With the advancements in CE technology, CE has rapidly expanded the indication for investigations of the GI tract. Given Imaging has installed more than 4,250 centers in about 60 countries and has sold >650,000 capsules. CE is a particularly useful tool for patients with suspected small-bowel disease, including OGIB, iron deficiency anemia, Crohn’s disease (CD), tumors, polyposis syndromes, and celiac disease. A recent clinical guideline has recommended CE as a first-line investigation tool in patients with OGIB. The first available video capsule, brand name M2A (mouth to anus; Given Imaging), was approved by the Food and Drug Administration (FDA) in 2001 as an adjunctive tool for small-intestine imaging. At present, there are five small-bowel capsule endoscope models on the market worldwide [3,4]. Capsule endoscope models with U.S. FDA approval consist of PillCam, EndoCapsule, and MiroCam. Although the various capsules are similar in size and shape, they differ in dimensions, frame rates, operating time, field of view, image sensor, and optical enhancements (Table 1). PillCam and MiroCam capture images by using a complementary metal oxide silicon sensor, whereas EndoCapsule and the OMOM capsule use a charge-coupled device [5]. In 2013, the third generation of PillCam SB3 was launched and received FDA clearance. This capsule system has improved image detail and adaptive frame rate technology (two to six frames per second [fps]), leading to increased visualization of the small bowel and improved efficiency [6]. The CapsoCam has four cameras that provide a 360° field of view, 12 to 20 fps, and 15 hours battery life. The CapsoCam camera takes images at a rate of 5 fps for the first 2 hours and thereafter at a rate of 3 fps, resulting in 12 and 20 fps, respectively. Smart Motion Sense Technology also enables the capsule to activate its cameras only during capsule motion [7].

To improve the specificity of small-bowel CE findings, fecal calprotectin (FC) is considered a noninvasive, “gold standard” marker of GI inflammation. An FC level of >100 μg/g is a good predictor of positive small-bowel CE findings, and FC >200 μg/g is associated with higher small-bowel CE yield (65%) and confirmed CD in 50% of patients [8].

Colorectal cancer (CRC) screening programs in high-risk populations were reported to result in a 90% decrease in CRC incidence. However, no more than 25% compliance has been achieved in screening programs [9]. Colon CE could be a good alternative in patients refusing conventional colonoscopy or when conventional colonoscopy is inappropriate or not possible. In a series of 328 consecutive cases, the rate of complete colon visualization before the end of the lifetime of the battery was 92.8% [10]. In two prospective studies with the newer colon capsule endoscope PillCam COLON 2 (Given Imaging), the sensitivity reached 84% and 89% for detecting polyps >6 mm [11,12]. Although colon CE showed similar detection capabilities when compared with conventional colonoscopy in some studies, conventional colonoscopy remains more accurate than colon CE, and allows the simultaneous removal of polyps. The colon capsule has a potential future for CRC screening; however, more data are needed to answer many pending uncertainties such as the best preparation method, best scoring method (CECDAI [CE CD Activity Index] or Niv score), best booster, and suitable indications.

In 2004, the PillCam ESO (Given Imaging), which is also capable of studying the esophagus, was developed and approved by the FDA. It has two lenses at both ends and takes 18 images per second over approximately 30 minutes to maximize visualization. Although CE can be used for detecting esophageal diseases such as esophageal varices, Barrett’s esophagus, and esophageal cancer, conventional upper GI endoscopy is still the gold standard.

Currently, the movement of the capsule is absolutely dependent on gravitational and peristaltic force. Thus, many methods have been proposed for self- or external ordinary positioning or propulsion (Fig. 1) [28-31]. Although there are differences among capsule models, they are classified into three types: magnetic force, motion of leg or paddle, and propeller. The magnetic-enabled PillCam and magnetic upper GI Olympus capsules have been devised for this purpose. The magnetic-enabled PillCam was based on the Niobe magnetic navigation system (Stereotaxis, St Louis, MO, USA). The core of this system consists of focused-field permanent magnets, made of a neodymium-iron-boron compound. These large magnets are mounted on automatically operated arms to be easily arranged and oriented on either side. In an in vivo experiment, the capsules showed an accuracy of 1° and a localization error of 1 mm [32]. In another study, the camera could be rotated in steps of 1.8°. Full 360° visualization was possible in the stomach but only a 45° visual field was possiblein the colon [33]. In 52 human subjects, a feasibility study on a magnetically guided capsule from Olympus demonstrated that visualization of the antrum, body, fundus, and cardia were at 98%, 96%, 73%, and 75%, respectively, and the feasibility of gastric examination was shown [34].

Endoscopic devices with flexible legs for ambulation have also been proposed. Legged locomotion mimicking inchworm motion has several advantages, including better adaptability to different geometries of the GI tract, higher velocity, and simplified adhesion induced by friction between the device and the tissue [35]. A new prototype with eight legs has been devised. The two leg sets (each leg set consists of four legs) open independently in opposite directions; the rear legs are useful for propulsion, whereas the front legs are useful for stopping. In in vitro tests, the eight-leg capsule showed a speed of 6 cm per minute, and capabilities of backward and vertical locomotion [36]. A paddling-based locomotion mechanism enhanced CE by using a paddling stroke. It provided fast locomotion speed and long travel distances. In one study, the mean velocity was 37.5 cm per minute in the extracted porcine colon and 17 cm per minute in the colon of a living pig [37]. Another study reported that CE with feedback controlled paddling had higher locomotion speed, showing an increase of 58% compared with the previous control method based on a given timer value [38]. A capsule endoscope with an integrated propeller has been developed, and recently, a novel capsule endoscope with four propellers has allowed for a reliable 3D locomotion if the capsule has neutral buoyancy. The number of blades per propeller usually varies from one to five, although three-blade propellers are commonly used [39]. However, this type was useful only for situations in which a large amount of liquid was present. Therefore, liquid intake is required for filling the GI cavity.

For better locomotion and steering, some groups have suggested a hybrid of the magnetic system and self-propelled capsule endoscope, as well as of the magnetic system and legged locomotion [40,41]. However, these methods require further development concerning the need for bulky and complex equipment for generating the magnetic field, and concerning accuracy and stabilization levels, which remain relatively low.

A tagging module can mark the precise location of a target lesion for future surgical or wired endoscopic therapy [42]. One prototype microbiopsy module consists of a trigger with a paraffin block, a rotating tissue-cutting razor with torsion spring, and a controller. It is constructed to operate sequentially so that the tissue sampling, sealing, and fixing are performed in one operation [43]. Another form with a microactuator has been designed to perform microbiopsy. A microspike was incorporated into the capsule endoscope to obtain biopsy specimens. Experimental tests demonstrated that the developed microactuator with microspike successfully extracted tissue samples from a pig’s small intestines [44]. One study reported that a magnetically maneuvered capsule with a nitinol clip-releasing mechanism successfully clipped an iatrogenic bleeding lesion in a pig model [45]. Two new capsules, Intellisite (Innovative Devices, Raleigh, NC, USA) and Enterion (Phaeton Research, Nottingham, UK), have been developed for the collection of absorption data in the GI tract and can be used in the future for drug delivery [46]. Nonvideo capsules that can deliver drugs with a pH-activated or temperature-activated release mechanism have also been evaluated. Wood et al. reported that a capsule endoscope prototype with pH, temperature, and pressure sensing, and a pin for anchoring with a holding mechanism, demonstrates the feasibility for targeted drug delivery [47].

The NEMO (nano-based CE with molecular imaging and optical biopsy) project is developing a new capsule that combines optical and maneuvering technologies, biosensing, and nanotechnologies to enhance the diagnostic and therapeutic potential of CE. The VECTOR (versatile endoscopic capsule for GI tumor recognition and therapy) project is in the process of developing a minirobot for the screening and surveillance of GI cancer, and for magnetic and legged motion, drug delivery, and tissue sampling [3,48]. A prototype coagulation capsule that employs an exothermic chemical reaction to generate heat through the interaction of calcium oxide and water has been tested [49]. This may be potentially useful for hemostasis through thermal coagulation. However, improvements in capsule maneuvering capabilities are necessary before these capsules can be further developed.