{'fraction_non_alphanumeric': 0.03225726593058375, 'fraction_numerical': 0.021116997573897112, 'mean_word_length': 4.985331160171877, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 2, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 4, 'zh_pornsignals.json': 0}}
Application of robotic technologies in lower gastrointestinal tract endoscopy: A systematic review

BACKGROUND Conventional optical colonoscopy is considered the gold standard investigation for colorectal tract pathology including colorectal malignancy, polyps and inflammatory bowel disease. Inherent limitations exist with current generation endoscopic technologies, including, but not limited to, patient discomfort, endoscopist fatigue, narrow field of view and missed pathology behind colonic folds. Rapid developments in medical robotics have led to the emergence of a variety of next-generation robotically-augmented technologies that could overcome these limitations. AIM To provide a comprehensive summary of recent developments in the application of robotics in lower gastrointestinal tract endoscopy. METHODS A systematic review of the literature was performed from January 1, 2000 to the January 7, 2021 using EMBASE, MEDLINE and Cochrane databases. Studies reporting data on the use of robotic technology in ex vivo or in vivo animal and human experiments were included. In vitro studies (studies using synthetic colon models), studies evaluating non-robotic technology, robotic technology aimed at the upper gastrointestinal tract or paediatric endoscopy were excluded. System ergonomics, safety, visualisation, and diagnostic/therapeutic capabilities were assessed. RESULTS Initial literature searching identified 814 potentially eligible studies, from which 37 were deemed suitable for inclusion. Included studies were classified according to the actuation modality of the robotic device(s) as electromechanical (EM) (n = 13), pneumatic (n = 11), hydraulic (n = 1), magnetic (n = 10) and hybrid (n = 2) mechanisms. Five devices have been approved by the Food and Drug Administration, however most of the technologies reviewed remain in the early phases of testing and development. Level 1 evidence is lacking at present, but early reports suggest that these technologies may be associated with improved pain and safety. The reviewed devices appear to be ergonomically capable and efficient though to date no reports have convincingly shown diagnostic or therapeutic superiority over conventional colonoscopy. CONCLUSION Significant progress in robotic colonoscopy has been made over the last couple of decades. Improvements in design together with the integration of semi-autonomous and autonomous systems over the next decade will potentially result in robotic colonoscopy becoming more commonplace.


INTRODUCTION
Conventional optical colonoscopy represents the gold standard investigation for lower gastrointestinal (LGI) tract pathology including colorectal cancer (CRC), polyps and inflammatory bowel disease [1]. Current generation colonoscopes consist of a semirigid flexible scope containing fibre optic bundles with a camera at the distal end allowing visualisation of the colonic lumen. The scope tip can be manoeuvred in two directions via twin-wheels located on the control shaft of the scope, where buttons controlling air insufflation, suction and irrigation mechanisms are also located. Passage of instruments through a working channel running along the body of the scope also allows the endoscopist to perform diagnostic and therapeutic interventions. Typically, a standard scope will have a diameter of 11-13 mm with a length of approximately 160 cm [2,3]. Though this model has undergone subtle refinements in recent years, the basics of the technology remain largely unchanged. While being a familiar, well developed and effective tool for LGI tract diagnosis and therapy, current technologies in optical colonoscopy remain imperfect and are subject to a number of inherent limitations. These include the limited field of view, challenges identifying and treating mucosal lesions proximal to haustral folds, procedure-related pain, and risk of perforation. Pain during colonoscopy is multifactorial in origin, most often resulting from gas distension, looping of the scope and stretching of the mesocolon [4]. Loop formation and mucosal scope trauma have the potential to cause significant iatrogenic injury to the bowel, especially in areas affected by disease [4,5] In addition, colonoscopy is associated with a long learning curve [typically > 200 procedures are required before 90% caecal intubation rates (CIR) are achieved [6,7]] and poor user ergonomics, which have been shown to result in musculoskeletal injury for the endoscopist [8].
Patient discomfort during LGI endoscopy is primarily responsible for 94.6% of colonoscopies being performed under intravenous sedation in Great Britain, and 96% in the United States [9]. However sedation does not improve CIR, increases discharge times and is costly [10]. Therefore, the development of better tolerated methods for endoscopic assessment of the large bowel with reduced sedation requirements is an urgent priority. The most serious complications associated with colonoscopy are perforation and bleeding, which occur with a frequency of 3-8 per 10000 and 1.6 per 1000 colonoscopies, respectively [1]. Though these are infrequent endpoints, addressing current physical limitations with the optical colonoscope may help to further diminish their likelihood [11]. Future technologies for colorectal tract assessment would ultimately benefit from being safer and better tolerated whilst simultaneously maximising on outputs in terms of key performance indicators such as achieving CIR ≥ 95% and adenoma detection rates (ADR) of ≥ 20% [1]. Recent advances in medical robotics offer the potential to overcome the disadvantages of conventional colonoscopy, and engineers have been seeking to develop robotic prototypes capable of endoluminal exploration and visualisation since the early 1990s [12]. In particular, the concept of 'front-wheel' actuation, in contrast to the 'rear wheel' pushing mechanism used in conventional colonoscopy has generated considerable interest, as this may possibly reduce procedural pain, the need for sedation and the incidence of iatrogenic colonic injury [13]. Robotic systems may offer a wider field of view and implementation of higher degrees of motional freedom may enhance manoeuvrability and luminal views, leading to improved ADR. The introduction of semi-automated and even fully automated robotic endoscopic platforms has the potential to flatten the learning curve and minimise endoscopist fatigue [14].
The successful application of robotic devices in coronary artery bypass procedures or valvular surgery, and in advanced bronchoscopy, highlight the potential utility of this advanced technology in circumstances where the operator is performing fine tasks within a restricted working environment [15,16]. The same should apply in endoscopy, though comparatively LGI endoscopy has been slow to embrace robotic technologies potentially because of perceived cost barriers, and a lack of understanding of how the technology can improve on the existing formula. Herein we provide a comprehensive narrative review of the state-of-the-art of robotics in lower GI endoscopy.

Search strategy
Systemic review principles were adhered to in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines[17] An electronic literature search was undertaken using EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL) databases (from January 1, 2000 to January 7, 2021). The following MeSH terms were used: "robot", "robotic", "robot assist", "colonoscopy", "flexible sigmoidoscopy", "proctoscopy". Original work reviewing the use of robotic technology in lower GI endoscopy (colonoscopy, flexible sigmoidoscopy or proctoscopy) utilising ex vivo or in vivo studies in animal and human colons were included. There was no limitation on language and type of bowel pathology studied (polyp, CRC, inflammatory bowel disease etc.). Studies evaluating non-robotic technology, robotic technology aimed at the upper gastrointestinal tract, robotic-assisted endoscopy for minimally invasive surgery, robot assisting devices for conventional colonoscopy (such as the The EndoDrive ® (ECE Medical Products, Erlangen, Germany) or the Endoscopic Operation Robot) [18] and paedia-tric endoscopy were excluded.

Data extraction
Two authors (HKSIS and EA) independently performed literature searches and determined eligibility of studies. Once consensus was reached on studies meeting predefined inclusion criteria, the following data were extracted from included studies: First author's name, country in which the study was performed, month and year of publication, study design, components of the robotic endoscopic platform, size/length of the endoscopic capsule or flexible scope, illumination method, visualization method, actuation method, data transmission method, aim of robot intention (visualization, diagnosis, treatment, other), degree of robot navigational assistance, type of colon model and results were collected.

RESULTS
A total of 814 records were identified through initial literature searching. Duplicates and obviously irrelevant abstracts were excluded at title and abstract level, leaving 62 articles, which were reviewed fully. Twenty-five articles were further excluded because they were: Review articles (n = 13); studies evaluating robotic devices using in vitro synthetic colon/other (n = 4); assessing robot assistance devices coupled to a standard colonoscope (n = 2); evaluating swallowable wireless capsules without active actuation mechanisms (n = 4); evaluating surgical rather than endoscopic platforms (n = 2). A total of 37 studies were included in the final qualitative analysis (Figure 1). For ease of interpretation of this review, studies have been classified according to mode of actuation, that is the principle active method of robotic motion for each technology. Modes of actuation were defined as EM (n = 13), pneumatic (n = 11), hydraulic (n = 1), magnetic (n = 10) and hybrid (n = 2).

EM actuation
EM actuation is where electrical energy is used to bring about mechanical motion. This is usually brought about by a tether (containing wires) attached to the robotic device and to an external power source. Wireless devices without a tether will require an internal battery to provide power which takes up space. The tether will provide additional weight and friction as it slides along the mucosa which the robot will need to overcome. Either way considerable power is usually required [19,20]. A summary of studies investigating this mode of actuation is provided in Table 1.
Two EM actuation robotic endoscopic systems were developed and received Food and Drug Administration (FDA) approval, though these are now no longer commercially available [19]. The Invendoscope SC40 (Invendo Medical, Kissing, Germany) is a motorised colonoscope, controlled by a joystick and actuated by an inverted sleeve mechanism and a driving unit with 8 wheels. It is 18 mm in diameter and has a visualisation module and a 3.2 mm working channel ( Figure 2). Two trials on humans have been carried out to evaluate this platform. The first, in 34 healthy volunteers showed a CIR of 82%, with 92% of patients 'pain free' and no acute complications were reported [21]. The purported strength of this system was the combination of a highly flexible endoscope shaft with the proprietary 'inverted sleeve' technology, which the developers believed could permit potentially 'painless' colonoscopy, as no direct forces are applied against the intestinal walls while the device passes through narrow intestinal convolutions. Invendo medical Gmbh was acquired by Ambu A/S with plans to release a single use robotic colonoscope in 2021 [19,22]. Another study in 61 asymptomatic individuals with an average risk of CRC willing to undergo CRC screening found a CIR of 98.4%, with a median caecal intubation time (CIT) of 15 min. Only 4.9% of patients required sedation [23]. The Neoguide Endoscopy System (Neoguide Endoscopy System Inc., Los Gatos, CA United States) has a scope diameter of 14-20 mm and consists of 16 actuator segments under EM control to bring about movement. It also contains a tip position sensor, an external position sensor and a 3.2 mm working channel. A trial on 10 individuals undergoing CRC screening or routine diagnostic colonoscopy showed a CIR of 100% with a median CIT of 20.5 min. Adenomas were successfully removed with snare or forceps and there was no evidence of complications at 30 d follow up [24]. With this platform, the position and angle of the scope's tip are encoded into a computer algorithm. As the scope moves forwards, the algorithm directs each successive actuator segment to assume the same shape/position that the tip had for that given insertion depth. The insertion tube thus changes its shape at different insertion depths in a "follow-the-leader" manner, which should minimise discomfort. Neoguide Endoscopy System Inc. was acquired by Intuitive Surgical Inc. and the technology translated to robotic lung biopsy [19]. Several other non-certified EM actuation devices have been developed and below these have been categorised further based on their distinct physical properties which bring about motion.
Legs: A 12-legged capsule was developed by Valdastri et al [25], comprising two motors, a bidirectional communication platform and a human machine interface (HMI) capable of semi-autonomous intrinsic EM actuation (Figure 2). The capsule measures 12.8 mm in diameter and 33.5 mm in length. The device was designed to strike a versatile balance between size and ability to traverse the bowel. The device was tested in a porcine gut model and was able to traverse the complete length of the colon (140 cm) at an average speed of 5 cm/min [25]. Though a little slower in terms of pace, this device highlights the potential for miniaturisation of devices in robotic endoscopy.  A legged colonoscope consisting of six legs covered in silicone and a Bowden cable connecting the device to an external motor and control system was tested in excised porcine colon of varying paths to determine locomotive efficacy and safety. It was able to travel at decreasing velocities of 9.5 mm/s, 7.1 mm/s and 5.1 mm/s on straight, 30 degree curved and 60 degree curved paths, respectively. No mucosal damage or perforations were observed during testing [26]. The diameter of the device is 16 mm without the legs deployed and 33 mm when they are.

Fins:
A novel capsular device, 170 mm in length and 30 mm in diameter, consisting of a front body with a clockwise helical fin and rear body with an anti-clockwise helical fin was developed by a team in Japan. The bodies are connected by a DC motor and the device is computationally reinforced with learning algorithms to improve effectiveness of motion through iterative learning. It was tested in ex vivo and in vivo porcine colon models and ex vivo trials demonstrated improved movement performance with learned algorithms. In vivo trials showed an average speed of 11 mm/min with no acute mucosal damage [27].
Paddles: A tethered capsule endoscope containing a camera module, DC motor and 6 paddles measuring 15 mm in diameter was evaluated in ex vivo porcine colon as well as in an in vivo porcine model (Figure 2). At a slope of 27.5 degrees (length: 32 cm) and 37.5 degrees (straight length: 62 cm), impressive forward motion speeds of 36.8 cm/min and 37.5 cm/min were achieved. The mean velocity reached in the in vivo model over a distance of 40 cm was 17 cm/min. A degree of minor paddle-trauma was noted on the mucosa which may present a safety concern[28].

Worm-like:
Wang et al [29,30] created two similar earth-worm like robotic endoscopes. The initial system consisted of a microrobot, controller and user interface. The microrobot in turn consists of a head cabin with the visualisation module and 3 mobile cells connected to the controller by an electric cable. Each mobile cell contains a linear electromagnetic driver [29,30]. The microrobot was able to travel along the porcine colon length (112 cm) in 7.3 min[29,30]. The worm-like device is pictured in Figure 2.
Later, a similar microrobot was created by the same team with two notable design adjustments: Each segment with this updated prototype is composed of a linear locomotor with its own micromotor, turbine-worm and wire wrapping-sliding mechanism, and the microrobot is entirely covered by an external soft 'bellow'. The soft bellow acts to increase the friction gradient between the robot and the colonic mucosa which should improve locomotion ability. This device was tested in in vivo porcine experiments and demonstrated average speeds of up to 2.2 mm/s, with no mucosal damage reported [31].
A robot with a camera, two clampers, three motors, 5 discs and 15 springs was created to allow worm-like flexible movement. It could be driven using a joystick and is 19 mm in diameter and 180 mm long. Motion ability and safety were tested in sheep colon in a straight or curved (84 degree bend) path. The device travelled at 18.4 cm/min and 10.5 cm/min in straight and curved colonic segments, respectively. No mucosal trauma was seen [32]. Overall worm-like devices appear safe with a variable speed.
Caterpillars: A robot with 3 elastic caterpillars, designed to expand the colonic lumen while causing little trauma was able to travel at 3 mm/s and achieve caecal intubation 50% of the time at 8.55 min in porcine colon placed within a human abdominal phantom [33]. Unfortunately, in an in vivo experiment, the robot failed to achieve caecal intubation as it had difficulty travelling through fluid and faeces [33].
Treads: A treaded (4 treads) robotic capsule with two motors, connected via a flexible tether to a control printed circuit board and laptop ( Figure 2) was tested in excised porcine colon and was able to move in forward and reverse directions at 40 mm/s even with the bowel wall collapsed [34]. The treads allow traction between the device and the colonic mucosa to allow effective locomotion. It was also able to pass tight haustra and make turns due to the presence of the second motor and resulting increased degrees of locomotion freedom. The device also had a visualisation module and channels for air, water and tools. Camera, insufflation, irrigation and biopsy tools all functioned effectively during in vivo porcine testing [34].

Electropneumatic actuation
Electropneumatic (EP) actuation involves the use of pressurised gas to bring about motion. The Aer-o-scope (GI View Ltd, Ramat Gan, Israel), Endotics [ERA Endoscopy S.r.l., Peccioli (Pisa), Italy] and Sightline Colonosight systems (Stryker GI, Dallas, Tex, Haifa, Israel) are all examples of FDA approved EP robotic systems with a visualisation module and channels for insufflation, suction and irrigation.
The Aer-o-scope system works by generating a gas (carbon dioxide) pressure gradient between a rectal balloon inflated in the anus and a balloon located at the tip of the scope. Safety mechanisms ensure that the pressure in the colon does not exceed 54 m bar. The scope is only 5.5 mm in diameter ( Figure 3). In vivo studies on healthy human volunteers (n = 12) or those requiring CRC screening (n = 56) have reported CIR ranging from 83%-98%, average CIT of 23 min and no acute complications other than mild mucosal petechiae in some instances [35,36]. Four of twelve patients required sedation [35]. In those undergoing CRC screening, the polyp detection rate was 87.5% and mucosal visualisation was rated as 'excellent' by participating endoscopists [30].  The Aer-o-scope provides a 360 panoramic vision system in addition to a complementary metal-oxide-semiconductor (CMOS) camera which allows improved visualisation. In an In vivo study with 12 anaesthetised pigs with surgically simulated colonic 'polyps' the Aer-o-scope visualised 94.9% of polyps compared to 86.8% achieved with standard optical colonoscopy (P = 0.002) [37].
The Endotics system consists of a flexible probe with a head, body and tail, EP connector and a workstation ( Figure 3). Two clampers located at the proximal and distal ends of the probe aid movement. Ex vivo testing using porcine colon has suggested that the stress exerted on the colonic wall using this device is 90% less than in standard colonoscopy [38]. This should in theory translate into a reduced need for analgesia and sedation. In fact, two human trials showed that Endotics was less painful on a scale of 1 to 10 (0.9 vs 6.9)[38] and did not require any sedation (0% vs 19.7%, P < 0.001) [39] compared to conventional colonoscopy [38,39]. This device can achieve CIR as high as 92.7% within 29 min [40]. Diagnostically, in individuals with a family history of CRC and/or polyps, the Endotics System showed a sensitivity, specificity, positive predictive value and negative predictive value of 93.3%, 100%, 100% and 97.7%, respectively [39]. The Endotics system has also demonstrated a short learning curve: Two blocks of consecutive patients underwent LGI endoscopy using the Endotics platform with improvements in CIR (85.2% vs 100%), intubation time (55 min vs 22 min, P = 0.0007) and withdrawal time (21 min vs 16 min) [40]. Importantly, in an evaluation of 102 patients previously having undergone failed colonoscopy, 95 patients (93.2%) underwent successful caecal intubation with the Endotics system [41]. The Sightline ColonoSight system consists of a reusable scope covered by a disposable sleeve and connected to an air pressure engine [42]. Shike and colleagues evaluated the performance of this system in 178 human study participants and reported a CIR of 90% with a mean CIT of 11.2 min. Scope advancement with this device is facilitated by self-propulsion of the instrument affected by an air-pressure-December 16, 2021 Volume 13 Issue 12 powered engine and LED illumination eliminates the need for fiber optics and an external light source.
Other non-certified EM actuation robotic devices include the "EndoCrawler" which consists of longitudinal and circumferential rubber bellow pneumatic actuators joined in four segments with a bending tube to allow steering between the first two segments [43]. When pressurised air enters the bellow, it extends longitudinally. It has a central hollow cavity for insufflation, irrigation, suction and instrument channels as well as charged coupled device cables to pass through. It has undergone ex vivo testing in human cadaveric colon which demonstrated clear visualisation capabilities and an average speed of 200 mm/min. In vivo assessment using a live porcine model also demonstrated some encouraging findings, though difficulties were encountered when attempting to negotiate sharp bends. These issues notwithstanding, this early prototype again demonstrates the potential for self-propulsive, remotely controlled robotic devices for endoluminal assessment [43].
In 2017, a simple colonoscopy robot consisting of the robot (tip with camera, latex tubing and anal fixture) with an external pneumatic circuit was developed.
Locomotion feasibility and safety was tested in porcine colon. The device was able to traverse the entire length of the colon in 71.4% of trials, able to traverse the entire length of colon with additional bends in 90.9% of trials, had an average speed of 28 mm/s with an average CIT of 54.2 s. The maximum propulsive force was 6 N i.e., an acceptable pressure on the colonic mucosa however balloon rupture led to damage including tearing of the porcine colon [44].
A further pneumatic device consisting of three segments, each containing two soft pneumatic balloons and two rigid connectors was developed and tested in excised pig colon. The balloons are twisted in the proximal and distal gripper segments but linear in the middle propulsion segment. A camera and channels for air flow and instruments are built in. The unactuated device is 22 mm in diameter. The robot travelled at 1 mm/s and was able to clearly visualise the colonic mucosa [45].
A summary of all studies evaluating robotic EM actuation systems for LGI endoscopy is provided in Table 2.

Hydraulic actuation
Hydraulic actuation uses a pressurised fluid medium such as water to progress through the colon. A meta-analysis of randomised controlled trials has previously shown that water immersion colonoscopy does significantly decrease pain scores and sedation rates without affecting the diagnostic quality or completeness of colonoscopy when compared with air intubation [46].
The "Hydraulic Colonoscope" system consists of a colonic vehicle (CV) connected to external pumps and valves via a tether. The CV contains a magnetic tracker and is surrounded by a balloon which may be inflated or deflated to create an appropriate seal with the colonic wall. The pump system is used to pump water into the colon behind the CV. An anal port prevents water from escaping the colon. Motion ability was trialled in porcine colon and compared to conventional colonoscopy. The device was able to reach the caecum in all attempts. There was no difference in the CIT or caecal pressure between the device and colonoscopy. However, significant differences were found in the maximum force exerted on the colon (0.63 N vs 2.2 N, P = 0.004), maximum anal pressure (1.53 kPa vs 4.53 kPa, P = 1 × 10 -7 ) and mean anal pressure (0.05 kPa vs 1.5 kPa, P = 0.0003) between the device and conventional colonoscopy, respectively [47] (Table 2).

Magnetic actuation
Magnetic actuation is brought about externally through magnetic fields created either by an external permanent magnet (EPM) or electromagnetic coils [48]. Control of this field is crucial for locomotion as controlling the field allows movement of the device in a particular direction and orientation. The main advantage of external magnetic actuation is that it allows a 'front-wheel' motion without the need for large internal actuating motors. When an EPM is used, small internal permanent magnets (IPMs) incorporated into the luminal robot are required to generate the magnetic field. A power supply is generally not required. The resulting device is therefore less bulky and more likely to reduce pain and the need for sedation. Additionally, there is more scope to incorporate other subsystems. The EPMs can be moved manually and the magnetic field controlled directly by the user to cause luminal device movement. However, movement is non-linear and therefore complex. Other disadvantages include the ongoing need for insufflation and the continuous contact between the device and the colonic mucosa due to the continuous attraction between the EPM and IPM [48]. The magnetic fields generated may also interfere with nearby equipment as  Ex vivo: The stress pattern was 90% less than with colonoscopy. In vivo: CIR was 27% for the endotics system compared to 82% with colonoscopy. The mean CIT was 57 min. The endotics system was described as less painful (0.9 vs 6.9). The endotics system has a higher diagnostic accuracy as it detected 2 polyps and 2 angiodysplastic lesions not identified with colonoscopy they are permanent and cannot be turned on or off [3]. Electromagnetic coils can improve control over the magnetic field however they do require a power supply [19]. We have further classified these devices into whether or not they are wireless or tethered.

Wireless capsules
A swallowable wireless capsule with the aim of therapeutic control of bleeding was developed [49]. It consists of a surgical clip, 4 IPMs and a bidirectional communication platform and is able to actively locomote via a magnetic link generated by its interaction with an EPM. The EPM is mounted on a passive hydraulic arm that is moved manually by the user. A HMI under direction by the controller controls clip deployment. When tested 10 times in ex vivo porcine colon, the clip release occurred 100% of the time and was instantaneous. Moving the capsule was effective and fast although it took 2-3 min to align it appropriately against the mucosa to be clipped. In vivo in a pig, 'good' movement and positioning of the device with the EPM was observed. The clip was released successfully onto the desired target and it remained in situ. The amount of tissue grasped was also satisfactory. This capsule was 12.8 mm in December 16, 2021 Volume 13 Issue 12 diameter and 33.5 mm in length [49]. Another wireless capsule with a set of IPMs, inertial and vision sensors and vision module, with an EPM mounted on a robotic arm was created [50]. The robotic arm was moved intelligently via closed loop steering and the HMI (Figure 4). Visualisation, motion feasibility and learning curve were tested in insufflated or collapsed porcine colon (500 mm) placed in a human abdominal phantom. In the collapsed colon, the device was only able to travel very short distances whereas there was a 100% success rate in traversing the whole length when the colon was insufflated with air. The average time required was 10 min. Novice medical doctors were able to drive the EPM in an effective way within 40 trials[50]. Using a robotic arm to steer the EPM was shown to provide better manoeuvrability and lesion detection rates compared to manual steering of the EPM [51].
Carpi and colleagues used the readily available PillCam capsule created by Given Imaging Ltd, Israel to visualise the small bowel and covered it in a magnetic shell to create a simple wireless capsule capable of magnetic actuation. The magnetic link was created between the shell and two EPMs controlled by a magnetic navigation system (Niobe, Stereotaxis, Inc, United States). This navigation system is already clinically in use in the field of robotic cardiology. A remote computer workstation and mouse was used to navigate the capsule. In vivo testing in a pig showed simply that such a capsule is capable of travelling through the colon without causing damage [52].
The magnetic controlled capsule endoscopy (MCCE) system (Chongqing Jinshan Science & Technology Group Co, Ltd) consists of an ingestible colon capsule with IPM and battery, an external magnetic manipulator with EPM, and an image transmission system. The capsule measures 27.9 mm in length and 13.0 mm in diameter. It was tested in 52 volunteers for CRC screening. The average time to reach the caecum was 3.63 h. Manoeuvrability of the capsule was good (94.3%) or moderate (5.77%). It was capable of providing good-quality pictures and identified 6 positive findings (polyps, diverticulum) which were confirmed by colonoscopy. All volunteers were able to swallow the capsule and excreted the capsule within 2 d. Complications included 7 mild adverse events (abdominal discomfort, nausea, and vomiting) lasting 24 h only [53].

Tethered capsules
Using the technology from [51] the "Magnetic Air Capsule", a device consisting of a capsule like frontal unit and a compliant multi-lumen tether was created [13]. The incorporation of the multi-lumen tether allows for intervention in addition to basic colonoscopy functions. The frontal unit contains a vision module, an IPM, a magnetic field sensor, and two channels, one for lens cleaning and the other for insufflation/suction/irrigation or instrument passage. The capsule is 11 mm in diameter, 26 mm in length and the tether is 2 m in length. 12 trials in 850 mm porcine colon placed in a human abdominal phantom with attached coloured beads (5 mm) mimicking polyps showed an 85% detection rate. 100% of which were successfully removed with a polypectomy snare. The mean completion time (inspection of the colon as well as removal of the 'polyps') was 11.3 min. Six trials in anaesthetised pigs showed device ability to navigate around bends and folds, retroflexion capability and successful operation of the working channels without a loss of magnetic link. In addition, there was no mucosal damage [13]. Using a similar prototype (Figure 5), visualisation and diagnostic ability was assessed 22 times in 850 mm of porcine colon and compared to that of colonoscopy. CIR for both was 100%. Compared to colonoscopy, pin detection rate was lower (80.9% with vs 85.8%) and procedure completion time (visualisation and diagnosis) was significantly longer [556 s vs 194 s ( P = 0.0001)]. There was no difference in intuitiveness score [54].
Further advancement led to the "Magnetic flexible endoscope" (MFE). This tethered robot has a standard visualisation module and working channels for instruments, irrigation and insufflation. Additionally, it has a unique retroflexion control algorithm to improve this repetitive but technically challenging skill. Autonomous retroflexion ability was examined 30 times in an anaesthetised pig. Successful retroflexion manoeuvres with a mean time of 11.3 s were performed 100% of the time. No acute tissue trauma or perforation was seen [55]. A comparison of different degrees of locomotion autonomy was performed recently using the MFE in two pigs [14]. Completion times for Direct robot operation vs teleoperation vs semi-autonomous operation vs colonoscopy showed similar results over distances of 45 cm (9 min 4 s vs 2 min 20 s vs 3 mins 9 s vs 1 min 39 s) and 85 cm (unable to reach marker vs 8 min 6 s vs 9 min 39 s vs 3 min 29 s). Intelligent and semi-autonomous control had NASA Task Load Index[56] mean ratings lower/less demanding than colonoscopy or direct robot operation [14].  Volume 13 Issue 12 An Endoo capsule with a permanent magnet, visualisation module, tether with 4 working channels for suction, insufflation, irrigation and instruments was developed in Italy within a European H2020 project [57]. The system consists of an external robot with EPM, a localisation system and medical workstation with a joystick. The workstation and joystick allow the user to control all functions of the Endoo capsule ( Figure 5). In addition, the vision system contains 4 green/blue UV-LEDs. Compared to colonoscopy CIR was 67% vs 100% at 9.5 min vs 3.5 min respectively. Interaction forces between the Endoo capsule and colonic wall as well as polyp detection rates was lower than colonoscopy [1.17 N vs 4.12 N; 87% vs 91% (P = 0. 16)]. The magnetic link was lost an average of 1.28 times per complete procedure, but it was restored in 100% of cases [57]. All studies are summarised in Table 3.

Hybrid actuation
Hybrid actuation involves the combination of different propulsive mechanisms to achieve motion. A wireless endocapsule consisting of a 3 legged mechanism, DC motor, battery and small IPMs was created and tested by Simi and colleagues ( Figure 6) [58]. Magnetic and EM mechanisms are combined here: The IPMs interact with an EPM to primarily move and orient the capsule while the legged mechanism is used to extract the capsule out of collapsed areas of the colon when it might otherwise get trapped. Motion feasibility was examined 10 times on 20 cm porcine colon and in 4 anaesthetised pigs. In the ex vivo trials, the average time taken to travel 20 cm and   [57], 2020 (Italy) Endoo system: An Endoo capsule with a IPM, soft tether connection with 4 working channels for suction, insufflation, irrigation and instruments; An external robot with EPM, forcetorque sensor and movable platform, localisation system and medical workstation with a joystick complete the system. The robot with EPM is controlled via the workstation but can also be steered manually. number of times the legs were activated was 4 min with 5 activations. The average speed was 5 cm/min. In the in vivo trials, the average time taken to travel 40 cm and number of times the legs were activated was 5 min with 5 activations. The average speed was 8 cm/min. The colon was not insufflated with air [58]. In Japan, a selfpropelling capsule was created by attaching a silicon resin fin with micro-magnet to the commercially available Pillcam SB2 capsule (Covidien, Dublin, Ireland). In the presence of a magnetic field and water, the fin vibrates and propels the capsule. When placed in the rectum and descending colon of a human subject, it was shown to be able to swim forwards and backwards without causing damage to the mucosa however it had difficulty by-passing the bend of the sigmoid colon [59] (Table 3). December

DISCUSSION
Medical robotics is realising its potential in a variety of healthcare disciplines, and the last couple of decades have seen increasing demand for robotic platforms designed specifically for endoscopy. In terms of LGI tract 'robo-endoscopy', significant strides have been made over this period, with five devices receiving FDA approval. These devices represent a heterogeneous group in terms of actuation modality (EM or pneumatic), and many studies have been performed using ex vivo models. These models, while able to demonstrate proof of concept, cannot effectively capture data on in vivo motion ability, pain perception or device safety. Nevertheless, the human data that is available suggests that the evaluated robo-endoscopic systems are able to locomote effectively (i.e., achieve CIR > 90% [23,24,36,[40][41][42]), to locomote safely (i.e., be associated with mild if any mucosal disruption or complications[21, 24,35,36,40,42])and to achieve endoscopic tasks with minimal associated pain[21, 23,35,39]. Reducing discomfort associated with LGI endoscopy represents a key directive in robotic endoscopy and in two trials, human participants gave the Invendoscope an average pain score of 1.96/6 and 2.6/6, which translated into 0% and 4.9% requiring sedation, respectively [21,23]. When compared to colonoscopy, pain scores and sedation rates were also significantly lower with the Endotics system [38,39]. Early data suggest that the Endotics system may even have superior diagnostic capabilities compared with conventional colonoscopy as indicated by its ability to detect lesions missed on colonoscopy [38]. These reports are certainly encouraging, though overall it is important to appreciate that most devices presented in this review remain in the relatively early phases of translational application, and few have met the goal of December 16, 2021 Volume 13 Issue 12 clinical deployment outside of academic institutions. An inherent limitation lies in the fact that most systems provide primarily diagnostic functionality, with large scale trials evaluating therapeutic robotic LGI endoscopy currently lacking. Improved reproducibility, enhanced procedural efficiency and a shorter learning curve have all been suggested as possible areas where robotic endoscopy could make a positive impact. In addition, they may offer a more comfortable system for the user, which may have potential to minimise fatigue and injury and ultimately this may equate to more years of professional service. More intuitive control and visualisation systems have the potential to shorten learning curves. For example, one trial evaluating a robotic endoscopic system suggested that only an average of 30 procedures was required for the user to achieve CIR, CIT and scope withdrawal time comparable to standard colonoscopy performed by an 'expert' [40].
From a broader perspective, it is important to acknowledge that this review has focused entirely on the specific application(s) of robotic systems in LGI endoscopy. However, robotic advances in this area are not made in isolation from advances in other luminal organs such as the upper GI tract or in natural orifice transluminal endoscopic surgery. Thus, it is likely that advances in one field will complement another.
One can anticipate that in the future, as the technology becomes more sophisticated, it should be possible to exploit the 'computational interface' that robotic endoscopy provides further, with the potential for integration of AI based algorithms and novel augmented reality systems for 'smart' therapeutics. It is doubtful whether these nextgeneration technologies will work to their full capabilities if operating within anything other than a robotic system. It is an exciting time in medical robotics with recent reports confirming the potential for the development of 'soft' robotic systems with inbuilt autonomic functionality [60]. Such systems are likely to represent the long-term direction of luminal robotics. In the near-to mid-term, the goal will be to continue to stimulate strong collaborative links between GI physicians and medical engineers in order to continue to refine design and functionality.