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2009 by the AGA Institute0016-5085/09/$36.00

doi:10.1053/j.gastro.2009.06.029doscopes. There are great advances being made in wire-s diagnostic and therapeutic technologies in gastroen-ology. This article gives an overview of the advancest will significantly impact the specialty of gastroenter-gy in the near future.

Wireless Diagnostic TechnologiesBravo pH TestingEsophageal pH testing have been the gold stan-

diagnosis of weakly acidic or non-acid reflux. Currentimpedance pH testing systems use nasopharyngeal cath-eters to measure changes in esophageal impedance (con-ductivity across 2 closely spaced electrodes) owing tointraesophageal refluxate or food bolus. The system usesdirectionality (anterograde indicating a swallow and ret-rograde indicating a reflux event) of the impedancechange to diagnose a swallow or a reflux event. Addi-tional pH sensors on the impedance catheter are used toe Future Is Wireless: Advances in Wchnologies in Gastroenterology

ENDER K. SHARMA

ision of Gastroenterology, Department of Medicine, Mayo Clinic in Arizona, Scott

rthur C. Clarke in his essay Hazards of Prophecy:The Failure of Imagination, proposed 3 laws of

diction. The first law is that, When a distinguishedt elderly scientist states that something is possible, healmost certainly right. When he states that somethingimpossible, he is very probably wrong. Others are notforward thinking when it comes to embracing inno-ion. The wireless music box has no imaginable com-rcial value. Who would pay for a message sent tobody in particular? were the comments of Davidrnoffs associates in response to his urgings for invest-nt in the radio in the 1920s. Although the associates probably neither elderly nor a scientist, he was al-st certainly in good company at the time. Skepticism

out new technologies has existed in all walks of life andall stages of history. Yet, every day new technologies

me online and affect every sphere of our lives, includ-medicine.

Advances in wireless technologies have tremendouslyhanced diagnostic and therapeutic capabilities in gas-enterology and have improved our ability to take careour patients. Furthermore, they have allowed patientsfreedom to not be physically tied to their physician ortesting facility, and have testing performed in the

mfort of their home. As gastroenterologists, advanceswireless technologies are allowing us to perform gas-intestinal (GI) diagnostic procedures with increasedSTROENTEROLOGY 2009;137:434 465Michael B. Wallace, Section Editor

eless Diagnostic and Therapeutic

Arizona

avo pH capsule (GIVEN Imaging, Atlanta, GA) is areless, radio-telemetry based, intra-esophageal pHnitoring system that eliminates the discomfort of anwelling nasopharyngeal catheter. The Bravo pH cap-

le measures 25 6 5.5 mm and is placed eithernsorally or transnasally with or without sedation afterher endoscopic or manometric localization of theer esophageal sphincter (LES). The pH capsule con-

ts of a battery, radio transmitter, and an antimony pHctrode at its distal tip to measure esophageal pH. The

electrode samples esophageal pH every 6 seconds andta are transmitted every 12 seconds for 48 hours to anernal receiver unit worn by the patient.1 A compositescore of 14 on any of the two 24-hour recordings

s a high sensitivity, specificity, and positive and nega-e predictive values, and an accuracy of 95%.2 The bravo

capsule is significantly better tolerated by the patientsd allows pH monitoring under more physiologic con-ions, improving the accuracy of the test in detectingRD. The Bravo pH capsule is primarily used to estab-

h the diagnosis of GERD in patients with atypicalptom, symptoms not responding to medication, or

nclusively establish the diagnosis before anti-refluxrgery. The Bravo pH testing should ideally be per-med while the patient is off antisecretory medications.

Wireless pH/Impedance Testing

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Imaging and Advanced Technology continuedess the pH of the refluxate. Recently, a wireless, im-dance-based pH monitoring system has been devel-ed. The battery-less system uses inductive links be-een 2 coils. An external coil forms a resonance circuitth a radiofrequency source worn externally by the pa-nt and a small coil with inter-digitated electrodes im-nted in the esophagus to detect changes in esophagealpedance. The impedance changes in the esophagus,sed by fluid passing, can be detected by either ampli-e or frequency modulation. The system in vitro and in

o has been shown to measure pH accurately usingpedance changes and may be better tolerated than therrent catheter-based impedance system.3 Impedanceting is primarily used to establish the etiology of

ptoms not responding to antisecretory medication ordetect reflux of non-acidic content as a source of

tients symptoms. The impedance/pH testing is ideallyrformed on maximal antisecretory therapy.

Wireless Whole Gut Pressure and pHMonitoring SystemThis Smart Pill system (SmartPill Corporation,

tiliGI, Buffalo, NY) consists of a wireless motilitysule, data receiver, docking station, computer, and

ta analysis software. The shape and dimensions of theart Pill capsule (cylindrical, 26.8 mm long 11.7 mm

diameter) are similar to the video capsule endoscopes.e capsule houses sensors for pH, temperature, andssure and wirelessly transmits this information at 434z using RF-technology. The capsule measures pH

nge, 0.059.0 pH units) with an accuracy of 0.5 pHits, pressure (range, 0 350 mmHg) with an accuracy of

mmHg and temperature (range, 25 49C) with anuracy of 1C. The data receiver is powered by re-

argeable batteries. After completion of study, the datadownloaded to a Windows PC-compatible laptop and

ta are analyzed. The initial studies reveal promisingults in determining the gastric and whole gut transiting the Smart Pill. However, the clinical utility ofious physiologic parameters throughout the GI tract

d their alteration in various disease states need to bether elucidated. SmartPill is approved by the US Food

d Drug Administration (FDA) for the measurement ofstric emptying in patients with suspected gastropare-.4 Another novel ingestible event marker system (Pro-s, CA) has been recently reported to measure physio-ic transit times with high detection accuracy. Theestible event marker system offers promise of a newysiologic monitoring system; however, its clinical util-in gastroenterology remains to be established.5Wireless GI ImagingGI endoscopy has been the mainstay of GI diag-

stics and therapeutics. A major paradigm shift in GI

ofofthedoscopy happened with the advent of wireless GI im-ing using capsule endoscopes. The capsule endoscopytem consists of an ingestible capsule, a data recorder,d a computer work station to download and analyze

capsule images. The small bowel capsule endoscopeasures 11 24 26 mm in dimension, weigh aroundg, and obtain 23 images per second. There are 5

sule endoscopy systems available: PillCam (GIVENaging), EndoCapsule (Olympus, Center Valley, PA),roCam (Intromedic, Seoul, Korea), OmOm capsule

nshan Science and Technology, Chongqing, China),d Sayaka (RF System Labs, Nagano, Japan); however,ly the PillCam and EndoCapsule are currently FDAproved for use in the United States. PillCam uses amplimentary oxide silicone chip and EndoCapsule usescharge couple device chip for imaging. Both thesesule endoscopes use RF-based communication tech-

logy. MiroCam is currently undergoing FDA approvalals in the United States and uses a complimentaryide silicone chip for imaging and the Human Bodymmunication technology for transmission of images.man Body Communication technology uses 2 externalsule electrodes to transmit and a single skin electrode

receive the data using the human body as an electricalnductor. This methodology uses less energy, allowing

capsule to obtain images at higher frame rate (3ages per second) and for a longer duration (11 hours)mpared with other capsule endoscopy systems. Prelim-ry data from OmOm capsule suggests that theOm capsule has comparable test characteristics to theer 3 capsule endoscopes. In addition, GIVEN imaging

s an FDA-approved esophageal capsule endoscopelCam ESO for the evaluation of esophageal diseasech as Barretts esophagus and esophageal varices and alon capsule endoscope PillCam Colon that is undergo-

FDA trials in the United States for the evaluation ofious colonic diseases. Both the esophageal and colonsule endoscopes have cameras at both ends. Thephageal capsule endoscope acquires images at 79/camera per second and the colon capsule endoscopeuires images 2 fps/camera per second.6

The future advances in capsule endoscopy system willprove the efficiency and diagnostic capabilities of thesedoscopes, and offer opportunities for therapy. Exter-lly rechargeable batteries using RF, microwave, ultra-

nd, or electric induction technology will eliminatettery life constraints and make prolonged capsule en-scopy, including tethered capsule endoscopy, possible.yaka (RF System Labs) is a new, battery-free capsuledoscope that uses induction charging to draw power.e camera is mounted on the side as opposed to the end

the capsule. The camera rotates along the long accessthe capsule taking 30 en face images per second over

entire inner surface of the entire GI tract. The cap-

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43ed images are transmitted to the receiver and thencessed into an extensive series of overlapped mosa-

ng images. These mosaic images are created to rep-ate a 6- to 8-meter-long digestive canal. The result is ae shaped tract that can be stored in a long and con-uous form and can be dissected to view in long form.y area of interest can also be magnified up to 75 timesthe screen for detailed viewing.7 Check cap is devel-

ing an imaging capsule aiming to provide a 3-dimen-nal (3D) reconstruction of the colon without the needclean the bowel. This imaging capsule contains a tiny,ar-like device that transmits x-rays with minimal ra-tion (the equivalent of a chest x-ray, or 1/300 of a

mputed tomographic colography), to the intestinalll, which are reflected back and captured by the imag-

capsule. The analysis of distances creates 3D imagesthe colons internal surface, enabling the detection ofnically significant polyps (Figure 1). Because x-rays,like optic alternatives, can see through colon contentd are transmitted a full 360radius around the capsule,wel cleansing is unnecessary and colonic folds do notstruct the view. The imaging capsule travels painlesslyough the colon, and is excreted naturally. A gastroen-ologist analyzes the data thats been transmitted to aist- or wrist-worn receiver; a colonoscopy is needed iflyps are detected.In addition, improvement in the chip technology andergence of hybrid imaging chips will further improveage resolution and will capture more image informa-n for digital image analysis of normal and pathology.e light imaging including recent integration of the

ji Intelligent Chromo Endoscopy (FICE) with PillCamsule endoscopy system, optical biopsies, and chemicalimmunologic tagging and imaging of pathology willther improve disease recognition. The Nano-basedThcapco

ure 1. A 3D reconstruction of a porcine colon using the check capging capsule. The blue circle highlights a 5-mm polyp that wasated in the porcine colon using an isodense submucosal siliconelants and was detected by the imaging capsule.

6sule-Endoscopy with Molecular Imaging and Opticalpsy (NEMO) project is a consortium of industry anddemic institutions that plan to develop a new capsule

doscopy system that will combine optical and nanohnologies, biosensing, and maneuvering technologiescreate a unique capsule endoscope capable of secretionalysis and detection of marked and deep tissue dis-es. The consortium predicts that the fusion of opticalages with data from molecular analysis may provide avel and effective device for mass screening for GI can-. In addition, advanced wireless imaging with capsulehnology will improve wireless laparoscopy and NOTESplications.Future improvements in the battery technology usingbon nanotubes and Bucky tubes will reduce the sized improve the efficiency of batteries that occupy thest space in a capsule endoscope, thus freeing up spaceadditional diagnostic and therapeutic component.

Pilot data from centers developing diagnostic and ther-eutic capsules have demonstrated the feasibility stud-of performing mucosal biopsies using a spring loaded

osby capsule type device guided by real-time imagingability and RF-controlled remote manipulation. Otherpsy devices that have been successfully demonstratedanimal modes include a capsule with a single-crystal

icon planar microspikes with protruding barbs for mi-scale biopsy that utilizes Micro-Electro-Mechanical

stems (MEMS) technology. Other capsules have used aational microbiopsy device consisting of a trigger witharaffin block, rotational tissue-cutting razor with asion controller designed to operate sequentially sot the tissue sampling, sealing, and fixing are achievedsingle operation8 (Figure 2). Prototype coagulationsules are being tested. In addition, the feasibility ofnipulating the capsule endoscope or creating a loco-tion or propulsion mechanism using external mag-

ts, electrostimulation, hydrojets, shape memory alloyils, and MEMS-based modular actuators have alreadyen demonstrated.9 The Versatile Endoscopic Capsule

gastrointestinal TumOr Recognition and therapyCTOR) project, funded by European Commission, is

veloping a minirobot endowed with actuation mod-s, mechanisms, sensors, embedded controls, and hu-nmachine interface with the task to navigate andervene in the GI tract for early detection of GI cancergure 3).Researchers at the City University and City CollegeNew York have developed a video capsule endoscopeled Compact Photonic Explorer (CPE), with theability to externally manipulate the capsule by re-te controlled radio signal and computer software.

e CPE measures 5 mm, and includes a transportsule that contains imaging, data transmission, and

llection capabilities. The CPE can detect disease and

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Imaging and Advanced Technology continuednitor bodily functions by combining imaging, po-ization, spectroscopy, fluorescence, and biosensorhnologies. The investigators claim that in the futureE will be able to perform therapies like laser tissueoval and tissue welding at precise locations within

ure 2. Prototype Rotational Micro Biopsy Capsule Device. (Cour-y Prof. Doyoung Jeon, Department of Mechanical Engineering,gang University, Seoul, Korea.)e intestinal tract. Olympus has announced that theyve developed wireless power supply, fluid samplingabilities, remote manipulation, drug delivery capa-

Figtheities, and ultrasound capabilities in their capsuledoscopes.

Engineering-Based Capsule forTargeted Drug DeliveryMultiple wireless capsules have been developed

targeted drug delivery for better understanding thearmacokinetics of various new drugs. However, the

e technology can be used to deliver the drug orerapeutic agent to a specific area of the GI tract,reby reducing the dose of the drug administered andociated side effects. The high-frequency capsule (Bat-le-Institute V, Frankfurt am-Maine, Germany) uses anernal RF trigger to melt a thread, thus releasing a

edle that pierces a balloon and delivers a therapeuticent at a specific site. The location of the capsule isnitored using fluoroscopy, which tends to be inaccurate

d may expose the patient to excessive radiation. Thestrotarget telemetric capsule (Gastrotarget, Tonawanda,) and Telemetric capsule (INSERM U61, Strasbourg

dex, France) use RF signal and complex localizationorithms to deliver the drug in a specific area of the GIct. Recently, IntelliSite Capsule (Innovative Devices,leigh, NC) and Enterion Capsule (Pheaton Research,ttingham, UK) have become popular tools for collect-absorption data in GI tract and can also be used for

geted drug delivery.10 iPill (Philips Research, Eind-ven, The Netherlands) is a prototype capsule that mea-res 11 26 mm and incorporates a microprocessor,ttery, pH sensor, temperature sensor, RF wireless trans-ver, fluid pump, and drug reservoir (Figure 4). The RFreless transceiver is used to communicate with a con-l unit outside the body. Using the information on pH

ange measured by the iPill, and data about gut transites, the iPills location in the gut can be determined

th fair accuracy. Targeted drug delivery is performed byiPills internal pump under the control of the micro-ure 3. Vision of VECTOR Capsule with different diagnostic andrapeutic capabilities.

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Imaging and Advanced Technology continued

43cessor, allowing accurate control of the drug deliveryfiles such as a burst, progressive release, or a multi-ation dosing. The iPill drug delivery system is cur-tly being evaluated in patients with Crohns disease

d colon cancer.11

Implantable MicrostimulatorThe GI tract is a complex neuromuscular organ

d various devices are being developed for GI neuro-mulation to treat a host of GI neuromuscular or mo-ty disorders such as gastroparesis, obesity, and GERD.estigators from The Johns Hopkins University School

Medicine have demonstrated the feasibility of the Bion

dvanced Bionics Corporation, Valencia, CA) a self-con-ned, battery-powered, remotely programmable, micro-mulator (7 g; 3.3 27 mm; Figure 5) in raising the LES

phtecmi

8ssure in both porcine and canine models. In the caninedy, the micro-stimulator was endoscopically implantedo the LES. The micro-stimulator was remotely turned onulting in a dose-dependent increase in the LES pressureall the dogs. The authors concluded that this minimallyasive procedure may be a novel approach to treatment ofRD and other GI motility disorders.12

ConclusionMultiple advances in wireless technology are on the

rizon and will significantly affect diagnostic and thera-utic gastroenterology and endoscopy. These advances willow us to look deeper, see better, and measure more

Figure 4. Philips Researchs in-telligent pill (iPill) for electronicallycontrolled drug delivery. The iPillis an 11- 26-mm capsule thatincorporates a microprocessor,battery, pH sensor, temperaturesensor, RF wireless transceiver,fluid pump, and drug reservoir.prestuintresininvGE

hopeallysiologic parameters in the GI tract. In addition, wirelesshnologies will help us to target and treat GI disease withnimal invasiveness, and improved patient safety and

comlawtheimClavangumaab

1.

measuring esophageal acid exposure. Am J Gastroenterol 2005;100;14661476.

2. Ayazi S, Lipham JC, Portale G, et al. Bravo catheter-free pHmonitoring: normal values, concordance, optimal diagnosticthresholds, and accuracy. Clin Gastroenterol Hepatol 2009;7:6067.

3. Hsu L, Tang S, Huang W, et al. An implantable, batteryless and

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Imaging and Advanced Technology continuedfort. In the words of Sir Arthur C. Clarke, in his secondof prediction, the only way of discovering the limits ofpossible is to venture a little way past them into the

possible; we are headed in that direction, wirelessly. Ifrkes third law of predictionthat any sufficiently ad-ced technology is indistinguishable from magicis any

ide, achieving what was previously impossible ought toke patients and gastroenterologists alike feel excited

out our wireless future.

ReferencesPandolfino JE, Schreiner MA, Lee TJ, et al. Comparison of the Bravowireless and Digitrapper catheter-based pH monitoring systems for

ure 5. Bion MicroStimulator (27 mm long 3.3 mm in diameter).wireless capsule with integrated impedance and pH sensors fordetecting the reflux of acidic and non-acidic materials. Gastroen-terology 2009;136:W1080.Rao SS, Kuo B, McCallum RW, et al. Investigation of colonic andwhole-gut transit with wireless motility capsule and radiopaquemarkers in constipation. Clin Gastroenterol Hepatol 2009;7:537544.Epstein M. Ingestible event marker system- a novel physiologically-sized device platform for frequent, repeated use. Gastrointest En-dosc 2009;69:AB 106.Swain P. The future of wireless capsule endoscopy. World JGastroenterol 2008;14:41424145.RF System Lab. Sayaka. Available from: http://www.rfamerica.com/sayaka/index.html.Kong K, Cha J, Jeon D, et al. A rotational micro biopsy device for thecapsule endoscope. Intelligent Robots and Systems, 2005. (IROS2005). 2005 IEEE/RSJ International Conference, August 26,2005, pp. 18391843. Available from: http://ieeexplore.ieee.org/stamp/stamp.jsp?arnumber1545441&isnumber32977.Menciassi A, Stefanini C, Gorini S, et al. Legged locomotion in thegastrointestinal tract. Proceedings of 2004 IEEE/RSJ Interna-tional Conference on Intelligent Robots and Systems. 2004. p.937942.

. Wilding I, Hirst P, Connor A. Development of a new engineering-based capsule for human drug absorption studies. Pharmaceuti-cal Science & Technology Today 2000;11:385392.

. Philips Technology. Philips intelligent pill technology. Available from:http://www.research.philips.com/newscenter/backgrounders/081111-ipill.html.

. Clarke JO, Jagannath SB, Kalloo AN, et al. An endoscopicallyimplantable device stimulates the lower esophageal sphincter ondemand by remote control: a study using a canine model. Endos-copy 2007;39:7276.

rint requestsddress requests for reprints to: Virender K. Sharma, MD, AGAF,ision of Gastroenterology, Mayo Clinic in Arizona, 13400 Easta Boulevard, Scottsdale, Arizona 85259. e-mail: sharma.nder@mayo.edu.

icts of interestr Sharma is a consultant for Intromedic.

dingr Sharma received grant support from Given Imaging, Olympus Inc.439

The Future Is Wireless: Advances in Wireless Diagnostic and Therapeutic Technologies in GastroenterologyWireless Diagnostic TechnologiesBravo pH TestingWireless pH/Impedance TestingWireless Whole Gut Pressure and pH Monitoring System

Wireless GI ImagingEngineering-Based Capsule for Targeted Drug DeliveryImplantable MicrostimulatorConclusionReferences