heel syndrome.

Advances in transcatheter valve therapies.

bladder pain syndrome: thinking beyond the bladder.

Advances in Computational Methods for Genetic Diseases.

Protein Microarrays with Novel Microfluidic Methods: Current Advances.

Targeted therapies for metastatic bladder cancer.