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Field Guide to Optical Biosensing

Table of Contents

Preface xiii

Glossary of Symbols and Notation xv

Introduction and Definitions 1Motivation 1What Is a Biosensor? 2Elements of a Biosensor 3Example: Immunochromatographic Assays 4

Types of Biosensors 5Non-optical Biosensors 5Optical Biosensors 6

Background 7History of Biosensors 7Early Milestones in the Development of Biosensors 8Later Milestones in the Development of Biosensors 9

Surface Functionalization and Immobilizationof Bioreceptors

10

Immobilization of Bioreceptors 10From Surface Functionalization to Analyte Capture 11Common Bioreceptors 12More Bioreceptors 13Usual Methods of Immobilization 14

Performance Parameters 15Precision and Accuracy 15Repeatability, Reproducibility, and Selectivity 16Sensitivity 17Measurand, Full-Scale, and Dynamic Ranges 18Signal-to-Noise Ratio 19Minimum Detectable Signal and Saturation 20Time Factors and Stability 21

Practical Aspects 22Resolution, Threshold, Calibration, and Hysteresis 22Linearity, Offset, and Overload 23


ix

Deviations from Ideality (Errors) 24The Ideal Biosensor 25

Fundamental Optical Sensing Mechanisms 26Fundamental Optical Processes 26Transmission, Absorption, and Scattering 27Optical Phase Difference and Optical PathDifference

28

Polarization 29Surface Plasmon Resonance 30Luminescence 31Photoluminescence 32Fluorescence 33Phosphorescence 34Fluorescence Polarization 35

Detection Methods, Techniques, andConfigurations

36

Absorbance Biosensors 36Infrared Spectroscopy 37Infrared Vibrational Modes 38Scattering Detection 39Resonance Rayleigh Scattering 40Transduction Based on Reflectance andTransmittance

41

Interferometric Biosensors 42Colorimetric Bioassays 43Biosensing Using Ellipsometry 44Photonic Crystals 45Fluorescence-Based Biosensing 46Fluorescence Polarization Detection 47Phosphorescence-Based Biosensing 48Chemiluminescence 49Bioluminescence 50Time-Resolved Fluorescence 51Evanescent Wave Biosensing 52Attenuated Total Reflection Spectroscopy 53Fiber-Optic Biosensors 54Near-Field Scanning Optical Microscopy 55

Table of Contents


x

Surface Plasmon Resonance Biosensors 56Real-Time SPR Sensing 57Phase-Sensitive Biosensing 58Optical Heterodyne Detection 59Polarimetry 60Photoacoustic Spectroscopy 61Raman Spectroscopy 62Surface-Enhanced Raman Scattering Detection 63Planar Optical Waveguides and Integrated Optical

Sensors64

Waveguide Interferometer Architectures 65Mach–Zehnder Interferometer 66Young Interferometer 67Hartmann Interferometer 68Dual Polarization Interferometry 69Bimodal Waveguide Interferometers 70Resonant Waveguide Grating 71Antiresonant Reflecting Optical Waveguides 72Hollow Waveguides 73Photonic Crystal Cavity Biosensors 74Resonant Optical Microcavities 75Beyond the Visible and Infrared Ranges 76Integrated Microfluidic Biosensors 77Lab-on-a-Chip Devices 78Bioimaging 79

Applications 80Medicine 80Infections Caused by Pathogens 81Airborne Diseases 82Point-of-Care Testing Techniques 83Home Monitoring 84Optical Biosensors for Therapeutic Drug Monitoring 85Food Safety 86Common Foodborne Pathogens 87Food Industry 88Biosensors for the Detection of Foodborne Pathogens 89Defense 90Important Biological Warfare Agents 91

Table of Contents


xi

Some Optical Biosensors for Biological Warfare Agents 92Homeland Security 93Environmental Applications 94Wearable and Implantable Biosensors 95Challenges in Biosensor Commercialization 96

Equation Summary 97

References 98

Index 106

Table of Contents


xii

What Is a Biosensor?

A biosensor1,2 is a self-contained measuring device thatcan detect an analyte of biochemical or biological origin andgenerate a quantifiable signal in response.

More specifically, a biosensor detects the analyte selec-tively and quantitatively using a biorecognition element(or bioreceptor), which provides specificity. A signaltransduction element (or transducer) produces a physicalsignal that is generally processed by an electronic system.


2 Introduction and Definitions

Early Milestones in the Development of Biosensors


8 Background

Sensitivity

The sensitivity of any detection device is defined as theratio of the change in sensor output to the change in thevalue of the measurand. Its value is given by the slope ofthe calibration curve, i.e., the marginal increase in outputfor a marginal stimulus increase.

For a sensor in which the output y is related to themeasurand x by the equation y 5 f(x), the sensitivity S(xa)at point xa is given by

SðxaÞ5dydx

��x5xa

The sensitivity of a biosensor should be sufficiently high toallow convenient measurement of the transducer outputsignal with electronic instrumentation used for signalprocessing. Also, it is often desirable to have constantsensitivity, as in the case of the calibration curve shownhere. Ideally, the sensitivity of a given biosensor shouldremain constant during its lifetime, although in practicethis parameter experiences variation.


17Performance Parameters

Transmission, Absorption, and Scattering

Transmission is the passage of electromagnetic radiationthrough a given material. As in the case of reflection, thereis direct transmission, also called regular transmission,when the process follows the laws of geometrical optics,and diffuse transmission, which leads to scatteredradiation. The overall transmission process is character-ized by its transmittance T, which is the ratio of theenergy flux reflected to the total amount of electromagneticflux incident on the surface.

Scattering is defined as the process of deflecting aunidirectional beam into many directions. As such, it willcomprise diffuse reflection, diffuse transmission, and othervolume light diffusion processes. It is characterized by S,the ratio between scattered and total incident radiation.

Absorption is the transformation of radiant power toanother type of energy by interaction with matter. This isusually heat, although the absorption of electromagneticradiation can trigger the emission of radiation by theabsorbent. This process is characterized by its absorp-tance A, defined as the ratio of the radiant energyabsorbed by a material to that incident upon it.

Adding the contribution of the four basic optical processesgives

Rþ T þ Aþ S5 1

This equation can be considered an expression of theprinciple of the conservation of energy. These magnitudes(T, R, A, and S) show a spectral behavior, i.e., a dependenceon wavelength. As such, the previous equation is valid forevery single wavelength.

Note that reflection, transmission, and scattering areoptical processes that leave the frequency of the incidentradiation unchanged.


27Fundamental Optical Sensing Mechanisms

Evanescent Wave Biosensing

When light traveling through a medium is reflected at theinterface with an optically-less-dense medium at an angleexceeding the critical angle, total internal reflection(TIR) occurs. An electromagnetic wave called an evanes-cent wave (EW) is generated close to the interface in theless dense medium. The EW travels parallel to theinterface of the two media but decays exponentially inamplitude with respect to distance into the medium oflower index of refraction. The expression of the EWpenetration depth d at a given wavelength l is given by

d5l

2pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffin21sin

2a� n22

q

where n1 and n2 are the index of refraction of the twomedia, and a is the angle of incidence. The penetrationdepth increases with a low refractive index contrast, a longwavelength, and an incident angle near the critical angle.

Optical interaction of the EW with analytes close to or atthe surface is used as a transduction technique. Thisinteraction can be monitored as, for example, a change inthe intensity of light emerging from the optically densermedium. This biosensing technique39 allows the continu-ous monitoring of the presence of analytes with minimalinterference from substances distant from the interface,i.e., at distances on the order of a light wavelength. EWbiosensors allow real-time analysis.


52 Detection Methods, Techniques, and Configurations

Antiresonant Reflecting Optical Waveguides

Antiresonant reflecting optical waveguide (ARROW)architectures confine light using antiresonant Fabry–Pérotreflectors. In ARROWs, waveguiding takes place in a thick,low-refractive-index layer (such as silicon oxide) ratherthan in a thin, high-refractive-index layer. The indices ofrefraction and the thicknesses of the individual claddinglayers must be properly adjusted to ensure high reflectivityfor the working wavelength and, therefore, optimal guidingcharacteristics. In a conventional ARROW, the index ofrefraction of the cladding is higher than that of the core,while in ARROW-B structures, it is lower.

Although ARROW modes are leaky, low-loss propagationover relatively large distances (typically micrometersrather than nanometers) can be achieved. Besides,ARROWs exhibit good sensitivity.

ARROWs may be either symmetrical or asymmetrical. Inthe first case, light confinement at both boundaries isachieved by antiresonant reflectors, while in the latter caselight is confined by an antiresonant reflector at oneboundary and total internal reflection at the other.Asymmetrical ARROWs are preferred for biosensing sincethe TIR boundary can be placed between the bioreceptorand the analyte.



Photonic Crystal Cavity Biosensors

Introducing disturbances to the periodic structure of aphotonic crystal, i.e., defects, can create specific modeswithin the band gap at well-defined wavelengths. As such,an incoming light beam with a wavelength correspondingto the defect mode will be confined to the defect area of thephotonic crystal. Since the spectral position of the resonantdefect mode is highly sensitive to any changes in the localenvironment close to the defect region, i.e., to variations ofthe effective index of refraction, these devices can be usedas biosensors. Defects can be realized by introducing pointor line defects in the structure of the photonic crystal, forinstance, by eliminating a single hole or a row of holes, orby substituting a hole with another one with a differentradius or index of refraction.

Photonic crystal cavities53 exhibit strong spatial andtemporal light confinement, in addition to a long photonlifetime, i.e., high quality factor Q. Accordingly, thesedevices greatly enhance the interaction strength betweenthe optical field and the defect region. These characteristicsmake photonic crystal cavities suitable for multiplexingand for very localized sensing. From a practical point ofview, a high Q translates into a low limit of detection, whilethe strong spatial confinement translates into very smallsensing areas and thus the need for less analyte and thepossibility for very high miniaturization degrees.



Infections Caused by Pathogens60

Type ofPathogen Disease

Virus Influenza (the flu)Common coldCoronavirus disease (COVID-19)MeaslesChickenpox (varicella)Shingles (herpes zoster)Viral gastroenteritisMeningitisHIV and AIDSHepatitis A, B, C, D, and EYellow feverWarts, including genital wartsDengue feverOral and genital herpes

Bacteria Bacterial gastroenteritis (e.g., salmonellafood poisoning or E. coli infection)TuberculosisStrep throatBacterial meningitisUrinary tract infectionCellulitisLyme diseaseGonorrhea

Fungus Oral candidiasis (oral thrush)Dermatophytosis (ringworm)Vaginal yeast infectionTinea pedis (athlete’s foot)Onychomycosis (fungal infection of the nail)Tinea cruris (jock itch)

Parasites MalariaHead lice infestationGiardiasisToxoplasmosisTrichomoniasisIntestinal worms


81Applications

Important Biological Warfare Agents70

Biological Agent Type Disease

Variola major Virus Smallpox

Marburg Virus Marburg hem-orrhagic fever

Lassa Virus Lassa hemor-rhagic fever

Machupo Virus Bolivian hem-orrhagic fever

Bacillus anthracis Bacterium Anthrax

Francisellatularensis

Bacterium Tularemia

Clostridium botuli-num, including itstoxins

Bacteriumproducing bot-ulinum toxin

Poisoning bytoxin

Ricin Toxin from theplant Ricinuscommunis

Poisoning byricin

Burkholderia mallei Bacterium Glanders

Burkholderiapseudomallei

Bacterium Melioidosis

Brucella melitensis Bacterium Brucellosis

Chlamydia psittaci Bacterium Chlamydiosis

Escherichia coliO157:H7, includingits shiga toxins

Bacterium Foodborne ill-ness, poisoningby shiga toxin

Rickettsiaprowazekii

Bacterium Typhus

Vibrio cholerae Bacterium Cholera

Staphylococcusaureus, including itstoxins

Bacteriumproducing agroup ofstaphylococcalenterotoxins

Staphylococcalinfections, poi-soning bystaphylococcalenterotoxins


91Applications

Wearable and Implantable Biosensors

Wearable biosensors75,76 are minimally or non-invasivesensing devices that are integrated into various wearables,such as clothes, watches, glasses, bandages, contact lenses,rings, and tattoos, or even into the skin. These devices arereceiving growing attention given their enormous potentialto measure and track a broad variety of physiologicalparameters, including blood pressure, heart rate, bodytemperature, and respiration rate.

Wearable biosensors can perform real-time measurementsof biochemical markers in biological fluids, such as sweat,saliva, tears, and interstitial fluid. Tracking these bio-chemical compounds (e.g., antigens, antibodies, abnormalenzymes, or hormones) will provide early warning of manyabnormal health conditions.

These devices provide improved comfort, in a great deal dueto the tremendous advance in the micro- and nano-fabrication techniques. In fact, aiming at improving wear-ability and ease of operation, multiplexed biosensing,microfluidic sampling and transport systems have beenintegrated, miniaturized and combined with flexible materi-als. Besides, with the universalization of smartphones andother mobile microelectronic devices,77 wearable andimplantable biosensors are receiving renewed attentionowing to the possibility of developing apps to monitor thedata measured by the sensor. These devices have becomewidely accepted by the public. It is expected that wearableand implantable optical biosensor technologies will have abroad impact on our daily lives in the next years.

An implantable fluorescence-based sensor that allows thecontinuous response to blood glucose concentrationchanges for up to 140 days has been demonstrated. Theimplanted fiber transmits fluorescent signals transder-mally, according to blood glucose concentration. A systemhas been developed for the direct, in vivo observation ofglucose Raman peaks to determine the glucose concentra-tion in blood.


95Applications

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