Keywords

1 Introduction

According to the literature, one of the most common complications related to indwelling urinary stents is microbial adhesion to their surface which leads to biofilm formation, and often thereafter to infection and, in some patients, urosepsis [1,2,3]. Bacteria in a biofilm can be up to 1000-fold more resistant to antimicrobial drugs [4]. The traditional methodology of using therapeutic intervention for developing an antimicrobial urinary stent very often lacks clinically meaningful benefit [5]. For that reason, urinary stent modifications using alternative methods and materials with antimicrobial functionality such as nanoparticle-based systems are being intensively investigated. Coverings or coatings, functionalization, blending and drug impregnation based on nanoparticles are mainly applied for these purposes [6]. In such a system i.e. product, nanoparticles may be used as the primary ingredient, constituent, or sub-constituent. Nanoparticles have demonstrated a broad-spectrum of antimicrobial properties against both Gram-positive and Gram-negative bacteria [7,8,9,10,11,12]. The growing interest toward antimicrobial potential of nanoparticles within the scientific community can be easily evaluated by searching the appropriate keywords through some of the recognized literature databases. According to one of them, SCOPUS, in the last 30 years more than 14,000 peer-reviewed documents have been published containing keywords such as “antimicrobial” and “nanoparticles” (Fig. 1). Interestingly, in the more specified search which refers only to the utilization of nanoparticles in urinary infections, it could be observed a similar profile i.e. growing tendency, except with a significantly lower number of published documents, (less than 2%). Even more interesting is the fact that when this search is expanded on the keywords such as antimicrobial + nanoparticles + urinary (ureteral) + stents, only two documents are listed. Although this type of searching has some limitations, it is obvious that, so far, the potential of the nanoparticles is not sufficiently investigated in this field.

Fig. 1
figure 1

Graphical presentation of documents that contain the mentioned keywords, published from 1987 up to now. Results are obtained from the SCOPUS database and the search is conducted on March 15th, 2021

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Until now, the antimicrobial mechanism of action of the nanoparticles is not fully explained but it is considered to be based either on induction of the oxidative stress [13], metal ion release [14], or non-oxidative mechanisms [15]. These mechanisms can occur also simultaneously (Fig. 2). In literature it has been anticipated that some nanoparticles neutralize the electric charge of the bacterial cell surface and consequently modify its penetrability, leading to bacterial death [16]. Also, nanoparticles may increase the production of reactive oxygen species resulting in constraints on the antioxidative defense system and thereafter mechanical damage to the bacterial cell membrane. So, nanoparticles can disrupt and penetrate the bacterial cell membrane, induce the creation of reactive oxygen species, stimulate intracellular antibacterial activity, and interact with DNA and proteins [16] (Fig. 2).

Fig. 2
figure 2

Nanoparticles exhibit antimicrobial activity through multiple mechanisms: cell wall disruption and alteration in membrane permeability, generation of ROS, nucleus/DNA damage, protein denaturation, inhibition of electron transport chain; and consequently the humpering of bacterial metabolic processes

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All these led to their pronounced antibacterial properties. The effect of nanoparticles on biofilm formation depends on several parameters such as the type of the nanoparticles (metallic, nonmetallic, polymeric, etc.), their morphology (size and shape), electric charge, hydrophobicity, composition, polar interaction, etc. [17]. For example, Slomberg and coauthors examined the efficacy of silica nanoparticles containing nitric oxide against Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus biofilms as a function of particle size and shape [18]. Smaller particles exhibited better nitric oxide delivery and enhanced bacteria killing compared to the larger ones. Also, the rod-like particles proved to be more effective than spherical particles in delivering nitric oxide and inducing greater antibacterial action throughout the biofilm. This chapter gives an extensive overview of the different types of nanoparticles and nanostructured materials for the prevention, control, or elimination of biofilm-related infections on urinary stents. It addresses polymeric nanoparticles, naturally derived antimicrobials, non-metallic and metal-based nanoparticles, production methods, characterizations as well as their applications.

2 Polymeric Nanoparticles

The most commonly used methods for achieving an antimicrobial effect of polymeric micro and nanoparticles are by controlled release of encapsulated/immobilized antimicrobial within the polymeric matrix [19,20,21,22,23] or by prevention of initial bacterial attachment by coating/covering of the surfaces by polymers [24,25,26,27]. It is considered a better option to inhibit the initial formation of biofilm, rather than trying to eliminate already colonized microorganisms. Surface coating and functionalization aim to have a bacteriostatic effect, while drug impregnation and blending can achieve a bactericidal effect [6]. Surface modification of catheters by polymers can be bioactive or biopassive. Biopassive coating is accomplished through the use of hydrophilic polymer materials, which prevent bacterial adhesion. The bioactive coating can refer to the coating of catheter surface with antimicrobial molecules or controlled release of antimicrobial from the particles on the surface [28, 29]. Water-soluble antimicrobials can be rapidly removed from catheters [5]. Drug-eluting stents showed uncontrolled drug release, potentiating the possibility of development of resistance, so recently researches focused on controlled release antibiotic, and antibiotic combination stent coatings.

Srisang et al. reported the synthesis of chlorhexidine loaded nanoparticles, in form of poly(-ethylene glycol)-block-poly(e-caprolactone) micelles, and poly(e-caprolactone) nanospheres, and coating of Foley catheter surface in multiple layers. In both cases, bacteria started to colonize the coated catheter only after 21 days, which indicates the prolonged release of chlorhexidine [30].

Non-adhesive hydrophilic implants are developed to prevent host irritation and bacterial adhesion [31]. Palmieri et al. designed a nanocomposite coating made of hydrophilic polymer polyethylene glycol and hydrophobic polyphenol curcumin deposited on the surface of graphene oxide nanoparticles. This coating decreased adherence and biofilm formation of Candida albicans on polyurethane catheters [32].

More research dealing with polymers such as poly(glycolic acid), poly(lactic-co-glycolic acid), polyamine, etc. are reported below since they are also involving non-metallic or metallic nanoparticles.

2.1 Naturally Derived Antimicrobials

Naturally derived antimicrobials such as essential oils, curcumin, enzymes, hyaluronic acid, and antimicrobial peptides in combination with synthetic antibiotics/nanoantibiotics [33, 34] are likely to exert sufficient inhibitory effect on uropathogens. These compounds are the basis of many modern pharmaceuticals, mainly antibiotics [35]. Due to low bioavailability, stability, and biocompatibility, they are often loaded into nanoparticles to improve their characteristics [36]. These nanosystems, comprised of phytochemicals or microbial metabolites, and especially in combination with nanoantibiotics [33], have the potential to be used as antimicrobial coating of urinary catheters [6].

Venkat Kumar et al. synthesized kanamycin–chitosan nanoparticles by ionic gelation, which were then covalently immobilized on polyurethane ureteral stents. These stents exhibited increased, synergistic antibacterial activity, which is suggested to be a result of the disruption of negatively charged bacterial membranes, due to the polycationic nature of these nanoparticles and therefore increased positive surface charge of stents [37].

Phenazine-1-carboxamide is an aromatic compound isolated from P. aeruginosa. It was used for functionalization of silica nanoparticles, which were then applied for coating of urethral stents, by Kanugala et al. They report promising antibacterial and antifungal activity on S. aureus and C. albicans, and also activity against mixed-species biofilms [38].

Kumar et al. reported functionalization of silver nanoparticles with Kocuran, an exopolysaccharide from Kocuria rosea [39]. These Kocuran-capped silver glyconanoparticles were used as a coating for silicone urethral catheters and showed significant antibacterial and antiadhesive properties against E. coli and S. aureus.

There have been attempts to inhibit biofilm growth by interfering with bacterial communication, quorum sensing. “Quorum quenching” molecules are compounds that interfere with quorum sensing by various mechanisms and can be utilized to create antibiofilm coatings. Nanocoatings made of α-amylase and acylase, capable of degrading bacterial exopolysaccharides and quorum sensing molecules, respectively, were deposited layer by layer on silicone urinary catheter surface. This coating exhibited inhibition of P. aeruginosa and S. aureus biofilms, consisting either of α-amylase or acylase, but especially in form of hybrid nanocoatings of both enzymes, which inhibited even mixed-species P. aeruginosa and E. coli biofilms [40]. NanoQuench was a European project for developing quorum quenching enzymes and nanoantibiotics for novel coatings, aiming to prevent biofilm formation on urinary catheters, with a focus on Gram-negative P. aeruginosa biofilms. One of the project’s results is antibiofilm multilayer nanovancomycin and acylase coating, which was shown to be efficient in-vitro [41].

Nanobiosystem composed of magnetite nanoparticles coated with Rosmarinus officinalis essential oil was efficient in reducing adherence to catheter surface, and biofilm formation by C. albicans and C. tropicalis [42].

Phytochemicals-capped gold nanoparticles were synthesized using Aegle marmelos leaf extract, for the further purpose of prevention of urinary catheter infections. Obtained nanotriangles exhibited major antimicrobial activity against S. aureus, P. aeruginosa, K. pneumoniae and E. faecalis [43].

3 Non-metallic Nanoparticles

A wide class of oxides, nitrides, silicide and carbide, hydroxyapatite, diamond-like carbon, and others are used as antimicrobials [16, 44, 45]. Surface coatings with these nanomaterials have gained significant attention due to their antimicrobial activity. Graphene-based nanomaterials have different surface chemistry (graphite, graphene oxide GO, and reduced graphene oxide RGO) and different microbial activity mechanisms. GO has a more potent antimicrobial effect against Escherichia coli when compared to graphite and RGO [46]. Amorphous carbon was also used as a matrix material for the incorporation of metallic clusters [47].

Laube and co-workers used diamond-like carbon (DLC) material for coating ureteral stents. They published an in vitro and in vivo study in which they observed that there was a reduction in encrustation, biofilm formation, and patients’ symptoms [48].

Nanostructured coatings of diamond-like carbon, molybdenum disulfide and tungsten disulfide nanoparticles were deposited on a polydimethylsiloxane substrate. These coatings were compared in terms of resistance to the formation of urinary deposits. It was found that tungsten disulfide was the most resistant to encrustations after 4 weeks of immersion in artificial urine [49].

To obtain functionalized catheter surface with improved resistance to microbial colonization and biofilm formation Fe2O3/C12 nanoparticles were coated on 2-((4-ethylphenoxy) methyl)-N-(substituted-phenylcarbamothioyl)-benzamide used as adsorption shell. This material showed improved resistance to Staphylococcus aureus and Pseudomonas aeruginosa, and did not show cytotoxicity [50].

Boron nitride (BN) has physicochemical properties similar to graphene-based nanomaterial, but it holds an advantage in terms of biocompatibility with human cells. Boron nitride composite with polyethylene was studied for biomedical applications. It was demonstrated that bacterial activity of BN/PE composite correlates with BN concentration [51].

Nitric oxide (NO) has been a well-known antimicrobial agent. Commonly used NO donor in the medical research S-Nitroso-N-acetyl-dl-penicillamine (SNAP) was impregnated in commercial urinary catheters [52].

It was shown that catheters have very high antimicrobial efficacy and effectively reduce biofilm formation over a longer period. However, the issue of NO storage remains, as the polymers are limited reservoirs for NO.

3.1 Metal-Based Nanoparticles

Metal-based nanoparticles are very popular antimicrobials [53]. They do not bind to a specific receptor in the bacterial cell which makes them have non-specific bacterial toxicity mechanisms and consequently makes the development of resistance by bacteria to be difficult. As a result, a large majority of metal-based nanoparticle efficacy studies performed so far have shown promising results in both Gram-positive and Gram-negative bacteria [54, 55]. Several review papers can be found regarding this subject, among few of them have been published most recently [17, 56,57,58].

In the field of urinary catheters, silver-based coatings are in use for over 20 years but their true efficacy is still a matter of debate [59, 60]. The narrow boundary between beneficial and toxic effects, especially in the prolonged applications remains a major concern in Ag utilization. One of the promising approaches to overcome the toxicity issue of Ag, is to functionalize it with more biocompatible compounds. As already mentioned above, Kumar et al., proposed the usage of exopolysaccharide Kocuran, as a capping and reducing agent of silver nanoparticles [39]. Related to the subject of Ag NPs functionalization, Ashmore and colleagues manage to coat Ag NPs with polyvinylpyrrolidone (PVP) and compared the antibacterial efficacy with the non-coated AgNPs [61]. As a result, a significant improvement in antibacterial efficacy was achieved. It is worth noting that two types of Ag-PVP NPs were prepared, either containing 10% of Ag or 99% and both of them have shown better antimicrobial properties against E. coli than non-coated AgNPs. In addition, the authors reported that Ag-PVP NPs also promote downregulation of the expression of genes that are involved in the cellular growth of E. coli.

Based on in vitro investigations of Giri and colleagues [62] reducing the surface charge of AuNPs broadens the therapeutic window, so a higher concentration of these particles can be used without toxicity concerns.

I. Carvalho et al. reported in their study, that deposition of Ag and Ag–Au bimetallic clusters on thermoplastic polyurethane tape (as one of the materials used in the ureteral stent manufacture) have positive outcomes [47]. The coating was performed by physical methods (sputtering and plasma gas condensation) and the authors characterized it as a promising for long periods, since the release of silver in artificial urine did not reach the maximum amount of coating even after 30 days. Nevertheless, these released Ag were sufficient for the prevention of biofilm formation and achievement of antibacterial effect against E. coli while preserving good biocompatibility. Comparing the antibacterial effects, amount of released Ag, and morphology of deposited Ag and Ag–Au clusters, the authors concluded that the size of the deposited cluster determines the mechanism and release kinetic of Ag. In the case of smaller homogeneously distributed clusters, the release of Ag ions is favored, while in the case of larger deposits the release of Ag NPs is the dominant process. In both scenarios, the bactericidal effect against E. coli was very similar. The other coatings investigated in this study achieved a slow Ag release and no antibacterial effect, suggesting that the release kinetics of Ag is directly responsible for the antibacterial properties of coatings.

Rocca et al. performed an interesting strategy in the coating of silicone catheters. The authors described a simple method for producing Au nanoplates by reduction of Au salt with gentamycin at elevated temperature [63]. The coating was performed in situ, during the synthesis procedure, and lasted only 15 min. Regardless of the duration of coating, deposited Au nanoplates were efficient in preventing the growth of three bacterial strains (S. aureus, P. aeruginosa and E. coli) after 18 h of incubation. The observed anti-biofouling effect of Au nanoplates was explained through the topographic change at the nano-scale level, which disrupts attachments of the bacterial cells. Additionally, the authors also confirmed the effectiveness of coating by testing it in stimulated flow conditions, using the physiological solution and syringe pump [63].

In the work performed by Ron et al., encrustation of silicone catheters was remarkably prevented in in vitro conditions, by coating with rhenium-doped molybdenum disulfide (Re:IF-MoS2) nanoparticles [64]. As the authors stated, these NPs displayed a unique tendency to self-assemble into mosaic-like arrangements, modifying the surface at the nanoscale to be encrustation-repellent. Encrustation investigation was conducted using a custom-built device and artificial urine. The effectiveness of Re:IF-MoS2 nanoparticles coating lies in their specific physicochemical properties such as negative charge, low surface free energy, and nanotexture, providing them a superior solid-lubrication behavior.

The second approach, besides stents coating, is the impregnation of nanoparticles in the drug-eluting stents. Recently, Gao et al. performed a thorough investigation of biodegradable stents with a renewable surface capable of contact killing of bacteria [65]. The renewable property was accomplished through surface degradation of poly(glycolic acid)/poly(lactic-co-glycolic acid) (PGA/PGLA) layer, while antibacterial properties were achieved by impregnation of hyperbranched poly(amide-amine)-capped Ag shell and Au core nanoparticles in PGA–PGLA. In vitro and in vivo testing have confirmed that this particular stent design provides good mechanical properties, high antibacterial activity, the low release of Ag ions, and good biocompatibility. According to the authors, the capping agent (poly(amide-amine) was most responsible for high bactericidal effects and low cytotoxicity of nanoparticles by providing a high-stabile structure. The stent degradation in artificial urine was gradual, constantly detaching adhered bacteria and proteins, and releasing enough amounts of nanoparticles. As a result, the authors reported good antibiofilm properties after 2 weeks-examination and lower levels of inflammatory and necrotic cells, 3 weeks after implantation.

A similar comprehensive approach in designing antibacterial and repellent coating was reported by Dayyoub et al. [66]. This group of scientists successfully developed a film of poly(lactic-co-glycolide) (PLGA) to release norfloxacin and Ag NPs, coated with tetraether lipid The strength of this multifunctional system lies in the fact that it consists of dual antimicrobial agents (norfloxacin is a broad-spectrum synthetic antibiotic almost exclusively indicated in the treatment of urinary tract infections) impregnated in the biodegradable matrix. The authors used this film to coat polyurethane and silicone sheets, which results in effective inhibition of bacteria adhesion, compared to uncoated sheets. Thanks to the fact that degradation of PLGA creates an acidic environment, it neutralizes alkali products of urea hydrolysis and thus reduces the encrustation, based on in vitro experiments in artificial urine that lasted two weeks.

Agarwala et al. investigated antibacterial/antibiofilm activity of iron oxide and copper oxide nanoparticles against multidrug-resistant biofilm forming uropathogens. They found that CuO nanoparticles are more effective as an antibacterial material than Fe2O3 nanoparticles [67].

Besides mentioned studies, a significant number of additional papers could be found regarding the antimicrobial activity of metal-based NPs and some of them are summarized in Table 1.

Table 1 Metal-based NPs used for prevention and treatment of UTI
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4 Conclusion

The effectiveness of nanoparticles against numerous bacterial strains including those that cause biofilm formations in urinary stents is well documented in many papers. However, the important issues that should be addressed in the nanoparticles utilization are the release from the inner surface of the stents and the stability of the coating. The harsh environment, to which the urinary stents are exposed, represents the obstacle that must be considered with great percussion when choosing the coating/impregnation technique and concentrations of nanoparticles. Literature data are constantly expanding with new findings regarding antibacterial activity, encrustation repellence, and biocompatibility, but lacking those regarding release profiles and how these profiles are influenced by the chemistry and flow conditions. Nevertheless, the reported studies have confirmed the nanoparticle-based strategy exhibit great potential and that it’s a matter of time when it will find its way to commercially available product.