Critical ReviewsTM in Biomedical Engineering, 42(1): 1-15 (2014)

10278-940X/14/$35.00 © 2014 Begell House, Inc. www.begellhouse.com

Ingestible Gastrointestinal Sampling Devices: State-of-the-Art and Future Directions Yaw Amoako-Tuffour1,* Mitchell L. Jones1,2,* Nabil Shalabi,3 Alain Labbé,2 Srikar Vengallatore,3 & Satya Prakash1,2,**

1Biomedical Technology and Cell Therapy Research Laboratory, Dept. of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street, Montreal, Quebec, H3A2B4, Canada 2Micropharma Limited, 4200 St-Laurent Blvd, 4th Floor, Unit 409, Montreal, Quebec, H2W 2R2, Canada3Department of Mechanical Engineering, McGill University, 817 Sherbrooke Street West, Montreal, Quebec, H3A2K6, Canada

* Equal contributors. **Address all correspondence to: Satya Prakash; Biomedical Technology and Cell Therapy Research Laboratory, Dept. of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street, Montreal, Quebec, H3A2B4, Canada; Tel: 1-514-398-3676; Fax: 1-514-398-7461; Email: satya.prakash@mcgill.ca.

ABSTRACT: Despite the significant contribution of gastrointestinal diseases to the global disease burden and the increasing recognition of the role played by the intestinal microbiota in human health and disease states, conventional methods of exploring and collecting samples from the gastrointestinal tract remain invasive, resource intensive, and often unable to capture all the information contained in these heterogeneous samples. A new class of gastrointestinal sampling capsules is emerging in the literature, which contains the components required for an autonomous intra-luminal device and preserves the spatial and temporal information of the gastrointestinal samples. In this paper, we identify the primary design requirements for gastrointestinal sampling capsules, and we review the state-of-the-art for different components and functionalities. We also suggest two design concepts, and we highlight future directions for this class of biomedical devices.

KEY WORDS: Autonomous ingestible device, electromechanical capsule, luminal intestinal content collection.

I. INTRODUCTION

Gastrointestinal diseases comprise a substantial por-tion of the global disease burden.1,2 In North Amer-ica and Europe, gastrointestinal cancers account for 25% of all cancer deaths.3 Bacterial populations in the gastrointestinal tract also play an important, though poorly understood, role in gastrointestinal and host physiology that has implications in meta-bolic diseases and obesity, which are both signifi-cant contributors to the disease burden.4–7

As the primary channel through which materials enter and exit the human body, the gastrointestinal (GI) tract, or alimentary canal, is a large repository of information. Histological samples (i.e., tissue and mucosal) contain information on the disease state of the GI tract itself. Samples of its contents, investi-gated with analytic techniques such as quantitative

polymerase chain reaction (qPCR), 16S pyrose-quencing, and mass spectrometry may reveal bio-markers from various locations throughout the body through marked increases or decreases in known analytes due to metabolic pathways being perturbed by disease. These histological, morphological, and biochemical indicators of disease have historically been collected through fecal sampling, visualization, and various endoscopic-assisted biopsy techniques. Though effective, these techniques are invasive and are often incapable of retrieving physical samples from the entirety of the small intestine. In the case of stool samples, spatial and temporal information are poorly preserved. Less invasive means of exploring the GI tract would increase the frequency at which these investigations could be conducted and could facilitate high-throughput screening (HTS) required to study and identify new biomarkers.

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In the year 2000, the first commercial endo-scopic capsule was made available by Given Imag-ing (Yoqneam, Israel).8,9 This capsule made it pos-sible to non-invasively image the GI tract, including the entirety of the small intestine, a location never before fully accessed by conventional tethered en-doscopic devices.8,9 Since then, researchers have been developing technologies capable of perform-ing a multitude of non-invasive procedures in the GI, such as drug delivery and tissue biopsy, which require more versatile control over the locomotion and positioning of devices in the GI tract.9–14 One application that has received relatively little atten-tion is the ability to collect the physical luminal content and exfoliates from the GI tract. These ma-terials are of interest because they contain elements of the microbiome and metabolome, which are potential biomarkers for disease. Biomarkers may indicate the future risk, or current progress, of a par-ticular disease prior to the development of clinical symptoms and thus increase the likelihood of inter-ventional success. The study of this ecosystem and its relation to various disease states could lead to a decrease in morbidity associated with these disease states. Collecting digestive fluids using stand-alone capsules has been mentioned only briefly in the lit-erature.10,15 To the best of our knowledge, only one stand-alone capsular device exists currently that is capable of performing fluid collection with results for in vivo sampling.15 However, numerous designs have been proposed for such medical devices and several of the disparate components required are ac-tively being developed. In this paper, we review the present state-of-the-art in ingestible gastrointestinal sampling devices.

II. GASTROINTESTINAL SAMPLING DEVICE DESIGN

Ingestible medical devices intended for clinical use must comply with guidelines set by the governing agencies in the target market (e.g., the Food and Drug Administration in the United States). These guidelines specify the materials and technologies that may be used in the device, minimum safety standards, as well as limitations to its operation,

such as acceptable levels of interference that it may generate or receive. Paramount in these guidelines is the demonstration that the device causes no harm during the course of its operation and can perform, to a specified degree, its intended functions. For minimally invasive gastrointestinal sampling de-vices, these guidelines translate into the following general requirements: (1) devices should be ingest-ible, capable of transiting safely though the GI, and retrievable; (2) devices should be designed to col-lect biologically relevant samples, whether liquid, solid, or a heterogeneous mixture, which may later undergo conventional and advanced analytical tech-niques; (3) sampling devices should be biocompat-ible and maintain structural integrity upon exposure to digestive and other bodily fluids; (4) for clinical use, medical devices should have fault tolerance in-corporated into the physical design and underlying software; and (5) the sample collection mechanism should not damage the structures of the GI tract.16

A. Size and Shape

The pyloric sphincter, the most restrictive fea-ture along the length of the human gastrointesti-nal tract, limits the dimensions of non-degrading ingestible devices.17 However, the risk of capsule retention is present throughout the length of the GI, and may be elevated in patients with clinical histo-ries of intestinal stenosis and Crohn’s disease.18,19 Commercial endoscopic capsules and “smart” pills designed for the adult population range in length from 18 to 35 mm and diameter from 6 to 12 mm. The incidence of capsule retention for devices within these dimensions is reported to be below 2%.20,21 The lower limit for the dimensions of gas-trointestinal sampling devices is the volume of bio-logically relevant sample required to perform the desired analysis, which depends on the application under consideration. For instance, sample volumes of 10–50 µL are typical for qPCR.22

B. Materials

The definition of biocompatibility depends on the nature of body contact (an ingestible capsule

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Ingestible Gastrointestinal Sampling Devices: State-of-the-Art and Future Directions 3

is considered a “surface device” in contact with a mucosal membrane) and the contact duration (in this case a prolonged >24 h < 30 d period of time).23 A biocompatible designation describes the absence of an adverse reaction, immunological or chemical, due to a given material in the pres-ence of human bodily fluids.24,25 These materials may range from degradable polymeric coatings, fluoropolymers, and elastomers, to durable ther-moplastics, metal and glass.26–30 Durable materials are preferred for the exterior of devices that are required to retain function and structural integrity throughout the length of the GI tract as is the case for endoscopic capsules, monitoring pills, and gas-trointestinal sampling devices. The use of different materials for various internal components may en-able functionalization of specific surfaces for in-teraction with proteins, antibodies, and other bio-markers.31 Compliant (elastic) materials have also been incorporated in capsule designs as protective diaphragms for pressure transducers, deformable reservoirs, and energy storage devices.

C. Control

The human GI tract is divided into anatomically and physiologically distinct segments with unique characteristics, functions, and pathologies. In cer-tain applications, the collection of eukaryotic cells leaving the sphincter of Oddi may be used to di-agnose pancreatic disease, whereas collection just after the ileocecal valve may be used to diagnose colonic disease. In other applications, mucosal samples may be used to assess coeliac changes. Thus, the control of sample collection is of central importance in the design of gastrointestinal sam-pling devices. Collection mechanisms aided by endoscopic imaging are under the direct control of the physician. Upon visualizing the desired sample location, the physician is able to manually actuate the collection mechanism. In contrast, autonomous sample collection methods may employ mechani-cal systems, chemical compounds, or microcon-troller units (MCUs) to control sample collection. A common control method for gastrointestinal sampling devices is the use of phase-change trig-

gers sensitive to specific chemicals and intestinal geographies.32,33 Enteric compounds that undergo significant physical changes upon exposure to spe-cific chemical compounds, enzymatic action, or environmental conditions are often used as trig-gers.32 Such compounds are best suited for appli-cations requiring relatively low precision, such as drug delivery, in which compound degradation and absorption may span several hours.33 Shape memory alloys (SMAs) may also be used in this manner; however, microcontroller units (MCUs) are typically required to initiate the resistive heat-ing required for phase change and mechanical actuation.34 Electromechnical systems controlled by embedded MCUs offer a high level of preci-sion and autonomy. These systems may be pre-programmed to react to specified environmental conditions, time, or location; they can be triggered externally upon reaching the target location; and they respond on the scale of microseconds.35 The major design considerations for an electromechan-ical sampling device are the power consumption and power supply, localization methods, means of communication with the external world, capacity for environmental awareness, and its sample col-lection mechanism.

D. Localization

Accurate device localization and sample timing are critical to determining the site of biopsy and inter-vention, rate and location of metabolic processes, and the bacterial profile of the GI tract. These de-tails can be used to target locations for sampling before ingesting the capsule or to trace the source of samples after testing. Three-dimensional track-ing of devices within the GI in real-time has proven challenging, as the intestines have few fixed ana-tomical locations and move freely within the peri-toneum.36 Further adding to this challenge is the patient’s natural movement over the course of gas-trointestinal transit. Radiographic methods, able to visualize through soft tissue, are inappropriate for continuous or intermittent imaging over the many hours (>30) required for device transit.37 The long duration of GI transit also makes impractical

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all methods requiring the continuous presence of human operators. For these reasons, autonomous localization methods are preferred for tracking devices inside the tract using timing, computer vi-sion, triangulation methods, inertial navigation and external monitoring.38–42 The most basic form of localization within the GI uses typical gastric and small bowel transit times as guidelines for deter-mining the physical location of the pill at a given time point. This method can be inaccurate because the transit times in any individual can vary signifi-cantly from statistical norms. However, it may be possible to standardize transit times through di-etary restriction (e.g., fasting state), bowel prepara-tion, and co-administration with prokinetic agents to help the motion of the device by overcoming stoppages at sphincter regions.9,43

Inertial navigation and positioning systems are based on the integration of measurements from an array of on-board multi-axial accelerometers and gyroscopes.44,45 This method is computationally in-tensive, requiring a large number of measurements as the capsule follows a complicated trajectory in-side the GI.46

Computer vision is being developed as a means to retroactively determine the location of endoscopic capsules. During the course of transit, an endoscopic capsule may take between 40,000 and 60,000 images, which are later reviewed for abnormalities.47 Algorithms based on pattern recognition and texture analysis have been dem-onstrated to accurately segment the GI tract into distinct anatomical regions of interest.47–49 These post-procedural techniques, however, are unable to provide real-time or actionable information to the transiting capsule, thereby preventing targeted sample collection.

A number of triangulation methods, analo-gous to the global positioning system (GPS), have been used to localize ingested capsules in three-dimensional (3D) space.41,42,50 The received signal strength indication (RSSI) uses the ingested device as a radio frequency (RF) emitter and an exter-nal sensor array to measure RF signal strength at fixed locations on the abdomen. The relative signal strengths are then used to calculate the 3D posi-

tion of the device.50 The average error with this method is estimated at approximately 38 mm due to varying signal attenuation by the differing body tissues.10,50 Time of arrival (TOA) is another form of triangulation in which the 3D position of the sampling device is calculated from the difference in reception time of an electromagnetic (EM) sig-nal at three receivers located externally on the ab-domen. A high degree of synchronization (within 1 ns) of the receivers is required to achieve 0.3-m resolution.51 Magnetic tracking is immune to atten-uation by body tissue. The strength of a magnetic field generated by a permanent magnet within the device is detected by a skin-mounted magneto-resistive sensor array to estimate 3D position with precision of approximately 3 mm.10,42 Magnetore-sistive tracking does not increase power consump-tion but is susceptible to interference by external magnetic fields and high-voltage electrical de-vices. Furthermore, the large permanent magnet diminishes potential sampling volume within the device. A general weakness of triangulation meth-ods is the positional error that occurs due to natural body movement.52

Conventional clinical imaging may be used to localize sampling devices. Ultrasound imag-ing is based on ultrasonic pulses transduced on the body’s exterior at low frequencies (100 kHz to 5 MHz) 11 and has been demonstrated as an effective localization method for medical devices within the GI.53 Radioactive tracers may also be placed in compartments within the medical device such that its transit through the GI may be tracked by gamma cameras.54 Imaging methods based on ion-izing radiation such as X-ray are not suitable for continuous device tracking.

E. Locomotion

Gastrointestinal sampling collection techniques based on endoscopy or double-balloon enteroscopy (or any tube-based technique) reach their target lo-cation through the application of force at the prox-imal end of the device. In contrast, the majority of ingestible electromechanical sampling devices reach their target locations, and continue to transit

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Ingestible Gastrointestinal Sampling Devices: State-of-the-Art and Future Directions 5

through the GI tract, passively under the force of peristalsis.55–57 Passive locomotion requires no pro-pulsive hardware but may be erratic. A number of active locomotion techniques have been developed for ingestible capsules: (1) micro-mechanical legs, paddles, or propellers;55,58–60 (2) the controlled ex-pansion of compressed gas to provide propulsion;11 or (3) propulsive forces transmitted by an exter-nal system, typically a magnetic field, in which devices have embedded magnets or coatings and are directed with an external magnetic driving de-vice.39,40,61 Furthermore, modifications to the mate-rial surface properties of a device could influence locomotion, such as micropillar polymer arrays coated with viscous oil that could improve adhe-sion to the microvilli of the intestinal mucosa.62–64

Externally driven locomotion systems rely on large magnetic field generators and are impracti-cal over the long course (>30 h) of GI transit.37,39 Locomotion mechanisms internal to the capsule are voluminous. In a 12-legged robotic capsule designed by Quirini et. al., the motors responsible for locomotion alone consumed greater than 20% of the available volume in a capsule sized ~11 × 26 mm.55 With the addition of an internal power supply, mechanical legs, controller, and support-ing mechanisms, little volume is left for physical sample storage or the mechanism used to collect the sample.

F. Environmental Awareness

Environmental sensors provide a means of de-vice localization within the GI tract and facilitate real-time decision making based on the surround-ing environment. Parameters typically measured include the gastrointestinal pH,65 pressure,66 tem-perature,67,68 oxygenation (i.e., measuring dis-solved oxygen), and oxidation/reduction using cyclic voltammetry, and electrical conductivity.8,69 The concentration of hydrogen ions (pH) can be measured using antimony and glass pH electrodes and ion-sensitive field-effect transistors (ISFETs), which have been implemented in a number of ingestible devices, including the SmartPill® GI monitoring system (Given Imaging, Israel) and

the Phillips-Medimetrics device.69–72 Acidity may be useful in monitoring intestinal activity. When combined with time, it can provide localization information for drug delivery or sample acquisi-tion.73 Notably, ISFET pH sensors are sensitive to changes in temperature and must be calibrated at regular intervals to provide accurate pH measure-ments.74

Temperature measurement is performed using thermistors, resistive thermal devices (RTDs), as is the case in the VitalSense® ingestible telemetric physiological monitoring system pill (Mini Mitter Co., Inc., Bend, OR),75 or by monitoring frequency shifts in temperature-sensitive crystals (CorTemp® Pill system by HQ Inc, Palmetto, FL, USA).14 Silicon diode temperature sensors and forward biased pn junctions have also been used for this purpose.69,72

Radiant energy can be a means of environmen-tal sensing for ingested devices. These technolo-gies include fluorescence endoscopy, optical co-herence tomography, confocal micro-endoscopy, light-scattering spectroscopy, Raman spectros-copy, and molecular imaging for optical biopsy or the use of transmission spectroscopy for detecting intestinal bleeding.76,77

G. Communications

Endoscopic and monitoring capsules routinely em-ploy wireless communication to transmit and re-ceive commands and to offload data.78,79 A major design consideration is the extent to which the data transmission rate and transmission distance affect power consumption. Wireless signals from ingest-ible medical devices must not interfere with stan-dard hospital equipment but must be sufficiently robust to overcome external interferences. The dedicated RF communication standard is the Med-ical Implant Communication Service, operating in the 402–405 MHz range, although other Industrial Scientific and Medical bands, such as 433.92 MHz, are acceptable.80,81 Several systems use electric-field propagation that exploits the human body as a conductive medium for data transmission, which may offer higher data rates with lower power con-

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sumption than existing RF technologies due to the elimination of power-consuming RF transmission components.14 Infrared communications protocols, such as IrDA, may also be used for short range, line-of-sight, data transfer between ingestible cap-sules and programmers, with marginal additional cost and design complexity.82,83

H. Power Supply

The power supply for electromechanical gastroin-testinal sampling devices may be integrated into the device or disconnected and external to the de-vice. Silver oxide coin cells and lithium polymer batteries are commonly used as internal power supplies for ingestible and implantable medical devices.35,84,85 External power supplies are used to achieve compact designs, to power inaccessible devices such as permanent implants, and to oper-ate devices with high energy consumption. Wire-less energy transmission through biological tissue is achieved by creating an inductive link between an external primary coil (worn around the patient’s torso) and a secondary coil (embedded within the capsule).57,86,87 Excitation of the primary coil in-duces electrical current in the secondary coil, pro-viding power to the device. Thus, external power supplies can lead to compact device designs with extended operational capabilities, but they require significant supporting infrastructure.

I. Sample Collection

Sample collection may be based on active and/or passive mechanisms. Active mechanisms gen-erally provide a high level of control and the po-tential to gather heterogeneous sample material. Passive mechanisms do not require power sup-plies and may be made more compact and basic in their design. For the purposes of this review, active sampling mechanisms are defined as those requir-ing the controlled release of mechanical energy to collect sample from the lumen of the gastrointes-tinal tract. Additionally, sampling in this context refers to the collection of physical material from the intestinal lumen as opposed to environmental

sensing and recording by a medical device during transit. Physical samples may further be subdivid-ed into live tissue, exfoliate, intestinal fluids, and solids.

Several active sampling mechanisms for in-gestible capsular devices have been described in the literature, utilizing shape memory alloys, com-pressed springs, air pressure, motors, and elastic materials to actuate plungers, pistons, and biopsy forceps.88–91 Electric thermoactuators are often used to trigger the release of stored mechanical energy by destroying a degradable material (e.g., nylon monofilament) that holds the actuating el-ement in a “high-energy” state.15 Shape memory alloys are unique in that they undergo conforma-tional changes with the application of electrical current and do not require a secondary trigger to release mechanical energy. A number of micro-pumps have been proposed for fluid sampling and drug dosing in smart pills. These include mechani-cal pumps based on electrostatic and piezoelec-tric forces and non-mechanical pumps based on electrokinetic principles such as electroosmosis.92 Though the mechanical micropumps have been demonstrated to achieve high pressures (31 kPa) and flow rates (850 µL min-1), they require very high supply voltages (200 V) to operate.93 Non-mechanical micropumps or electrokinetic pumps, such as those driven by electro-osmotic, capillary, or electrohydrodynamic forces, require fluid that is polar, free of particulate matter, and non-viscous.92 These requirements are incompatible with the het-erogeneous and highly variable luminal contents of the GI tract.

Passive collection mechanisms include micro-fluidic capillary tubes and the selective exposure of absorptive materials to the fluid of the GI.94,95

III. GASTROINTESTINAL SAMPLING CAPSULES

An intestinal biopsy capsule, popularly known as the Crosby Capsule, was developed by in 1957 to perform jejunal biopsies.88 The device is a stainless steel cylindrical capsule with rounded ends mea-suring 11 mm in diameter and 20 mm in length. A

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Ingestible Gastrointestinal Sampling Devices: State-of-the-Art and Future Directions 7

5-mm-diameter aperture on the side of the capsule serves as the port of entry for the mucosal sample, and a separate 2-mm-diameter aperture at the end of the device accommodates polyethylene tubing. At-tached to the external end of the polyethylene tube is a syringe through which pneumatic control of the sampling mechanism is exerted. The sampling mechanism consists of a knife atop a cylindrical block. The cylindrical block is attached to a spring under both torsion and linear compression in its initial state. At the desired site of sample collection (indicated by the length of tubing ingested), the sy-ringe piston is drawn to create a vacuum within the polyethylene tube. This vacuum draws in mucosa through the 5-mm sampling aperture and triggers the release of the cylindrical block. As the block advances, the attached knife rotates and biopsies the mucosa. Though the Crosby Capsule was dem-onstrated to provide biopsies with high diagnostic value in disorders such as Celiac Sprue, Whipple’s Disease, Abetalipoprotinemia, and Agammaglobu-linemia, there were a number of challenges associ-ated with its use,96 including bleeding and perfo-ration.97,98 Additionally, withdrawal of the device from the patient occasionally required the intrave-nous injection of 15 mg propantheline bromide in 10 mL of saline to relax pyloric spasm.99

In 1996, Gu and Gu applied for a patent de-scribing a pill-shaped container with a hollow body, opening, seal, and a vacuum interior.94 Upon reaching the target sampling location, indicated by pH, enzymatic activity, or the presence of a par-ticular chemical compound, the seal would dis-solve, allowing intraluminal contents to enter the storage area. The capsule could be subdivided into as many as three subcompartments, each with its own vacuum, opening, and seal. The seals differ in thickness to vary degradation rates, allowing the administrator to collect samples from different locations along the GI tract. Enteric compounds are also used as seals in microfluidic sampling de-vices. In a patent application by Sprenkels et al., a microfluidic-based GI fluid sampling concept is described that uses capillary forces to draw in samples from the GI.95 Prior to administration, the channels are sealed with enteric compounds sensi-

tive only to the fluids targeted for sampling col-lection. Upon contact with these fluids, the seals dissolve and allow the passage of fluid into the channels under capillary motion. These devices offer passive, solid-state designs that are inde-pendent of external infrastructure. In both design categories, however, no provision is made for re-sealing the chambers following sample collection, and the design remains susceptible to downstream contamination. Furthermore, the designs require a priori knowledge of the target fluids and cannot accommodate variations in physical or chemical composition of intestinal fluid.

Cui et al. designed a sampling capsule using micromechanisms based on microelectromechani-cal systems (MEMS) technologies. The capsule uses miniaturized pistons to elute medication into the GI tract and simultaneously draws luminal content into the sampling chambers.15 At 10.2 mm in diameter and 30 mm in length, the polycarbon-ate capsule elutes an average drug volume of 0.5 ml and captures an average sample volume of 0.2 ml. The position of the device is tracked us-ing a combination of microscale magnets embed-ded in the capsule and a Hall sensor array fixed on a waistcoat worn by the patient. Commands are transmitted to the device from an external RF signal emitter. Three internal silver-oxide batter-ies (1.55 V, 40 mAh, 9.5 mm × 2.09 mm) provide electrical power for operation. This MEMS-based design contains many important elements for au-tonomous gastrointestinal sampling such as GI localization, wireless communication, and large sample volume. However, the device is limited to collecting a single liquid sample that is not isolat-ed from downstream contaminants, and the rela-tively small ports are susceptible to obstruction by particulate matter in the GI tract. These limitations also apply to another mechanical sampling tool, designed by Park et al. in 2008, to perform tis-sue biopsies in the GI.89 The sampling mechanism, which was designed to augment the capabilities of existing endoscopic capsules, consists of a torsion spring that can be released using a resistive heater to locally melt a polymer string; a slider-crank mechanism to convert rotary motion into transla-

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tion; and a toothed lance that extends into the lu-men of the GI tract and retracts into the capsule with tissue trapped in its teeth.

A concept for an advanced sampling capsule was described in a 2003 patent application by Tang et al. which utilizes counter-rotating cylindrical blades to collect samples from the lumen of the GI tract.91 This device is designed as an in vivo diag-nostic tool with an on-board micro-spectrometer and biosensors. It uses miniaturized motors in the sample collecting mechanism and has the ability to transmit information wirelessly to an external receiver. To our knowledge, this design has not yet been prototyped and characterized.

Table 1 summarizes the technologies that are currently used or in development for sampling the GI tract.

IV. DEVICE CONCEPTS AND FUTURE DIRECTIONS

The future of GI exploration lies in small, autono-mous sampling devices that can provide research-ers and clinicians with high levels of specificity, localization, and sensitivity. A survey of the litera-ture revealed numerous approaches to achieve this goal. Based on this review, and taking into con-sideration the diverse design requirements listed earlier in this document, we conclude that it is feasible to develop an autonomous gastrointestinal sampling device consisting of an electromechani-cal system controlled by an onboard microproces-sor that will be propelled by peristalsis along the GI tract. The device will be equipped with an in-ternal power supply and its position will be tracked using a combination of transit time and localized environmental changes. Finally, the device will be equipped with an active sampling mechanism to accommodate a diverse set of materials collected from the GI tract. Multiple, and discrete, samples will be collected and isolated from contaminants until their recovery.

Adhering to the precedents established by commercial endoscopic capsules with respect to dimensions, component materials, power supply, and intestinal locomotion allows the develop-

ment of a new sampling capsule to benefit from past and ongoing research on the safety of endo-scopic capsules and their ability to transit safely through the gastrointestinal tract without causing discomfort. Control of the sampling device will be implemented through an onboard Microcontroller Unit (MCU). The MCU will be expandable and interface with communications modules, ADCs, switches, and non-volatile memory. Following the development phase of a GI sampling device, its components may be integrated into an Application Specific Integrated Circuit (ASIC) to further min-iaturize the device.

Three-dimensional localization of a sampling devices using one of the numerous triangulation methodologies such as RSSI, and magnetoresistive tracking, may be of limited value due to the poten-tial for large errors to be introduced by torsional and abdominal movement, individual variability, and intestinal mobility within the abdominal cav-ity. For the purposes of targeted sampling within the GI, greater value may be obtained from the de-tection of transition points along the GI tract and/or fixed anatomical markers. Gastric emptying and colonic emptying times are the most variable com-ponents of GI transit.37 Provided the relatively con-sistent transit time of the small intestine, a basic timing mechanism coupled with an environmental sensing system to detect the transition into and out of the small intestine could be utilized as a totally independent auto-localization system within the capsule. The efficacy of localization techniques may be assessed by radiographic imaging such as scintigraphy.107

Most commercially available endoscopic and environment sensing capsules are intended for sin-gle usage and are not retrieved. As such, ongoing wireless RF communication is required to offload recorded data and images to an external device. The proposed GI sampling capsule, in contrast, must be retrieved to study the sampled contents. The mandatory retrieval of the capsule allows any relevant transit data (e.g., timings, environmental recordings, and error logs) to be stored onboard the device rendering real-time data transmission unnecessary, except when the user wishes to trig-

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Ingestible Gastrointestinal Sampling Devices: State-of-the-Art and Future Directions 9

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Critical ReviewsTM in Biomedical Engineering

Amoako-Tuffour et al.10

ger sampling based on external interpretation of transmitted data. An autonomous device, however, should be able to trigger sampling independently; thus, a communication link is only required imme-diately prior to and following transit. Short-range IR communication could provide this functionality at minimal cost and with moderate design com-plexity. Furthermore, unlike RF, optical commu-nication is not susceptible to interference or mali-cious attacks during transit in the GI tract.109 This ideal device configuration is further described in Table 2.

Figures 1 and 2 illustrate what this new class of devices might look like and how they could operate based on the features highlighted in this review (Table 2). The concepts comprise electro-mechanical systems housed in protective plastic enclosures. They feature microcontroller units (MCUs) and communications modules such as RF transceivers. MCUs offer versatility, as their capabilities may be expanded using additional

modules such as Analog-to-Digital Converters (ADCs). ADCs allow a variety of sensors to be incorporated into the system so that the device can be aware of the surrounding intestinal envi-ronment as well as its own orientation and ac-celeration within the intestine. An active sample collection mechanism is implemented using a miniature motor to achieve the necessary level of control over the sampling process and to account for physical and chemical variations in the mate-rials being sampled. Concept A is powered with a lithium polymer battery cell and Concept B is powered with two silver-oxide coin-cell batteries. Each device contains a minimum of three sam-pling chambers, each with a capacity of approxi-mately 100 µL, to ensure a biologically relevant sample quantity for a wide range of analytical processes. Multiple sampling chambers are dis-crete and isolated from contamination to facilitate redundant sampling or distributed sampling with a single capsule.

TABLE 2: Design of an ideal GI sampling device

Specification Examples ReferencesDimensions Length: 18–35 mm

Diameter: 6–12 mmPillCam, SmartPill 9,47,79

Materials (external) Biocompatible thermoplastics and alloys

Polycarbonate,Polyethylene, PEEK, PTFE, PMMA medical

grade silicone, stainless steel

15,25,88

Locomotion Passive, peristaltic pressure Norika, enterion, BRAVO pill,

9,15,79,110,111

Control Onboard MCU, with ADC, radio module, UART/USART, high

current output

ATMEL ATMega48 35,55

Localization Environmental sensing, timing PH-ISFET, solid state manometer, RTD

51

Communications Low-power wireless RF, ANT, infrared 112

Sample Luminal content (liquid, solid;), mucosa, exfoliate

Target size: 3 × 100 µl

Cui drug delivery and sampling pill (> 200 µl)

15,94,95

Power Internal (battery) Silver oxide, lithium, lithium ion

78,84,85

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Ingestible Gastrointestinal Sampling Devices: State-of-the-Art and Future Directions 11

V. CONCLUSIONS

With the high disease burden associated with gas-trointestinal ailments and the potential to infer other disease states from biomarkers and the microbi-ome found in the gastrointestinal tract, the need for non-invasive GI sampling techniques is becoming evident. Existing GI exploration techniques such as

endoscopy, colonoscopy, and double-balloon enter-oscopy are capable of collecting luminal and tissue samples for biopsy from much of the digestive tract, but they are invasive, resource-intensive, and thus ill-suited for high-throughput research required to identify novel biomarkers and observe physiologi-cal processes in the GI tract. These limitations, in addition to the very high cost of the medical proce-

FIG. 1: Gastrointestinal sampling pill Concept A

FIG. 2: Gastrointestinal sampling pill Concept B

Critical ReviewsTM in Biomedical Engineering

Amoako-Tuffour et al.12

dures, also make the existing methods unsuitable as easily administered diagnostic, monitoring, and in-tervention tools. The commercial device cost will be highly dependent on the components used, produc-tion volume, regulatory requirements, and other fac-tors. The device-associated cost will, however, be easily offset by the reduction in the cost of medical procedures and the improved quality of the samples collected. Beyond the development of a candidate device, the collected samples must be characterized to ensure that they are representative of the locations targeted for sampling. The continued development of this device class will yield a greater understand-ing of the relationship between the GI contents and various disease states and serve as a powerful re-source in the discovery of disease biomarkers and development of novel therapies.

ACKNOWLEDGMENTS

The authors acknowledge the contributions from Starfish Medical. This work was supported by Mi-cropharma Limited. M.L. Jones and S. Prakash acknowledge a conflict of interest as they are co-founders and shareholders of Micropharma. A. Labbé is employed by Micropharma.

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