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Kishor Kumar Sadasivuni
John-John Cabibihan
Abdulaziz Khalid A M Al-Ali
Rayaz A. Malik Editors
Advanced Bioscience and Biosystems for Detection and Management of Diabetes SpringerSeriesonBio-andNeurosystems Volume13
SeriesEditor
NikolaKasabov ,KnowledgeEngineeringandDiscoveryResearchInstitute, AucklandUniversityofTechnology,Penrose,NewZealand
EditorialBoard
Shun-ichiAmari,MathematicalNeuroscience,RIKENBrainScienceInstitute, Wako-shi,Saitama,Japan
PaoloAvesani,NeuroinformaticsLaboratory,UniversityofTrento,Trento,Italy
LubicaBenuskova,DepartmentofComputerScience,UniversityofOtago, Dunedin,NewZealand
ChrisM.Brown,DepartmentofBiochemistry,UniversityofOtago,North Dunedin,NewZealand
RichardJ.Duro,GrupoIntegradodeIngenieria,UniversidadedaCoruna,Ferrol, Spain
PetiaGeorgieva ,DETI/IEETA,UniversityofAveiro,Aveiro,Portugal
Zeng-GuangHou,ChineseAcademyofSciences,Beijing,China
GiacomoIndiveri,InstituteNeuroinformatics,UniversityofZurichandETH Zurich,Zürich,Switzerland
IrwinKing,TheChineseUniversityofHongKong,HongKong,HongKong
RobertKozma,UniversityofMemphis,Memphis,TN,USA
AndreasKönig,UniversityofKaiserslautern,Kaiserslautern,Rheinland-Pfalz, Germany
DaniloMandic,DepartmentofElectricalandElectronicEngineering,Imperial CollegeLondon,London,UK
FrancescoMasulli,DIBRIS,UniversityofGenova,Genova,Genova,Italy
JeanPhilippeThivierge,SchoolofPsychology,UniversityofOttawa,Ottawa,ON, Canada
AllessandroE.P.Villa,UniversitedeLausanne,Lausanne,Switzerland
TheSpringerSeriesonBio-andNeurosystemspublishesfundamentalprinciplesand state-of-the-artresearchattheintersectionofbiology,neuroscience,information processingandtheengineeringsciences.Theseriescoversgeneralinformatics methodsandtechniques,togetherwiththeirusetoanswerbiologicalormedical questions.Ofinterestarebothbasicsandnewdevelopmentsontraditionalmethods suchasmachinelearning,artificialneuralnetworks,statisticalmethods,nonlinear dynamics,informationprocessingmethods,andimageandsignalprocessing.New findingsinbiologyandneuroscienceobtainedthroughinformaticsandengineering methods,topicsinsystemsbiology,medicine,neuroscienceandecology,aswell asengineeringapplicationssuchasroboticrehabilitation,healthinformation technologies,andmanymore,arealsoexamined.Themaintargetgroupincludes informaticiansandengineersinterestedinbiology,neuroscienceandmedicine,as wellasbiologistsandneuroscientistsusingcomputationalandengineeringtools. Volumespublishedintheseriesincludemonographs,editedvolumes,andselected conferenceproceedings.Bookspurposelydevotedtosupportingeducationatthe graduateandpost-graduatelevelsinbio-andneuroinformatics,computational biologyandneuroscience,systemsbiology,systemsneuroscienceandotherrelated areasareofparticularinterest.
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· John-JohnCabibihan ·
AbdulazizKhalidAMAl-Ali · RayazA.Malik
Editors
AdvancedBioscience andBiosystemsforDetection andManagementofDiabetes KishorKumarSadasivuni
Editors
KishorKumarSadasivuni CenterforAdvancedMaterials
QatarUniversity Doha,Qatar
AbdulazizKhalidAMAl-Ali KINDICenterforComputationResearch Doha,Qatar
John-JohnCabibihan DepartmentofMechanicalandIndustrial Engineering
QatarUniversity Doha,Qatar
RayazA.Malik WeillCornellMedicalCollegeinQatar Doha,Qatar
ISSN2520-8535ISSN2520-8543(electronic) SpringerSeriesonBio-andNeurosystems ISBN978-3-030-99727-4ISBN978-3-030-99728-1(eBook) https://doi.org/10.1007/978-3-030-99728-1
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Preface Diabetesisaseriouspublichealthissuethataffectspeopleallovertheworld.Asthe worldpopulationages,theprevalenceofthischroniccomplicatedmetabolicillness increasesatanalarmingrate.Itwillhavethegreatestinfluenceinunderdeveloped countries.Becausediabetesisachronic,complicatedmetaboliccondition,amultidisciplinaryteamofhealthprofessionalswithexperienceindiabetesmanagement shouldofferdiabetescareinconjunctionwiththepatientandfamily.Despitethefact thatdiabetesmellituswasrecentlygivenprioritystatusbytheWHO,manypublic healthplannersarestilluninformedofitsscopeanditsconsequences.Therisingincidenceoftheconditionandthelong-termexpenseoftherapyforbothpatientsand thehealthsector,aswellastheeconomiccosttonations,areallfactorstoconsider. Adultprevalenceratesrangingfrom7%to25%havebeenobservedinstudiesdone indiversecommunitiesthroughouttheregion.Furthermore,agrowingnumberof nationsarereportingtheemergenceoftype2diabetesmellitusatayoungage.The goalofincorporatingdiabetesmellitusintoprimaryhealthcareistodeveloproutine screeningmethodstoidentify,monitor,andmanagediabetes’sfrequentcomplications.Treatmentshouldjustfocusnotonlyondecreasingbloodglucoselevels,but alsoonaddressingothernoncommunicablediseaseriskfactorsincludingsmoking, dyslipidemia,obesity,inactivity,andhypertension.Notonlyisdiabetescareinshambles,butsoisourknowledgeoftheprocessesthatunderpinclinicalproblemsassociatedwiththeillness.Themajorgoalsincaringfordiabeticpatientsaretoprevent oratleastslowthedevelopmentofclinicalcomplicationssuchasmicro-vascular (eyeandkidneydisease)achievedthroughbloodsugarandbloodpressurecontrol, andmacro-vascular(coronary,cerebrovascular,andperipheralvascular)achieved throughlipids,hypertension,andsmokingcontrol.However,wedonotunderstand howincreasedbloodglucose,circulatinginsulin,andchangedbloodpressureaffect thepathophysiologyofbloodarteriesandcauseseriousorganfailure.
Asaresult,inthelackofsuchaknowledgefoundation,currenttreatmenttechniquesfocusonriskmanagement.Ifwewanttocontrolthisconditionproperly, weneedtostartmonitoringdiabetesearlyandkeepituptodate.Theearlydetectionofvariationsinbloodglucoselevelsisthefoundationofdiabeticcare.Effectivetreatment,especiallyforundetectedhypoglycemia,requirescarefulandtimely
monitoring.Bloodglucoselevelsareusuallycheckedbeforeameal,twohoursafter, andbeforebedtime.Althoughthedevelopmentofbloodglucoseself-monitoringin recentdecadeshasencourageddiabetestreatmentinthequestforeuglycemia,its cumbersomeusemayresultininsufficientdatacollectionofbloodglucose.The pattern,frequency,level,andtimingofbloodglucosechangeshavebeentracked usingcontinuousglucosemonitoring.Diabetesdiagnosisandmanagementneed precise,sensitive,consistent,quick,andattentiveglucosemonitoringfrequently. Diabetescancreatevariousvascularandneurologicalissuesthatimpactmultiple organsystemsintheshortandlongtermifnottreatedproperly.Regularcommunitybasedscreeningandpromptdiagnosisinundiagnosedpatients,sufficientpatient educationandsupport,continuousmedicaltreatment,psychologicalcounseling,and societalsupportareallrequiredtoavoidacuteconsequences.Accuratebloodglucose monitoringwhileenhancingglycaemiccontrolandpatientqualityoflifeisoneof themostdifficultelementsofdiabetesmellitustreatment.Regularmonitoringbythe doctororthepatientisnecessarytokeepthediabetespatient’shealthfromworsening.Theserecommendationsareintendedtoaidinthestandardizationofdiabetes treatmentattheelementary,secondary,andtertiarylevelsandadvisepolicymakers aspartofeffortstoenhancehealthcare.Aboveall,wemustallendeavortoimprove diabetesmellituspreventiontoreducethisincreasingburden.
Thisbookintendstoofferrecentworkcarriedontheleadingtechnologiesfor noninvasive(NI)andminimallyinvasive(MI)glucosemonitoringsensors,devices presentlyfoundinthefieldofmedicinesciences.Thetypeofframeworkusedfor accuracydeterminationandnewapproachesundertakenbyscientistshavebeen discussed.Thisbookalsomentionstheupcomingtrendstobeseenindiabeticdiagnosisandmanagementbyusingthemachinelearningandartificialintelligence.We hopeyouenjoyreadingthebookandfinditusefulwhetherthisishelpingpatients orhealthprofessionalstomanagediabeticsanditscomplicationsusingthecurrent innovativetechnologies.Thebookwillsummarizethattheinventionandreplacementofuseofnewtechnologieswiththeexistingonesforglucosedetectionarethe futurefordiabeticpatients.
Doha,QatarKishorKumarSadasivuni
John-JohnCabibihan AbdulazizKhalidAMAl-Ali RayazA.Malik
Contents Introduction ......................................................1
KishorKumarSadasivuniandMithraGeetha
ReviewofEmergingApproachesUtilizingAlternative PhysiologicalHumanBodyFluidsinNon-orMinimallyInvasive GlucoseMonitoring ................................................9
SunghoonJang,YuWang,andAndreJang
CurrentStatusofNon-invasiveDiabetesMonitoring ..................27
SreedeviParamparambath,IshwarMarutiIslampure, T.Sabitakala,MuniRajMaurya,HajarMorsy,SwathiYempally, SureshMuthusamy,SenthilKumarRamu,SanthiyaPandiyan, RaghadAbuznad,AlaaElsafiahmed,AeshahAlruwaili, MunaIbrahim,PeterKasak,RavikumarRamluVidule, AnkanagariSrinivas,andKishorKumarSadasivuni
ANewSolutionforNon-invasiveGlucoseMeasurementBased onHeartRateVariability ..........................................55 MarjanGusev
OpticBasedTechniquesforMonitoringDiabetics ....................67
HannanehMonirinasabandFarzanehFathi
SPRAssistedDiabetesDetection ....................................91 ChoudharyArjunSunilbhai,Md.SabirAlam, KishorKumarSadasivuni,andJamilurR.Ansari
InfraredandRamanSpectroscopyAssistedDiagnosisofDiabetics .....133 NicoleM.RalbovskyandIgorK.Lednev
PhotoacousticSpectroscopyMediatedNon-invasiveDetection ofDiabetics .......................................................165 DeepakDevadigaandT.N.Ahipa vii
ElectricalBioimpedanceBasedEstimationofDiabetics ...............181 PedroBertemes-Filho
MillimeterandMicrowaveSensingTechniquesforDiagnosis ofDiabetes ........................................................199
NithushaKallingal,M.S.Sajna,MizajShabilSha,MithraGeetha, IshwarMarutiIslampure,NagendraPrasadDevarapalli, MuniRajMaurya,AsanAbdulMuthalif,SumayaAl-Madeed, RavikumarRamluVidule,AnkanagariSrinivas, andKishorKumarSadasivuni
DifferentMachineLearningAlgorithmsInvolvedinGlucose MonitoringtoPreventDiabetesComplicationsandEnhanced DiabetesMellitusManagement .....................................227 Wai-kitMingandZonglinHe
TheRoleofArtificialIntelligenceinDiabetesManagement ............243 AmineRghioui,JaimeLloret,andAbdelmajidOumnad
ArtificialIntelligenceandMachineLearningforDiabetesDecision Support ..........................................................259
JosepVehi,OmerMujahid,andIvanContreras
CommercialNon-invasiveGlucoseSensorDevicesforMonitoring Diabetes ..........................................................273
ManickamTamilselvi,PandiaRaj,RavikumarRamluVidule, andSrinivasAnkanagari
FutureDevelopmentsinInvasiveandNon-invasiveDiabetes Monitoring .......................................................293
FrédéricHarb,WilliamS.Azar,HildaE.Ghadieh,RachelNjeim, YoussefTawk,JosephCostantine,RouwaidaKanj,andAssaadA.Eid
Introduction KishorKumarSadasivuniandMithraGeetha
Abstract Effectivediabetesmanagementbeginswithbloodglucosemonitoring. Diabeticcaregoesbeyondmonitoringbloodglucoselevels.Thisincludesoverall health,includingbloodpressure,weight,cholesterollevels,sleep,mood,medications,andeye,kidney,andfoothealth.Monitoringbloodsugarisfundamentalto managingdiabetes.Microandmacrovascularcomplicationsarereducedwithregular glucosetesting.Despitetherecentdevelopmentofminimallyinvasiveglucosemonitoringtechniques,mostglucosemonitoringmethodsareinvasive,painful,timeconsuming,andexpensiveinthelongrun.Inordertoimprovethequalityoflife forpatientswithdiabetes,non-invasive,needle-free,andCGMapproachesare needed.Thepurposeofthischapteristoprovideanoverviewofdifferentchapterscoveringvariousdevicesandsensorsforinvasive,minimally-invasive,andnoninvasiveglucosemonitoringcurrentlyavailableonthemarketorindevelopment,as wellastheiraccuratereal-timeresponseandsensitivity.
Keywords Diabetesmellitus · Glucose · Monitoring · Medications · Blood pressure
Diabetesmellitus,oftenknownasdiabetes,isasetofmetabolicdiseasescharacterizedbyelevatedbloodsugarlevelsinthehumanbodyoveranextendedtime.Several differentpathogenicmechanismscausediabetes.Thesecanrangefromautoimmune destructionof β-cellsofthepancreas,resultingininsulininsufficiency,toanomalies thatresultininsulinresistance.Type1diabetes(β-celldestruction,usuallyleading toabsoluteinsulindeficiency),type2diabetes(rangingfrompredominantlyinsulin resistancewithrelativeinsulindeficiencytopredominantlyaninsulinsecretory defectwithinsulinresistance),andgestationaldiabetesmellitus(GDM-anydegree ofglucoseintolerancewithonsetduringpregnancy)arethemostcommontypes. Theglobalprevalenceofdiabeteswasprojectedtobe463millionpeoplein2019 [1].Dataindicatesthatdiabetespatientshavesurgedworldwide,withIndiabeing
K.K.Sadasivuni(B) M.Geetha CenterforAdvancedMaterials,QatarUniversity,Doha,Qatar e-mail: kishor_kumars@yahoo.com
©TheAuthor(s),underexclusivelicensetoSpringerNatureSwitzerlandAG2022 K.K.Sadasivunietal.(eds.), AdvancedBioscienceandBiosystemsforDetection andManagementofDiabetes,SpringerSeriesonBio-andNeurosystems13, https://doi.org/10.1007/978-3-030-99728-1_1
secondonlytoChinaregardingthenumberofpeoplewithdiabetes.Accordingto theInternationalDiabetesFoundation,thenumberofindividualsdiagnosedwith diabeteswouldriseto628.6millionin2045,accountingfor6–7%oftheglobal population[2].Diabetesratesgrowasthepopulation,obesity,physicalinactivity, andunhealthydietallrise.TheWorldHealthOrganizationandtheInternational DiabetesFederationhaveidentifieddiabetesasaseriousglobalproblem[3].
Theconventionalviewofdiabetesmellituspathophysiologyremainsthathereditarypredispositionunderpinsdiseaseprogression,withgeneticmutationsaffecting thestagesofbeta-cellactivity,insulinsecretion,contactwithtissuecells,insulin receptorsynthesis,andinsulinactioninsidecells.Theimmunesystemtargetsand killstheinsulin-producingbetacellsinthepancreasinpatientswithdiabetestype 1.Asaresult,thebody’sinsulinsynthesishalts.Type-2diabetesmellituscancause antibodiesagainstisletbeta-cellantigenstobeeliciteddirectlyincertainpeople. Inalldiabetesmellitus,diabetestype2accountsfor80%ofallcases.Becauseof beta-cellmalfunction,thisformofdiabetesiscausedbyarelativeinsulindeficit. Theseindividualshaveaverygradualprogressionofinsulininsufficiency,andthey areclassifiedashavinglatentautoimmunediabetes(LADA)withadelayedonset. Gestationaldiabetes(Type3)hasbecomeamajorpublichealthconcernduringa woman’spregnancy.Placentaproducesplacentalgrowthhormone(PGH)andproinflammatorycytokinessuchastumornecrosisfactor-alpha(TNF-)duringahealthy pregnancy.Insulinsensitivityisreducedinadiposetissue,liver,andskeletalmuscle duetothesevariables.Thisdiseasedoesnotaffectallpregnantwomen,butitdoes raisethedangersassociatedwithpregnancy.Itcanoccasionallycausedifficultiesfor babiesandcanalsoobstructthenormalbirthingprocess.However,afterthedelivery ofachild,thissyndromelargelysubsides.
Chronichyperglycemiacancauseseriousissuesinaperson’sbody,including damagetoandevenfailureoforganslikethekidneysandheart[4].Diabeticcomplicationsmightincludeblindness,renalillness,neurologicalandcirculatorydisease, limbamputations,stroke,andcardiovasculardisease[5].Patientsmayhavepolydipsia,polyuria,andpolyphagiaduetopersistenthyperglycemia.Diabeticcomplicationsmightalsoincludecardiovasculardiseaseandmortality[6].Othercomorbidities associatedwithdiabetesincludediabeticfoot,diabetesretinopathy,ketoacidosis,and neuropathy.Recentresearchhasdiscoveredastronglinkbetweenglucoselevelsand heartratevariability(HRV).Thisstrategyfocusesondiabetespatientsandalleviates theirfinancialandhealth-relatedproblems[7].Forpatients,atechnologythatmight giveanearlyidentificationofsuchproblemscouldbelife-changing.
In2017,thetotalcostofdiabetes-relatedhealthcareintheUnitedStateswas predictedtobeover$327billion.AccordingtotheMayoClinic,quittingsmokingand keepingthebloodpressureandcholesterolundercontrolaretwoofthetoptenstrategiestoavoiddiabeticproblems.Regularexerciseanddrinkingwaterastheprimary beveragearenotonthislist,buttheyareequallyvital.Diabetescanbemanagedwitha balanceddietand,eventually,insulininjections[8].Sleepdisruptionappearstohave aroleindiabetes,justasdiabetescancreateissueswithsleep.Sleepdeprivation raiseshungerhormoneghrelinandlowerssatietyhormoneleptinlevels[9].People whosufferfromsleepproblemsaremorelikelytoseekconsolationinhigh-sugar
mealsChapter“ReviewofEmergingApproachesUtilizingAlternativePhysiological HumanBodyFluidsinNon-orMinimallyInvasiveGlucoseMonitoring”.Optimizing glycemiccontrolbyreducingbloodglucoselevelshasbeenshowntoreducetherisk ofmicrovascularcomplicationsandlong-termmacrovasculardisease[10].Because Type1DMpatients’insulinproductionbybetacellsisreduced,pharmacological stimulationofinsulinsecretionorinsulinabsorptionisnolongerenoughtokeep theminaeuglycemicstate,andexternalinsulinsupplementationistheonlywayto keepthemthere.
Thebasisofdiabetesmanagementistimelyrecognitionofthevariationofblood glucoselevels.Effectivetherapy,especiallyforundiagnosedhypoglycemia,isonly feasiblewithgoodandearlymonitoring.Normally,bloodglucoselevelsaretested beforeameal,twohoursafterameal,andbeforegoingtobed[11].Althoughthe introductionofself-monitoringofbloodglucose(SMBG)hasinspireddiabetescare inrecentdecadesinthepursuitofeuglycemia,itsinconvenientusagemayresultin inadequatebloodglucosedatacollecting.Continuousglucosemonitoring(CGM) hasmonitoredthepattern,frequency,level,andtimeofbloodglucoselevelfluctuations.Diagnosisandmanagementofdiabetesneedregularglucosemonitoring thatisaccurate,sensitive,dependable,fast,andattentive.Withoutadequatecare, diabetescancausearangeofvascularandneurologicalproblemsaffectingvarious organsystemsintheshortandlongterm.Toavoidacuteeffects,regularcommunitybasedscreeningandtimelydiagnosisinundiagnosedindividuals,adequatepatient educationandsupport,ongoingmedicaltreatment,aswellaspsychologicaltherapy, andsocietalsupportareallnecessary.Oneofthemostdifficultaspectsofdiabetes mellitustherapyiscorrectlymonitoringbloodglucosewhileincreasingglycaemic controlandpatientqualityoflife.Topreventthediabeticpatient’shealthfromdeteriorating,regularmonitoringshouldbeperformedbyeitherthedoctororthepatient Chapter“CurrentStatusofNon-invasiveDiabetesMonitoring”.
Self-monitoringbloodglucoselevelsgiveaconsistent,trustworthy,andreliable methodofdetectingbloodglucoselevels.It’scriticaltomonitorglucoselevelsin diabeticpatientsfrequently[12].ThecurrentstandardofcareforDMdiagnosis isvenousplasmaglucosetesting.Currently,allhomebloodglucosemonitoring techniquesneedpiercingtheskintogetabloodsample.Becausethetreatments areinvasive,thistechniqueinhibitspatient’scooperationandhasseveredisadvantages[13].Thisinvasiveprocedureaidspatientsinidentifyingandavoidinghypoglycemiaandhyperglycemia.Variousmethodshavebeendevelopedtoassessglucose levels,includingcapacitive,coulometric,optical,enzymatic-electrochemical,and non-enzymaticelectrochemicalmethods[14].Themajorgoaloftheseinvestigations istocreatealesspainfulmethodandreduceinfectionrisk[15].
Thenon-invasivemethod,whichisarelativelynewtechnology,reliesonthe body’sglucosesignals.Iteliminatestheneedfor“fingerpricking”andallowsfor continuousbloodglucosemonitoring.Anovelmethodformeasuringglucoselevels usinganECGmonitorhasbeendevised.TheECGistransmittedtoasmartphone whereitistemporarilystoredandcalculatedheartratevariabilitycharacteristics. Thealgorithmthenestimatesahuman’scapacitytoregulateglucoselevelsusing advancedmachinelearningapproaches.Thisstrategyfocusesondiabetespatients
4K.K.SadasivuniandM.Geetha
andalleviatestheirfinancialandhealth-relatedproblemsChapter“ANewSolution forNon-invasiveGlucoseMeasurementBasedonHeartRateVariability”.
Proceduresinvolvingtheapplicationoffluorescentlighttothebodyinaspecific placeandtechniquesinvolvingtheimplantationofasensorinthesubcutaneous tissuecauseinterferencewiththeprocessfromsurroundingsignalssuchasultravioletandvisiblelight.Theprimaryrecognitionelementsutilizedintheconstructionof sensorsincludereceptors,antibodies,enzymes,nucleicacids,lectins,andmicrobes [16]Chapter“CommercialNon-invasiveGlucoseSensorDevicesforMonitoring Diabetes”.Abiosensorisatransducerthatconvertsabimolecularbindingevent capturedonthesurfaceofabio-receptorintoareadablephysicalquantity[17].The interactionoftheopticalfieldwithananalyteasadetectingelementcompletesthe optical-basedbiosensor[18].Alabelandanopticalsignalenhancer,suchasgold nanoparticles,fluorescentorluminouslabels,areusedinalabel-basedsensingtechnique.Thenewestmanufacturingprocessesandthemajorproblemsassociatedwith theuseofSPR,LSPR,SPRimaging,andPCbiosensorstodetectdiabetesbiomarkers arereviewedinChapter“OpticBasedTechniquesforMonitoringDiabetics”.
In2017,over51millionindividualsgloballyusedglucometers,withroughly 12%havingtype1diabetes,implyingtheyareforcedtotakeinsulintherapyanduse glucometerstomonitorthatmedicationbydefault.Diabeticpatientsmustpayfor constantorfrequentself-monitoringandbloodglucosetestingstrips(asmuchas$1 perstrip)orcontinuousglucosemonitoringsensors($350permonth),glucagon,and othermedications.Cardiovasculardiseaseaccountsformorethanaquarterofthe expendituresassociatedwithdiabetespatients.Regularfingerprickingorcontinuous glucosemetersandfrequenttripstocardiologistsarethemostcommontreatments fortheseproblems.Arecentlyproposedapproachaddressestheseissueswitha singlesystem.Simultaneously,thesolutionprovidesagadgetforcontinuouscardiac arrhythmiaandassessesaperson’scapacitytoregulatebloodglucoselevels.
Thefirstindicatorsseeninchildrenwithdiabetesarepro-insulinautoantibodies orinsulin(PAA/IAA).HighaffinitedIAAagainstpro-insulinwasalsolinkedtohigh IAAlevelswithHLADPB1*04.HbA1cisn’ttheprimarymethodfordiagnosing diabetes,butitdoesofferenoughinformationtodoso.Thesediseasesmaybeeasily diagnosedusingaboron-basedprobeproducedusingatargetedapproachandaids inrecognizingsugaronthecellsurface.Becauseoftheirgreatstabilityandstrong selectionratetowardsglucose,mostglucosesensorsuseglucoseoxidase(GOx). Mulyantietal.developedsoftwarethatwassemi-numericalandusedthetransfer matrixapproach.Theyalsodiscoveredthattheconcentrationofglucosehasasignificantimpactontheresonantwavelengthshift.Jamiletal.[19]showedthattheK-SPR techniquewithnano-laminatedAu–CrisextremelyeffectiveindetectingcreatinineandureaChapter“SPRAssistedDiabetesDetection”.Acousticspectroscopy isanothermethodfordetectingglucosesignalsusingopticalbeams;however,it suffersfromscatteringeffects,resultingininsensitivity.Multi-modalspectrography IC,whichcombinesimpedanceandnear-infraredmethods,mayalsobeusedtoassess glucoselevels.Inordertoremovediversesystemicnoises,newpracticesexploitindirectdielectriccharacteristicsofthetissuesurroundingtheblood.Theapplicationof theGaborfilterfortheanalysisoffacialcontourdataisanewapproachfordetecting
diabetes[20].Theconcentrationofacetoneinhumanbodiesisextremelylow(0.1–0.8ppm),howeverindiabetesmellitus,thisamountrisesto1.8–5.0ppm[21].Due toketonicspecies,notablyacetoneandaceto-aceticacid,whicharegeneratedwhen fattyacidsarebrokendown,peoplewithdiabetesmellitushaveinsulinproblem hormonesintheirbodies[22].Manyresearchershaveachievedabiosensorapproach fordiabeticdiagnosissinceexhalebreathacetoneisasimplediabetesbiomarker.
Theirradiationofasamplewithmonochromaticlightcausesmoleculesinthe sampletoscatterincidentlight,resultinginvibrationalspectroscopy.Theresulting spectrumdescribestheabsorptionoflightbythemoleculesinthesampleasafunction offrequency,measuredinwavenumbers.Thesespectracanbeusedtodistinguish betweendistinctfunctionalgroupsinamaterialChapter“InfraredandRamanSpectroscopyAssistedDiagnosisofDiabetics”.Surprisingly,thephoto-acousticapproach isatechnologythatallowsforahighlevelofsensitivitythroughouttheanalysis procedure.Itgoesthroughthebasicprinciplesofphotoacousticspectroscopyand howtheymaymonitorglucoselevelsChapter“PhotoacousticSpectroscopyMediated Non-invasiveDetectionofDiabetics”.
ElectricalbioimpedancecanbeusedinbothDCandACapplications.Georg SimonOhmdefinedtheimpedanceZinOhm’slawin1827,whereZisacomplex number.ArthurKennelly[23]wasthefirsttoexpressitintermsofareal(R)and imaginary(jX)portion,whereZ = R + jXand“j”istheimaginaryoperator.Alipid layercoverseachcell,primarilyforiontransportandprotection.Acellmembrane mayberepresentedasacapacitorconnectedtoaresistorinparallel.Rm(cellular membraneresistance)canberegardedassignificantlygreaterthanRext(resistance ofextracellularmedium)atlowerfrequenciesduetothecellmembrane’sunique isolatingcharacteristic.Thisactionpreventstheioniccurrentfrompenetratingthe cell,forcingittopassthroughtheextracellularmedia.Dependingonthefrequencyof theexcitationalternatesignal,biomatologicalmaterials,particularlytissue,exhibit variabledispersiontotheappliedelectricalfield.Thisisduetothedifferenttypesof freeionsfoundinextracellularandintracellularfluid.Theionicpotentialgenerated bytheexternalexcitationsignalwillpromotetheflowoffreeionsatlowerfrequencies,althoughthecellmembraneobstructsthisflow,resultinginahighimpedance. Ontheotherhand,higherfrequenciesallowtheioniccurrenttopassthroughthe cellmembranesandintracellularcontents,loweringtheresistanceinmostsituations Chapter“ElectricalBioimpedanceBasedEstimationofDiabetics”.
Millimeterandmicrowavesensingtechniqueshavethepotentialtodevelopa medicaldevicethatnon-invasivelymeasuresbloodglucosewithouttheneedfor fingerpricking,adropofblood,andtheuseofateststripe;thisallowsforthe leastamountofhassleandthebestwaytodealwithsamplestoexamineanddiagnosebloodglucoselevelsChapter“MillimeterandMicrowaveSensingTechniques forDiagnosisofDiabetes”.Toenhancehealthoutcomes,artificialintelligence(AI) isincreasinglybeingusedinmedicinetodiscoverpatternsincomplicatedcollectionsofclinicallygathereddataandself-monitoreddata.Machinelearning(ML) givescomputersthecapacitytolearnwithoutbeingexplicitlyprogrammedahead oftime.Clinicalknowledgeisenhancedbymachinelearningalgorithms,which havebeendemonstratedsuperiortoutilizingonlyoneindiseasetreatmentChapter
“DifferentMachineLearningAlgorithmsInvolvedinGlucoseMonitoringtoPrevent DiabetesComplicationsandEnhancedDiabetesMellitus”.Diabeticpatients,clinicians,andsmarthealthcaresystemsareallareaswhereartificialintelligencemay aidandimprovediabetestreatment.AItechnologiesondiabetesallowformore effectivedataprocessingandtoolsandgadgetstohelppatientscontroltheircondition.PatientswithdiabetesnowhavenewusesforAI,suchaspatientsurveillance, fastdecision-making,andriskprediction[24].SeveralsophisticatedArtificialIntelligencesystemshavebeenwidelyutilizedtoenableadvancedanalysesandgive tailoredmedicalhelptodiabeticpatientsChapter“TheRoleofArtificialIntelligence inDiabetesManagement”.
Withtheriseinavailabledataandprocessingcapacity,data-driventechniquesare provingtobemoreefficient.DSShasbecomemoreefficientbecauseofimprovementsinAI/MLandglucosesensortechnologies[25].AdiabeticDSSmaybe dividedintotwocategories:patientDSSandclinicalDSS(CDSS)Chapter“ArtificialIntelligenceandMachineLearningforDiabetesDecisionSupport”.Researchers havemostlyconcentratedonthemanufacturingofelectrodesurfacesinordertobuild nonenzymaticglucosesensors[26].Long-termbloodglucosecontrolindiabeticindividualshasbeendemonstratedtoextendlifeexpectancy[27].Chapter FutureDevelopmentsinInvasiveandNon-invasiveDiabetesMonitoring outlinesthenon-invasive glucosemonitorsthatareusedtomanagediabetes.Thebenefitsanddrawbacksof themostrecentcommercialremoteglucosemonitoringsystemshavebeenevaluated Chapter“FutureDevelopmentsinInvasiveandNon-invasiveDiabetesMonitoring”.
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ReviewofEmergingApproaches UtilizingAlternativePhysiological HumanBodyFluidsinNonorMinimallyInvasiveGlucose Monitoring SunghoonJang,YuWang,andAndreJang
Abstract Diabetescancausevariousacuteaswellaslong-termcomplicationsin patientswithbloodsugarlevelsofover600mg/dL,suchasblindness,kidneydisease, nervousandcirculatorysystemdisease,limbamputations,stroke,andcardiovasculardisease(CVD).Frequentandregularbloodglucosemonitoringbydiabetics andphysiciansisanessentialstepinthemanagementofdiabetes.Overthelastfive decades,therehavebeennumerousattemptstodevelopviablepainless,non-orminimallyinvasivebloodglucosemonitoringtechniquestoreplaceallexistinginvasive methods,suchashomebloodglucosemonitoring,whichusuallyrequiredrawinga bloodsamplebypiercingtheskin(typically,onthefinger).Thismethodstrongly discouragesthepatients’complianceandhasseriousdrawbacksastheprocedure isinvasive,causingdiscomfort,pain,andpotentialrisksofinfectionortissue damage.Itishighlydesiredtohavealternativenon-invasivebloodglucosemonitoringtechniques.Thisreviewinvestigatestheprinciplesofthreemajoremerging generaltechnologies,namelyoptical,RadioFrequency(RF)/microwave,andelectrochemicalglucosemonitoringtechnologies.Theseglucosemonitoringtechnologies canbeclassifiedas15specifictechniquesthatusemultivariateregressionanalysestocorrelatefeebleoptical,RadioFrequency(RF)/microwave,orelectrochemicalsignalsfromvariousbodyfluidstophysiologicalglucoseconcentration.This reviewalsooffershow-toutilizeglucose-sensingtechniquestotargetvariableareas bysamplingphysiologicalhumanbodyfluidsasanalternativediagnosticmedium toblood;forexample,interstitialfluid,urine,sweat,ocularfluids,andsalivaall
S.Jang(B) Y.Wang
DepartmentofComputerEngineeringTechnology,NewYorkCityCollegeofTechnologyof CUNY,300JayStreet,Brooklyn,NY11201,USA
e-mail: sJang@citytech.cuny.edu
Y.Wang
e-mail: yWang@citytech.cuny.edu
A.Jang
DepartmentofPhysiologyandNeurobiology,UniversityofConnecticut,Storrs,CT,USA
e-mail: Andre.Jang@uconn.edu
©TheAuthor(s),underexclusivelicensetoSpringerNatureSwitzerlandAG2022 K.K.Sadasivunietal.(eds.), AdvancedBioscienceandBiosystemsforDetection andManagementofDiabetes,SpringerSeriesonBio-andNeurosystems13, https://doi.org/10.1007/978-3-030-99728-1_2
containtracesofbloodglucose.Thefeasibilityofadoptingtheseemergingtechnologiesinthecommercialmarketisdiscussedregardingsafety,cost-effectiveness, datamanagement,andaccuracy.
Keywords Bloodglucosemonitoring · Diabetics · Non-orminimallyinvasive · Optical · RF/Microwave · Electrochemical · Targetingareas · Physiological humanbodyfluids
1Introduction Diabetesmellitus,commonlyreferredtoasdiabetes,isadiseaseinwhichthebody doesnotproduceorproperlyuseinsulin,causinghighbloodsugarlevelsovera prolongedperiod.Thischronicdiseaseisamongthetopleadingcausesofdeath globallythatrequirelong-termmedicalattention[1].Often,diabetescanleadto manyseriousmedicalproblems.Theseincludeblindness,kidneydisease,nervous andcirculatorysystemdisease,limbamputations,stroke,andcardiovasculardisease (CVD)[2, 3].Accordingtodatafromthe2020NationalDiabetesStatisticsReport, diabeteswastheseventhleadingcauseofdeathintheUnitedStates,andanestimated 34.2millionchildrenandadultsor10.5%oftheUnitedStatespopulation,including 7.3millionundiagnosedpeople—2.8%ofallU.S.adultshavediabetes.Theestimated directandindirectcostsofdiabetes-relatedhealthcareintheUnitedStateshaverisen toapproximately$327billionannuallyin2017from$188billionin2007,a$90 billionindirectmedicalcosts.Diabetesisadisproportionatelyexpensivedisease; intheUnitedStates,theindividualmedicalcostperpersonassociatedwithdiabetes increasedfrom$8417to$9601between2012and2017.In2017,theindividual costofhealthcarewas$16,750fordiabetes,whileabout$9600ofthisamountwas attributedtodiabetes[4, 5].
Therecentmulti-centerNIHstudieshaveindicatedthatthehealthrisksassociated withdiabetesaresignificantlyreducedwhenthebloodglucoselevelsarewelland frequentlycontrolled,indicatingthatitisprudenttomeasurethebloodglucoseas oftenasfiveorsixtimesaday.Thus,itisveryimportantthatpropermonitoringbe donebydiabeticsathomeorwork[6].Atpresent,allexistinghomebloodglucose monitoringmethodsrequiredrawingabloodsamplebypiercingtheskin(typically, onthefinger).Thismethodstronglydiscouragesapatients’complianceandhas seriousdrawbacksbecausetheproceduresareinvasive[7].
Additionally,arecentMayoClinicreportlisted10waystoavoiddiabetescomplications.Theirrecommendationsincluded:(1)Committomanagingyourdiabetes. (2)Donotsmoke.(3)Keepyourbloodpressureandcholesterolundercontrol.(4) Scheduleregularphysicalsandeyeexams.(5)Keepyourvaccinesuptodate.(6) Takecareofyourteeth.(7)Payattentiontoyourfeet.(8)Consideradailyaspirin. (9)Ifyoudrinkalcohol,dosoresponsibly.(10)Manageyourstress[8].However, notincludedinthislistarejustasimportantasregularexerciseandchoosingwater asyourprimarybeverage.
2AlternativePhysiologicalBodyFluidstoBlood Sinceanon-invasivemethodofmonitoringbloodglucosewouldpresentmajoradvantagesoverexistinginvasivetechniques,manyresearchgroupshaveattemptedto proposenumerousattractivealternativesintermsofnon-orminimallyinvasive glucose-sensingtechniqueswithinthephysiologicalglucoseconcentrations(18–450mg/dl)inhumanblood.Theseapproacheshavedemonstratedpromisingresults throughin/exvivoandinvitroexperimental/clinicalglucoseevaluations.Through ourpreviousstudy,weattemptedtoreviewthenumberofemergingnon-orminimallyinvasivetechniquesandmethodsandprovidedacomprehensivelistinterms ofapplyingalternativephysiologicalbodyfluidsasopposedtoblood[9].
Physiologicalbodyfluidsarehighlycomplexmixturesofavariableconcentration ofcells,proteins,macromolecules,metabolites,smallmolecules,includingglucose [9, 10].Althoughbloodisthemostcommonlystudiedbodyfluidandisconsidered asthegoldstandardmediumfordetectingglucoseconcentration,otheremerging biologicalbodyfluidssuchasinterstitialfluid(IF),urine,sweat,saliva,orocular fluids,aremoreaccessibleduetothesignificantadvanceofnanotechnology.The amountofglucosecontainedinthebiologicalbodyisproportionaltoitsconcentration intheblood.Thesefluidshavebeenutilizedasattractivealternativesamplemedia fornon-invasivecontinuousmonitoring.Theglucoselevelinthesebodyfluidsis identicaltotheglucoseconcentrationinthebloodplasma.Table 1 summarizesthe comparisonandcontrastofthekeyaspects,includingglucoseconcentrationfor diabeticsandnon-diabetics,pHlevel,andtimelagofthevariousphysiologicalbody fluidsunderthecurrentreview.
Blood hasbeenthegold-standardmediumforglucosemonitoringsincemeasurementscarriedoutinthisfluidwerefirstintroducedin1953[25, 26].Bloodis
Table1 A summaryofrelevantglucoseconcentrations,timelag,andpHvaluesmeasuredin physiologicalbodyfluidsofdiabeticsandnon-diabetics
Bodyfluid Glucose concentrationfor non-diabetics (mg/dl)
Glucose concentrationfor diabetics(mg/dl)
Blood 70–130[2, 11] 36–720[2, 11, 12] 7.35–7.45[10, 12] –
Interstitialfluid 65–118[13, 14] 35.8–400[12–14] 7.20–7.40[10, 12] ~10[14, 15]
Urine 10.8–27.1[16, 17] 50.1–100[16, 18] 4.50–8.00[10, 12] ~20[16, 19]
Sweat 1.1–1.98[10, 12, 20] 0.18–18.0[10, 12, 20] 4.60–6.80[10, 12] ~20[18]
Saliva 4.14–10.3[12, 21, 22] 9.91–31.9[21–23] 6.20–7.40[10, 12] ~15[23]
Ocularfluids 1.8–9.0[18, 24] 9.01–90.1[18, 20, 24] 6.50–7.50[10, 12, 24] ~10[10, 24]
Timelagisthetimerequiredtodiffusebloodfromthecapillariestothetissues[9]
complexplasmacontainingmetabolitesandelectrolytes(sodium,potassium,chloride,calcium,bicarbonate,glucose,urea,andcreatinine)[10].Thesensorusingelectrochemical/amperometricenzymeelectrodesandtransducers,employedthenonorenzymeglucoseoxidase(GOx)andglucosedehydrogenase(GDH)utilizingthe biochemicalreaction,hasbecomethemostpopularandcommerciallyavailableblood glucosemonitoringmethodinthemarketbecauseofitssuitablesensitivity,wide selectivity,goodreproducibility,andeasymanufacturabilityatrelativelylowcost, althoughitisaninvasivemethod[26].Severalnon-invasivemethodsareusedtodetect andmonitortheglucoselevelintheblood,includingAbsorbancespectroscopysuch asNearandMidInfraredspectroscopy,Ramanspectroscopy,Photoacousticspectroscopy,Fluorescencespectrophotometry,Bio-impedancespectroscopy,Optical coherencetomography,andThermalemissionspectroscopy[27–37].
Interstitialfluid istheextracellularfluidthatfillsthespacesbetweenmostof thebody’stissuecellsandmakesupasubstantialportionoftheliquidenvironmentofthebody.Ithassignificantpotentialformedicaldiagnosticsasit closelyresemblesbloodplasmaincompositionbutcontainslessprotein[10, 38].Sincetinymolecularbiomarkersareexchangedasbiochemicalinformation betweenbloodandsubcutaneousISFthroughdiffusion,thecorrelationbetween ISFandbloodcanbeusedtoindirectlyobtainthediagnosticinformationof patients.Methodsformonitoringglucoseviatheskinhavebecomeverypopular inrecentyears,wheretheseapproacheshavebeendevelopedtocounteractthe challengesassociatedwithpatientcomplianceandinvasivemonitoring.Someof theseapproachesincludeReverseiontophoresis,Electrochemicalmethods,Electromagnetictechniques,Metabolicheatconformation,Microwaveresonator-based technique,Sonophoresis,andBio-impedancespectroscopy[39–47].
Urine isacommonlycollectedsampleforclinicalandnonclinicaltesting,especiallyduetotheeaseofcollection,usuallywithoutinvasiveprocedures.Urineis composedofinorganicsaltsandorganiccompounds,includingproteins,hormones, andawiderangeofmetabolites,includingglucose[10, 48].Itisrelatedtoapplying anenzymeandnanomaterials-basedbiosensorasimportantmethodsformonitoringglucoseconcentrationwithinthephysiologicrange,includingColorimetric biosensingutilizingEnzymaticnanomaterials,Laser-generatedphotonicnanosensor, andPhotoniccrystal-basedbiosensor[48–51].
Sweating isaprimarybiologicalroleofthermoregulation.Sweatisconsideredone ofthemostaccessiblebodyfluidsforglucosedetection.Sweatiseasilyaccessible forsamplingwithsufficientquantitiesandrapidreproductioncomparedtoallother bodyfluids.Sweatisanacidicelectrolyte-richfluid,anditsproductionisinducedby exercise,resultinginthesecretionofmetabolites,suchaslactate,glucose,alcohol, anduricacid[10, 12].Morerecentstudiessuggestadirectcorrelationbetween sweatandbloodglucoseconcentration,althoughglucoselevelsinsweatareofa muchsmallerconcentrationthanthoseinblood.Wearablesweat-basedcontinuous glucosemonitoringbiosensorsincludenon-orEnzyme-basedelectrochemicaltechniques,Opticalfiberlong-periodgrating(LPG),andElectrochemicallyenhanced
iontophoresisintegratedwithfeedbacktransdermaldrugdeliverymoduleareunder development[43–45, 52–55].
Saliva isincreasinglyrecognizedasanattractivediagnosticfluidbecauseitcanbe collectednon-invasivelywithoutemployingspecificdevicesortrainedpersonnel. Morerecentstudiesinvestigatedandconfirmedasignificantcorrelationbetween salivaryandbloodglucoselevelsindiabeticsandnon-diabetics.Salivaisacomplex mixtureof99.5%waterand0.5%electrolytes(amylase,lipase,mucin,glycoproteins,glucose,andantimicrobialenzymes)[10, 56].Salivacanbeutilizedas analternativetobloodandcanbemonitoredbyanon-invasivemeasuringsalivaryglucose.Somenon-invasivetechniquesforsalivaglucosemonitoringhave beenstudiedincludeEnzyme-basedelectrochemical/Amperometric/Colorimetric nano-biosensorandFunctionalizedcarbonnano-tubeFET/organicelectrochemical transistor[23, 43–45, 56–61].
Ocularfluids includetears,aqueoushumor,andvitreoushumor,whicharepromising fluidsbecausetheglucoseconcentrationofocularfluidsishighlycorrelatedto bloodglucose.Monitoringtheglucoseconcentrationinthefluidsisconsidered arelativelynewtechniquethatisaworthwhilealternativetoinvasivemethods forrepetitiveorcontinuousmonitoring.Ocularfluidsexcretedfromthebody asanextracellularfluidcontainglucosewater,mucin,lipids,lysozyme,lactoferrin,lipocalin,lacritin,immunoglobulins,glucose,urea,sodium,andpotassium[10, 12, 23].Researchworkingtowardsnon-invasivemonitoringmethods ofglucoseintheocularfluidsconsistsofChronoamperometrictechnique,Electrode/electrochemicallyembeddedcontactlens,CMOS/Amperometricneedle-type electrochemicalmethod,Opticalcoherencetomography(OCT),Fluorescencespectrophotometry,Ocularspectroscopy,andOpticalpolarimetry[62–68].
3EmergingNon-orMinimallyInvasiveGlucose MonitoringTechniques Throughtheliteraturesearchforthecurrentreview,welearnedthattechniques fornon-orminimallyinvasivemonitoringglucoseviatheskinhadbecomethe mostpopularapproachinrecentyears,wherethesemethodshavebeendevelopedto counteractthechallengesassociatedwithpatientcomplianceandinvasivemonitoring [18, 27].Thedescriptionandtargetareasoftheleadingapproachesarepresentedin Table 2,mainlyclassifiedasOpticaltechnology,includingAbsorbancespectroscopy, Ramanspectroscopy,Photoacousticspectroscopy,Opticalcoherencetomography (OCT),Fluorescencespectrophotometry,Ocularspectroscopy,andMetabolicheat conformation.Theavailabilityofthenon-orminimallyinvasiveglucosemonitoring devicesinthemarketisalsoshowninTables 2, 3 and 4,respectively.Somedevices havebeenwithdrawnfromthemarketduetoinaccuracy,unreliability,inconsistency,
Summarizestheprincipleandtargetareas/bodyfluidsofthelatestspecializedapproachesintermsofemergingnon-orminimallyinvasiveglucose monitoringtechniquesaftermainlyclassifyingcategoriesasopticaltechnology
Targetareas(bodyfluids)
Fingertip,palm,forearm,innerlip,andearlobe(blood andinterstitialfluid)[ 12 , 27 , 28 ]
Description
Measurestransmittance,reflectance(includingdiffuse reflectance),andinteractionofthelightwhendirected overthesampletissuesforanalyticalpurposes. Near-infraredabsorptionspectroscopy( NIR )usesabeam oflightwith750–2500nm.Mid-infraredabsorption spectroscopy( MIR )uses2500–10,000nm,whichare focusedonthebodytodetermineglucoseconcentration withintissues.Thelightandsampletissueinteractions producemolecular-specificvibrationalinformationofthe absorptionandscatteringphenomenonintheinfrared spectraldomain[ 12 , 27 , 28 ]
Finger,arm,eye,wrist,hand(ocularfluidsandblood)
[ 27 , 29 ]
Appliesaspectroscopictechniqueusingthescattering phenomenonofmonochromaticlighttoobserve vibrationalandrotationalstateswithinmolecules.When single-wavelengthlighthitsatarget,itproducesscattered lighttravelinginalldirections.Thedegreesofscattering duetoglucosemoleculesarepurelydependentontheir concentrationlevels[ 27 , 29 ]
Finger,arm,andearlobe(bloodandinterstitialfluid) [ 12 , 30 , 69 ]
Employslaserpulseswithawavelengththatisabsorbed byaspecificmoleculeinthebodyfluidtoproduce localizedheating,dependentonthespecificheatcapacity ofthetargetedtissue,andmeasurestheeffectoflight absorptiontodetectaglucoseconcentrationinblood basedonthevelocityofultrasonicwavesgeneratedin glucosesolutionbythephotoacousticprincipal[ 30 , 69 ]
(continued)
Table2
Opticaltechnology
Specifictechnique
a,b,c
Absorbancespectroscopy
Ramanspectroscopy
b,c
Photoacousticspectroscopy
b,c
Table2 (continued)
Forearmandeye(ocular/interstitialfluidsandblood)
[ 31 , 32 ]
c Includesopticalmethodswithultrasound,impedance, andheatcapacitance.Thistechniqueappliesthe principlesoflowcoherenceinterferometrywithcoherent radiationanddeterminestheglucoseconcentration presentbydetectingthechangesofopticalcharacteristics ofbio-tissuesatmicrometerresolutions,including intensity/delayofthereflected/scatteredandtransmitted lightuponinteractionwiththesubcutaneoustissueby employinganinterferometerwithcoherentlight,witha wavelengthbetween800and1300nm[ 31 , 32 ]
Finger,abdomen,upperarm,andeye(blood, ocular/interstitialfluids)[ 33 , 34 ]
Appliestheprincipleoffluorescentlightemissionofan ultravioletlaserbeam(340–400nm)afterabsorbing radiationofadifferentenergylevelwhichcausesa wavelengthdifference.Themeasurementofthe concentrationofglucosemoleculesinthebloodis conductedutilizingasensitiveproteinandintensityof fluorescencewhichareproportional[ 33 , 34 ]
Eye(tears)[ 35 , 36 ]
Utilizesthespeciallydesignedhydrogel-baseddisposable tearglucose-sensingcontactlenses,whichchangecolor dependingontheglucoseconcentrations.The fluorescenceresponsefromthelensescanbemonitored usingsimpleexcitationandemissiondetectiondevices andservesasthetoolforbloodglucosedetectionsfrom thetears[ 35 , 36 ]
(continued)
Opticaltechnology
Opticalcoherencetomography(OCT)
Fluorescencespectrophotometry a,c
Ocularspectroscopy c
Table2 (continued)
Fingertip,earlobe,andforearm(bloodandinterstitial
fluid)[ 12 , 41 , 42 ]
Measuresphysiologicalparametersassociatedwiththe generatedquantityofmetabolicheatdissipation,blood flowrateoflocaltissue,anddegreeofbloodoxygen saturationbetweentheskinandcontactedconductor correspondingtotheglucoseconcentrationbyemploying thesystemconsistingofthermal,humidity,infrared,and opticalsensors[ 41 , 42 ]
Eye(ocularfluids)[ 67 , 68 ]
Appliesthephenomenonoftheopticalactivity,whichisa certainrotationofthepolarizedplaneoftheincidentlight (400–780nm)passingthroughtheaqueoushumorofthe eyeandglucose,knownasanopticallyactivemolecule. Whenthelightispassedthroughthecorneaandacross theanteriorchamberoftheeye,thepolarimetricsignal thatisconvertedintoatime-varyingvoltagebythe photodetectorvarieslinearlywithchangesinglucose concentration[ 67 , 68 ]
a,b,c
Opticaltechnology
Metabolicheatconformation
c
Opticalpolarimetry
a Commerciallyavailable
b Withdrawnfromthecommercialmarket
c Underdevelopment
Summarizestheprincipleandtargetareas/bodyfluidsofthelatestspecializedapproachesintermsofemergingnon-orminimallyinvasiveglucose monitoringtechniquesaftermainlyclassifyingcategoriesaselectrochemicaltechnology
Targetareas(bodyfluids)
Wrist,arm,andleg(sweatandinterstitialfluid)[ 12 , 39 , 40 ]
Table3
Electrochemicaltechnology
Description
Appliesapassageoflowelectricalcurrenttoenhance thetransportofbothchargedandpolar,neutral compoundsacrosstheskintodriveionsbetweentwo electrodesfromtheinterstitialfluidandontotheskin’s surface,wheretheycanbeanalyzedintermsofglucose concentration.Transdermalreverseiontophoresis(RI) isanon-invasivetechniquethatcansamplebodyfluids acrossintactskintoachievethepurposeofblood glucosedetection[ 39 , 40 ]
Finger,arm,andskin(blood,saliva,urine,tears, interstitialfluid,andsweat)[ 10 , 12 , 43 , 44 ]
Analyzestheglucoseoxidationthattookplaceinthe presenceofGOx,oxygen,andwatertoformgluconic acidandhydrogenperoxide.Thehydrogenperoxideis thenelectrochemicallyoxidizedattheelectrode,which convertsglucoseoxidaseactivityintoananalytical electricalsignalinproportiontoglucoseconcentration basedontherateofglucoseoxidationbydioxygen, measuredbytheformationofhydrogenperoxide. Highlyselectiveenzymaticreactionscanbeusedto diminishtheinfluenceofelectroactiveinterfering species[ 43 , 44 ]
(continued)
Specifictechnique
Reverseiontophoresis a,c
Enzymaticelectrochemicalelectrode a,c
Table3 (continued)
Finger,arm,eye,andskin(blood,saliva,urine,tears, interstitialfluid,andsweat)[ 12 , 43 , 45 ]
Usesmetal–organicframework(MOF)-based nanocompositesandprovidesanalternativetoan enzymaticmethod,whichisimpossibletoimplantinto thehumanbodyforthelongtermandinsitu monitoringsincetheimmobilizedenzymewould degradequickly.Cost-effectivenon-enzymatic amperometricglucosebiosensorswithhighsensitivity, selectivity,andstabilitycouldbecommerciallymore feasible[ 43 , 45 , 46 ]
Finger,arm,eye,urine,andskin(sweat,tears,and urine)[ 12 , 19 , 48 , 49 ]
Determinestheglucoseconcentrationwiththeaidofa colorreagent.Whenglucoseisoxidizedbyglucose oxidaseintoD-gluconicacidplushydrogenperoxide, thehydrogenperoxideisthendetectedwithahighly specificcolorimetricprobe.Inanenzymaticanalysis, thecolorreactionisprecededbyareactioncatalyzed byanenzyme[ 48 , 49 ]
Electrochemicaltechnology
Non-enzymaticamperometricelectrode a,c
Colorimetricdetection a,c
a Commerciallyavailable
b Withdrawnfromthecommercialmarket
c Underdevelopment
Summarizestheprincipleandtargetareas/bodyfluidsofthelatestspecializedapproachesintermsofemergingnon-orminimallyinvasiveglucose monitoringtechniquesaftermainlyclassifyingcategoriesasRF/microwavetechnology
Targetareas(bodyfluids)
Finger,hand,wrist,arm,andearlobe(interstitialfluidandblood) [ 12 , 70 –74 ]
Table4
Description
RF/microwavetechnology
Specifictechnique
Thumb,upperarm,wrist,andabdomen(interstitialfluidandblood)
[ 12 , 69 , 75 , 77 , 78 ]
Utilizestheinteractionbetweenelectromagneticwavesand biologicaltissuessincemicrowaves’reflection,transmission,and absorptionarecloselyrelatedtothedielectricpropertiesof tissues,wherethedielectricconstantvarieswithglucose fluctuations.Microwavescaneasilypenetratebiologicaltissuesof millimeterthickness,soglucoseconcentrationvariationinISFhas muchhighersensitivityonphaseandmagnituderesponseofthe sensorthanitsvariationsinblood[ 70 –74 ]
Microwaveresonator-based a,c
Measurestheglucose-dependentelectricalimpedancechangesas afunctionoffrequencyandprovidesproofofachangeinblood impedancewithglucoselevelfluctuations.Impedanceisrecorded asafrequencybypassingRFcurrentbetween100Hzand 100MHzacrosshumanbiologicaltissuesandskin.Theglucose moleculeismeasuredbyitsconcentration-dependentinteraction withredbloodcells[ 75 –78 ]
Bio-impedancespectroscopy a,c
Arm,wrist,andabdomen(interstitialfluidandblood)[ 12 , 69 ]
Useslow-frequency(20kHz)ultrasoundtoincreaseskin permeabilityandcausesexpansionandcontractionofgaseous inclusionsthatopenpathwaysforinterstitialfluidstotransport glucosetotheepidermis,whereitismeasuredtransdermallywith thecombinationofthelow-profilecymbalarrayandan electrochemicalglucosesensorconsistingofamperometric electrodesandanovelglucoseoxidasehydrogel.Thistechnique createsmicroporesintheskintoenabletheinterstitialfluid containingglucosetocomeoutside[ 69 , 79 ]
a,c
Sonophoresis
a Commerciallyavailable
b Withdrawnfromthecommercialmarket
c Underdevelopment
andotherissues.Meanwhile,othershaveneverbeenintroducedduetotheirunclear circumstanceissues.
ElectrochemicaltechnologyincludesReverseiontophoresis,Enzymaticelectrochemicalelectrodes,Non-Enzymaticamperometricelectrodes,andColorimetric detectionmethod,allpresentedinTable 3
RF/MicrowavedetectiontechnologyincludesMicrowaveresonator-based method,Bio-impedancespectroscopy,andSonophoresis,presentedinTable 4
4Conclusions Thisstudyaimedtopresentandreviewthelatestspecializedapproachesinemerging non-orminimallyinvasiveglucosemonitoringtechniquesaftermainlyclassifying categoriesasoptical,electrochemical,andRF/Microwavemethods.Theseglucose monitoringmethodsconverttheweakoptical,electrochemical,orelectromagnetic signaltoglucoseconcentration.Wealsoinvestigatedthenon-orminimallyinvasive glucosemonitoringtechniqueswhichutilizevariousphysiologicalbodyfluidsasan alternativediagnosticmedium.Thesetechniqueshaveagreatpotentialformonitoringbloodglucoselevelsastheyincreaseaccuracy,selectivity,sensitivity,and reliabilityofthemeasurementthatwouldsatisfymedicalusecriteriaandmeetthe expectationasalessexpensivealternative.
Ourcurrentstudylearnedthatopticalandmicrowavemethodshaveadvantages overelectrochemicalmethodsbecausetheyofferpurelynon-invasiveandcontinuous monitoringwithoutstimulatingdiscomforttothehumanbody.However,invasiveor minimallyinvasiveelectrochemicalglucosemeterswithmoreadvancedenzyme andelectrodematerialshavesignificantlyimprovedbecausetheyareconsidered morereliableandaffordable.Electrochemicaldiagnosticdevicesareequippedwith software-basedanalyticalperformanceanddatamanagement,capableofupdating devicefeatureswithoutrecalibration,andlessexpensive.Therefore,thecurrentdominatingelectrochemicalglucosesensorsinthecommercialmarketwillnotbeeasily replacedeveniftheyareinvasiveuntilpromisingnon-invasiveglucosemeterswith themoresensitive,efficient,intelligent,robust,andreliablemeasurementsthatcan satisfymedicalusecriteriaisintroducedtothemarket.
5FutureTrends Thisreviewcoverstheresearchprogressofthelatesttechnologiesandtheirmethods ofnon-orminimallyinvasiveglucosemonitoringwithalternativephysiologicalbody fluidssuchasinterstitialfluid,urine,sweat,ocularfluids,andsalivainsteadofblood glucoseconcentration.Considerableprogresshasbeenmadeindevelopingviable non-orminimallyinvasiveglucosesensorsinrecentyearsduetodevotedresearch effortsandtherevolutionofbiomaterials,medicine,nanotechnology,andcomputer
science.Althoughtherehavebeenmanydedicatedresearcheffortswithnumerous progressionstodevelopanon-orminimallyinvasiveglucosemonitoringsensor, therearestillseveralobstaclestoachievingacceptableglucosemonitoringbecause ofthecomplicatednatureoftheoperationandmeasurementprocess.
Throughourmorerecentsearches,wealsolearnedthatseveralnon-orminimallyinvasiveglucosemonitoringdevicesusingoptical,electrochemical,and RF/microwavetechnologieshadbeenintroducedcommerciallyinthemarket,and othersareclosetocommercializing.However,weconcludedthatthesemethods arestillfarfrombeingclinicallyreliabletomeetmarketexpectations.Theyrequire furthersystemicdevelopmentandclinicalevaluationsduetoalackofconsistency, stability,accuracy,andreliability.Theremarkableadvancesinanemergingtrendto integrateaseriesoffunctionalmodules,dataminingalgorithms,wirelesscommunications,machinelearningalgorithms,andcomputationalsignalprocessingledto significantachievementsallowingthecreationofnewhypothesesthatenabledeeper understandingandfurtherinvestigationsofnon-orminimallyinvasiveglucosemonitoringdevices.AI-drivenwearablemonitoringdevicesmaybeintroducedtothe currentmarket,makingitpossibletocollectadiverserangeofcontinuousphysiologicalsignalstoaccuratelymonitorthefollowing:glucoselevelsindiabetics, sweat,anxiety,heartrate,bloodpressure,nutrition,calorieintake,andCOVID19relatedsymptomsinadvance.Furthercontinueddevelopmentofsophisticated decisionsupporthardwareandsoftwaresystemswillyieldgreatopportunitiesto introducemorereliableandaffordablenon-invasiveglucosemonitoringsystemsin thebroadcommercialmarketformedicalusewithintheverynearfuture.
Acknowledgements WewouldliketoacknowledgetheassistanceprovidedbyEileenDengfor reviewingandeditingthismanuscript.
ConflictofInterest None.
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