Incidence of catheter-associated urinary tract infections (CAUTI) continues to be a major clinical concern, with serious implications for patients and considerable impact on healthcare facilities and resources. For long-term catheter users, there is also the increased risk of catheter blockage through the formation of crystalline encrustations due to pH changes in the urine, mediated by the action of urease-producing bacteria such as Proteus mirabilis. For both CAUTI and blockage, current management and treatment methods have limited success, with often repeated use of antibiotics, which in turn lead to increased risk of resistance development, or more frequent catheter changes to avoid emergency call-outs if blocked. There is an urgent need for alternative strategies and approaches. 

The Nanovibronix® Uroshield® device uses low frequency ultrasound surface acoustic waves (SAW) that travel across the catheter surface. It consists of a small control unit and an actuator which is attached to the catheter close to the leg bag and needs to be changed every 30 days. The intention is that the device prevents the attachment of bacteria and subsequent formation of biofilms on the catheter surfaces, with biofilms strongly implicated in both CAUTI and blockages. 

In the current work, a series of studies are investigating the action of the Uroshield®, firstly in controlled laboratory tests using simple flow and bladder model systems, and also in a small patient trial with collection of microbiological and qualitative data. These data will help us understand the mode of action of SAW and potential for this as a therapeutic treatment to prevent and control CAUTI and blockages.

Laboratory testing:
Initial testing has used a simple flow and an artificial bladder system to track biofilm development in uncoated silicone catheters over time, with and without the Uroshield® device. The simple system consisted of the catheter with tip and balloon removed, being connected to a media supply via a peristaltic pump, with waste collected in a leg bag. The glass bladder model has been described previously (1) with the catheter left intact. For both systems, a physiologically correct artificial urine medium (AUM) (2) was used. Three uropathogenic bacterial species were tested; Escherichia coli, Proteus mirabilis and Pseudomonas aeruginosa. Control catheters (no attached Uroshield®) were used for comparison. At defined time points, catheters were removed and biofilms examined using episcopic differential interference contrast (EDIC) microscopy and culture analysis (3). 
Patient testing:
To further understand the impact of the Uroshield® on microbial communities within catheters and the experience of users, a small patient study was completed. A total of 26 participants were recruited and gave informed consent, with all providing user feedback and a subset providing samples for microbiological analysis. Participants retained their usual catheter and all had scheduled catheter changes due to repeated blockages. For those completing the microbiological study, a urine and catheter sample was sent at three points: prior to use of Uroshield®; at scheduled catheter change after one use of Uroshield®; at next scheduled catheter change after two uses of Uroshield®. Urine samples were analysed by culturing onto UTI chromogenic agar. Catheter samples were analysed by taking three sections: tip, mid and near leg bag connection point. Biofilms were removed and analysed by culture in the same way. Additionally, for all samples, 16S sequencing was completed to provide identification of key microbial species.  
All participants were contacted by a research nurse and interviewed about their experience using the Uroshield® device. They also completed the ICIQ quality of life questionnaire before (baseline) and after (follow-up) using the Uroshield®.

Laboratory testing
The combination of biofilm removal and subsequent culture analysis, and examination using EDIC microscopy allowed qualitative and quantitative assessment of biofilm development on the catheter lumens with and without application of the Uroshield® over time. EDIC microscopy permits rapid, non-contact examination of the surface and does not cause any disruption to the biofilm structure. For the three bacterial species tested (E. coli, P. mirabilis and Ps. aeruginosa), differences were found following use of the device. The differences varied between species and depending on the area of the catheter (e.g. tip, mid or close to leg bag connection). Decreases of up to 99.8% following inoculation with P. mirabilis and after 48 hours were found at the catheter tip, but for Ps. aeruginosa there was no change at the tip but a reduction of 89% across the main length of the catheter. For E. coli, which does not readily form monospecies biofilms, a decrease of 97% was observed across the catheter. 
Patient testing
Microbiological analysis of patient samples showed all participants to have colonised urine and catheters prior to the start of the study. The microbial community structure differed between participants, with each individual having communities made up of a range of species. Catheters also contained unique communities between participants and differed dependent on section of catheter and were not always linked to the community structure found in the urine. Following use of the Uroshield®, these communities changed with regards to structure and diversity. 
Qualitative analysis of participant interviews indicated a number of key observations which could be divided into four themes: effectiveness; lifestyle adaptation; personal challenges; future development. Under effectiveness, 17/20 participants reported some benefit from the device, with several individuals commenting on a change in sediment and approximately one-third noticing a reduction in the frequency of catheter blockages and the need for unscheduled catheter challenges (Figure 1a-b).

Both the laboratory testing using controlled models and the small-scale patient testing produced results which suggest a positive effect of the Uroshield® device on CAUTI and catheter blockage. The laboratory study did demonstrate decreases in biofilm formation, but this did vary between species and across the catheter structure. Biofilms are generally polymicrobial and such controlled studies do not account for the added impact of the immune response (known to be affected by ultrasound). The data from the patient study produced interesting microbiological observations with the suggestion that the device could be impacting the urinary, and catheter, microbiome by increasing microbial diversity. The qualitative assessment indicated the favourable opinions of the majority of the participants and certainty that the Uroshield® was having a positive effect.

The Uroshield® device requires further testing and investigation to fully understand its mechanism of action. However, the positive reported outcomes and the data from these preliminary studies indicate an effect on the community structure of the microbial populations found in the urine and forming the biofilm. This indicates potential for developing a healthy urinary microbiome by use of low frequency ultrasound, thus avoiding long-term use of antibiotics and the risks associated with such strategies.

Maierl, M., Jörger, M., Rosker, P., Reisner, A. (2015). In vitro Dynamic Model of a Catheterized Bladder and Biofilm Assay. Bio-protocol 5(2):e1381. DOI: 10.21769/BioProtoc.1381.
Brooks, T., Keevil, C.W. (1997). A simple artificial urine for the growth of urinary pathogens. Letts Appl. Microbiol. 24:203-206.
Wilks, S.A., Fader, M.J., Keevil, C.W. (2015). Novel insights into the Proteus mirabilis crystalline biofilm using real-time imaging. PLoS ONE 10(10):e0141711.

Continence 7S1 (2023) 100733
DOI: 10.1016/j.cont.2023.100733