- To develop and test the safety and feasibility of a novel anti-biofilm mechanism configured for wireless capsule endoscopy (WCE) in a sheep bladder model.
wireless capsule endoscopy
For patients diagnosed with TCC of the bladder, cystoscopy is currently considered to be the ‘gold standard’ for bladder cancer surveillance. Because tumour recurrence may occur many years after the initial diagnosis, long-term bladder monitoring in these patients is advocated; however, cystoscopy is an invasive procedure and follow-up according to established international guidelines is often arduous for patients . Moreover, from an economic standpoint, it is considered the single most expensive cancer to treat in the USA . The current limitations of standard white light cystoscopy make it an attractive option for improvement.
Wireless capsule endoscopy (WCE) is a novel technology developed for use in the gastrointestinal tract to enable real-time image transmission from the bowel lumen to an outside receiving console . The capsule comprises a camera, energy source, transmitting device and a light source. The external working console includes a receiving antenna, navigation system, and software for image processing and data recording. Although it would seem appealing to use similar technology in the urinary tract , in fact, long-term dwelling in urine would probably result in surface encrustation by biofilm leading to obscured image transmission and increased risk of urinary tract symptoms or infection. For this reason, we developed a unique anti-biofilm technology designed for WCE dwelling in urine. The purpose of this study was to assess the safety and feasibility of our novel anti-biofilm mechanism in a sheep bladder model.
We developed a novel WCE device for long-term bladder monitoring. The device comprises a miniature capsule (Fig. 1) integrated within an inflated balloon (Fig. 2). The capsule includes an image sensor that transmits high-quality digital images from within a cavity, a Radio Frequency (RF) transmitting unit, an energy source and a sealed housing. At present, the WCE is designed to dwell in bladders for a maximum period of 2 years. An image can be transmitted from the bladder on demand, controlled by a technician or physician at a side console. The size of the capsule is adapted to fit the lumen of a standard resectoscope sheath (26 F): in its deflated state its diameter is 7 mm and its length is 25 mm. On inflation, the balloon diameter increases to 32 mm (Fig. 3).
A unique technology was developed to prevent biofilm formation on the surface of the WCE. The device is housed within a silicone balloon which is filled with mineral oil (rather than isotonic or hypertonic clear fluids). The surface of the balloon has semi-permeable properties, and when residing in hypertonic urine it allows continuous diffusion of oil at a mean rate of 3 × 10−4 mL/h. Thus, the total volume lost after 2 years should not exceed 6 mL, which encompasses ∼ 20% of the initial oil volume, allowing the device to float. While the continuous friction between the balloon external surface and bladder wall removes a portion of the subtle oily film layer, the diffusion rate is sufficient for its regeneration. This step is of paramount importance to prevent biofilm from attaching to the balloon external wall and to guarantee clear image transmission. Moreover, the continuous permeation of oil minimizes accumulation of surface proteins potentially preventing adherence of bacteria. The balloon surface is a hydrophobic unidirectional membrane preventing urine from diffusing in.
A female sheep was selected for this trial to provide a model resembling the human bladder. Approval from the institutional animal care and ethics committee was obtained. To assess the efficacy and durability of our newly developed anti-biofilm technology, the camera was replaced with a resolution target placed inside the capsule allowing evaluation of the quality and transparency of the capsule surface via standard cystoscopy (Fig. 4). Insertion of the device was carried out under general anaesthesia using a standard protocol for anaesthesia and pain control. The sheep was placed in a supine position and cystoscopy (Wolf GmbH, Mainburg, Germany) was performed. Using a 26-F standard resectoscope and the designated deployment tool, the implant was introduced into the bladder in a deflated state. While still attached to its deployment apparatus, the capsule was inflated with mineral oil (30 mL) using a standard syringe. Pulling the deployment device backwards releases the capsule inside the bladder cavity, allowing it to float freely (Fig. 5).
Cystoscopy under general anaesthesia was performed at 3, 12 and 20 weeks after insertion of the capsule. A resolution target placed inside the balloon, consisting of a metal sheath engraved with fine linear notches, was used to test the transparency of the capsule surface. Clear segregation between the notches was considered a surrogate for adequate quality image. Postoperatively and after each cystoscopy the sheep was monitored closely for bloody urethral discharge, haematuria or any other apparent voiding difficulties. Specifically, staff, supervised by a veterinarian, confirmed that spontaneous voiding was uninterrupted and not associated with behavioural abnormalities. The voiding pattern was recorded on a daily basis during the first 2 weeks and biweekly thereafter. Urine cultures, complete blood count and basic metabolic profile were assessed routinely once a month. Signs of discomfort or pain were recorded. At study termination the sheep was killed and the capsule was extracted. A scanning electron microscope was used to evaluate the degree of biofilm formation compared with a standard latex catheter immersed in urine for 3 days.
The WCE was retained in the bladder a total of 5 months. No notable adverse effects or behavioural changes were noted during the entire follow-up period. Blood evaluation was unremarkable and all urine cultures were negative.
Figures 6-8 show the images obtained during study cystoscopies. At week 3, the resolution target was well defined and notches clearly visible. A small area of biofilm formation was noted at one side of the capsule (Fig. 6). A similar image was obtained after 12 weeks, i.e the notches were clearly visible (Fig. 7A). The biofilm viewed on previous cystoscopy disappeared and clear demarcation between the balloon and anchoring point was apparent (not covered with oil), suggesting that the anti-biofilm mechanism prevents encrustation effectively (Fig. 7B). The capsule maintained a clear surface after 20 weeks, as confirmed by cystoscopy (Fig. 8A), and upon retrieval (Fig. 8B). Notably, the volume of oil in the balloon did not change substantially and the device could still float when placed in sterile saline. A clear surface with no biofilm formation was also confirmed using a scanning electronic microscope (Fig. 9A), as opposed to rapid encrustation on a standard Foley catheter immersed in urine for 3 days (Fig. 9B).
Wireless capsule endoscopy was first developed in the early 1990s for bowel inspection. Iddan et al.  reported the first WCE that allowed visualization of the entire human small bowel. Manipulating a tiny camera within a human's hollow organ to obtain serial imaging of the mucosal surface appeared to be superior to any available solution for small bowel imaging . Although other methods of monitoring the bladder do exist, adopting the concept of WCE in patients who require lifelong bladder cancer surveillance seems appealing; however, as opposed to a single image transmitted immediately after capsule deployment , lengthy dwelling of foreign bodies in urine will ultimately result in surface encrustation, limiting the ability to obtain serial images. In the present study, we demonstrated the efficacy of a novel anti-biofilm mechanism allowing our capsule to reside in a sheep bladder for 5 months without biofilm encrustation, UTI or associated adverse side effects.
To date, white light cystosocpy has been the most commonly used method for the diagnosis and monitoring of bladder cancer. Yet, its true false-negative and false-positive rates remain unknown. Pavone-Macaluso et al. , for example, compared flexible cystoscopy to rigid cystoscopy and observed a false-negative rate of 8% for flexible cystosocpy. This false-negative rate can, apparently, be overcome with increasing experience, but the consequence of a learning curve on missing tumours with metastatic potential has not been addressed. False-positive findings on cystosocpy are likewise a matter of concern. Svatek et al.  showed that biopsying a suspicious lesion observed during office cystoscopy in patients with a history of TCC resulted in a false-positive rate of 67% and a false-positive rate of 90% in patients without a history of TCC. The authors concluded that a large number of patients with suspicious cystoscopic findings might undergo unnecessary biopsies. Ongoing research is invested in enhancing the performance characteristics of available endoscopes (blue light cystoscopy and narrow-band imaging cystoscopy) [8, 9] while decreasing the discomfort associated with cystoscopy (virtual cystoscopy and thinner tubes). Thus, a WCE device with an automated sequence for imaging the entire bladder and digital image processing to improve the accuracy of detecting mucosal abnormalities would theoretically decrease the false-negative rate of white light cystoscopy and at the same time prevent unnecessary invasive intervention with its attendant morbidity . Whether this would translate into improved oncological outcomes remains to be studied.
Schrag et al. , reviewing a database of 6717 patients with bladder cancer, showed that only 40% of patients actually adhere to follow-up guidelines and concluded that the actual practice of surveillance for patients with superficial bladder cancer differs substantially from recommended standards. Theoretically, if bladder imaging can be acquired by technicians or via home-based retrieval devices, WCE can potentially shift the labour associated with bladder cancer monitoring from the practising urologist to ancillary health team providers; this approach can theoretically lead to a reduction in costs for healthcare systems.
Several limitations of the present study must be emphasized. First, we assessed the efficacy of a unique anti-biofilm mechanism to overcome surface encrustation. Bladder images were obtained via cystoscopy rather than transmitted to an outside console using wireless technology. Miniature cameras are commercially available for routine use in the gastrointestinal tract and will be integrated in the next phase of capsule development. Second, an efficient navigation system to manipulate the capsule in bladders has yet to be fully developed. Magnet-aided navigation recently described by Kommu  could potentially be used to steer the capsule along the bladder surface. Third, while animal trials are a mandatory prerequisite to ensure safety, the lack of observed impact on voiding symptoms or animal discomfort cannot be translated to human subjects. Although some assumptions can be made based on our experience with indwelling catheters or stents, further research in humans using validated questionnaires is required to determine the true influence of WCE on quality of life. Last, the present study was terminated after 5 months. Bladder monitoring is generally required for substantially longer periods and should be addressed in future WCE trials.
In conclusion, we have demonstrated the effectiveness of a novel technology to prevent biofilm accumulation on the outer surface of a designated capsule sustained in a urine environment. Our findings will ultimately be implemented in WCE of the bladder in patients requiring cystoscopic surveillance.
Amos Neheman is the Medical Director and Co-Founder of Real-View-Medical. Ofer Yossepowitch and Claude Schulman are on the advisory board of Real-View-Medical.