Handbook of Biophotonics (3-Volume Set)

2007 Pages·54.947 MB·English

by  Popp J., Tuchin V.V., Chiou A., Heinemann S.H. (Eds.)

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Introduction to Biophotonics
MarionJu€rgens,ThomasMayerh€ofer,andJu€rgenPopp
1.1
DefinitionofandGeneralIntroductiontoBiophotonics
1.1.1
Definition
Biophotonics is an emerging multidisciplinary research area, embracing all light-based
technologies applied to the life sciences and medicine. The expression itself is the
combinationoftheGreeksyllables“bios”standingforlifeand“phos”standingfor
light.Photonicsisthetechnicaltermforallmethodologiesandtechnologiesutilizing
lightoverthewholespectrumfromultravioletthroughthevisibleandtheinfraredto
theterahertzregion,anditsinteractionwithanymatter(Figure1.1).
Beyondthisdefinition,biophotonicsisascientificdisciplineofremarkablesocietal
importance.Forhundredsofyears,researchershaveutilizedlight-basedsystemsto
explorethebiologicalbasicsoflife.Aftertheinventionofthelightmicroscopedating
backtotheseventeenthcenturyandthesystematicimprovementsintroducedbyCarl
Zeiss,ErnstAbb(cid:2)eandOttoSchottinJenainthenineteenthcentury,itbecamean
essentialtoolinthelifesciencesandmedicineandhadacrucialinfluenceonthe
workofbiologistsofthistime,suchasErnstHaeckel.Sincethen,itsimportancehas
grownevenstronger.Today,ultrahighresolvingmicroscopesenableustoobserve
cellularstructuressmallerthan20nmacrossandtheirfunctions,andthustostudy
diseasesrightattheirorigin.Wealsobenefitgreatlyfromphotonictechnologiesin
medicalpractice–infactbothindiagnosisandintherapyofdiseases.Forexample,
laserscalpelshavebecomeroutinetoolswhichreducetheexpenseofmanysurgeries,
sometimesevendowntoanambulantintervention(“keyholesurgery”).Duetonovel
photonictechnologiessuchasfluorescenceendoscopyandphotodynamictherapy
(PDT),sometypesofcancercanberecognizedmuchearlierandtreatedmoregently
thanseveralyearsbefore.Inophthalmology,opticalcoherencetomography(OCT)
has become the gold standard for detecting morphological changes in the eye by
adding the third dimension, helping to obtain high-resolution 3D images of the
retinaanddiagnoseprevalentdiseasessuchasglaucomaandmaculardegeneration.
HandbookofBiophotonics.Vol.1:BasicsandTechniques,FirstEdition.
EditedbyJu€rgenPopp,ValeryV.Tuchin,ArthurChiou,andStefanH.Heinemann.
(cid:1)2011Wiley-VCHVerlagGmbH&Co.KGaA.Published2011byWiley-VCHVerlagGmbH&Co.KGaA.
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Figure1.1 Sheddinglightonlife:biophotonicsutilizeslight-basedtechnologiesforapplicationsin
medicineandthelifesciences(fluorescenceimage:PCOAG).
The widespread use of biophotonic systems and methods is also reflected in
economic terms. Regarding market shares as well as growth rates, biophotonics
belongstothemostimportantsectorsoftheglobalphotonicsmarket[1,2].
1.1.2
VisionsConnectedwithBiophotonicsResearch
The controlled use of light has already revolutionized life in many respects
(Figure1.2).Thereishighhopethatlightasatoolwillprovidefurtherbreakthroughs
inthelifesciencesandmedicine,andalsoincloselyrelatedtopicsandsubjectssuch
asnutrition,theenvironmentandwell-beingingeneral.Acurrentexamplefromthe
fieldofmedicineisanovelapproachfortheearlyrecognitionofAlzheimer’sdisease,
whichso far is consideredincurable. Inthenextfew years,fluorescence imaging
could provide reliable early recognition and help to verify novel therapeutic
approaches which aim at an early intervention in the future [3]. Basically, light
allows us to explore cellular structures and functions rapidly and with utmost
sensitivity and precision. At the same time, light allows us to manipulate tissues
andcellularstructureswithoutdamagingthem.Thesefeaturesmakelightaunique
toolforthewholerangeofmodernmedicine:
1) Understandingdiseasesonamolecularlevel:Lighthelpstoexplorefundamental
life processes on a cellular and molecular level, and thus to develop novel,
targetedtherapies.
2) Earlyrecognitionofdiseases:Lightallowsustorecognizechangesonthecellular
scaleasearlysignsofdiseases,evenlongbeforemanifestsymptomsoccur.The
earlieristhediagnosis,thebetterarethechancesofhealing.
3) Targetedtreatmentofdiseases:Lightmeasuresandcuresinacarefulmanner,
pavingthewaytowardsminimallyinvasivemedicine.
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1.1 DefinitionofandGeneralIntroductiontoBiophotonics 3
Figure1.2 Visionsconnectedwithbiophotonics(photographs:LMUMunich/BIZ,Worldof
MedicineAG,FraunhoferIZM).
4) Preventing diseases: Light can measure a multitude of health-relevant para-
meters, including endogenous parameters such as genetic dispositions and
physiologicalconditions,andalsoexogenousparameterssuchaspathogensin
air, water,and food. This helps to monitorthehealth stateof individuals and
possible harmful influences, which is an important prerequisite to prevent
diseases.
Thus the term “biophotonics” covers a wide spectrum of biomedical questions
fromunderstandinglifeprocessestoprevention,earlyrecognition,andtherapyof
diseases.Attentionshouldbepaidtoanalternativeuseofthetermasacomplement
totheterm“biomedicaloptics.”Inthatcontext,thefieldofbiophotonicsonlycovers
applicationsofphotonicsinthelifesciencesandfundamentalbiomedicalresearch
suchastheinvestigationofcellularprocesses,whereasthefieldofbiomedicaloptics
coverstheclinicalapplicationsoflightindiagnosticsandtherapy.Thisdistinction
seemstohaveevolvedhistorically,astheterm“photonics”wasonlycoinedabout50
yearsago,whenlight-basedtechnologieswerealreadywellestablishedinmedicine.
Inthisbook,theterm“biophotonics”isusedforbothmentionedareas.Furthermore,
itreachesintothefieldsofenvironmental,foodandpharmaceuticalanalysisandthus
evenappliestothefieldsofprocesscontrolandsecurityapplications.Theauthors
consider this definition more conclusive, more purposeful and more forward-
looking, as it provides a holistic perspective. This approach advances a likewise
holistic,modernhealthcare,andparticularlythegroundbreakingparadigmchange
from the treatment of diseases towards health maintenance. Moreover, the close
linkingofdiagnosis,therapy,preventiveandfollow-upcarepavesthewaytowards
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personalized medicine. This promises major benefits not only for individual
patients,butalsoforsocietyasawhole:Personalized,targetedtherapiescanhelp
significantlyinlimitinghealth-carecosts,andthusinfacingthechallengesassociated
withpopulationagingandtheconsequentincreaseinage-relateddiseases.
1.1.3
WhyPhotons?
What makes light an ideal tool in medicine and the life sciences? A multitude of
favorablepropertiesoflightandlight-relatedtechnologies:
1) Spatial scale: six orders of magnitude: Light as a tool helps to observe and
manipulateobjectsonascalefromseveralnanometerstocentimeters(Figure1.3).
This opens up a whole range of biomedical applications, reaching from the
detectionandmanipulationofmacromoleculestosubcellularmanipulationand
macroscopicdiagnosisandsurgeryoftissue.Thisisahugeadvantage,asnovel
diagnostic options that work in single cells can be directly adapted to the
inspection of cellular networks and tissues. In clinical diagnostics, values can
beintegratedopticallyusingarbitraryvolumes.
2) Timescale:from10(cid:2)15to106s:Usingtheultrashortlightpulsesoffemtosecond
lasers, extremely fast processes can be analyzed or manipulated with the
required high precision in time. On the other hand, light sources are stable
enough for long-term monitoring of structures and processes, even covering
several days. The repeated application of short light pulses also allows the
monitoring of changes in fast processes over long time periods. Photonics is
theonlyavailabletechnologytocoverthisimmensetimescale.
3) Multiple functionality: Optical technologies allow the determination of very
differentfeaturesofmolecules,cells,andtissue:
a) Morphologicalfeatures[e.g.,bymeasuringreflection,transmission(absorp-
tion),andscattering]
b) Chemicalfeaturesandtheirchanges(usingspectroscopy,e.g.,Ramanand
fluorescence)
c) Mechanicalfeatures(usingopticaltrappingandholography)
d) Movement(using,e.g.,Dopplerspectroscopyanddynamiclightscattering
measurements).
4) Compatibility: Optical methods can be combined smoothly with one another.
This applies to different diagnostic methods, and also to combinations of
diagnostic and therapeutic methods. Moreover, measurements can similarly
Figure1.3 Characteristicsizeofselectedobjectsofbiomedicalinterest.
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be performed in the spatial and temporal domain. This wide compatibility
facilitatesamultitudeoffeedback-controlledtherapiesonthemicroscopicand
macroscopic scales. Optical methods can also be combined with non-optical
methodsand with otheradvanced technologies suchasnanotechnology (e.g.,
nanoparticles, optically activatable nanocapsules, optical nanostructures) and
microsystemtechnology(e.g.,integratedmicrooptics,microfluidics).
5) Practicability:Apartfromtheirfundamentalproperties,opticaltechnologiesalso
offerimportantpracticaladvantages.Amongthemarecontactlessapplication,
even in therapy, and the easy transmission of energy and signals using light
conductors.Theapplicationoflighthasnooronlyminorsideeffectsandthus
enjoyswideacceptanceamongpatients.Moreover,optoelectroniccompounds
have become increasingly compact and inexpensive to produce (e.g., laser
diodes), which allows the development of reasonably priced systems. The
mentioned properties and advantages are unequaled by any otherbiomedical
tools,betheyultrasound,X-ray,ormagneticandnuclearmedicaltechnologies.
Like no other technology, photonics is suited as cross-sectional technology to
masterabroadvarietyofbiomedicalchallenges.
1.1.4
FieldsofApplicationandTechnology
The scientific discipline covers a broad range of applications and technologies
(Figure 1.4). The following overview cannot provide a complete list of them, but
Figure1.4 Lightmeasuresfast,gently,andwithhighprecision,andthusholdsuniquepotentialfor
medicalapplications.Thisincludesbothmedicalpracticeandfundamentalresearchinthelife
sciences(photograph:IPHTJena).
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isratherintendedasafirstmapforreaderswhoarenewtothisfield.Theemerging
disciplinecoversagrowingmultitudeoftechnologiesandapplications;moreover,
many applications in medicine and the life sciences require the combined use of
differenttechnologies.
& ImportantFieldsofApplication
Fundamentalbiomedicalresearch:Cellbiology,molecularbiology:understand-
ingoflifeprocesses,andalsotheoriginandgenesisofdiseases,onacellular
andmolecularlevel.
Pharmacologicalresearch:Drugdevelopment,forexample,targetevaluation,
high-throughput screening (HTS) and/or high-content screening (HCS) of
drugcandidates,drugdelivery.
Laboratorytests,pointofcare(POC)diagnostics:Analysisofbodyliquids,for
example, in allergology, immunology, hematology, cardiology, epidemiology,
endocrinology, medical microbiology; Optical sensing, for example, optical
oximetry.
Clinicaldiagnostics,therapycontrol,andtherapy:(Methodsinclinicalroutine
ortesting):seeTable1.1.
Regenerativemedicine:Stemcellresearch,tissueengineering,transfectionof
geneticmaterial.
Environmental monitoring, food safety: On-site testing and monitoring of
harmfulcompoundsinair,water,andfood,forexample,pathogens,finedust,
pollen,chemicals.
Process control: Controlling composition and quality of pharmaceuticals,
nutritionandcosmetics.
Securityapplications:Detectionofharmfulbiologicalandchemicalsubstances
andweapons.
& ImportantMethodsandTechnologies
Spectroscopy
. Absorption(THz,microwaves,IR,UV–Vis).
. Emission(allfluorescencemethods:one-photon/multi-photonfluorescence,
FRET,FRAP,FLIM,FLIP).
. Elastic and inelastic light scattering (e.g., Rayleigh, Raman, CARS, SRS,
SERS,TERS,Mie,LIDAR).
LightMicroscopy
. Fluorescencemicroscopy(observingautofluorescenceorusingfluorescence
labels, e.g., proteins), including sub-diffraction techniques (optical nano-
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scopy,e.g.,STED,NSOM,PALM/STORM,structuredillumination)and3D
imagingtechniques(e.g.,confocalandmulti-photonexcitationmicroscopy).
. RamanMicroscopy(CARS,SRS,TERS).
. Other contrast methods, for example, phase contrast microscopy, digital
holographicmicroscopy(DHM).
MultimodalApproaches,MolecularImaging
. Combinations of molecular techniques, for example, spectroscopy, and
imaging techniques, for example, microscopy. Spectroscopy can provide
molecular information for each spot of a microscopic image to deliver
multidimensional images of the examined cells or tissues. This allows
visualization of cellular functions and following of molecular process in
livingorganismswithoutperturbingthem.
. Othermultimodalapproachesalsoincludecombinationswithnonphotonic
technologies,forexample,PETimagingandPCRassays.
Chip-BasedAnalysis
. BiochipsforPOCdiagnostics(“lab-on-a-chip”).
TherapeuticMethods
. PDT, controlled release of bioactive agents, Laser-in-situ Keratomileusis
(LASIK), low-level laser therapy (LLLT), laser-induced thermotherapy
(LITT).
OpticalMicromanipulation
. Optical tweezers, optical stretcher, laser catapulting, cell sorting and cell
positioning.
OpticalComponents
. Innovative light sources and detectors, optics and optical devices for
biophotonics, e.g., ultrafast lasers, adaptive optics, fiber endoscopes.
EnablingTechnologies(NotPhotonicsBased,YetPreliminary)
. Forexample,micro- and nanofluidics, nanoparticles,biochemistry (evalua-
tion of targets, development of markers), data modeling (image analysis,
chemometrics), data management (user-oriented GUI, handling massive
amounts of data, integrating information from multiple channels), system
integration.
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Table1.1 Importantfieldsofapplicationinclinicaldiagnostics,therapycontrol,andtherapy.
Medicaldiscipline Fieldofapplication Examples
Cardiology, Intracoronarydiagnostics Imagingofatheroscleroticplaques
angiology Microcirculation
Imaginglasersurgeryof
atrialfibrillation
Varicoseveintreatment
Dentistry Dentaldiagnosis Caries,stress/cracks,pulpvitality,
periodontaldisease
Dentallasersurgery Endodontictherapy,ablationofsoft
(restoration,prosthetics) andhardtissueandofrestorative
materials
Dermatology Skindiagnosis(structural Melanomaandnonmelanomaskin
andfunctionalimaging) cancers,actinickeratosis,skin
injuries,tissuevasculature,atopic
dermatitis,acne,psoriasis.Age-related
skinconditions,evaluationof
transdermalprocesses(e.g.,drug
andagentdelivery)
Skintherapy Photonictherapy,photodynamic
therapy,andsurgeryofabove-men-
tioneddiseases
Gastroenterology Endoscopyandopticalimaging Laryngoscopy
PDTofBarrett’sesophagus
Laboratory Pathogendetection Detectingandidentifyingpathogensand
medicine hostresponseincaseofsepsis
Oncology Tissue-basedcancerdiagnostics Tumordetection,stagingandgrading
basedonvisualinspectionandmolec-
ularanalysisofbiopsies
Invivocancerdiagnostics Endoscopicdetectionoftumors
Intraoperativecancerdiagnostics Tumorborderdelineation
PDT
Ophthalmology Structuralandfunctional Retinalangiographyandstructural
ocularimaging imaging,cornealsurface
Eyeasdiagnosticwindow EarlyrecognitionofAlzheimer’sdisease
tothebody
Ocularlasertherapy Corneal(refractiveeye)surgery,retinal
surgery,forexample,treatmentof
glaucoma,AMD,andcataract
Urology Endoscopicdiagnosis Ureteroscopy,prostatectomy
Minimallyinvasivesurgery Removalofbenignhyperplasia,
strictures,andrenalcalculi
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1.1.5
SocietalRelevanceofBiophotonics
1.1.5.1 FightingPrevalentandSevereDiseases
Themotivationofbiophotonicsresearchismostoftenthebattleagainstthemost
prevalentandseverediseasesofmankind.Asanexample,manyresearchstudiesin
Germany are currently focusing on diseases such as cancer, cardiovascular dis-
eases,eyedisordersandinfections[4].Forcomparisonpurposes,Figure1.5lists
the leading causes of death as published by the World Health Organization
(WHO)[5].
Inordertoensureasustainableandcapablehealthcare,theroleofbiophotonics
will probably grow even more in the next decades. The reason is the ongoing
demographicchangeinindustrializedcountries,whichisabouttoconfronttheir
healthcaresystemswiththeirgreatestchallenges.Thecasenumbersofage-related
diseasessuchasdementia,cardiovasculardiseases,andlossofsightareexpectedto
risesharplyinthecomingdecades.Atthesametime,thefinancialresourcesof
publichealthcaresystemswillprobablystagnateandthusnotkeeppacewiththe
expectedincreaseincostsfortreatmentandnursingcare.Here,biophotonicscan
meeturgentneeds:Early,targeted,andgentleinterventionscouldattenuateoreven
avoid diseases and thus improve the quality of people’s lives, especially for the
elderly.Thiswouldalsohelpsavingsoftherapeuticcostsandeconomicfollow-up
costs.Thedimensionsoftheabove-mentionedeffectsareestimatedbyanumberof
forecastsandstudies:
1) Demographic change in industrialized countries: All developed countries are
facingrapiddemographicchangestowardsanagingsociety.Akeyfigurefor
health care systems is the “elderly dependent ratio” (EDR), indicating the
numberofpeopleaged65yearsorabove,expressedasapercentageofpeople
ofworkingage(Figure1.6).AccordingtoaforecastbytheUnitedNations[6],
theEDRisexpectedtoincreasefromcurrentlyabout23%to45%by2050in
developed regions. Here, the group of working age is defined as those aged
from15to64years.AlthoughevenintheWesternworldthepaceandextent
ofthisagingprocessdiffersignificantly,thetrenditselfholdstrueworldwide.
Asaconsequence,considerablyfewerpeopleofworkingagewillbeavailable
to fulfill the intergenerational contract and help bear health expenses in a
solidarity-basedsystem.Extremepressureonthepublichealthcaresystemis
expected,forexample,inGermany.Here,thenumberofpeopleaged80years
or above will probably more than double from 2007 to 2050. At the same
time, the group of people of working age (here 20–64 years) will probably
decrease by nearly one-third. Whereas today about three people of working
age correspond to one elderly person, this ratio will shrink to 1:6:1 by
2050 [7].
2) Growingcasenumbersofage-relateddiseases:Asthedescribeddemographic
changestemsnotonlyfromanimprovedhealthcarebutalsofromothereffects
(e.g.,decreasingbirthrates),onecannotconcludethatpeoplewillagehealthier