Component based design of a drug delivery capsule robot

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ContentslistsavailableatScienceDirect

Sensors

and

Actuators

A:

Physical

jo u r n al hom e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / s n a

Component

based

design

of

a

drug

delivery

capsule

robot

Marco

Beccani

a,∗

_,

_Gregorio

_Aiello

c

_,

_Nikolaos

_Gkotsis

a

_,

_Hakan

_Tunc

b

_,

_Addisu

_Taddese

a,b

_,

Ekawahyu

Susilo

a

_,

_Péter

_Völgyesi

b

_,

_Ákos

_Lédeczi

b

_,

_Elena

_De

_Momi

c

_,

_Pietro

_Valdastri

a

a_STORM_Lab,_Department_of_Mechanical_Engineering,_Vanderbilt_University,_Nashville,_TN_37235-1592,_USA

b_Institute_for_Software_Integrated_Systems,_Department_of_Electrical_Engineering_and_Computer_Science,_Vanderbilt_University,_Nashville,_TN_37212,_USA c_Department_of_Electronic,_Information_and_Biomedical_Engineering,_Politecnico_di_Milano,_Milano_20133,_Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received30December2015 Receivedinrevisedform4April2016 Accepted13April2016

Availableonlinexxx Keywords: Surgicalrobotics

Medicalcyber-physicalsystems Drugdelivery

MedicalCapsuleRobots Designenvironment Embeddedmicro-systems

a

b

s

t

r

a

c

t

Since the introduction of Wireless Capsule Endoscopy (WCE) researchers have started exploring the design space of Medical Capsule Robots (MCRs): embedded micro-systems that can operate autonomouslywithinthehumanbodyandcandiagnose,prevent,monitor,andcurediseases.Although theresearchintheareaofMCRsisanactivetopicandhasgrownexponentially,currentdevicesprovide onlylimitedfunctionalitiesbecausetheirdesignprocessisexpensiveandtimeconsuming.Toopenthis researchfieldtoawidercommunityand,atthesametime,createbetterdesignsthroughadvanced toolsupport,inourpreviousworkswepresentedadesignenvironmentfortherapiddevelopmentof MCRs.Inthispaper,thisenvironmentwasadoptedtodesignaDrugDeliveryCapsule(DDC)basedona coil-magnet-pistonmechanism.Theforceofthecoilactingonthemagneticpistonandthedrugrelease profileweremodeledandassessedonbench-topwithamaximumrelativeerrorbelow5%.Then,invivo trialswereperformedtovalidatetheDDCfunctionalitywithascheduleddrugreleaseprofilefora5h and24minprocedure.Theresultingdesignenvironmenttemplateisavailableopensourceforfurther developmentofdrugdeliveryapplicationsaswellastoserveasguidelineinprototypingnovelMCRs addressingotherclinicalneeds.

1. Introduction

Theintroductioninyear2000ofthePillCambyGivenImaging [1]showedthatembeddedmicro-systemscanbeusedtoreachthe moreremoteregionsofthehumanGastrointestinal(GI)tract.Since then,millionsofpatientshaveswallowedthisself-contained wire-lesscameratogetanon-invasivediagnosisofdiseasesinthesmall intestine.Unfortunately,thisapproachisnoteffectiveforother dis-trictsoftheGItract,suchasthecolonandthestomach,wheremore deadlyformsofcancerusuallydevelop[2].Themainreasonforthis isrelatedtothelackofadvancedfunctionalities,suchasactive loco-motion[3],advanceddiagnosisandtissuemanipulation[4],biopsy sampling[5],ordrugdelivery[6].

Inrecentyears,theresearchcommunityhasaddressedthisissue bydevelopinganumberofroboticsmartcapsules,referredinthis paperasMedicalCapsuleRobot(MCR).MCRstypicallyenterthe humanbodythroughnaturaloriﬁcesorsmallincisionsandcan per-formendoscopyandsurgerybyinteractingwiththesurrounding environmentwithsensorsand/oractuators.

∗ Correspondingauthor.

E-mailaddress:marco.beccani@vanderbilt.edu(M.Beccani).

ThedesignprocessofMCRshoweverischallengingbecauseit hastoaddressseverecross-cuttingconstraintssuchassize(togain non-invasiveaccess,MCRdiameterislimitedtoabout1cm),power consumption(limitedspaceforbatteryisavailableonboard),and failsafeoperation(MCRoperatesdeepinside thehumanbody). Therefore,MCRdesignanddevelopmentrequiressigniﬁcantskills andeffortsinembeddedsystems,miniaturizedelectronics, pack-aging,debugging,andmechanical miniaturizationofthedevice. Customcircuitboardsandmechanicalenclosureshavetobe engi-neered,whichmakesMCRdevelopmentanexpensiveandtime consumingprocessthatisonlyaccessibletoalimitednumberof groupsintheresearchcommunity[7].

Because many of the MCRs developed in the past share equivalenthardware andsoftware componentssuchasspeciﬁc sensors,dataprocessing,actuation,andwirelesscommunication, webelievethatitisindeedpossibletosystematizethedesignof MCRs.Thiswouldlowerthebarrierofentrytothisﬁeldtoresearch groupsthatdonothavetheresourcestodevelopMCRsfromthe groundup.

Inourpreviousworks,wepresentedourcontributionstowards the creation of an environment for the rapid design and development of MCRs [7–9]. The basic elements of the inte-grated design environment are shown in Fig. 1. At the time

http://dx.doi.org/10.1016/j.sna.2016.04.035

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Fig.1.TheelementsoftheintegrateddesignenvironmentforMCR.

of writing, the design environment includes a library of hard-waremodulesbuiltupfromourexperiencewithexistingcapsule designs[10].Thehardwarecomponentsincludefundamental ele-mentsofMCRdesignsuchassensors(inertialsensors,encoders, vitalsignsensors),actuators(DCmotors,coils,illumination,servo motors,steppermotors),batteriesandvoltageregulators,wireless transceiversworkingatdifferentcarrierfrequencies,and micro-controllers(MCUs),whichserveasbuildingblocksforthesystem. Aﬂexiblebackboneenablesplug-n-playconnectivityofuptosix hardwaremodules.Eachofthehardwaremodulesiscoupledwith asoftwarecomponentandintegratedinanopen-sourceweb envi-ronmentavailableatpillforge.github.ioforthedeveloperto implementspeciﬁcMCRapplications.

Inthiswork,wepresenthowthedesignenvironmentcanbe adoptedto develop a Drug Delivery Capsule(DDC)based on a coil-magnet-pistonmechanismforcontrolleddeploymentofdrug doses over time. As a result of this work, we have created a designtemplatefortheDDC.ThistemplateaimstoprovideMCR researchersasolutionthatshortensthedevelopmenttimeofnew DDCsbasedonthesameorasimilaractuationprinciple.Template parameterssuchasthedrugviscosityanddeploymentschedules canbeadjustedaccordingthespecificsoftheapplication.Theforce exertedbythecoil-magnet-pistonmechanismandthedrugrelease profileovertimehavebeenmodeledandcharacterized experimen-tally.Beyondthespecificapplicationofcontrolleddrugdelivery, thisworkalsoillustrateshowtheopen-sourcedesignenvironment wehavedevelopedcanbeusedtorapidlydesignanMCR.

Thispaper isorganizedasfollows: Section2 brieﬂypresents thestateof theartfor drugdeliveryMCRs, Section3illustrates themechanical,electrical,andembeddedﬁrmwareandsoftware design considerationsfor thedeveloped MCR.This sectionalso describesthedesign environmentand thedesigntemplate that havebeencreatedfortheMCR.Section4presentstheexperimental assessmentonbenchandinvivoresults.Sections5and6include respectivelyadiscussionandconclusions.

2. Clinicalmotivationfordrugdeliverysystems

Theformulationofdrugsthatallowforreproducibleabsorption proﬁlesfortargetingspeciﬁcareasoftheGItractrepresentsamajor bottleneckincurrentdevelopmentoforallyadministered medica-tions[11].Thisismainlyduetounpredictablegastrictransittime andphysiochemicalcharacteristicsoftheGItractthatdifferfrom patienttopatient[12].

Theavailabilityofacontrollabledrugdeliverysystems(DDS) mayreducetoxicityassociatedwithsystemicadministrationand preventtheformationofantibodiestodrugs,particularlyinthecase ofcoloncancerorinﬂammatoryboweldiseasetherapies[13].These aretwoextremelycommondiseases,withcolorectalcancerbeing

abletodeployaliquiddrug.Kimetal.[21]proposedathree-axis Helmholtzcoilcapsulewhichmoveswitharotationalmotionand deploysadrug.Woodsetal.[22]integratedaholdingmechanism insidethecapsuletoresisttoperistalsisandaneedleforlocaldrug deployment.TheMAARScapsule,presentedin[23],iscomposed ofmagneticsemi-hardmodulesanddeploysasingleshotofdrug uponademagnetizationprocess.Yoetal.[24]recentlyproposed anMCRwherethedrugreleasecanbetriggeredthroughareed switch.Finally,Hafezietal.[25]developedaningestiblesensorthat allowspatients,families,andphysicianstomonitorprescription complianceanddrug-adherencepatternsinrealtime.

While each of these capsules taken alone solves a specific problem,noneofthemoffersacompletesolutiontoachievean intelligentrelease ofa drugona specifictarget. Inorder todo that, multiple functionalities need to becombined and several designiterationsneedtobetested.Thankstothemodularapproach adoptedinthiswork,wehavedoneafirststepinthatdirection byimplementingacontrollablemechanismfordrugreleaseand anintelligentscheduler.Thesecomponentstakeonlypartofthe availableslotsontheflexiblecircuitbackbone,leavingspacefor addingotherfunctionalmodules,suchaslocalizationand/oractive positioncontrol.

3. Designconsideration

3.1. Principleofoperation–mechanismconsideration

ReferringtoFig.2,wheretheprincipleofoperationoftheMCR ispresented,theDDCmechanismconsistsofadrugchamber,two coils,and themagnetic piston.The drugchamber(d=7.94mm, l=6.35mm,volume=314.42mm3₎_is_hosted_in_a_cylindrical

enclo-suretogetherwithanaxiallymagnetizedcylindricalpermanent magnet acting asa piston (D54-N52, K&JMagnetics,USA). The DDCshellandthedrugchamberwereprototypedwithanObjet30 3Dprinter(Stratasys,USA)withVerowhitematerial.The clear-ancebetweentheouterdiameterofthemagneticpistonandinner diameterofthechamberwas0.4mm.Thisvalueguaranteedalow frictionwiththemagnet,resultinginnoleakageofthedrugand theactuatingmechanism.Thedistalcollaredgeofthechamberhas twelvecircularholes(eachwitharadiusofrh=0.8mm)fromwhere

thedrugisreleasedintotheenvironment.Thenumberofholesand theirradiushasbeenchosensuchthatthedrugisdeployed uni-formlywithoutbeingaffectedbycapillarity.Incasetheapplication requiresadrugwithadifferentviscosity,thenumberofholesas wellastheirdimensioncanbeadjusted.Thecombinationofproper drugviscosityandaperturesizepreventsthedrugfromleakingfor anypossibleorientationofthecapsule.Benchtrialsshowedthat theproposeddesignisabletodeploysolutionswithaviscosityup to1000cP,whichishigherthanwater(0.89cP),blood(between3 and4cP)andair(0.018cP).

Toactuatethemagneticpiston,twocoilsaremountedatboth sidesofthedrugchambersuchthat,whentheyareactivated,the

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Fig.2.PrincipleofoperationoftheDDC(a).Whenthecoilsareactivated(b)the magneticpistondeploysthedrugoutsideofthedrugchamber.

currentIinducestwostaticmagneticﬁeldsalignedalongthesame axis,havingthesamemagnitude,butoppositedirections.

TheforceF(dz)inducedbythetwocoilsonthemagnetic pis-ton can be expressed as a function of the relative position dz of thepiston with respectto thetwo coils.The trend of F(dz) wasmodeledwithCOMSOLmultiphisics(COMSOLMultiphysics, Stockholm,Sweden)andexperimentallyveriﬁedasdiscussedin Section4.ConsideringthesurfaceofthemagneticpistonS,wecan derivethepressureP(dz)inthechamberasafunctionofthe mag-neticpistonpositiondz:

P(dz)=F(dz)

S . (1)

UsingtheHagen-Poiseuille’sequation[26],wecanthenexpress thefluidflow ˙V asa functionofthepressureassumingthatthe radiusoftheholesissmallerthantheirlength,thedrugisa New-tonianfluid,andthemotionoftheresultingdrugflowacrossthe holesislaminar.Undertheseassumptions,wehave:

˙V=n·P(dz) Rh ,

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whereRh=8l/r4isthehydraulicresistance,isthedynamic

vis-cosityofthedrug,whilel,randnarethelength,theradiusandthe numberofholesinthechamber,respectively.

Fromtheﬂux ˙V,it ispossibletoderivethequantityofdrug releasedMas

M= ˙V·tact. (3)

withtactbeingthetimeperiodwhenthecoilisactive.

CoildimensioningThe magneticforceacting onthepistonis proportionaltothemagneticﬁeldBgeneratedbythecoilsas

F= B2·A

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Fig.3. PictureoftheembeddedelectronicsoftheDDCbeforefoldingtheﬂexible circuit.Thelateralconnectorsattheoppositesidesoftheﬂexiblecircuitareused forprogramminganddebuggingthemodulesandareremovedbeforeintegration intothecapsuleshell.

whereFistheforce,Bisthemagneticﬁeld,Aisthesectionofthe coil,andisthemagneticpermeabilityofthemedium(i.e.,air, therefore=0r0).SinceBisaproportionaltothecurrentI,

thecoildimensions,andthenumberofturns,weneedtooptimize thethreequantitiestoachieveenoughforcetopushthemagnet alongthechamberagainstthedrug.

Ontheotherhand,theamountofcurrentinthecoilislimited bythepowerdissipatedbyitsinternalresistanceasheat.Forsafety reasons,thecapsuletemperatureshouldnotincreasebymorethan 1◦C[27].Sincethecoilsaremountedinaparallelconﬁguration, theirtotalresistanceisRTC=1/2RCwithRC resistanceofasingle

coil.Themaximumcurrentthatcanﬂowthroughthecoilwire with-outcausinga1◦Cincreaseisequalto800mA.Adoptingavalueof 700mAforthecurrent,andconsideringthatthecoilissuppliedat 3.3V,wehave:

RTC= V_I =3.3_0.7 =4.71 (5)

thus RC=9.42 for each coil. Since the wire resistivity is

=17.421·10−9manditsissectionSw=1.5386·10−8m2,the

lengthofthewireLresultsin: L=R·Sw

=8.32m. (6)

Consideringthatthewireiswrappedaroundacircumferenceof Cin=0.0157m,thenumberofturnsNresultsin

N= L Cin =

8.32

0.0157=530.394≈530 turns. (7) Oncewrapped,thecoilresultsinadiameterof10mm,alengthof 18mm,andaninductanceof1.5mH.

3.2. HardwareArchitecture

ThehardwarearchitectureforthepresentedMCRconsistsof twoseparatesystems:abasestationandtheDDCitself.Thebase station[7]wasusedtoexchangewirelessdatabetweentheMCR andtheuserinterface.Inthisparticularapplication,theusermight desiretochangethedeliveredtherapyscheduleafterthecapsule hasbeeningested,thusthebasestationistheonlywaytointeract withtheDDC.

TheDDCelectronicsconsistsofthreeembeddedmodules:the MCU,a433MHztransceiver,andthepoweringandbattery mon-itoringmodule.Themodules,aremountedonourflexiblecircuit. These components are shown in Fig. 3 beforethe flexible cir-cuitisfoldedtofit acapsule-shapedshell.Theremainingthree emptyslotsontheflexible circuitcanbeusedin thefuture to add other functional modules. The MCU moduleis based ona

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municatesviaSerialPeripheralInterface(SPI)withthe433MHz transceiver(CC1101,TexasInstruments,USA)module.Thedriver for the coil actuation circuitry consists of a power p-channel MOSFET(STR2P3LLH6,STMicroelectronics,SUI),whichhasbeen mounteddirectlyontopoftheﬂexiblecircuit.Thetwocoilsare connectedtothedrainoftheMOSFET.Thismodulecanprovide upto800mA.TheMOSFETgateisdrivenbyaMCUdigital out-putwithaPulseWidthModulation(PWM)signal.Finally,power totheDDCisprovidedbya30mA/hLiPorechargeablebattery (LP-FR30,PlantracoLTD,USA).Accordinglytothedrugscheduler,the DDCdeploysthedrugonlyatspeciﬁctimes.Thebatterylifetime thereforehastobeoptimizedtominimizetheMCRpower con-sumption.ThisisachievedbyrunningtheMCUinlowpowermode, andactivatingitsperipheralinterfaces(e.g.,wireless communica-tion,actuation)ondemand.Table1showsthepowerconsumption oftheDDCembeddedelectronicsduringdifferentoperatingmodes. All the documentation related to the base station as well totheotherminiaturehardwaremodules isavailable at pill-forge.github.io.

3.3. Designenvironmentandscheduler

Developinganembeddedapplicationcanbeintimidating for noviceusers.Applicationsareusuallycodedwithlow-level lan-guages like C, which presents a barrier for researchers whose expertiseliesintheapplicationsofMCR.Inaddition,settingup toolchainsandthenecessarysoftwarelibrariesforaspeciﬁc tar-getdeviceisusuallycumbersome.Toalleviatethesehardships,we havedevelopedaweb-basedvisualsoftwaredesignenvironment [7].

Thedesignenvironmentprovidesahigherlevelofabstraction forapplications,makingiteasierfordeveloperstoreasonabout theirsoftware.Ausercancompilehis/herapplicationthroughthe designenvironmentanddownloaditsbinariesthroughtheweb interface.Sincethecompilationisprocessedontheserverside,the userdoesnotneedtoinstallanyadditionaltools.

We applieda proven model-based methodology [28] tothe MCRdomain.Thismethodallowedustovisuallyrepresent soft-waremodelsspeciﬁctoMCRandtogeneratethecorresponding software artifacts. The compositional features of model-based development’sprovideadditionalabstractionsthatcan encapsu-late the underlying complexities. The design environment was implementedusingtheWeb-basedGenericModelingEnvironment (WebGME), which is a modeling tool used to design domain-speciﬁcvisualmodelinglanguages[29].

WehavechosenTinyOSasthecoreoperatingsystemforthe MCR.TinyOSisanevent-driven,operatingsystemcommonlyused insmallresourceconstraineddevices[30].Itscomponentbased paradigmlendsitselfnaturallytothemodel-basedmethodology ofourdesignenvironment.Hence,amodelinglanguagewas cre-atedusingWebGMEtorepresentTinyOSlanguageconstructs.A onetoonemappingofTinyOSsoftwarecomponentstoWebGME’s notion of components allows users to create applications and

thebasestation,thescheduleandviscosityblocksareconnectedto atemplatedrugdeliverybaseapp,whiletheheartbeatratevalue blockisconnectedtoatemplatedrugdeliveryMCRapp’sport.MCR sendsastatusmessageperiodicallytothebasestation.Thestatus messagesusedforthecommunicationprotocolbetweenMCRand thebasestationaswellastosignaltothebasestationthattheMCR isstillalive(hencethenameheartbeat).Oncethecommunicationis establishedbetweenthedevices,theremainingpercentageofdrug isusedasthepayloadinthestatusmessages.Theheartbeatrate valuedeterminesthefrequencyofmessagessendfromtheMCR.In addition,thetemplateappshaveattributestosettheradioaddress forwirelesscommunication.

TheinternalstructureofthescheduleblockcanbeseeninFig.4. Theblueobjectrepresentsthebeginningofaschedule,thegreen elementsrepresentstheamountofdrugtobereleased.Blueand greenelementsareconnectedwithtimeconnections.Theschedule blockdictateswhatpercentageofdrugshouldbereleasedinthe speciﬁedtimeintervals.

Oncethescheduleandtheparametersareset,ausercan com-piletheapplicationbyrunningthecompilerpluginviathearrow buttonlocatedontopleftofthedesignenvironment.The genera-tortraversestheinputdataandfeedsittothetemplateapp.The appgetscompiledontheserverside,theresultingbinaries,inturn, canbedownloadedbytheuser.Thesoftwareisavailableathttps:// github.com/pillforge/drug.delivery.

4. Deviceexperimentalassessment

ExperimentaltrialsaimedtoassessandcharacterizetheDDC functionalitywereperformed.Theinteractionforceexertedfrom thetwocoilsonthemagneticpistonwasmodeledand experimen-tallyvalidated.WealsoveriﬁedthattheDDC,onceprogrammed withascheduler,deliveredtheamountofdrugexpectedfromthe releaseproﬁledescribedinSection3.1.Finally,thereliabilityand functionalityofthedeviceweretestedinaninvivotrialsonacanine model.

4.1. Validationoftheinteractionforcebetweenthecoilsandthe magnet

Theinteractionforcebetweenthecoilsandthemagnethasbeen modeledusingﬁniteelementanalysis(COMSOL)byassumingthe twocoilsasHelmholtzcoilswiththefollowinggeometricaland electricalparameters:numberofturnsN=531,resistivityofthe wire=17.421·10−9m2_,_radius_of_the_coil_r

c=2.5mm,current

ﬂowingineachcoilIc=350mA,diameterofthewiredw=0.2mm,

andlengthofthecoilL=1cm. Themotionof themagnetic pis-tonoccurs along thezdirectionoftheDDC, thuswe extracted fromthesimulationthenumericalvaluesfortheinteractingforce F(dz)asafunctionofthepistonpositionintothedrugchamber. Thesamequantitywasthenexperimentallymeasuredwiththe setuppresentedinFig.5.Arapidprototypingpart(Objet30,Objet

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Fig.4.ThedesignenvironmentshowingBaseandMCRappswiththehighlightoftheschedule.

GeometriesLtd,USA)wasdesignedtomounta3-axisforce sen-sor(NANO17,ATIIndustrialAutomation,USA)withthecoilsand thedrugchamber. Opposite tothe chamber,the magnetic pis-tonwasmountedattheendeffectorofasix-degree-of-freedom

Fig.5. TheexperimentalsetuptoassesstheforceF(dz)insidethedrugchamber whilethecoilsareactive.

roboticmanipulator(RV6SDL,MitsubishiCorp.,Japan).Whilethe coilswereactive,themagneticpistonwasmovedinsidethe cham-berforitsentirelength,whiletheresultingforcewascollected usingaUniversal(SerialBus(USB)dataacquisitionboard(NI-PCI 6224,NationalInstruments,USA)atasamplingrateof100Hz.

Thegraphofthemodeledforceandtheexperimentaldataare representedinFig.6.Theplotshowsaparabolicandsymmetric trendfortheforce,whichreachesitsminimumexactlyatthe cen-terofthechamber,halfwaybetweenthecoils.Therelativeerror betweentheﬁniteelementsimulationandtheforcesensordata was3.4%(=±2.5mN).

Inordertovalidatetheeffectofgravityonthedrugdelivery mechanism,thetrialswereperformedwiththecapsuleassuming differentorientations.Sincethecontributeofgravitationalforceis negligiblecomparedtothemagneticforcegeneratedbythecoil, themechanismwasabletowithstanditregardlessofthecapsule orientation.

Fig.6.Experimentaldatameasuredfromtheloadcellcomparedtotheﬁnite ele-mentanalysissimulation.

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releasewastriggered,theMCRwasplacedonadigitalscale (Ameri-canWeighScales,Inc,USA,resolution0.01±0.005g)anditsweight recorded.Thequantityofsolutionreleasedwithtime wasthus derivedfromthecapsuleinitialweight,whenthedrugchamber wascompletelyfilledup.Tendifferentexperimentaltrialswere thenperformed.Theresultsofoneofthetrialforthetwodifferent viscosityisshowninFig.7,wheretheexpecteddrugdeployment profile(inblue)iscomparedtotheactualexperimentalprofiledata (inred).Repeatabilitytestsfordelivering10%ofthedrugloaded intothechamberresultedinanaveragedrugaliquotof72␮Lwith astandarddeviationof0.28␮L.

Agoodmatchingoftheexperimentaldatawiththeexpected drugreleaseproﬁlewasobserved.Overall,therelativeerrorforthe quantityofdrugreleasedvs.itsexpectationis2.4%±1.8%.Current consumptionofthedevicematchedthevaluesreportedinTable1 witharelativeerrorequalto3%.Inparticular,thecurrentinthe coilwas695mA.

4.3. Invivotrial

TheinvivotrialwasperformedatVanderbiltUniversityunder protocolM/14/014,thatincludedotherdevicesandexperiments, usinga25kgfemaledogundergeneralanesthesia.TheDDCdrug chamberwasﬁlledwithasolutionof60%water and40% lubri-cantwithagreendye,resultinginadynamicviscosityof0.05Pas. Thecapsulewasthenprogrammedtoscheduleadrugdeliveryof 7␮Levery15suntilallthedruginthechamberwascompletely deployedforatotalof6doses.

TheDDC wasinsertedfromthe anusintothecolon using a standardcolonscopeandleftinplacefortheamountoftimeneeded forthetrial.Thesamecolonscopewasusedtoobservethereleaseof thedrugunderinsufflationofthecolon.Fig.8showsthesequenceof theDDCdeployingascheduleddrugdoses:thedrugreleaseisfirst triggered(A),thenthedrugstartstoflowoutsideofthechamber (B)andreachesthecolontissue(C).

Fig.7. Predicteddrugdeliveryproﬁle(inblue)comparedwiththeexperimental data(inred)foroneofthetrial.(Forinterpretationofthereferencestocolorinthis ﬁgurelegend,thereaderisreferredtothewebversionofthisarticle.)

ThecurrentconsumptionoftheDDCduringthetrialwas esti-matedasin[31]usingthefollowingaveragecurrentconsumptions: ¯I =

iIiTi

iTi , (8)

where Iiand Ti arethe currentconsumption from Table1 and

thetimeintervalrelatedtoasingleactionperformedbytheDDC, respectively. For our particular application ¯I resulted equal to 28mA.Adopting a battery witha capacity of250mAh, wecan expect a maximum lifetimeof T=250/288hand 50min.The invivotrialshowedthatthedevicewasabletooperateforatleast 5hand24min.Afterthat,allthedrugwasdeployedandthetrial wasconsideredasconcluded.Incasethatalongeroperatingtime wereneeded,batterylifetimecanbefurtherextendedby increas-ingtheMCUsleepintervals.Crohn’sdiseaseandulcerativecolitis areinﬂammatorysmallboweldiseasesthataretypicallytreatedby releasingcontrolledquantitiesofdrugsoveraperiodoftime.While thetypicaltransittimefor50%offoodinthesmallbowelisupto threehours,humanclinicaltrialsinthisGItractforsimilarMCR,

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Fig.9.(a)ApictureoftheﬁnalDDCprototype,wheretheembeddedelectronicswasdevelopedviacustomdesign.Thedeviceis25mmlongforadiameterof16mm.(b) Thedrugstarstobereleasedand(c)iscompletelydeployed.

(e.g.theIntellicap)haveshownanaveragesmallboweltransitofup to5h.Theactualbatterylifetimeguaranteesenoughtimeforthe devicetooperatewhiletravelingacrossthesmallbowel.However, sincethedeliverytimeandthequantityofdrugdeployedcanbe adjustedwiththescheduler,differentdiseasescanbetargeted.The purposeoftheanimaltrialwastoqualitativelyassessthe function-alityoftheDDCinaclinicalscenario.Themainlimitationofthe trialcomparedtoaclinicalscenariowasthatthedevicewasnot swallowed,becauseoftheprotocoltrialtime.Thegoalofthetrials wastoassessifthedevicewasabletoproperlyoperateinsidea constrainedenvironment,beingabletorespondtowireless com-mands,andreliablyactuatethemechanism.Forthispurpose,we firsttriedthedevicewithoutinsufflation.Afterthescheduledtime ofdrugdelivery,weinsufflatedthecolonandwecheckedproper deploymentofthedrug.Atthispoint,werunatrialwithinsufflation tocaptureavideofootage.

5. Discussion

Asdiscussedin [7],themainpurposeofourmodulardesign environmentistoacceleratethetime-to-prototypefortheearly validationofdesignhypothesisintheﬁeldofMCRs.The time-to-prototypedependsprincipallyonthecomplexityofthehardware andsoftwareoftheMCRaswellastheskill-setandexperienceof thedeveloper.

Inparticular,hardware complexityconsistsofcircuitdesign, assemblyofminiaturecomponents,andtesting.Whileacustom approach requires the developer to go through these iterative stepsuntilthedesiredlevelofminiaturizationandperformance isachieved,ourmodulardesignenvironment providestheuser withminiaturizedhardwaremodulesandaﬂexiblecircuitfor eas-ierconnectivity.Thesamedegreeofminiaturizedconnectivitycan beachievedincustomdesignswithﬂexiblePCBcablesorhybrid PCBsolutions,buttheyareknowntobeexpensiveforthelow vol-umesthataretypicalforresearchandproof-of-conceptvalidation [32].

SoftwarecomplexityconsistsofwritingefficientembeddedC codetoimplementthevariousfunctionsofanMCRandto com-municatewithexternalcomponentssuchassensors,actuatorsand wirelessbasestations.Instead,ourmodulardesignenvironment providesthedeveloperwithasetofsoftwarecomponents,which canbe customizedaccording totherequirementsof the appli-cation.Ultimately,theexperienceandskill-setofthedevelopers involveddetermineshowefficientlythedescribedhardwareand softwarecomplexitiesaremanaged.Exactquantitativebenefitsof ourcomponentbaseddesignfurtherdependonthespecificsofthe application,however,togivetothereaderanideaofthetimeand costoutcomes,theswimmingcapsuleMCRdescribedin[7],has beendevelopedandassembledinlessthantwomonthswithan overallestimatedcostof15,000USD(includingmaterialsand sup-portforpersonnel)comparedtoninemonthsandanestimatedcost of50,000USDfortheMCRpresentedin[33].

Itisworthmentioningthatthehardwareplatformwepropose, beingasystemmadeofmodules,isnotoptimizedforanyparticular application.Thus,MCRsbuiltwithourplatformaregenerallylarger thantheircustomcounterparts,asshowninFig.3comparedto Fig.9.

6. Conclusions

Inthiswork,wepresentedacomponentbaseddesignofaDDC robotbasedonacoil-magnet-pistonmechanism.Thisdeviceaims toprovideacontrolleddeploymentofdrugdosesovertimewitha scheduler.Thedrugviscosityanddeploymenttimecanbesetinthe applicationtemplateforthedesignenvironmentaccordingtothe desireddrugreleaseprofile.Themagneticforceaswellasthedrug releaseprofilehavebeenmodeledandthenexperimentally veri-fied.Themodelsfortheforceandthereleaseddrugprofileshowed relativeerrorsbelow5%whencomparedtotheexperimentaldata. ThefunctionalityoftheDDCwasalsosuccessfullyassessedina clinicalscenarioviaaninvivotrial.

Inthiswork,wevalidatedthehypothesisthata coil-magnet-pistonmechanismisaviablesolutionforascheduleddrugrelease. However,theDDCthatwedevelopedbyassemblingthe preexis-tingmodulesfromourlibraryresultedinasizethatisimpossibleto swallow.Therefore,oncewewereconﬁdentwiththe coil-magnet-pistonmechanism operation, wescaleddownourdesign toan ingestiblesizebydesigningacustomﬂexiblecircuit.TheDDC rep-resentedinFig.9is16mmindiameterand25mminlengthwith adrugreservoirof201.06mm3_._This_capsule_contains_a_scaled

ver-sionofthecoil-magnet-pistonmechanismdescribedinthispaper anditiscapableofdeployingdrugswithviscositiesupto700cP. TheDDCweightwasdecreasedfrom18gto12g,whilepower con-sumptionintheTxorRxmodeandintheDrugDeploymentmode werereducedfrom33.8mAto24.2mAandfrom748mAto418mA, respectively.

Beyondthespeciﬁcdesign,modeling,and assessmentof the proposedcoil-magnet-pistonmechanism,themaincontribution ofthisworkistoillustratehowourcomponentbaseddesign envi-ronmentcanbeleveragedfortheearlyvalidationofanovelMCR design.Allthehardwareandsoftwarecomponentsdescribedinthis paperareavailableopen-sourceatpillforge.github.ioandcan beusedasatemplatebytheMCRresearchcommunity.

FutureworkaimstoexpandtheDDCtemplatewithmodules formagneticlocomotion[3],anchoringforlocalizeddrugdelivery, andmagneticlocalization[34]towardtheendgoalofintelligent drugdeliveryintheGItract.

Acknowledgment

Thismaterialisbaseduponworksupportedinpartbythe Van-derbilt Institutein Surgery and Engineeringand in partby the NationalScienceFoundationundergrantsnumberCNS-1239355 and IIS-1453129. Any opinions, ﬁndings and conclusions or

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EngineeringfromUniversityofPisa,Pisa,Italy,in2010 andthePh.D.degreeinMechanicalEngineeringfrom Van-derbiltUniversityin2015. Heis currentlyapostdoc researcherattheembeddedandrealtimesystemlab (MLAB)attheUniversityofPennsylvaniainPhiladelphia. Hisresearchinterestincludesembeddedsystemdesign forminiaturizedwirelessmedicalroboticsforcapsular endoscopyandroboticsurgery,andmodelbaseddesign ofmedicaldevices.

GregorioAielloreceivedtheB.Sc.,andM.Sc.degreesin BiomedicalengineeringfromPolitecnicodiMilano,Milan, in2014,and2015,respectively.Heiscurrentlyaresearch scholaratARMALab,mechanicalengineeringat Vander-biltUniversity,Nashville,TN,USA.During2015hewasan internstudentatSTORMlab,Mechanicalengineeringat VanderbiltUniversity,whereheworkedtothedesignof MedicalCapsuleRobot.

NikolaosGkotsisiscurrentlyanundergraduate Mechan-icalEngineeringstudentatVanderbiltUniversity.Forthe last12monthshehasbeendoingresearchattheSTORM LabofVanderbiltUniversity,withmainfocusonMedical CapsuleRobots.Hehasalsobeendoingresearchonsoft robotictissuepalpation.

HakanTuncisaPh.D.studentandaresearchassistantattheInstituteforSoftware IntegratedSystems,VanderbiltUniversity.Hisresearchfocusesondesign environ-mentforminiaturemedicalrobotics.

AddisuZ.TaddeseisaPh.D.studentatVanderbilt Univer-sity.Hisresearchfocusesonminiaturemedicalrobotics andtheirapplicationinsurgicalprocedures.HeisanNSF graduatefellowandstudentmemberofIEEEandACM.

EkawahyuSusiloisaPostdoctoralScholarin Mechan-icalEngineering,VanderbiltUniversity.Hismajorisin wirelessembeddedsystemdesignandminiaturization forlow-powerapplications.HereceivedhisPh.D.degree, withhonor,fromScuolaSuperioreSant’Anna(SSSA),Pisa, Italyin2009.HejoinedDecawaveLtd.in2010, develop-ingRTLSalgorithmusingIEEE802.15.4aUWBPHY/MAC compliantdeviceswith10cmprecisioninthree dimen-sionalcoordinates.Currently,heisjoiningSTORMLabat VanderbiltUniversity.

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PeterVolgyesiisaResearchScientistattheInstitutefor SoftwareIntegratedSystemsatVanderbiltUniversity.He isoneofthearchitectsoftheGenericModeling Environ-ment,awidelyusedmetaprogrammablevisualmodeling tool,andWebGME–itsmodernweb-basedvariant.As PIontwoNSFfundedprojectsMr.Volgyesiandhisteam recentlydevelopedalow-powersoftware-deﬁnedradio platform(MarmotE) andacomponent-based develop-menttoolchaintargetingmulticoreSoCarchitecturesfor wirelesscyber-physicalsystems.

AkosLedecziisanAssociateProfessorofComputer Engi-neeringandaSeniorResearchScientistattheInstitutefor SoftwareIntegratedSystemsatVanderbiltUniversity.He hasanM.Sc.fromtheTechnicalUniversityofBudapestand aPh.D.fromVanderbilt,bothinElectricalEngineering.His researchinterestsincludewirelesssensornetworksand modelintegratedcomputing.

Elena De Momi, MSc in Biomedical Engineering in 2002,PhDinBioengineeringin2006,currentlyAssistant ProfessorinElectronicInformationandBioengineering Department(DEIB)ofPolitecnicodiMilano.Shewas co-founderoftheNeuroengineeringandMedicalRobotics Laboratory,in2008,being responsibleoftheMedical Roboticssection.ShehasbeenanAssociateEditorofthe JournalofMedicalRoboticsResearchandofthe Interna-tionalJournalofAdvancedRoboticSystems.

PietroValdastrireceivedtheMaster’s(Hons.)degreein ElectronicEngineeringfromUniversityofPisa,Pisa,Italy, in2002andthePh.D.degreeinBiomedicalEngineering fromScuolaSuperioreSant’Anna,Pisa.Afterﬁveyears asAssistantProfessorwiththeDepartmentof Mechan-icalEngineering, Vanderbilt University, Nashville,TN, USA,heisnowFullProfessorandChairofRoboticsand AutonomoussystemsattheUniversityofLeeds,UK.Pietro ValdastriistheDirectoroftheSTORMLabandasenior memberofIEEE.Prof.ValdastrireceivedtheNational ScienceFoundationCareerAwardandtheRoyalSociety WolfsonResearchMeritAwardtostudyanddesign cap-sulerobotsformedicalapplications.