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By Dr David Maddison In the 1966 movie “Fantastic Voyage”, a human rescue team is ultra-miniaturised in order to travel into the body of an injured scientist in order to repair damage to his damaged brain. We can’t do that (yet!), but we can now swallow capsule which will make a slow trip to the farthest reaches of the alimentary canal, taking pictures all along the way. M ost older readers will be familiar with an endoscopy (from the Greek word “endo” meaning inside and “skopeein” meaning to see) – and especially a colonoscopy procedure which is an internal inspection of the gut and especially the bowel to check for the presence of cancer or pre-cancer. (If you are over 55, you should have a colonoscopy arguably every few years). The gut (otherwise known as the alimentary canal) comprises the roughly tubular structure that starts at the mouth and ends at the anus and is associated with the absorption of nutrients from food. When food is eaten it passes down the oesophagus to the stomach and then the small intestine, followed by the large intestine and rectum. Oesophagus Stomach Small Bowel Tumour Modern endoscopes consist of a flexible steerable tube with a camera and light, along with various optional tools for biopsy, minor surgical procedures and sensors (eg, for pH) on the end. Endoscopes are inserted at either end of the gut but they can only reach as far as the duodenum at one end (gastroscopy) and the large intestine and possibly a portion of the lower part of the small intestine (ileum) at the other (colonoscopy). This means that almost all the small intestine is inaccessible. In humans, the large intestine is roughly 1.5 metres long, the distance from mouth to the duodenum is about 0.5 metres and the small intestine is six metres long. So, of the roughly eight metres of the gut, only two metres is Bleeding Ulcer Crohn’s Disease Angiectasia Coeliac Disease Some images of various organs and diseases obtained with the MiroCam camera-in-a-capsule. 28 Silicon Chip Australia’s electronics magazine siliconchip.com.au accessible by conventional endoscopy. One way to image the small intestine (and the colon) is via a “virtual endoscopy” in which data from CT and MRI scans are processed to produce images. However, the texture and colour of the organ cannot be visualised and there is a limit to the resolution. Nor is there an ability to take biopsy samples or remove polyps. But now there is “capsule endoscopy”. Lights, camera, action . . . This swallowing a miniature “capsule” which contains a light, camera, transmitter and other electronics. About the size of a large vitamin pill, it travels through the alimentary canal via the natural action of peristalsis (the wave-like contraction of muscles that propel food and waste through the gastrointestinal tract). This idea is not new, having first been tried in 1957 to measure pressure in the small intestine of patients with dysentery. However, the electronics required to send video data is far more complex than to send simple data such as pressure and it is only now, with miniaturised electronics, that the feat of sending video data can be achieved. As an aside, we featured a much more recent “capsule” in the May 2018 issue of SILICON CHIP, siliconchip.com.au/ Article/11060), which measures gut gases and transmits the data via radio. What can it diagnose? While capsule endoscopy was originally developed to image the small intestine it is now used to image all areas of the gut. So it is now possible to diagnose conditions and diseases such as intestinal bleeding, unexplained iron anaemia, Crohn’s disease, tumours in various locations, coeliac disease, gastrointestinal polyps and damage to the mucosa of the small intestine. There are some contraindications to the technique preventing its use by patients who have conditions such as narrowing and obstructions in the gut and motility disorders. Initial development The first device of this nature was invented by an Israeli, Gavriel Iddan, in the 1990s. He had been thinking about Tear down by a third party of a PillCam. One YouTuber has also made some videos of the tear down of some capsules he acquired. “Pill camera teardown” https://youtu.be/osAKuPGhK3I and “Another pill-cam teardown” https://youtu.be/ bH6i3bfie_E siliconchip.com.au Australia’s electronics magazine August 2018  29 the problem of imaging the gastrointesthe stomachs of pigs, using microtinal tract since 1981, when he learned waves. In 1997 Paul and Gavriel from his gastroenterologist neighbour collaborated on the issue of wireabout the problem of the inability to imless transmission and in 1999 Paul age the small intestine. Swain had the honour of being the Iddan co-founded Given Imaging in first person to swallow a capsule 1998 to develop his prototype and it was endoscope. released with US FDA approval and EuThere is little information pubropean approval in 2001. lished on the specifics of how PillAt the time there were suitable camCam transmits data but according eras until CCD (charge coupled device) to a test result published by Boscamera chips small enough to fit through ton Scientific in 2008, the PillCam the narrow confines of the small inteschecked for electromagnetic comtine became available. patibility operated at 434MHz with Parts of a typical endoscopic capsule. But CCD chips consumed a lot of power Image source: Robert Koprowski, a radiated power of 1μW (-30dBm). and the batteries that could be fitted into University of Silesia. This frequency is one of a range a capsule-sized device only lasted for 10of different frequencies allocated 15 minutes. It was also not practical for a physician to wait by international agreement for a variety of uses and known around for the capsule to pass through the body, watching as the ISM (industrial, scientific and medical) bands. images being transmitted to a monitor. Nor were available Given Imaging was bought by Irish company Covidien memory capacities enough to store large video images. in late 2013 for US$860 million and Covidien was then The problem was solved when Gavriel decided to have purchased by US company Medtronic in 2015. the patient wear a recording device for data that was to be Gavriel Iddan was saddened by the sale, who thought it transmitted from the device through the body to a receiv- was “unfortunate and unnecessary”. er. This allowed the data to be reviewed by a physician at a later time. The problem of camera power consumption Areas of use was also potentially solved with the invention of CMOS Today there are three main uses for endoscopic capsules: camera chips after he read a 1993 paper by Eric R. Fos- small and large intestine and the oesophagus. For use in sum entitled “Active pixel sensors: are CCDs dinosaurs?” the small and large intestine one camera is typically (but A CMOS camera would use about one percent of the not always) used to conserve battery life as the time of paspower of a CCD. Later, Eric Fossum went on to work with sage can be eight hours or more. A relatively modest video Given Imaging. frame rate is satisfactory, to preserve battery life. In 1994 Gavriel, with another Israeli, Gavriel Meron, For use in the oesophagus two cameras can be used at opstarted to look for sources of funding and started assem- posite ends of the device, and a high frame rate is required bling a team of physicists and engineers. due to the rapid passage of the capsule when swallowed His original patent, awarded in 1997, envisaged using a and battery life is then of little relevance. In other words, CCD chip and a filament lamp which consumed too much as much data has to be obtained in as little time as possible. energy to be practical. It was clear then that suitable offA typical capsule endoscope system consists of the capthe-shelf, miniature, low-power-consumption cameras were sule itself, a system to acquire the wirelessly transmitted not available and they would have to develop their own. data or a memory system to store video data on board with One of the team, Dov Avni (whose speciality was analog certain models and software to allow a proper interpretavideo) was given the job of creating a new miniature cam- tion of the video. era and light source from scratch. A typical capsule consists of a camera with lens, LED/s Once Dov had come up with a CMOS-based design, for illumination, a microprocessor for system control, a Gavriel Meron went to Sarnoff Corporation in the US with battery for power, a transmitter and of course a case that a view to their manufacturing the device. However, their is biocompatible and of a size, shape and smoothness that senior researcher concluded that the thermal noise intro- is least likely to become trapped. duced to the camera operating at body temperature would Today there are a number of capsule endoscope systems be too great and would lead to an unacceptable signal-to- on the market – we will take a look at some of them and noise ratio. their different features. Following this Tower Semiconductor in Israel was approached as they had then developed a means to solve PillCam the noise problem when a CMOS imaging chip operates PillCam is the original at higher temperatures. This made it possible for Gavriel capsule endoscopic capMeron to develop and produce swallowable, disposable sule by Given Imaging and electronic capsules. They were also the first to utilise Shuji it is now available in sevNakamura’s invention of the white LED as a light source eral models: PillCam SB3, in a commercial optical device. PillCam Colon 2 and the PillCam UGI System. The SB3 model is designed to image the small bowel Transmitting the video and uses adaptive frame rate technology that alters the Getting a video signal from within the body was coin- video frame rate from between 2 and 6 fps. according to cidentally being looked at by Paul Swain in the UK, who whether the capsule is moving through the bowel slowly was transmitting video signals from small cameras from or quickly. Camera resolution is 340 x 340. It is 26mm long 30 Silicon Chip Australia’s electronics magazine siliconchip.com.au and weighs 3g. Colon 2, designed for imaging the colon., is 32mm long and weighs 2.9g. It has two cameras, with each camera having a wide 172° angle of view for 344° total. The device has an adap- PillCam Recorder tive frame rate of 3, which is worn by the patient to record PillCam SB3 small between 4 and video data. It can sensor array for 35 fps. Adaptive also display a camera smaller patients frame rate conview in real time. such as children. trol is designed to prevent the transmission of unneeded data’ such as when the device is moving slowly and relies on bidirectional communication between the data recorder and the device. The Colon 2 can function for up to ten hours. PillCam UGI, with two cameras, is intended to image the upper gastrointestinal tract (oesophagus, stomach and duodenum). The UGI operates at 35 fps for the first 10 minutes and 18 fps for the last 80 minutes of a procedure. MiroCam wireless is designed to observe the receiver in its small intestine and has a charging wide viewing angle; the dock. Navi model is designed to be positionable in areas of interest with an external magnet; the Green model has excellent battery life and is claimed to be “eco-friendly” (it is not clear from manufacturer literature what particular attribute makes it eco-friendly). Unlike other capsule endoscopes which use radio to transmit data, the MiroCam uses electric field propagation. This is said to provide a longer battery life than radio and uses two electrodes on the capsule, the body as the transmission medium and electrodes on the skin to receive the transmitted data. A battery life of up to 11 hours is possible. MiroCam videos: This video shows a MiroCam inside a pig, being manipulated by an external magnet “MiroCam Navi Magnetically controlled Wireless Capsule Endoscopy Demonstration Video in porcine mod” https://youtu.be/hoQvjP9MCQA A corporate instructional video can be seen at “IntroMedic’s Mirocam Capsule Endoscopy System” https://youtu.be/32N9tNmvT7w Left: MiroCam magnetic device to manipulate location of some models of capsule. Right: MiroCam electrode belt. Alicam ALICAM is a capsule (made by Infiniti Medical, LLC www.alicamvet.com/) intended specifically for dogs. ALI stands for ambulatory light-based imaging. In this device the video data is stored on the device which is retrieved by the owner after the device has passed through the animal. It is then returned to the supplier where a report is produced and sent to the animal’s veterinarian. Unlike “Rapid” software suite for use with PillCam. MiroCam MiroCam is a capsule developed by Korean company IntroMedic (www.intromedic.com/eng/main/) It has dimensions of 10.8mm by 24.5mm and is available in a variety of models. Camera resolution is 320 x 320. The device comes in three main types: the Regular model siliconchip.com.au Image of duodenum observed with the OMOM capsule. Australia’s electronics magazine August 2018  31 Dispose, reuse and cost? Most capsule endoscopes are disposable and no attempt is made to retrieve them after use. except for the devices that store imagery on board, such as the CapsoCam Plus for people and the AliCam for dogs. Since there are very high research and development costs for these products it would seem more preferable make a small profit from each unit sold than to pay a high price for a reusable device. Even in the case of the aforementioned devices that are retrieved to recover the data, they are not reused after data retrieval. In the United States these capsules typically cost around $US500. Cheapest is the OMOM which is US$250. No pricing data was available for Australia but the Medicare item number for the capsule endoscopic procedure is 11820 with a scheduled fee of $AU2039, presumably including the cost of the device. humans, a dog would probably try to tear off a recording harness of the type worn by people. OMOM Made by the Chinese Jinshan Science & Technology (Group) Co, Ltd (http://english.jinshangroup.com/ capsuleendoscopy.html), the OMOM capsule has a battery life of ten hours and a recording system is worn on a special belt fitted around the waist while the procedure is in progress. Camera resolution is 640 x 480. EndoCapsule EC-10 The EndoCapsule EC-10, made by Olympus, features a single camera with a 160° view, a relatively long battery life of up to 12 hours and a 3D tracking feature to estimate its approximate position by the use of radiolocation techniques. Camera resolution is 512 x 512. The software has features to accelerate the reviewing time by not showing duplicate images. Its dimensions are 11mm x 26mm and it weighs 3.3g. A 360° view of a patient with Crohn’s disease obtained with CapsoCam Plus. Note the very high level of detail. CapsoVision (CapsoCam Plus) CapsoVision (www.capsovision.com/) have developed a product called CapsoCam Plus that is unique in that it stores video data in on-board memory so no external data recording harness is needed It also generates a 360° view from four centrally-mounted cameras and appears to be identical to the AliCam for use in dogs Unlike most other capsule devices this one has to be retrieved so the data can be downloaded. A special retrieval kit is supplied for the patient to retrieve the capsule after it is expelled. Video: “See the 360° Difference in Capsule Endoscopy with CapsoCam Plus” https://youtu.be/mIltjan2z6Q Check-Cap Check Cap Ltd (www.check-cap.com) is an Israeli company that have developed a device now in clinical trials. The device has the same general appearance as other capsule endoscopes but uses ultra-low-dose X-rays rather than light as the imaging medium and allows for a colonoscopic procedure with no preparation apart from swallowing the capsule along with one tablespoonful of X-ray contrast agent. The device is called C-Scan Cap and is specifically designed for colorectal cancer screening. (Some people are uncomfortable with or inadequately perform the preparation process for conventional colonoscopy) Its position in the body is tracked by radiolocation and it uses X-rays to produce both Compton back-scattered photons and X-ray fluorescence photons. The difference between these signals provides the distance from the capsule to the colon wall and thus the information required to build a 3D map of the colon. The capsule has an X-ray source which is collimated and rotated to produce three beams which are emitted and then subsequently detected by proprietary X-ray photon counting electronics. Information from the capsule is collected by three patches worn on the patient’s back, along with a recording device. Video: “C Scan” https://youtu.be/pjBj7IIuPWg RF System Lab. (Sayaka) The Sayaka (http://rfsystemlab.com/en/sayaka/) is a battery-free endoscopic camera by Japanese company RF System Lab. that offers 360° imaging with a rotating central camera. Olympus EC-10 showing 3D tracking feature. The present location and past track of the device is displayed. See videos “ENDOCAPSULE 10 System: 3D Track Function” siliconchip.com.au/link/aakj and “Capsule Endoscopy Animation – Olympus EndoCapsule” siliconchip.com.au/link/aakk 32 Silicon Chip Exterior view of C-Scan Cap . . . and without its outer case. Australia’s electronics magazine siliconchip.com.au The ability to acquire 360° images makes it similar to the CapsoCam Plus device which utilises four stationary cameras to do the same task. Power is beamed to the device via microwaves and there is a microwave video transmitter on board that can capture video at up to 30fps. It has been under development for many years but does not appear to be on the market as yet. Video: “Sayaka: Next-generation capsule endoscope” https://youtu.be/UHYPfcESvR0 Videos and other resources Bravo pH capsule *A paper from 1962 entitled “Telemetering from within the body using a pressure-sensitive radio pill”. This includes circuit diagrams and construction details which may be of interest. http://gut.bmj.com/content/gutjnl/3/2/181.full.pdf The Bravo device was designed by Given imaging (who developed the PillCam – see above) but it is not a pill camera – it is designed to measure and test acid levels (pH) arising from gastric reflux. The capsule is inserted into the oesophagus with a “conveyor” instrument whereby it is attached to the oesophageal wall via a vacuum where it remains attached for up to 96 hours, before falling off and passing through the gut to be expelled in the usual way. Acidity is measured in the area of the lower oesophageal sphincter, the area affected by gastroesophageal reflux disease which causes heartburn. During measurement period of 96 hours the patient wears a recording device. Its dimensions are 6.0mm x 6.3mm x 26mm. Video: “Bravo Training Video” https://youtu.be/th6nR2PrWjE Jinshan Wireless pH capsule Jinshan also sells a wireless pH measurement device but which appears to be similar to the Medtronic device. The device has dimensions of 6.0 x 5.5 x 26.5mm and weights 1.4g. Video: “JINSHAN pH Capsule Feature Video” https:// youtu.be/LDnNGugiOy8 Data transmission rate One source cites a typical data transmission rate from an endoscopic capsule operating at 434MHz as 267kb/s with a typical transmission distance of a number of centimetres. There are usually a number of antennas attached to the patient so the maximum transmission distance to the nearest antenna would be about half the thickness of a patient’s body. Limitations on the wireless data transmission rate can be improved with variable frame rate technology to make sure repeat images are not transmitted. An alternative introduced with the CapsoCam Plus is to record the images on internal memory but it has the disadvantages that real-time viewing is not possible and retrieval of the capsule is necessary. Future developments Current capsule endoscopes are normally propelled passively by the gastrointestinal tract, although some can be manipulated with an external magnet. Designs are being investigated that use some sort of propulsion mechanism such as arms to propel the device along or stop it at an area of interest – to perhaps take a biopsy, for example. One example of a propulsion system successfully tested in a pig gut was developed by an Italian team in 2009 but there seems to have been no further development since then. Another area of interest is capsule devices with chemical sensors on board such as described in the May 2018 SILICON CHIP article. 34 Silicon Chip * The following video shows a capsule endoscope’s view of a tape worm infestation whereby the host (both of the show and of the tape worm!) deliberately ingested tape worm eggs for the exercise. “An investigation of Michael Mosley’s tapeworms - Infested! Living with Parasites - BBC Four” https://youtu.be/JeDD0HdecGk *A video about an early “radio pill” to measure pressure in the digestive tract. “Radio Pill (1961)” https://youtu.be/INJwjt8dkoU Beyond that, there is a possibility of incorporating more advanced sensors and diagnostic systems, such as on-board testing for certain biochemical markers indicative of certain conditions or diseases. Also under development is a capsule endoscope with a drug reservoir to deliver medication to a specific area. Minor surgical procedures such as the removal of polyps are other future possibilities. Specific location drug delivery Another development is that of delivering drugs to specific parts of the alimentary canal. While not necessarily in an endoscopic capsule – for example, see the pill currently being researched to reverse diabetes (opposite) – researchers are working on methods of delivering precise drugs to precise areas, where they will either do the most good or, indeed, not cause damage to other organs. Holding mechanism fully deployed Rotatable outlet port Medication chamber piston Removable cap Dome lens Dispensing needle fully deployed Static outlet ports Conical spring Capsule endoscope can also deliver up to 1ml of a drug. Stephen Woods, Imperial College, London. More room without batteries Batteries occupy a significant volume of the capsule, so their removal would allow more internal space, for additional electronics or sensor equipment. Wireless power transmission with microwaves or electromagnetic induction is currently under study. Devices with internal memory and no external reading equipment required such as the CapsoCam Plus device could be sent to people in remote locations who cannot attend a clinic. They could receive a diagnosis by collecting the used capsule and sending it to a clinic for analysis. Another important area of development is smart software to reduce the reviewing time of the video by the gastroenterologist. This might include systems to automatically identify and classify disease or other abnormal conditions. Australia’s electronics magazine siliconchip.com.au “SURGERY IN A PILL”: A Possible Cure for Type II Diabetes? Diabetes is said to be the biggest challenge confronting the Australian health system, with up to 1.7 million people having the disease. Of these, it is estimated that up to half a million don’t realise they suffer from it. An illustration of how the pill coats the intestine, mimicking the effect of bariatric surgery. (Credit: Brigham and Women’s Hospital, Boston, USA and Randal Mckenzie) D iabetes occurs when the body’s ability to produce or respond to the hormone “insulin” is impaired, resulting in elevated levels of sugar in the blood and other (abnormal) metabolism of carbohydrates. The result can be wild swings in the amount of blood sugar as the brain tries to adjust levels. Often it overshoots, resulting in too low a level (known as a “hypo”, short for hypoglycemia) which often results in the victim collapsing. Too high a level (a hyperglycemia) can introduce a wide range of life-threatening problems. Type 1 diabetes (10% of cases) is normally present from birth (or a very young age). Type 2 diabetes, also known as the lifestyle disease, usually manifests itself later in life and accounts for 85% of cases. It’s one of those diseases which “sneaks up on you” but uncontrolled diabetes has numerous serious health risks: eye damage (through to blindness), limb damage (4,400 amputations due to diabetes every year) along with increased risk of many other problems such as stroke, heart attack and more. Can diabetes be cured or reversed? While there are some exceptions, the answer is, in most cases, no. It can, however, normally be controlled to a large extent. Most type 2 diabetics do this with a mixture of lifestyle change (a change of diet and more exercise being the chief ones) plus, in most cases, medication – either by tablet, or multiple injections of synthetic insulin each day to replace what the pancreas cannot produce. However . . . For some years, researchers have identified a connection between the apparent reversal of type 2 diabetes following bariatric surgery (commonly known as gastric-bypass surgery), where portion of the stomach is “closed off” to limit food intake. The exact mechanism at play is still unclear but it seems to operate independently of the weight loss that comes as a consequence of the procedure. One recent study comprising 20,000 patients found that gastric bypass surgery completely cured 84% of patients with type 2 diabetes. Promise from a Pill! A research team at Brigham and Women’s Hospital, Boston, USA, has developed medication which can potentially mimic the effects of bariatric surgery – without the surgery! siliconchip.com.au by Ross Tester It is thought that gastric bypass surgery is effective in reversing type 2 diabetes as it improves the body’s glucose management, by pushing digestion processes further into the intestine. This can fundamentally alter how the body absorbs nutrients. The team members searched for a starting material that would have just the right properties to adhere to the small intestine and then dissolve within a matter of hours. They selected a substance known as sucralfate, an FDA-approved drug that is used in the treatment of gastrointestinal ulcers. The team further engineered the substance into a novel material that can coat the lining of the intestine without requiring activation by gastric acid. The engineered compound, referred to as LuCI (Luminal Coating of the Intestine), can be made into a dry powdered form that can be encapsulated as a pill. So far, the new substance has only been tested on rats but the results are extremely encouraging. After a meal, blood sugar levels rise and can stay elevated over time. However, one hour after LuCI was administered to the rats, the response to glucose was lowered by 47%. The team found that this response was temporary, and after three hours, the effect essentially disappeared. While further research is needed (including human trials), this new oral stomach-lining compound, administered simply by swallowing a pill or capsule with meals, may effectively mimic this process without the need for major bariatric surgery. Original material from a report in “Nature” magazine, 11 June 2018. Also sourced from Brigham and Women’s Hospital via EurekAlert SC Australia’s electronics magazine August 2018  35