Keywords

1 Introduction

Urinary stent coatings are a strategy to tackle certain complications associated with the use of the materials previously mentioned on in previous chapters. The latest innovations in surface coatings focused on the prevention of those problems, thus reducing further costs with treatments. As previously mentioned on this book, device-associated infections and encrustation are considered the major challenges, and, in an attempt to prevent such morbidity, several strategies were developed. Hence, coatings have been designed to improve quality of life for patients, reducing the friction, inhibiting uropathogens survival or attachment on stents, and avoiding the deposition of urinary crystals that triggers encrustation [1,2,3]. In the light of current knowledge regarding biofilm formation mechanisms, coating solutions can be divided, according to its purpose, in anti-adhesive coatings and bactericidal coatings.

2 Anti-adhesive Coatings

The anti-adhesive, or antifouling, strategies avoid the adhesion of microorganisms by preventing the attachment or allowing an easy detachment (Fig. 1). The key drive force to create these designs was the high resistance of biofilms to conventional antibiotic therapies. Therefore, the surface modification approaches usually provide the anti-adhesive properties with great antibacterial effects and low toxicity associated [4].

Fig. 1
figure 1

Anti-adhesive coatings confer resistance to microorganism and protein adhesion. Distinct surface modifications can impair these processes, without directly causing bacterial death

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2.1 Hydrophilic and Hydrophobic Coatings

To prevent microorganism adhesion and encrustation on medical devices, both hydrophilic and hydrophobic solutions can be used [4, 5]. Hydrogels consist in hydrophilic crosslinked polymers, with ability to swell and retain large amounts of water [6]. When used as coatings for ureteral stents, hydrogels are exposed to urine, which allows its absorption by the polymeric structure. The hydration layer facilitates stent placement by reducing friction, potentially increasing patient comfort [2, 6]. This type of hydrogel on stent surface acts as a barrier, reducing adhesion of microorganisms and providing antifouling properties to the stent [6]. In an in vitro study, poly(N,N-dimethylacrylamide) (PDMAA) hydrogel network on ureteral stents reduced significantly the adherence of the most common uropathogens [7]. In a recent study with 104 patients, hydrogel-coated ureteral stents proved to be a superior option, comparing with uncoated commercial polyurethane ureteral stents. For treatments between 1 and 3 months, patients with hydrogel-coated stents reported lower side-effects rate and complications [8].

Similar to hydrogels, hydrophilic poly(vinyl pyrrolidone) (PVP) and polyethylene glycol (PEG) are capable of absorbing water, which provides a beneficial lubricious effect when used as coatings [9]. Besides that, after an in vitro study over a 14-week period with artificial urine, PVP-coated silicone and polyurethane stents presented significantly less encrustation than the uncoated ones [9]. PEG is also considered a antifouling agent for biomedical applications [10], however its thermal, oxidative, or hydrolytic degradation and the difficulty to generate a dense coating impair its utilisation. To overcome this, PEG can be conjugated with 3,4-dihydroxyphenylalanine (DOPA), an important amino acid in marine adhesive proteins [11]. In vitro, DOPA conjugated PEG coating proved to significantly resisted the attachment of uropathogens, comparing to control, while in vivo, using rabbit model, it was reported a reduction of 75% in the number of stent adherent organisms [12]. Although the potential of PVP and PEG for urological use has already been proven in studies [9, 11,12,13], validation in more complex models is still lacking.

Furthermore, antifouling hydrogel based on natural polysaccharide has a high clinical relevance in the urinary context. Polysaccharides are present on the surface of many microbial cells, mediating most of the cell–surface and cell–cell interactions that are highly responsible for biofilm formation [14]. However, it is also undoubtedly that several polysaccharides widely distributed in nature are actually able to inhibit or destabilize biofilm formation. Among polysaccharides, heparin, a highly-sulphated glycosaminoglycan, is widely known for its ability to inhibit bacterial attachment and its effects have been observed mostly on cardiovascular field but also on ureteral stents [15]. Heparin-coated stents were able to successfully remain encrustation-free during 6 weeks of indwelling time, while uncoated stents present biofilm formation only after 2 weeks [16]. In line with this study, in a long-term study involving patients, heparin-coated stents presented no signals of encrustation up to 10 months after insertion [17]. Besides heparin, hyaluronic acid is another polysaccharide tested as coating for urinary devices. Using a validated in vitro encrustation model, covalently bound hyaluronic acid catheters were associated with less encrustation than the control, silicone [18]. Despite these promising results, up to date, clinical relevance has never been assessed. Chitosan, a biodegradable polysaccharide, also displays antimicrobial properties and, due to its biocompatibility, it is possible to use it for biomedical applications [19]. Chitosan-based coating resisted biofilm formation by bacteria and yeast, over a 54-h experiment, with reductions in biofilm viable cell numbers ranging from 95 to ≈ 99.99%, comparing to control [20]. In another static study, the development of a chitosan/poly(vinyl alcohol) (PVA) hydrogel successfully reduced protein absorption and provide antimicrobial properties to segmented polyurethane urethral catheters [21].

Due to its superhydrophilicity, zwitterionic coatings also emerged as highly effective antifouling strategy. Nowadays, there are three major classes of zwitterionic materials based on poly(phosphorylcholine), poly(sulfobetaine), and poly(carboxybetaine) [14, 22]. Zwitterionic coatings form a hydration layer surrounding the ionic surface, preventing non-specific protein adsorption and conferring a high resistance to microorganisms adhesion [23,24,25,26,27]. In an in vitro assay, a bioinspired surface functionalization with phosphorylcholine proved to enhanced lubrication and bacterial resistance to the surface of titanium alloy biomedical implants [28]. Recently, 2 zwitterionic polymers, poly(sulfobetaine methacrylate) (pSBMA) and poly(carboxybetaine methacrylate) (pCBMA), were used as coating for silicone surfaces. The coated material showed the antifouling properties provided by the zwitterionic polymers, proving that this is a promising approach for ureteral stent coatings [29]. Applying this rationale, Fan et al. [30] revealed that these type of coatings showed strong antimicrobial activity, as confirmed by the low number of viable adhered bacteria on silicone-based urinary devices. Another SBMA antifouling zwitterionic coating was tested in a urinary catheter for 1 week, using a dynamic system simulating the real usage conditions of the device. Besides increased hydrophilicity and reduced protein adsorption, results showed a biofilm formation reduction by 80% compared to the biofilm produced on the urethra of uncoated catheters, and by about 90% in the case of the biofilm produced on the catheter balloon. Moreover, this coating did not affect the viability of the human fibroblasts, showing increased potential for clinical use [23]. In addition, it is also possible to create layer-by-layer zwitterionic surface modification, as evidenced by Li et al. [31], using a polydopamine (PDA) layer, then a monolayer of 3-aminopropyl triethoxysilane (APTES) and finally the zwitterionic polysulfobetaine (PSB) layer. When tested in vitro, this construct dramatically reduced the protein and bacterial adhesion [31]. The research on hydrophilic coatings for ureteral medical devices is growing exponentially and it has already been translated nowadays in commercially available options, such as AQ® from Cook Urological, SL-6 from Applied Medical, HydroPlus™ from Boston Scientific, and heparin-based coating Endo-Sof™ Radiance™, from Cook Urological.

Hydrophobic coatings have also been applied on ureteral stents, among each polytetrafluoroethylene (PTFE) or teflon. Teflon has a wide range of applications, however, for this Chapter is only important to highlight its capacity to reduce biofilm development. This effect results from its resistance to Van der Waals forces, and, possibly, also due to the lower coefficient of friction [32]. Teflon-coated metal stents were associated with decreased reaction of epithelial cells to metal, resulting in increased biocompatibility. Additionally, an in vivo study performed in canine ureters with metallic self-expanding stents PTFE-covered proved that the benefits of this coating go beyond antimicrobial effects, as these formulations effectively prevented the luminal occlusion caused by urothelial hyperplasia [33]. The described results were obtained 5, 10, 15, and 30 weeks after insertion, suggesting that PTFE-covered stents have clinical relevance for short and intermediate treatments [33]. More currently, superhydrophobic surfaces have become an emerging topic due to its water-repellent and self-cleaning properties [34]. Superhydrophobic soot coatings can be created by deposition via combustion flame synthesis, followed by functionalization using plasma polymerization and/or fluorination. In an in vitro assay, the anti-bioadhesion activity of these coatings was proven, since the proliferation of Pseudomonas species was significantly inhibited [35]. Although recent, this rationale is promising and it is a valid approach to investigate in the urological context.

Antifouling properties can also be provided by amphiphilic polymers, which combine both hydrophilic and hydrophobic parts. An amphiphilic polymer synthesized with dodecyl methacrylate (DMA), poly(ethylene glycol) methacrylate (PEGMA), and an acrylic acid (AA) successfully coated the surfaces of commercial catheter material and reduced bacterial adhesion, under static and dynamic conditions [36]. In a in vivo experiment, mice were observed over a 4-day period, and it was conclude that this amphiphilic coating effectively resisted S. aureus adhesion [36]. Nonetheless, further research is needed to fully assess the clinical relevance of this approach.

2.2 Diamond-Like Carbon Coatings

In 2004, Norbert Laube’s research group [37] described for the first time the use of diamond-like carbon coatings (DLCs) on urological devices. This form of amorphous carbon material combines antimicrobial activity with its inert nature, biocompatibility, lubricity and durability features. The in vivo and in vitro studies demonstrated DLCs was capable of relieve patient symptoms, infections and encrustations [38, 39]. This coating was further tested in patients, during almost 7 years. With a stent removal frequency of less than 6 weeks, no crystalline biofilm formation was observed and due to the low friction, patients reported a less painful experience [5]. Nowadays, DLCs are a commercial option in the ureteral stent market (Ureteral Stent Set—CarboSoft), due to their promissory effect on reducing biofilm formation, the risk of encrustation and urinary tract infections, even for long-term treatments.

2.3 Topographical Modifications

As verified previously, nature is a valid source of inspiration to create new and improved solutions for medicine. Antifouling systems based on active topographies exist in nature, e.g. wings of insects, such as cicadas and dragonflies, and even in the human body, where the lung epithelial cells repel microbes with beating cilia [40]. Inspired by nature, topographical modifications, at micrometer and nanometer scale, can be engineered in urinary devices to provide the desired effect. This technology was tested in the urinary context by Gu et al. [41], that created a urinary catheter with micron-sized pillars that can beat at a programmable frequency. This active topographic design not only prevented biofilm formation, but also removed established biofilms of the studied uropathogens, including E. coli, P. aeruginosa, and S. aureus. Under flow of artificial urine, the coated catheters remained clean at least during 30 days, while control catheters were blocked by E. coli biofilms within 5 days [41]. While topographical modifications strategies are still relatively in its infancy, they represent a valid method to achieve the desired antifouling effects.

2.4 Polymer Brushes

Polymer brushes form an antifouling surface, since these structures impair the adsorption of biomolecules, decreasing the attachment of microorganisms and consequent biofilm formation [42, 43]. Alves et al. [44, 45] demonstrated the potential of this strategy for urinary tract devices, evaluating distinct polymer brushes, namely poly[N-(2-hydroxypropyl) methacrylamide] and also poly[oligo(ethylene glycol) methyl ether methacrylate], under adequate hydrodynamic conditions. The results showed that the surface area covered by bacteria was decreased up to 60% when compared with the control. Gultekinoglu et al. [46] designed polyurethane ureteral stents with polyethylenimine (PEI) brushes. In static conditions, this construct effectively presented bactericidal activity against E. coli and P. mirabilis, without any cytotoxic effect on L929 and G/G cells, proving to be a good candidate for antifouling and antimicrobial strategies for ureteral stents. Validation on more complex models is a key factor for the further development of this approach.

2.5 Quorum-Sensing-Based Coatings

In the light of current knowledge about bacterial mechanisms, it is possible to create a quorum-sensing-based solution to prevent bacterial adhesion on ureteral stents. Quorum-sensing is a cell–cell communication process used by bacteria to monitor cell population density, allowing bacteria to synchronize the gene expression as a group [47]. The disruption of this process impairs bacteria capacity to form biofilm, which may be used an alternative approach to tackle antimicrobial resistance [48]. Although the study of quorum-sensing-based coatings is still at an early stage, some auspicious results were already available [49, 50]. A layer-by-layer coating was developed comprising acylase and α-amylase, which are able to degrade bacterial quorum-sensing molecules and extracellular matrix, respectively. This multilayered coating demonstrated 30% higher antibiofilm efficiency against common uropathogens, such as E. coli and P. aeruginosa [49]. Additionally, under both static and dynamic conditions, this innovative coating on silicone urinary devices significantly reduced the occurrence of biofilms with single-specie and mixed-species, suggesting that it can be a suitable option for ureteral stents [49]. In an in vivo study, using rabbit as model, results proved that the quorum-quenching and matrix degrading enzyme construct inhibited the biofilm formation up to 7 days. Considering the resistance mechanisms of bacterial biofilms, it can be hypothesized that inhibiting biofilm formation would later increase the bacteria susceptibility to antimicrobials, even at subminimal inhibitory concentrations [49]. More recently, furanone, a quorum-sensing inhibitor, was used as a coating for urinary catheters, resulting in a complete blockage for Candida sp. adhesion, under static conditions [50]. This practice is still incipient and more validation is required in order to pass from the bench to the bedside.

3 Bactericidal Coating

In contrast to anti-adhesive coatings, bactericidal coatings prevent the attachment of microorganisms, but also trigger their death. In the case of ureteral coatings, most approaches are designed to trigger bacterial death, however, other uropathogens are also affected [4].

3.1 Release of Antimicrobial Agents

The successful development of an effective coating with eluting proprieties required the identification of the most promising antimicrobial agents, that for the urinary tract context may include antibiotics and metals composites (Fig. 2).

Fig. 2
figure 2

Bactericidal coatings trigger bacterial death, either through the release of antimicrobials agents or by contact-killing approaches

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3.1.1 Antibiotics

In case of ureteral stents-associated infections, the use of prophylactic antibiotics as a systemic therapy can trigger the development of further microbial resistance, without avoiding the attachment of the already resistant uropathogens [51]. The rationale behind the use of antibiotics in coatings consists in the opportunity of enhance the antimicrobial effects locally, without the adverse effects of a systemic therapy. Several antibiotics, such as ciprofloxacin, norfloxacin, ofloxacin, gentamicin, chlorhexidine, were incorporated on ureteral devices, and its efficacy was proven against the common uropathogens [52,53,54]. After a meta-analysis study, it was demonstrated that this strategy is effective for short-term implants, however the release profile of this type of compounds, with an initial burst release followed by concentrations that are not inhibitory, may not actually be translated into a favorable therapeutic effect [55]. In fact, for long-term implants, this strategy favors the development of microbial resistance, creating an infection even more difficult to treat [32].

3.1.2 Metal-Based Coatings

Metal, metal oxide, or composite nanoparticles are suitable alternatives as antimicrobial agents, being able to prevent biofilm-associated infections on medical implants [56]. The broad-spectrum antimicrobial mechanism of silver is well-known [57, 58] and it was one of the pioneer approaches in the urologic devices to prevent device-associated infections [59]. Its application is already approved by Food and Drug Administration (FDA) for the urinary context, namely for urinary catheters [26]. Over the years, numerous studies, including clinical trials, proved the effectiveness of the silver coatings against device-associated infections. In 2014, in a multicenter cohort study, Lederer et al. [60] reported that the silver alloy hydrogel catheter (Bardex I.C.), used for at least 3 months, inhibit in almost 50% the number of reported cases of symptomatic device-associated infections, comparing to standard catheters. Nonetheless, contradicting studies described the ineffectiveness of this strategy, reporting no significant differences between the use of the device with or without the silver coating [61, 62]. This type of coating was reported as ineffective in long-term catheterization, as it easily loses antimicrobial activity, and some clinical trials have demonstrated the occurrence of bacterial resistance in the intermittent catheterization. Additionality, comparing with other antimicrobial catheters, the cytotoxicity to host cells is still high [47,48,49]. This lead to conclude that silver could be a good candidate to tackle uroinfections, however there is still room for improvement. Novel silver materials have been studied over the last years, and up to date silver nanoparticles and silver nanoclusters are the most promising materials, within this area, for urinary stent coatings. Besides releasing antibacterial silver ions, silver nanoparticles with less than 100 nm can be incorporated by bacteria, leading to structural damages and, ultimately, causing cell death [63, 64]. Silver nanoclusters, due to its size < 2 nm, demonstrated an improved antimicrobial efficiency compared with the silver nanoparticles [26, 66,67,67]. An ex vivo study, using a set-up that mimics the biological conditions during stenting, silver nanoclusters were associated with less 45% of friction, comparing with the uncoated ones, which can indicate less pain to the patient [68].

Throughout the years, other metal-based approaches gained prominence due to their antibacterial properties, with emphasis on zinc oxide, with its intrinsic antimicrobial activity and biocompatibility [69]. Synergistically combination of zinc oxide films and the 2-hydroxyethyl methacrylate (HEMA) hydrogel by Laurenti et al. [69] created a barrier layer that in vitro prevented the unbeneficial burst release of zinc oxide. This advantageous effect results from the incorporation of a pH-triggered delivery system that controls the sustained release of this material. These findings indicated that the design is an encouraging candidate for urinary tract devices. Within metal-based coatings, a distinct concept using copper-bearing stainless steel was already evaluated in an in vivo rabbit model. Stents were analyzed 20, 40 and 80 days after implantation, and copper-bearing stainless steel coating was associated with less adherent microorganisms and deposited crystals, with significant differences comparing to uncoated control [70]. The conclusions drawn in this study represent a major advance for this strategy and further boost its use in urinary tract devices.

3.2 Contact-Killing

Within contact-killing coatings are included surfaces that exhibit antimicrobial activity without releasing antibiotics or other biocidal agents.

3.2.1 Antimicrobial Peptides (AMPs)

AMPs are antimicrobials effective against both Gram-negative and Gram-positive strains, viruses, and fungi, representing one of the most promising alternatives to conventional antimicrobial agents [71]. Usually, AMPs are short peptides with cationic charge and a great portion of hydrophobic residues, around 50%. This positive charge and amphiphilic nature allow AMPs to interact with several types of bacteria. The mechanisms of action are diversified, which confers AMPs a broad-spectrum of antimicrobial activity [71]. The disruption of cytoplasmic membrane [72], autolysin activation, inhibition of DNA, RNA, and protein synthesis [73] are some of the mechanisms already described in literature. A recent in vitro study of Wang et al. [74] revealed that AMPs can in fact reduce biofilm formation on medical tubes used in urology up to 7 days, which corroborates the use of this material in urological devices. In vitro assays demonstrated that chemo selective covalent immobilization of Dhvar5 AMP, a synthetic peptide derived from the histatins family, on thin chitosan coatings resulted in the decrease of bacterial colonization [75]. Wang et al. [74] demonstrated, in a 7-day in vitro test, that a customized and bought AMP, Bmap-28, incorporated into a biodegradable hydrophilic polyurethane was capable of inhibit bacterial biofilm formation of P. mirabilis and delay catheter obstruction caused by encrustation.

3.2.2 Enzyme-Containing Coatings

In the recent past, enzymes have been considered as a new generation of antimicrobial agents, targeting microbial growth and biofilm formation [76]. A cellobiose dehydrogenase functionalized urinary catheter was evaluated in artificial urine, over 16 days, resulting in the reduction of the viable S. aureus by 60%, and in the decrease of biofilm formation by 70%, comparing to control [77]. Other enzyme, the protease α-chymotrypsin (α-CT), was covalently immobilized on polyethylene surfaces. Using a Center for Disease Control (CDC) biofilm reactor it was proven that this strategy significantly impacted E. coli biofilm formation [78]. More studies will be further needed to fully validate this approach.

3.2.3 Bacteriophages

A recent and promising approach to prevent bacterial contamination on ureteral stents is the use of bacteriophages, i.e., viruses that infect bacteria, and then use bacterial cell as a factory to multiply themselves [79]. Bacteriophages are an attractive therapeutic agent, with highly specificity and very effective for the targeted pathogen. In case of lytic phages, the mechanism of action consist in the disturbance of the bacterial metabolism, inducing cellular lyses and consequent death [79]. Khawaldeh et al. [80] described a successful bacteriophage therapy for refractory P. aeruginosa urinary tract infection, in a 67-year-old woman that underwent extensive intra-abdominal resections and pelvic irradiation for adenocarcinoma, followed by bilateral ureteric stent placement to relieve obstruction. This patient has received multiple courses of gentamicin, ceftazidime, ciprofloxacin and meropenem over a 2-year period, with consecutive failures. During the study, no bacteriophage-resistant bacteria were reported, and the therapy resulted in symptomatic relief and microbiological cure, where repeated courses of antibiotics combined with stent removal had failed [80].

4 Conclusions and Future Perspectives

Coatings are an effective approach to improve urinary devices, reducing the most common complications experienced by patients during treatments and avoiding the even more challenging need to search for completely new materials associated with less morbidity. Currently for ureteral stents, hydrophilic and diamond-like carbon coatings are commercial options associated with an enhanced performance of devices, comparing with uncoated ones. These commercially available approaches are all anti-adhesive coatings, and, in the general overview, this type of strategy appears to be a superior alternative than bactericidal coatings. Designs that trigger uropathogen death are usually associated with higher toxicity, and, in some cases, it can even favor the development of microbial resistance, which can hamper the infection treatment. With the present knowledge about antimicrobial mechanisms and inspired by nature, more cutting-edge alternatives, able to confer antimicrobial properties to the inner and outer parts of stents, will surely appear. The correct validation of those strategies, according to international standards, is a very important step for the rise of innovative and effective solutions for urinary stents.