Diseases of the urinary tract, such as incontinence, overactive bladder, interstitial cystitis, bladder cancer and bacterial infections, are widespread in individuals of different ages and gender. However, their incidence increases in elderly people, who represent the population segment of developed countries in continuous growth and whose therapeutic treatments consequently have great impact on healthcare expenses. Particularly, bladder cancer is one of the most diagnosed tumors in the male population worldwide, and is the one with the highest cost from diagnosis to death as well as the fifth most expensive for overall treatment (Leal et al., 2016).

The therapy of the above-mentioned pathologies has mainly involved the systemic administration of drugs by the oral route in some cases coupled with the instillation of liquid formulations directly into the bladder through catheters. Because systemic treatments fail to effectively target the affected tissues, they generally require higher drug doses in order to reach therapeutic concentrations in situ. This may lead to overwork of the organs responsible for elimination, which, in the case of elderly people most likely receiving multiple chronic therapies, may increase the risk for complications and onset of side effects. On the other hand, the catheterization procedure used for the local administration of drugs into the bladder is particularly invasive, poorly tolerated and may require to be carried out by specialized personnel often involving repeated hospitalization periods. Furthermore, it has a major impact on the patient quality of life, from a social and relational point of view, causing psychological discomfort, depression, personal disesteem and a sense of loss of control over the bladder function. From an occupational point of view, an increase in the number of absences, not only for therapy administration but also as a consequence of the discomforts arising, is often recorded. As a common side effect, the repeated insertion of catheters for intra-bladder instillation of drugs causes inflammatory phenomena and infections. 10 to 30% of subjects undergoing short-term catheterization develops bacteriuria, often asymptomatic, and after longer-term catheterizations bacteria are found in urine samples from almost all treated subjects. Infections associated with the use of the short-term catheters have been shown to prolong the average hospitalization time from 2.4 up to 4.5 days and have also been correlated with an increase in hospital mortality. Thanks to early detection procedures, in about 75% of patients, bladder cancer is found limited to the mucosa/submucosa area, and this percentage increases when patients under 40 are considered (Babjuk et al., 2019). To reduce mortality and prevent recurrence, the treatment of bladder cancer involves surgical resection and, after surgery, chemotherapy with repeated instillation of anticancer drugs into the bladder. The effectiveness of the current chemotherapy is limited not only by the high risk of dropout of patients due to the problems mentioned above, but also by the difficulties in keeping the active molecules inside the bladder for a sufficiently long period of time and promoting their penetration into the wall. Such difficulties are worsened by the urgency to urinate immediately after installation and by the progressive dilution of the bladder content over time.

The strong therapeutic, social and economic interests related to the vast population affected by diseases of the urinary apparatus have given a decisive boost in recent years towards the identification of drug delivery strategies able to overcome all the issues previously discussed.

The present review aims at presenting a brief excursus through the evolution of intravesical administration of drugs focusing on the development of delivery systems capable of maintaining effective concentrations of bioactive molecules within the bladder for strategic periods of time. Indeed, special emphasis was placed on indwelling solid dosage forms for prolonged release, also covering 3D and 4D printed devices.

The urinary bladder is a hollow organ, placed in the anterior part of the pelvic cavity, responsible for the collection and short-term storage of waste substances from the systemic circulation, coming from the kidneys, and their elimination as urinary fluids (Standring, 2005). Its shape, relative position and dimensions vary according to the gender, filling state and condition of the adjacent organs. When empty, the bladder is similar to a tetrahedron, while in the state of maximum filling, under normal conditions around 400–600 mL, tends to assume a pseudospheric shape (Fig. 1).Fig. 1

Schematic of urinary bladder. Adapted from (Hamza, 2020).

The fundus, also called body of the bladder, is the portion that constitutes the deposit of urine, where the two ureters coming from the kidneys define a triangular-shaped area together with the internal urethral orifice. The bladder neck, having a length of about 2–3 cm, is connected by the urethra to the external urinary meatus that in females also corresponds to the urine exit point, while in males continues into the anterior urethra that runs along the penis.

The bladder wall is made of muscular and epithelial tissues. The mucosa at the interface with the urinary space consists of the uroepithelium, or urothelium, resting on a lamina propria. It is a transitional epithelial tissue composed of at least three layers: a basal cell layer attached to a basement membrane, an intermediate layer, and a superficial layer composed of large hexagonal cells (diameters of 25–250 μm) known as “umbrella cells”. The urothelium plays a critical role as a permeability barrier to urine (Khandelwal et al., 2009). Epithelial integrity is maintained through complex processes of migration and proliferation, to restore cell number, and of differentiation to restore function. Basal epithelial cells, which have been suggested to have stem-cell-like properties, typically exhibit very slow (3–6 month) proliferative rates. When the bladder is empty, the urothelium takes on a wrinkled appearance, while it stretches and appears smoother as the amount of urine collected increases. This change is made possible by the ability of the umbrella cells to modify their shape and of the intermediate cells to slide over one another, varying the thickness of the intermediate layer in relation to the state of filling of the organ, without loss of the urothelial barrier function. The bladder muscular layer, which overall constitutes the detrusor muscle, consists in a series of interconnected smooth muscle fibers arranged in different directions: while the fibers belonging to the inner and the external layer mostly show a longitudinal direction, those located in the middle area are characterized by a circular orientation. These three layers converge into the bladder neck and, together with the spiraliform smooth muscle fibers of the urethral sphincter, provide the sphincteric mechanism responsible for urination. Such a process is ruled by a cortical autonomous stimulus, which is triggered by the stretching of bladder and urethra walls and causes both the contraction of the muscle tissue here located and the relaxation of the internal urethral sphincter. However, urine release is also under voluntary control, as a voluntary cortical stimulus is needed to allow the relaxation of the external urethral sphincter. The presence of approximately 150–200 mL of urine in the bladder initially stimulates urination, which is controlled by myovesical plexus sending signals for voiding to detrusor muscle. The latter controls the extent and frequency of bladder emptying.

Considering the bladder role in the homeostasis of the human body, it is evident how any change in its functionality would necessarily be associated with inconveniences of different severity (GuhaSarkar and Banerjee, 2010; Kolawole et al., 2017; Zacchè et al., 2015). These could be caused either by the natural aging process or by the activation of an inflammatory response, and also be brought about by the onset of various diseases (e.g. infections and cancer). Particularly, some chronic vesical pathologies, such as atonic and hyperactive bladder, interstitial cystitis and cancer, are characterized by high current incidence, major discomfort for the patient and limited efficacy as well as tolerability of available treatments. Moreover, such diseases are often followed by opportunistic infections, which can in turn become recurrent.

Atonic and hyperactive bladder, as well as urinary incontinence, relate to an alteration in the control of the muscular activity of bladder wall and sphincters responsible for urination (Chen and Kuo, 2019; Li and Liao, 2016). More in detail, while in the atonic bladder syndrome the contractility of the detrusor muscle is limited and associated with difficulties in performing the emptying process, in the hyperactive bladder disease there is an increased contractility of the organ, thus causing urgency and increased frequency in urination and nycturia. In urinary incontinence, the sphincter control is seriously reduced or lost, with difficulties in, or impossibility of, controlling the urine flow. These diseases are pretty common, showing huge diffusion, and their incidence increases with aging, being slightly higher in men. The treatment generally requires a pharmacological therapy acting on the cholinergic system, chiefly responsible for the modulation of the detrusor muscle tone, on the one hand, and the use of invasive mechanical methods, such as the application of catheters for the correct draining of urine, on the other.

Interstitial cystitis is a painful chronic syndrome with higher incidence in women, mainly associated with a damage in the glycosaminoglycans (GAGs) layer with a loss of vesical epithelium functionality (McLennan, 2014). Symptoms include pelvic pain, urinary frequency, urgency and nycturia. Etiology is linked to alteration of urothelium GAGs, with activation of mast cell, autoimmune reaction and central sensitization. Unfortunately, the therapy is based on empirical studies and suffers from low efficacy. It is limited to the use of a combination of painkillers to be administered systemically and anesthetics instilled in situ.

Finally, bladder cancer is one of the most common neoplastic pathologies, the etiology of which lies in the abnormal growth and proliferation of bladder wall cells. Although it generally affects the inner bladder surface (i.e. superficial tumors), a small percentage of cases in which tumor cells may infiltrate the muscular layer of the bladder is also described (i.e. muscle-invasive cancer). The onset of cancer impacts the normal activity of the bladder, causing hematuria, frequency and urgency in urination together with dysuria. First-line treatment of non-muscle-invasive bladder cancer envisages surgical resection of the tumor followed by local instillations, repeated over time, of different chemotherapeutic agents (e.g. epirubicin, mitomycin, Bacillus Calmette-Guérin) to prevent recurrence and progress into muscle-invasive bladder cancer (Babjuk et al., 2019; Yoon et al., 2020).

Local treatment of bladder diseases, despite being a poorly acceptable choice for the patient, exhibits the advantage of reducing the side effects of specific drugs. Indeed, substances that would not be considered safe when administered via other routes, such as dimethyl sulfoxide and botulinum toxin, have been approved for intravesical infusion. Moreover, compared to the oral route, partial elimination due to the first-pass effect can be avoided, thus allowing possibly lower drug strengths to be used. Local administration is made by instilling liquid formulations containing one or more drugs into the bladder cavity, through a catheter inserted directly into the urethra of the patient; such liquids can be left in situ for a pre-determined time lapse before being excreted or withdrawn.

The use of catheters is a widespread practice, not only exploited to support the treatment of urinary system diseases, but also for diagnostic purposes. However, catheterization causes inconvenience and discomfort to the patient, which is generally treated by local application of ointments or gels containing anesthetic drugs having short-lasting efficacy (usually limited to minutes).

Indwelling urethral catheters (IUCs), also named Foley catheters, are designed to remain in place for many days or weeks and to be held in position by an inflated balloon in the bladder. They are typically used to enable urinary bladder emptying in the case of pathologies impairing natural urination or to drain urine when the patient is bedridden. The tube of the catheter has two separated lumens, or channels, running down its length. One lumen, open at both ends, drains urine into a collecting bag; the other has a valve on the outer end and connects to the balloon at the inside tip. The balloon is inserted through the urethra and positioned deflated inside the bladder. Then it is inflated with a prefixed volume of sterile water to maintain the position and avoid accidental slipping out. For removal, the balloon is deflated, and the catheter is simply pulled out. Prolonged release of an anesthetic for reducing the pain induced by IUC has been recently proposed by Kim and co-authors, who designed a drug-loaded polymer strand releasing lidocaine up to 7 days (Kim et al., 2021). The thin poly(lactic-co-glycolic acid) (PLGA) strand was wrapped around the external tube of the urinary catheter and released the drug from the surface thus alleviating the discomfort associated with the presence of the device (Fig. 2).Fig. 2

Schematic of the fabrication procedure of strand-wrapped indwelling urethral catheters for lidocaine release. Reprinted with permission from (Kim et al., 2021).

When urinary catheters are placed in the bladder through the urethra for days or weeks, long-term residence often entails other complications such as the onset of infections. These are generally caused by bacteria found in the external area close to the urinary orifice, such as Escherichia coli, Enteroccoccus fecalis, Proteus mirabilis and Pseudomonas aeruginosa, which could reach the bladder either during catheter insertion or by moving upstream through the catheter cavity from the drainage bag where they can proliferate. Once in the bladder, such microorganisms form complex structures called biofilms that make penetration of drugs, and thus the relevant action, even more difficult. In any case, the elimination of pathogens is fundamental to avoid worsening of infections and further problems, and it generally requires systemic and local administration of antibiotics.

Several papers reported on the coating of urinary catheters with drug-containing formulations in order to reduce such a risk. For instance, salicylic acid-releasing polyurethane acrylate polymers, silver nanoparticles, antibacterial polycationic nanospheres and chlorhexidine-loaded poly(ethylene glycol)-block-poly(ε-caprolactone) micelles were investigated (Francesko et al., 2016; Gefter et al., 2018; Nowatzki et al., 2012; Srisang and Nasongkla, 2019; Thomas et al., 2015).

A further issue involved in therapies based on intravesical administration of drugs, particularly those for bladder cancer, is given by the poor permeability of urothelium, which may represent a tough barrier to be crossed especially by molecules with high molecular weight (Yoon et al., 2020).

In addition to the problems associated with the poor urothelium permeability, it should be considered that the maximum residence time of drugs instilled into the urinary bladder is approximately of 2 h and their concentration is constantly diluted by excreted liquids drained by ureters, with consequent need for frequent instillations to maintain the desired therapeutic properties. Even though drug elimination after the instillation treatment can be deferred by restricting the liquid intake, which reduces the production of urinary fluid, and urinating before intravesical infusion, compliance issues may arise especially when elderly patients are involved, for whom holding the urge to urinate and complete bladder emptying are often problematic. Moreover, the large variability in the residence of drugs in situ makes it difficult to define personalized therapeutic regimens for individual patients, thus implying the application of rigid therapeutic protocols.

For all of these reasons, the distress caused by catheterization and discomfort of frequent treatment regimens are connected with high dropout rates, with severe consequences especially in the case of bladder cancer.

Based on the above considerations, it is clear that the local therapy of urinary bladder diseases is a challenging goal. The success of such treatments necessarily depends on proper exposure of the organ to the drug (Wang et al., 2021). Therefore, strategies to improve the outcome of intravesical pharmacological treatments have been aimed at maintaining effective drug levels in situ through the use of delivery systems able to be retained and release the drug into the organ for a prolonged period of time and/or enhancing permeation of locally administered drugs throughout the bladder wall.

Considering the current medical treatments of urinary bladder diseases and their prevalence in the population, development of advanced delivery systems conveying reduced though effective drug doses directly to the site of interest appears a priority in the pharmaceutical area. Direct and indirect savings as well as social benefits arising from use of intravesical delivery systems would especially be provided by devices that, once inserted into the bladder, may be retained within the organ and yield sustained release of the drug for the desired time frame, at least hours, requiring no other specific intervention. Indeed, this could limit the need for catheterization, reduce involvement of trained healthcare personnel and enhance the perceived quality of life for the patients. Furthermore, the decreased number of catheterizations could remarkably lower the incidence of secondary infections.

Given the growing interest in precision medicine, the possibility of personalizing the pharmacological therapy in terms of type as well as dose of drugs and release performance is also of utmost interest. Among the various formulation strategies described for bladder retention and delivery, systems based on externally-triggered expansion, elastic or smart materials have mainly been proposed, fabricated by different techniques. Particularly, the use of 3D and 4D printing, when dealing with shape-memory polymers, has been proved specially suited for fabrication of customizable therapeutic systems. Allowing patients to lead a regular daily life in spite of the disease conditions they have to face and, at the same time, receive a less invasive and more effective therapy, could result in an increase in the well-being of the treated subjects and in a greater adherence to the treatment, with further improvement of life expectancy.

The authors report no conflicts of interest.