Video capsule endoscopy has moved a long way since

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1 Imaging and Advanced Technology Ralf Kiesslich and Pankaj Jay Pasricha, Section Editors Video Capsule Colonoscopy: Where Will We Be in 2015? RAMI ELIAKIM Department of Gastroenterology, Rambam Health Care Campus, Bruce Rappaport School of Medicine, Technion Israel Institute of Technology, Haifa, Israel Video capsule endoscopy has moved a long way since the small bowel capsule was introduced by Iddan et al in Nature in 2000, 1 and later by Lewis and Swain at the American Digestive Diseases Week. Capsules for the esophagus and colon were introduced thereafter and second generation capsules were developed since then by Given Imaging (Yokneam, Israel) the PillCam SB2 for the small bowel, PillCam ESO2 for the esophagus, and recently PillCam COLON2 capsule for the colon. A nonvideo, second-generation Agile patency capsule was also developed to confirm functional patency of the gastrointestinal (GI) tract. Three additional companies have introduced competitive small bowel video capsules, all of which are in use in the European Community; some are cleared by the US Food and Drug Administration as well. These include the Japanese EndoCapsule, the Korean Miro capsule, and the Chinese OMOM capsule. This review focuses on the colon capsule. The colon capsule system consists of an ingestible video capsule that has 2 imagers, one at each end of the capsule, for viewing the colonic mucosa. The capsule moves through the GI tract by the natural effects of peristalsis while transmitting images via an antenna-lead array to a data recorder device carried by the patient. The recorded images are then transferred to a workstation loaded with RAPID software, for formal review and report generation. Recently, Spada et al 2 published a meta-analysis of the first-generation PillCam COLON, from which they concluded that the capsule s sensitivity for detecting patients with polyps and significant colonic findings compares favorably with other imaging colorectal cancer screening strategies such as CT colography or barium enema. The new second generation PillCam COLON2 capsule has new technical features which significantly improved its performance compared with the first-generation capsule 3 (Figure 1): Wider angle of view of 172 degrees on each dome (vs 156 degrees of the first-generation colon capsule) allowing nearly 360-degree viewing of the colon from both ends. New data recorder (DR3) incorporating 3 important new features: Bidirectional communication with the capsule to change capsule s frame rate from 4 to 35 frames/sec depending on its rate of movement in the colon (so-called adaptive frame rate technology), thus preserving battery time on the one hand when the capsule is virtually stationary, and allowing maximal luminal coverage when capsule is in motion on the other hand. The second feature is the possibility to give the patient or physician customized reminders/alerts on the LCD panel of the DR3 at different time points. The data recorder, upon entrance of the capsule to the small bowel, alerts the patient to take laxative boosts and prokinetic drugs and notifies the patient when the procedure is completed. 3 The third feature is real-time visualization capability the images acquired by the capsule can be visualized in real time on the LCD panel of the DR3 when desired. Polyp size estimator integrated with the new RAPID reading software, which allows us to simply estimate polyp size by drawing a line between the 2 ends of polyp and visualize its estimated size, independent of its distance from the capsule dome. These new technological advances have been shown to improve capsule s performance, reaching 88% sensitivity and 89% specificity for the detection of patients with polyps equal or 10 mm compared with conventional colonoscopy serving as the gold standard. 3 Flexible spectral intelligent color enhancement (FICE) feature to improve image quality and pathology visualization and to make the examination interpretations easier is also integrated in the new Rapid 6 software of Given Imaging. There are some preliminary data that its use may improve visualization of standard pathologies over images projected using the regular light source 4 (Figure 2). The technological improvements integrated with PillCam COLON2 are indeed impressive and seem to 2010 by the AGA Institute /$36.00 doi: /j.gastro GASTROENTEROLOGY 2010;139:

2 Table 1. Future Expectations From Wireless Capsule Colonoscopes 1 Minimize or preclude bowel preparation 2 Home procedure 3 Shorter video reading time 4 Whole gut visualization (mouth to anus) 5 Maximal angle of view and better definition 6 External/internal maneuvering of capsule 7 Biopsy (virtual?) 8 Therapeutic options Figure 1. Technical improvements incorporate in the second generation PillCam Colon capsule endoscope. (Left) The new data recorder [DR3] is capable of bidirectional cross-talk between the capsule and the recorder, allowing a changeable, adaptive frame rate. Another feature is the ability for real time viewing of the image. (Right) The polyp size estimator, showing the size of the polyp once the cursor has been put between 2 edges. enhance polyp detection. But this is not enough! In our dreams we see an even better colon capsule with more options and capabilities (Table 1). Minimize or Preclude Bowel Preparation The system will produce easier preparations, which will replace the use of 4-L polyethylene glycol solution with some pill cleansers that are enteric coated, allowing them to open and start their effect in distal small bowel/cecum, as the basic cleansing materials of the colonic content. Produce safer materials than sodium phosphate, that will help to propel the capsule faster to the colon, or even better, smart visualization through colonic content should be developed to minimize or preclude bowel preparation at all. Home Procedure The system should be capable of home use. In the future, the patient should receive the Colon Capsule Endoscopy kit, containing the capsule, sensors, and data recorder that will allow him or her to perform the entire procedure in the privacy of its home, possibly as a weekend procedure, thereby avoiding the need to take time off from work. The new data recorder can alert the patient of each and every move of the capsule and of actual instruction to take certain boosts as needed. If necessary, on-line visualization can be performed via Wi-Fi. Short Video Reading Time Currently, the typical reading time of PillCam COLON2 video is 40 minutes. Future systems should allow significantly shorter reading times, possibly by automated detection and alerts to the person interpreting the video of existing pathologies, be it polyps, arteriovenous malformations, inflammation, and so on (ie, a pathology indicator ). Whole Gut Visualization (Mouth to Anus) Whole gut visualization can provide a comprehensive examination and diagnosis of pathologies of the entire gut in a single procedure, just as the original inventors dreamt. Because the colon capsule has 2 domes and an adaptive frame rate, it can nicely visualize the esophagus. One can use an external maneuvering device to control capsule movement, examine the stomach, and move the capsule faster to the small bowel, which can then be visualized, followed by the colon without extra burden to the patient. Figure 2. The Fujinon FICE technology incorporated in the RAPID software. (A) The conventional view. (B D) Various settings of the system, enabling enhancement of vascularization, surface structure and contrasting between the vascular network and background mucosa. Adapted with permission. 4 Maximal Angle of View and Better Definition We need to maximize the angle of view to 180 degrees from each dome, to not miss pathologies. The 1469

3 propellers that function on demand in various parts of the digestive tract. 7 The third approach would be a combination of the 2 mentioned that is, a magnet for the upper tract and an internal device for the small/large bowel. Such a device from an Italian group has been tested in pigs. One can easily foresee what can be done with such devices in the colon or entire gut, allowing fast advancement of the capsule once swallowed and, then, a very thorough examination of the gut and colon, biopsy, and treatment. Figure 3. The Sayaka endoscope. This is the outlay of this 23 9-mm capsule endoscope that maps the inner gut while rotating through the digestive system, taking 30 pictures per second and has a 360-degree angle of view. conventional small bowel capsules have an angle of view ranging between 140 and 154 degrees. The new PillCam Colon capsule has a 172-degree angle of view from each side, allowing almost 380-degree views of the bowel wall. A Japanese company describes a small, 23 9-mm capsule endoscope on its website, the Sayaka Endoscope, which maps the inner gut while rotating through the digestive system, taking 30 pictures per second with a 360-degree angle of view (Figure 3). 5 To the best of our knowledge, no human studies have been conducted with this capsule, which has been described on the web for 5 years. The future capsule endoscope will probably provide higher resolution (high-definition) photos. External/Internal Maneuvering of Capsule Transforming the existing capsule into a more active device requires adding either external or internal appendages that will allow it to propel through the GI tract. Recently, Swain et al 6 have conducted the first human volunteer study in which they transformed a wireless colon-based capsule (Given Imaging) so that it could contain a stack of neodymium iron boron magnets in one of its domes, allowing it to be manipulated with an external, handheld magnet (joy stick). The capsule was manipulated for 10 minutes in the esophagus and stomach. 6 Olympus and Siemens have introduced a similar concept to the Japanese pill as well. The second approach is to add to the capsule parts such as paddles/ Biopsy (Virtual?) Current guidelines referring patients from diagnostic procedure based on polyp visualization, such as virtual colonoscopy, to therapeutic treatment rely mostly on lesion sizes. Thus, patients with polyps 10 mm are referred to colonoscopy and those with polyps 6 mm may not even be reported, debate remaining for polyps ranging between 6 and 10 mm. This may expose patient to risks associated with small cancers or unnecessary colonoscopy. Thus, biopsy capability (virtual?) can identify the risky lesions regardless their size, optimize referral to therapeutic treatment, and improve patient management. In addition to the FICE feature already included with the capsule reading software, one can speculate on using other single or multimodalities such as oxygen demands and spectral analysis together to improve visualization, pathology detection and patient management. In vivo molecular diagnostics might be implemented as well, either on tissue (eg, polyp) or luminal secretions to diagnose pathologies. One may inject or give fluorescent-labeled antibodies/bids that bind to unique antigens/proteins on tissue and later are detected by the capsule via a specific fluorescence light detector. Similarly, these antibodies can detect specific antigens in luminal secretions and the complex attached/detected by the capsule using reflection or fluorescence. Virtual biopsy has been discussed extensively in a former review by Sharma. 8 At least 2 such devices exist and are being tested in animals. The Korean rotational micro biopsy capsule device, containing a trigger part and a biopsy part (Supplemental Figure 1), and the VECTOR capsule (Versatile Endoscopy Capsule for GI TumOr Recognition and therapy), part of the European Union effort to develop capsules with recognition abilities, anchoring devices, virtual biopsies, and even drug delivery (Supplemental Figure 2). Although in early stages of development, these will certainly advance us huge steps forward in our ability to give precise diagnosis and treat pathologies that are found. 1470

4 Therapeutic Options Apart from the VECTOR project, other companies such as Phillips, has launched a drug delivery pill (intelligent pill [ipill]), which incorporates a microprocessor, batter, ph sensor, temperature sensor, a radiofrequency transceiver, a fluid pump, and a drug reservoir, all in an mm pill that will open and deliver the drug in the designated area in the bowel, allowing targeted therapy to inflamed sites, arteriovenous malformations, and tumors (Supplemental Figure 3). Summary Thus, as I foresee it, in the future we will probably have 2 kinds of capsules. There will be a diagnostic capsule applying the improvements in image quality, angle of view, pathology detection, virtual biopsies, and advances in software and communication. This capsule will practically cover all the GI tract from mouth to anus (just as the original inventors dreamt and named it). Another capsule will be a therapeutic capsule applying the advances of the maneuvering abilities via a joystick, anchoring abilities as well as the drug delivery abilities and possibly options for mechanical therapy. Supplementary Material Note: The first 5 references associated with this article are available below in print. The remaining references accompanying this article are available online only with the electronic version of the article. To access the remaining references, as well as additional online-only data, visit the online version of Gastroenterology at doi: /j.gastro References 1. Iddan G, Meron G, Glukhovsky A. Wireless capsule endoscopy. Nature, 2000;405: Spada C, Hassan C, Marmo R, et al. Meta-analysis shows colon capsule endoscopy is effective in detecting colorectal polyps. Clin Gastroenterol Hepatol 2010;8: Eliakim R, Yassin K, Niv Y, et al. Prospective multicenter performance evaluation of the second-generation colon capsule compare with colonoscopy. Endoscopy 2009;41: Pohl J, Aschmoneit I, Schuhmann S, et al. computed image modification for enhancement of small-bowel surface structures at video capsule endoscopy. Endoscopy 2010;42: RF System lab. Sayaka. Available: Reprint requests Address requests for reprints to: Rami Eliakim, MD, Chief of Medicine, Head Department of Gastroenterology, Rambam Health Care Campus, Bat-Galim, Haifa, 30196, Israel. r_eliakim@ rambam.health.gov.il; fax: Conflicts of interest Dr Eliakim has served as consultant and speaker for Given Imaging. 1471

5 1471.e1 Imaging and Advanced Technology GASTROENTEROLOGY Vol. 139, No. 5 References (Online Only) 6. Swain P, Toor A, Volke F, et al. Remote magnetic manipulation of a wireless capsule endoscope in the esophagus and stomach of humans. Gastrointest Endosc 2010;71: Kim HM, Sunkwook Y, Kim J, et al. Active locomotion of paddlingbased capsule endoscope in an in vitro and in vivo experiment (with video). Gastrointest Endosc 2010;72: Sharma VK. The future is wireless: advances in wireless diagnostic and therapeutic technologies in gastroenterology. Gastroenterology 2009;137: Supplemental Figure 2. The 3 prototypes of the VECTOR project have propelling, diagnostic and therapeutic options. Adapted with permission. 8 Supplemental Figure 1. The prototype of the Korean Rotational Micro Biopsy Capsule device. Adapted with permission. 8 Supplemental Figure 3. The prototype of the Phillips drug delivery intelligent pill (ipill). This mm capsule contains a microprocessor, battery, ph sensor, temperature sensor, REF transceiver, fluid pump, and drug reservoir. Adapted with permission. 8