sensors Review
Whispering-Gallery Mode Resonators for Detecting Cancer Weeratouch Pongruengkiat and Suejit Pechprasarn * Faculty of Biomedical Engineering, Rangsit University, Pathum Thani 12000, Thailand; [email protected] * Correspondence: [email protected]; Tel.: +66-92-997-2200 (ext. 1428) Received: 11 July 2017; Accepted: 6 September 2017; Published: 13 September 2017
Abstract: Optical resonators are sensors well known for their high sensitivity and fast response time. These sensors have a wide range of applications, including in the biomedical fields, and cancer detection is one such promising application. Sensor diagnosis currently has many limitations, such as being expensive, highly invasive, and time-consuming. New developments are welcomed to overcome these limitations. Optical resonators have high sensitivity, which enable medical testing to detect disease in the early stage. Herein, we describe the principle of whispering-gallery mode and ring optical resonators. We also add to the knowledge of cancer biomarker diagnosis, where we discuss the application of optical resonators for specific biomarkers. Lastly, we discuss advancements in optical resonators for detecting cancer in terms of their ability to detect small amounts of cancer biomarkers. Keywords: optical resonator; whispering-gallery mode; optical waveguide; evanescent wave; label-free; biosensor; cancer; sensor platform; instrumentation
1. Introduction Cancer, a hazardous non-communicable disease, is currently the main challenge in healthcare. Cancer Research UK shows that more than 14.1 million people had cancer in 2012 [1]. Despite the growing fatal rate of the disease, cancer develops in stages attributed to different hazard levels; the faster the cancer is detected, the higher the chance it can be cured. Figure 1 shows the survival rates for ovarian stromal cancer and cervical cancer visualized from the 5-year survival rates, which predict the chance of survival for those years [2]. Cancer is usually divided into four stages: Stage I, cancer is small and contained within the organ of origin; Stage II, cancer has grown larger but has not spread to other organs; Stage III, cancer has spread to nearby tissues and can reach the lymph nodes; and Stage IV, metastatic cancer; cancer has spread to other organs in the body. A, B, and C are used to indicate the substage, e.g., lung carcinoid tumor stage IIA [3]. However, the number staging system is an abstraction that describes the disease progression. Healthcare professionals typically describe the disease stage using the tumor-node-metastasis (TNM) system. T evaluates the size of the cancer and its area of spread to nearby tissue on a scale of 1–4; N defines whether the cancer reaches a lymph node on a scale of 0–3; M indicates whether the cancer has spread to another organ, and the value is binary: either 0 or 1 [4]. Table 1 shows the relations between the two systems.
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Figure 1. 1. Graphs cancers. It is thatthat at the Figure Graphs plotted plottedbetween between5-year 5-yearsurvival survivalrates ratesversus versusstages stagesofof cancers. It clear is clear at (a) initial stage of cancer development, patients have significantly larger chances of being cured. the initial stage of cancer development, patients have significantly larger chances of being cured. Ovarian stromal tumor [5],[5], (b)(b) Cervical cancer [6].[6]. (a) Ovarian stromal tumor Cervical cancer Table1.1.The Therelationship relationshipbetween betweenthe the number system and TNM system of cancer for cervical cancer Table number system and TNM system of cancer for cervical cancer [7]. [7]. Number System
TNM System
Number System TNM System Stage 0 0 Tis,Tis, N0, N0, M0 M0 Stage Stage I T1, N0, M0 Stage I T1, N0, M0 Stage IA T1a, N0, M0 Stage IA T1a, Stage IB T1b, N0, N0, M0 M0 Stage N0, M0 Stage II IB T2,T1b, N0, M0 Stage IIA II T2a,T2, N0,N0, M0 M0 Stage Stage III T3, N0, M0 Stage IIA T2a, N0, M0 Stage IIIA T3a, N0, M0 Stage T3,T1–T3, N0, M0 Stage IIIB III T3b, N0, M0 or N1, M0 Stage T3a, Stage IVIIIA - N0, M0 Stage IVAIIIB T4,M0 N0,or M0T1–T3, N1, M0 Stage T3b, N0, Stage IVB T1–T3, N0–N3, - M1 Stage IV Stage IVA T4, N0, M0 Stage IVB T1–T3, N0–N3, Even now, early diagnoses for cancer are scarce. A qualitative studyM1 in 2015 asserted that late diagnosis is the result of difficulty in making appointments, worry regarding doctor availability, and Even now, diagnoses for cancerofare scarce. qualitative study in 2015 asserted that late unwillingness to early learn of the development cancer [8]. A Apart from the emotional concern of scarring diagnosis is the result of difficulty in making worry regarding doctor availability,even and from unfortunate discovery, the findings reflectappointments, the difficulty in accessing diagnostic technologies unwillingness to learn ofCurrently, the development of canceris[8]. Apart from the emotional concern of scarring in developed countries. cancer detection still based on highly invasive, time-consuming, fromcostly unfortunate discovery, the findings reflect the difficulty in accessing diagnostic technologies and processes. evenWhen in developed countries. Currently, detection is stillof based on or highly point-of-care (POC) diagnosis wascancer introduced, the concept real-time, at leastinvasive, shorter time-consuming, and costly processes. diagnosis time was heralded as the future of healthcare. The actual definition of POC diagnosis is When diagnosis was introduced, thecare concept of real-time, or first at least shorter testing at orpoint-of-care near the site(POC) of patient care whenever medical is needed [9]. The biosensor diagnosis timemeter was heralded as the futureinof actual definition of diagnosis POC diagnosis was a glucose that became popular thehealthcare. late 1980sThe [10,11]. However, POC is not is a testing at or near thedawn site ofof patient care whenever medicalpatients’ care is needed first biosensor was new concept. At the civilization, doctors visited homes[9]. andThe performed diagnosis a glucose meterwithout that became popular in the medical late 1980s [10,11].The However, POC medical diagnosiscomplex is not a was new and treatment today’s centralized centers. centralized concept. Atinthe civilization, doctors visitedthe patients’ and performed diagnosisOver and introduced thedawn early of 17th century [12], enhancing mobilityhomes of technology and knowledge. treatment without today’s centralized medical centers. The centralized medical complex was time, and as the world population increased exponentially, more patients have become dependent on introduced the early 17th century enhancing theoverwhelming mobility of technology andhealthcare knowledge. Over this system. in The demographic growth[12], has resulted in an demand for services. time, and as theand world population increased exponentially, patientsofhave become dependent on The diagnostic treatment capability are then limited by more the capacity the available technology. this Diagnosis system. The demographic growth has resulted in an overwhelming demand for healthcare requires novel tools and instruments. Based on the concept of reducing diagnostic services. diagnostic treatment capability limited byrole the in capacity of the ideology available times andThe steps, modernand biosensors have come to are playthen an important fulfilling technology. of POC. Some cancers now can be detected at an early stage using less invasive and lower-cost Diagnosis requires novel tools and instruments. Based on the of reducingsensor diagnostic procedures [13–15] through advancements in sensor technologies suchconcept as electrochemical [16], times and steps, modern biosensors have come to play an important role in fulfilling the ideology of POC. Some cancers now can be detected at an early stage using less invasive and lower-cost
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procedures [13–15] through advancements in sensor technologies such as electrochemical sensor [16],
optical sensor, or piezoelectric sensor [14]. thankstotothe thediscovery discovery of cancer biomarkers (cancer optical sensor, or piezoelectric sensor [14].This This is is thanks of cancer biomarkers (cancer markers), which have allowed biosensor detection to be more specific [17]. In particular, the optical markers), which have allowed biosensor detection to be more specific [17]. In particular, the optical biosensor has high sensitivity and can detection[17,18]. [17,18]. One technique gaining biosensor has high sensitivity and canperform performlabel-free label-free detection One technique gaining the the attention of biosensor researchers theoptical optical resonator. resonator. Figure thethe publications on this attention of biosensor researchers is is the Figure2 2shows shows publications on type this type of optical sensor. of optical sensor.
Figure 2. Figure shows how numberof ofarticles articles on optical resonators evolved Figure 2. Figure shows how thethe number on fix fixin infigure figurelabel label optical resonators evolved between 1999–2016. graph showsincreasing increasing trends trends in study. Remark: TheThe datadata werewere between 1999–2016. TheThe graph shows inthis thisarea areaofof study. Remark: Web of Sciencedatabase database(www.webofknowledge.com) (www.web of knowledge.com) with thethe keyword “Optical gathered gathered fromfrom the the Web of Science with keyword “Optical Resonator”, and then the category filter “Optics” was applied [19]. Resonator”, and then the category filter “Optics” was applied [19].
Optical resonators enhance light guide properties for detection in the environment. The sensors
Optical resonators lightinguide properties for detection theresonators, environment. The sensors are based on light enhance confinement waveguide structures, such as in ring Fabry-Perot are based on lightwhispering-gallery confinement in waveguide structures, such as(WGR) ring resonators, Fabry-Perot resonators, resonators, mode (WGM) resonators and high-contrast gratings. whispering-gallery resonators (WGR)research and high-contrast gratings. Currently, there is Currently, there mode is high(WGM) growth in optical resonator because of their promising properties, such as high sensitivity, low response time, compactness, and immunity to electromagnetic high growth in optical resonator research because of their promising properties, such as high sensitivity, interference [17,18,20,21], whichand are unlike other to waveguide sensors orinterference fiber sensors,[17,18,20,21], in which sensor low response time, compactness, immunity electromagnetic which dimension light–matter interaction. resonators determine the interaction length by the are unlike otherlimits waveguide sensors or fiberOptical sensors, in which sensor dimension limits light–matter quality (Q) factor [22], the dimensionless of temporal confinement light resonating inside interaction. Optical resonators determinequantity the interaction length by the of quality (Q) factor [22], the the sensor [23]. WGR and ring resonators are emerging cancer detection technologies known for their dimensionless quantity of temporal confinement of light resonating inside the sensor [23]. WGR and easy fabrication and high performance. These aspects allow the sensors to perform early detection ring resonators are emerging cancer detection technologies known for their easy fabrication and high when cancer biomarker concentrations are still low. This is the first review of such technologies for performance. These aspects allow the sensors to perform early detection when cancer biomarker cancer detection. concentrations stillsensors, low. This first review of such technologies cancer detection. Unlikeare other suchisasthe electrochemical sensors, which usuallyfor require probe labeling or Unlike sensors, such as electrochemical sensors, whichmodification usually require labeling analyte other modification [24], optical resonators require no chemical of theprobe analyte [21]. or Optical resonators[24], can optical diagnoseresonators different cancer in amodification short time [17,25–27]. These [21]. analyte modification requirebiomarkers no chemical of the analyte properties also can match the concept of POC diagnosis. Opticalin resonators have[17,25–27]. wide-ranging Optical resonators diagnose different cancer biomarkers a short time These applications. As label-free biosensors, most optical resonators eliminate the pre-detection procedures properties also match the concept of POC diagnosis. Optical resonators have wide-ranging applications. by removing, or at least shortening, sample preparation time. label-based sensing, the biological As label-free biosensors, most optical resonators eliminate theFor pre-detection procedures by removing, sample must undergo analyte marking, for example, with a fluorescent dye or radio marker. This not or at least shortening, sample preparation time. For label-based sensing, the biological sample must only requires extra cost for the labeling material, but also causes undesirable delay between sample undergo analyte marking, for example, with a fluorescent dye or radio marker. This not only requires collection and analysis. This delay and labeling approach can result in changes in both the physical extraand costchemical for the labeling but also causes undesirable delay between sample collection and propertiesmaterial, of the analyte [17,25,28–30]. analysis. In This and approach can resultofinoptical changes in bothand theevaluate physicalthe and chemical thisdelay review, welabeling introduce the fundamentals resonators various properties of and the analyte sensors, describe [17,25,28–30]. WGR and ring resonators in more detail. Then, we provide an overview of In this fabrication review, weand introduce the fundamentals of optical resonators and and evaluate thetheir various sensor preparation. We briefly introduce cancer biomarkers discuss sensors, and describe WGR and ring resonators in more detail. Then, we provide an overview of sensor fabrication and preparation. We briefly introduce cancer biomarkers and discuss their detection. We then review recent works on the application of optical resonators in cancer biomarker detection focused on early stage detection. We also discuss how the high sensitivity of the optical resonators
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plays an important role in the early stage cancer diagnosis and how these optical technologies can potentially save lots of lives. 2. Fundamentals of Optical Resonators 2.1. Performance Parameters of Optical Resonators Similar to other biomedical sensors, optical resonators are defined by sensitivity, limit of detection (LOD), resolution, dynamic range, and selectivity. Sensitivity describes the change in output upon a change in the physical properties of the sensor. For optical resonators, sensitivity is the ability to transduce the change (binding) on the resonator surface into an output, i.e., spectral shift. This can be described as the shift of resonant wavelength (δλ) or the difference of light intensity (δI) at a particular wavelength when the analyte is bound to the surface. The units are usually given as nm/RIU (wavelength shift over refractive index unit) and W/(m2· RIU) [31]. LOD is the minimum quantity of analyte to be detected by the sensor in the actual detection environment. The LOD is limited by noise source, efficiency of the optical detector in the optical system, and the amount of light that can be detected [32]. Optical system noise can come from: (1) thermal noise, (2) microphone vibrations (3) dark current of the detector and (4) shot noise of the optical detector and loss due to material defects. These amounts of noise will introduce losses in the optical resonator [33–35]. The LOD for optical resonators is normally defined by two parameters: First, the RIU and surface coverage, given as pg/mm2 , or it can be described as sample concentration in the molar unit. Label-free sensors are normally described by RIU, while surface coverage/sample concentration are used in both labeled and label-free sensors [36]. RIU can be converted to other physical parameter of analyte by using response unit. In optical sensors, it has been well established and validated over a wide range of different proteins that one response unit of 10−6 RIU is equivalent to 1 pg/mm2 . By knowing the sensing area size, the mass on the sensor can be determined. Similarly, with a known molecular weight, one can determine the number of molecules on the sensor [32]. Selectivity describes the ability to distinguish between the desired analyte and others in the environment. Whenever the analyte does not specifically bind to the sensor, it results in errors to the output signal. Biosensors are now equipped with biologically selective species such as antibody-antigen [37] or enzyme-substrate [38]. However, synthetic substances have also been developed; aptamer is one such example [39]. The process of introducing the binding material to the resonator surface to optimize selectivity is termed surface functionalization. Unlike other sensors, biomedical sensor development aims to reduce the sample volume, especially when the analyte requires invasive extraction procedures from a patient, such as a blood sample. The other parameter is the Q-factor, introduced earlier as the basic parameter for determination of the lifetime of light resonating in the waveguided resonator. The Q-factor can be defined as: Q = ω0 τ = 2πv0 τ =
ω0 ∆ω FW HM
(1)
where ω 0 is the angular frequency. The linear frequency of the mode is described by v0 . τ is the time for the field intensity to decay by the factor of e, the so-called cavity ring down lifetime. According to the equation, ∆wFWHM is inversely proportional to τ and determines the line width: the uncertainty of the frequency of resonance in angular frequency; FWHM stands for full width at half-maximum. The highest Q-value reported so far is 2 × 1010 on the spheroidal crystalline WGMR with a resonant wavelength of 1300 nm [40]. For amorphous material, it is 8 × 109 with a 633 nm resonant wavelength [41]. 2.2. Light Coupling Light coupling is commonly referred to as evanescent wave coupling in optical resonator research. It can be described as inducing light on another medium without contact. As two optical guide
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2.2. Light Coupling Light are coupling commonly referred to distance, as evanescent wave coupling in optical resonator components placediswithin evanescent zone light is coupled into the resonant structure research. It can be described as inducing light on another medium without contact. As two optical aided by a phase-matched evanescent field. A tunable laser source is commonly used for input; the guide components are placed within evanescent zone distance, light is coupled into the resonant wavelength of the source can be adjusted. At the matching wavelength, the intensity dip can be structure aided by a phase-matched evanescent field. A tunable laser source is commonly used for observed using a photodetector. As mentioned earlier, the optical resonator interaction length is the input; the wavelength of the source can be adjusted. At the matching wavelength, the intensity dip effect of a Q-factor. The length is described by: can be observed using a photodetector. As mentioned earlier, the optical resonator interaction length is the effect of a Q-factor. The length is described by: Qλ (2) Le f f = Q λ2πn Leff = (2) 2π n From Equation (1), L is the effective interaction length and n is the refractive index of the eff
the resonators effective interaction length and refractive index of thethe From Equationof(1), Leff isring resonator. Q-factors typical range from 104 to 10n9 . isλ the is resonant wavelength; 4 resonator. Q-factors is of determined typical ring by resonators rangecondition: from 10 to 109. λ is resonant wavelength; the matching wavelength the resonant matching wavelength is determined by the resonant condition: 2πrne f f λm = 2π rneff for m = 1, 2, 3, . . . (3) m for m = 1, 2, 3, … λm = (3) m where r describes the outer radius of the ring resonator; neff refers to the effective refractive index, where r describes the outer radius of the ring resonator; neff refers to the effective refractive index, which is sensitive to the binding event on the surface; m is the mode number; λm is the resonant which is sensitive to the binding event on the surface; m is the mode number; λm is the resonant freefree-space wavelength of the tunable laser. space wavelength of the tunable laser. Optical resonators mostly structures:the thefirst firstserves serves the system Optical resonators mostlyconsist consistof oftwo twooptical optical waveguide waveguide structures: the system as as anan input wherelight light enters and signal is detected the end. other end. inputand andoutput output waveguide, waveguide, where enters and thethe signal is detected at theat other The Theother other structure is the resonator structure, which confines the light propagated from the first structure is the resonator structure, which confines the light propagated from the first structure. structure. There are various techniques for coupling the light, the most common being tapered coupling. There are various techniques for coupling the light, the most common being tapered coupling. Examples of of methods (Figure3)3)include includetapered tapered coupling [42], Examples methodsfor forilluminating illuminatingresonator resonator structures structures (Figure coupling [42], prism coupling [43], angled waveguideside sidecoupling coupling[39,45,46], [39,45,46], free-space prism coupling [43], angledfiber fibercoupling coupling[44], [44], planar planar waveguide free-space coupling or or direct illumination coupler[49]. [49]. coupling direct illumination[47,48], [47,48],and andpolished polished half-block half-block coupler
Figure 3. Various types of optical coupling. (a) Tapered; (b) prism; (c) angled fiber; (d) planar Figure 3. Various types of optical coupling. (a) Tapered; (b) prism; (c) angled fiber; (d) planar waveguide side; (e) free-space; (f) polished half-block coupler. waveguide side; (e) free-space; (f) polished half-block coupler.
Tapered coupling has 99.8% coupling efficiency [50]; the losses are the result of material Tapered coupling has 99.8% coupling [50]; the Comparable losses are theefficiency result of material absorption, scattering, and bending lossesefficiency from fiber stress. has been absorption, reported scattering, and bending losses[49]. fromExperimental fiber stress. Comparable has prism been reported for the half-block coupler studies have efficiency shown that coupling for hasthe half-block coupler80% [49]. Experimental have shown prism coupling hasasapproximately 80% approximately efficiency [51,52].studies Angle-polished fiberthat coupling, also known “pigtailing,” has efficiency [51,52]. Angle-polished fiber coupling, also known as “pigtailing,” has 60% efficiency [44]. Tapered coupling has the advantages of not only higher coupling efficiency but also ease of fabrication
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and preparation. Despite theircoupling lower coupling efficiency, the other coupling methodsefficiency are of research 60% efficiency [44]. Tapered has the advantages of not only higher coupling but interest, as they can provide more robustness [18]. also ease of fabrication and preparation. Despite their lower coupling efficiency, the other coupling methods are of research interest, as they can provide more robustness [18]. 2.3. Whispering-Gallery Mode 2.3.Lord Whispering-Gallery Mode WGM in 1878, as he whispered on one side of the curved wall inside Rayleigh discovered St. Paul’s Cathedral UK). Hisinvoice be heard 40 away This demonstrated Lord Rayleigh(London, discovered WGM 1878,could as he whispered onmone side[53,54]. of the curved wall inside theSt.phenomena of the(London, acousticUK). wave which could40travel along the This edgedemonstrated of the gallerythe hall Paul’s Cathedral His(sound), voice could be heard m away [53,54]. with negligible loss. As he observed this phenomenon, he also proposed that electromagnetic waves phenomena of the acoustic wave (sound), which could travel along the edge of the gallery hall with could travel loss. withAsthis mode. Inthis 1961, the WGMheofalso optical lightthat waselectromagnetic first reported waves in a spherical negligible he observed phenomenon, proposed could microstructure [55].mode. Instead of thethe curved whispered voice, the light entirely travel with this In 1961, WGMwall-guided of optical light was first reported in awas spherical internally reflected in Instead a confined cavity. Later on, WGMswhispered in liquid voice, were also studied. microstructure [55]. of the curved wall-guided the light was Following entirely Lord Rayleigh’s discovery, Debye and Later Mie published two important theoretical works. Lord Debye internally reflected in a confined cavity. on, WGMs in liquid were also studied. Following Rayleigh’sthe discovery, and Mie published two important theoretical works. Debye determined resonantDebye eigenfrequencies for dielectric and metallic spheres in 1909 [56].determined Mie studied the resonant wave eigenfrequencies dielectric and spheres in 1909 [56]. Mie studied electromagnetic scattering infor microspheres [57].metallic These later became widely discussed in both electromagnetic wave scattering in microspheres [57]. These later became widely discussed in both theoretical and experimental works [53]. theoretical and experimental works [53]. was discovered in a microsphere resonator. Crystalline Optical WGM, as mentioned earlier, Optical WGM, as mentioned earlier, discovered in a microsphere resonator.inCrystalline calcium fluoride (CaF2 ) was fabricated as thewas resonator. A pulsed laser was illuminated a tangential calcium fluoride (CaF 2) was fabricated as the resonator. A pulsed laser was illuminated in a tangential direction to the sphere. The detected output laser showed transient oscillation instead of spikes from to the sphere. detected instead ofwas spikes from thedirection input, confirming theThe presence ofoutput WGM laser [55]. showed In 1981,transient WGM inoscillation liquid resonators observed the input, confirming the presence of WGM [55]. In 1981, WGM in liquid resonators was observed for the first time. In the experiment, a liquid droplet was optically levitated by a laser beam, and the for the first time. In the experiment, a liquid droplet was optically levitated by a laser beam, and the scattered light was detected [58]. WGR have many optics and optoelectronics applications and are scattered light was detected [58]. WGR have many optics and optoelectronics applications and are studied in both passive and active mode [59]. The previous applications for passive mode include studied in both passive and active mode [59]. The previous applications for passive mode include optical and photonic single resonator filters [60,61], high-order filter or cascade resonators [62,63], optical and photonic single resonator filters [60,61], high-order filter or cascade resonators [62,63], tunable filters [64], WGM filters in optoelectronic oscillator (OEO) [65,66], and sensors, which can tunable filters [64], WGM filters in optoelectronic oscillator (OEO) [65,66], and sensors, which can be be biological, biological,chemical, chemical, mechanical [67–70]. active-mode is commonly as a oror mechanical [67–70]. The The active-mode WGMWGM is commonly utilizedutilized as a laser laser source, and involves wave mixing devices such as continuous-wave (CW)-WGM laser, i.e., source, and involves wave mixing devices such as continuous-wave (CW)-WGM laser, i.e., thethe miniature laser [55,71], [72], switches switchesand andmodulators modulators [73], OEO [74], miniature laser [55,71],resonator-modified resonator-modified scattering scattering [72], [73], OEO [74], pulse propagation andand generation, andand wave-mixing oscillator [59].[59]. TheThe comparison of WGM of sound pulse propagation generation, wave-mixing oscillator comparison of WGM of and optical light is shown Figurein4.Figure 4. sound and optical light isinshown
Figure Comparisonofofmechanical mechanicalwave wave and and electromagnetic electromagnetic wave shows how Figure 4. 4. Comparison waveWGM. WGM.(a) (a)Diagram Diagram shows how WGM occurs: sound travels from one side of the gallery to another in the structure of St. Paul’s WGM occurs: sound travels from one side of the gallery to another in the structure of St. Paul’s Cathedral where WGM was first observed; (b) WGM of light: light is totally internally reflected within Cathedral where WGM was first observed; (b) WGM of light: light is totally internally reflected within the small curved cavity [54,75]. The phenomenon can be observed as light trapped inside the spherical the small curved cavity [54,75]. The phenomenon can be observed as light trapped inside the spherical structure [76]. structure [76].
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2.4. Detection Mechanism Total generates an anevanescent evanescentwave waveononthe theresonator resonator surface. This allows Total internal reflection generates surface. This allows the the resonator to detect any analyte the environment with the resonator. Fundamentally, resonator to detect any analyte in theinenvironment boundbound with the resonator. Fundamentally, optical optical resonators are sensitive to the refractive index. The analyte molecules to the resonator resonators are sensitive to the refractive index. The analyte molecules bindingbinding to the resonator surface surface a shift in the effective refractive [33,77]. The measurement is processed by plotting cause acause shift in the effective refractive indexindex [33,77]. The measurement is processed by plotting the the graph between light intensity versuswavelength, wavelength,i.e., i.e.,the the so-called so-called spectral spectral shift. The surface graph between light intensity versus surface molecule density is related to the the spectral spectral shift shift and and can can be be described described by by the the first-order first-order perturbation perturbation theory [68,78,79]. [68,78,79].
α exσαex σ δλ δλ == 2 2 2 − n− )rf f er )r λλ ε 0ε(0n(ring nring n2bu buffer
(4) (4)
Equation (3) reveals reveals the the relationship relationship between between molecule molecule surface surface density density (σ) (σ) and spectral spectral of of microring resonator, where whereλλisisresonant resonantwavelength wavelength and is the of resonant wavelength; and δλ δλ is the shiftshift of resonant wavelength; ε0 is εconstant vacuum permittivity, polarizability for molecules; nbuffer are the vacuum permittivity, αex is α excess polarizability for molecules; nring andnnring bufferand are the refractive ex is excess 0 is constant refractive index of the microsphere resonator and buffer solution, respectively, r is the ring index of the microsphere resonator and buffer solution, respectively, while r is the while ring radius. Figure radius. Figure 5 depicts the optical resonator system. 5 depicts the optical resonator system.
Figure 5. 5. Diagram Diagram shows shows the the optical optical resonator resonator system system and and analysis. analysis. (a) (a) Optical Optical resonator resonator system: system: the the Figure resonator. The detector is equipped to measure the the laser guided by a coupling waveguide excites the resonator. intensity dip of the resonant wavelength at the end of the coupling waveguide (Detector 1) or intensity dip of the resonant wavelength at the end of the coupling waveguide (Detector 1) or scattered Graph the of absence light at resonant wavelength. When the scattered light (Detector 2). (b) light (Detector 2). (b) Graph shows theshows absence light atofresonant wavelength. When the analyte analyte on the surface, a wavelength can be observed by both modes. binds onbinds the surface, it causesitacauses wavelength shift thatshift can that be observed by both modes.
3. Optical 3. Optical Resonator Resonator Types Types Optical resonator resonatortypes types defined by geometries their geometries and materials. The of examples of Optical are are defined by their and materials. The examples geometries geometries range from the heavily used mirroring [37,67,80–82] to microspheres [27,83–85], range from the heavily used mirroring [37,67,80–82] to microspheres [27,83–85], microgoblets [86], microgoblets [86], disks [21,80,87], microtoroids and bottles [20]. disks [21,80,87], microbubbles [88,89],microbubbles microtoroids [88,89], [90], and bottles [20].[90], Resonators generally Resonators generally utilize dielectric material. However, in recent research, there is increasing utilize dielectric material. However, in recent research, there is increasing interest in polymer-based interest in polymer-based structures. Polymers are usedoptions to expand materials options with that might structures. Polymers are used to expand the materials that the might be compatible other be compatible with other systems such as electronics, and polymers can be manufactured more easily systems such as electronics, and polymers can be manufactured more easily than typical silicon-based than typical silicon-based structures [80,82,91]. resonators canbiosensing also integrate with other structures [80,82,91]. Optical resonators can alsoOptical integrate with other systems such as biosensing systems as microfluidics lab-on-a-chip [92].inThe main types studied in microfluidics [81] orsuch lab-on-a-chip (LOC)[81] [92].orThe main types(LOC) studied biomedical applications, biomedicalfor applications, especially for cancer detection, configurations basedand on microring especially cancer detection, are configurations based are on microring [17,92–95] spherical [17,92– optical 95] and spherical optical resonators [27]. resonators [27]. Optical resonators evanescent wave-based sensors [36],[36], which can Optical resonators or oroptical opticalresonant resonantsensors sensorsare are evanescent wave-based sensors which be fabricated as a microstructure with different geometries. The sensors trap light inside their can be fabricated as a microstructure with different geometries. The sensors trap light inside their microcavities, allowing allowing the the optical optical rays rays to to resonate resonate in in the the confined confined space space aided aided by by light light coupling coupling via via microcavities, optical waveguides. waveguides. Optical resonators are are used used not not only only for for biomedical biomedical detection detection [21,96,97] [21,96,97] but but also also optical Optical resonators for gas detection [98], environmental control [87], toxin detection [99], temperature detection [70,100], microforce detection [67], single protein detection [90] and even nanoparticle detection [101,102].
of the optical fiber, which will melt the fiber. The molten material soon forms a spherical shape with the aid of surface tension. The sphere has low surface roughness, helping the sensor achieve dramatically high Q-factors in the range of 106 to 109. The sensor has a very low LOD: 10−8 to 10−9 RIU [68,78]. The configuration is utilized in miniature scale detection, down to the single molecule. Figure 6 depicts Sensors 2017,the 17, setup. 2095 8 of 25 Unlike ring resonators, the 3D geometry of a microsphere resonator means it has various methods for coupling, i.e., tapered coupling, prism coupling, angled fiber coupling or even direct for gas detection [98],coupling environmental control [87], toxin have detection [99], temperature detectionmultiple [70,100], illumination. Prism and half-block coupling the advantage of illuminating microforce detection [67], single protein detection [90] and even nanoparticle detection [101,102]. microsphere resonators simultaneously [27]. Microsphere resonators are also considered easy to fabricate. As mentioned above, the principle 3.1. WGM Microsphere Resonators is based on melting a waveguide fiber and allowing the surface tension to reform the material into a These (3D) introducing heat to one of sphere. Thethree-dimensional heat applied to the tipresonators of fiber canare betypically flame orfabricated an electricby arc. The melted fiber, e.g.,end silica the optical fiber, which will melt the fiber. The molten material soon forms a spherical shape with the (SiO2), will need to retain a minimum value of surface energy, forming a sphere. Then, the material aid of surface The sphereishas low surface roughness, helpingof thethe sensor achieve microsphere dramatically solidifies aftertension. the heat source removed. Despite the simplicity fabrication, 8 to 10−9 RIU [68,78]. The high Q-factors the range of 106 to 109The . Thefused sensorfiber has aisvery lowsensitive LOD: 10−to formation hasinlow reproducibility. very the environment and configuration utilized in miniature scale down to the single molecule. 6 depicts contamination.isAlthough the sphere size candetection, be adjusted by selecting the desired size Figure of the preheated the setup. fiber, some errors still occur during experiments [103].
Figure 6. Example Example of of microsphere microsphere configuration. Shown is an example of a microsphere with tapered coupling. The microsphere utilizes the WGM principle to resonate light inside its cavity. The analyte onthe the microsphere surface causes the change in the refractive The resonant binding on microsphere surface causes the change in the refractive index. Theindex. resonant wavelength wavelength is as also shifted as a result. is also shifted a result.
3.2. Ring Resonators Unlike ring resonators, the 3D geometry of a microsphere resonator means it has various methods for coupling, i.e., tapered coupling, prism coupling, angled fiber coupling or even direct illumination. 3.2.1. Microring and Microtoroid Optical Resonators Prism coupling and half-block coupling have the advantage of illuminating multiple microsphere The term “microring resonator” often refers to a planar ring resonator, the configuration being resonators simultaneously [27]. a microscale waveguide in a circular This resonator has the advantage ease of Microsphere resonators are also geometry considered(Figure easy to7).fabricate. As mentioned above, the of principle fabrication Silicon or siliconfiber nitride commonly utilizedtension as the toresonating The is based on [82]. melting a waveguide and is allowing the surface reform thestructure. material into resonator waveguide can theelectric same substrate, meaning all a sphere. and The coupling heat applied to the tip of also fiberbe canfabricated be flame on or an arc. The melted fiber, structures on same chip. The ring diameters value range of 10 surface μm to 10energy, mm [78,87,92,99,104]. Microring e.g., silica are (SiO will need to retain a minimum forming a sphere. Then, 2 ),the resonator arrays can also bethe fabricated and is have been commercialized. Genalyteof(San CA, the material solidifies after heat source removed. Despite the simplicity the Diego, fabrication, USA) manufactures microring that can 128 is tests within 15 min [105]. There are microsphere formation has lowresonators reproducibility. Theperform fused fiber very sensitive to the environment threecontamination. main approaches to the fabrication process. The is deepbyultraviolet lithography, and Although the sphere size can befirst adjusted selecting (DUV) the desired size of the main fabrication technique metal-oxide[103]. semiconductor (CMOS). The resolution preheated fiber, some errorsfor stillcomplementary occur during experiments is comparably rough to other techniques (100 nm). The UV wavelength is 248 nm or 193 nm. The 3.2. Ringmethod, Resonators second electron beam lithography (EBL), has higher resolution in the range of 10 nm. This method creates fewer flaws than DUV, the trade-off being the longer fabrication time. Lastly, 3.2.1. Microring and Microtoroid Optical Resonators The term “microring resonator” often refers to a planar ring resonator, the configuration being a microscale waveguide in a circular geometry (Figure 7). This resonator has the advantage of ease of fabrication [82]. Silicon or silicon nitride is commonly utilized as the resonating structure. The resonator and coupling waveguide can also be fabricated on the same substrate, meaning all structures are on the same chip. The ring diameters range 10 µm to 10 mm [78,87,92,99,104]. Microring resonator arrays can also be fabricated and have been commercialized. Genalyte (San Diego, CA, USA) manufactures
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microring resonators that can perform 128 tests within 15 min [105]. There are three main approaches to the fabrication process. The first is deep ultraviolet (DUV) lithography, the main fabrication technique for complementary metal-oxide semiconductor (CMOS). The resolution is comparably rough to other techniques (100 nm). The UV wavelength is 248 nm or 193 nm. The second method, electron beam lithography Sensors 2017, 17,(EBL), 2095 has higher resolution in the range of 10 nm. This method creates fewer flaws 9than of 24 DUV, the trade-off being the longer fabrication time. Lastly, nanoimprinting lithography (NIL) requires nanoimprintingfrom lithography requires pre-processing from the to earlier twoand techniques. pre-processing the earlier(NIL) two techniques. The polymer is applied a mold, then curedThe to polymer is applied to a mold, and then cured to solidify. The mold is later utilized to create the replica solidify. The mold is later utilized to create the replica of the structure with waveguide materials. The of the structure withcan waveguide materials. The polymer mold itself can also be the resonator [106]. polymer mold itself also be the resonator [106].
Figure Diagramshows showsan anexample examplecommon commonmicroring microringoptical opticalresonator resonatorsetting. setting.A A tunable tunable laser laser Figure 7. 7.Diagram sourceprovides providesthe theoptical opticalinput inputthrough throughthe thecoupling couplingwaveguide. waveguide.The The coupling coupling illuminates illuminates the the source Thecoupling couplingwavelength wavelengthcan canbe beobserved observedusing usingaaphotodetector photodetectorand andan an analytic analytic resonator structure.The resonator structure. instrument such instrument suchasasa acomputer. computer.The Thewavelength wavelengthshifts shiftswhen whenthe theresonator resonatoris is bound bound with with the analyte, altering the refractive index. altering the refractive index.
The resulting resulting Q-factor Q-factor of of ring ring resonators resonators use use to to be be comparably comparably low low (10 (1044)) [62,107] [62,107] against against The microsphere and microtoroid configurations. This is the result of residual flaws during the microsphere and microtoroid configurations. This is the result of residual flaws during the microfabrication. The other reason is because optical wave leakage occurs as the resonator is microfabrication. The other reason is because optical wave leakage occurs as the resonator is connected connected to the[58]. substrate [58]. The surface of roughness of isthe device is oftenduring generated during the to the substrate The surface roughness the device often generated the fabrication fabrication process. This considered as defect which lead generate noise, resulting in lowering process. This considered as defect which lead generate noise, resulting in lowering the quantitythe of quantity of Q-factor as discuss in previous session. However, ultra-high Q ring resonator was Q-factor as discuss in previous session. However, ultra-high Q ring resonator was discovered later. discovered later. The modification of the direction coupling to the resonator instead of a The modification of the direction coupling waveguide to the waveguide resonator instead of a traditional single traditional single straight bus waveguide [108,109]. straight bus waveguide [108,109]. Microtoroids, on on the the other other hand, hand, were were invented invented to to address address the the signal signal lost lost problems problems of of ring ring Microtoroids, resonator. Even though, microtoroids are WGM-based optical resonator, the device is fabricated resonator. Even though, microtoroids are WGM-based optical resonator, the device is fabricated onon a a chip like microringresonator resonatorfabrication. fabrication.The Themicrotoroid microtoroidstructure structureisisraised raisedabove abovethe the substrate substrate chip like inin microring by the the post, post, preventing preventing any any leak leak from from evanescent evanescent scattering scattering to to the the substrate substrate [110]. [110]. As As aa result, result, aa high high by 8 [23]. Microtoroids can be fabricated using lithography, Q-factor can be observed, with values up to 10 8 Q-factor can be observed, with values up to 10 [23]. Microtoroids can be fabricated using lithography, reactive ion ion etching, etching, and and xenon xenon difluoride difluoride (XeF (XeF2)) etching. etching. Hence, array of of microtoroids microtoroids can can be be reactive Hence, an an array 2 fabricated. The fabrication process is as follows: The resonator substrate, SiO 2, is deposited on a fabricated. The fabrication process is as follows: The resonator substrate, SiO2 , is deposited on a silicon silicon substrate. Then, etching is create used to 2 disk. The post is created by removing the substrate. Then, etching is used to thecreate SiO2 the disk.SiO The post is created by removing the substrate substrate below the disk via XeF 2 isotropic etching. Finally, the CO2 laser illuminates the structure, below the disk via XeF2 isotropic etching. Finally, the CO2 laser illuminates the structure, and the edge and the edge of the disk melts and forms a smooth aidedtension by surface tension [29,111,112] of the disk melts and forms a smooth toroid aided toroid by surface [29,111,112] (Figure 8). (Figure 8). The smoother surface generates less noise due to the surface roughness. However, microtoroid has a difficulty of coupling since the resonators are perched atop of silicon pillar, resulting in difficulty of coupling alignment [113,114]. In addition, during the process of CO2 laser illumination melt the resonators, the diameter of microtoroid is shrink. This lead to difficulty of monolithically integration for a micortoroid resonant cavity with an on-chip waveguide [113,115].
Figure 8. Microtoroid resonator fabrication process. (1) SiO2 is deposited on a silicon wafer; (2)
reactive ion etching, and xenon difluoride (XeF2) etching. Hence, an array of microtoroids can be fabricated. The fabrication process is as follows: The resonator substrate, SiO2, is deposited on a silicon substrate. Then, etching is used to create the SiO2 disk. The post is created by removing the substrate below the disk via XeF2 isotropic etching. Finally, the CO2 laser illuminates the structure, and the edge of 2095 the disk melts and forms a smooth toroid aided by surface tension [29,111,112] (Figure Sensors 2017, 17, 10 of 25 8).
Figure Microtoroid resonator fabrication process. (1) SiO is deposited on a silicon wafer; (2) Figure8. 8. Microtoroid resonator fabrication process. (1)2 SiO 2 is deposited on a silicon wafer; Hydrofluoric acid etching is applied to create the disk structure on top of the wafer; (3)wafer; XeF2 etching (2) Hydrofluoric acid etching is applied to create the disk structure on top of the (3) XeF2 illuminates the structure to smoothen the toroidthe is etching used to iscreate structure; (4) CO2 laser used atopost create a post structure; (4) CO laser illuminates the structure to smoothen 2 structure. toroid structure.
3.2.2. Optofluidic Ring Resonator (OFRR) OFRR is also a ring resonator configuration. The resonator is used to overcome the disadvantage of low Q-factor in microring resonators and the low reproducibility of microsphere resonators [116]. The OFRR uses a microscale SiO2 capillary with a diameter in the range of hundreds of micrometers. However, the wall thickness can be thin, i.e.,
Whispering-Gallery Mode Resonators for Detecting Cancer Weeratouch Pongruengkiat and Suejit Pechprasarn * Faculty of Biomedical Engineering, Rangsit University, Pathum Thani 12000, Thailand; [email protected] * Correspondence: [email protected]; Tel.: +66-92-997-2200 (ext. 1428) Received: 11 July 2017; Accepted: 6 September 2017; Published: 13 September 2017
Abstract: Optical resonators are sensors well known for their high sensitivity and fast response time. These sensors have a wide range of applications, including in the biomedical fields, and cancer detection is one such promising application. Sensor diagnosis currently has many limitations, such as being expensive, highly invasive, and time-consuming. New developments are welcomed to overcome these limitations. Optical resonators have high sensitivity, which enable medical testing to detect disease in the early stage. Herein, we describe the principle of whispering-gallery mode and ring optical resonators. We also add to the knowledge of cancer biomarker diagnosis, where we discuss the application of optical resonators for specific biomarkers. Lastly, we discuss advancements in optical resonators for detecting cancer in terms of their ability to detect small amounts of cancer biomarkers. Keywords: optical resonator; whispering-gallery mode; optical waveguide; evanescent wave; label-free; biosensor; cancer; sensor platform; instrumentation
1. Introduction Cancer, a hazardous non-communicable disease, is currently the main challenge in healthcare. Cancer Research UK shows that more than 14.1 million people had cancer in 2012 [1]. Despite the growing fatal rate of the disease, cancer develops in stages attributed to different hazard levels; the faster the cancer is detected, the higher the chance it can be cured. Figure 1 shows the survival rates for ovarian stromal cancer and cervical cancer visualized from the 5-year survival rates, which predict the chance of survival for those years [2]. Cancer is usually divided into four stages: Stage I, cancer is small and contained within the organ of origin; Stage II, cancer has grown larger but has not spread to other organs; Stage III, cancer has spread to nearby tissues and can reach the lymph nodes; and Stage IV, metastatic cancer; cancer has spread to other organs in the body. A, B, and C are used to indicate the substage, e.g., lung carcinoid tumor stage IIA [3]. However, the number staging system is an abstraction that describes the disease progression. Healthcare professionals typically describe the disease stage using the tumor-node-metastasis (TNM) system. T evaluates the size of the cancer and its area of spread to nearby tissue on a scale of 1–4; N defines whether the cancer reaches a lymph node on a scale of 0–3; M indicates whether the cancer has spread to another organ, and the value is binary: either 0 or 1 [4]. Table 1 shows the relations between the two systems.
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Figure 1. 1. Graphs cancers. It is thatthat at the Figure Graphs plotted plottedbetween between5-year 5-yearsurvival survivalrates ratesversus versusstages stagesofof cancers. It clear is clear at (a) initial stage of cancer development, patients have significantly larger chances of being cured. the initial stage of cancer development, patients have significantly larger chances of being cured. Ovarian stromal tumor [5],[5], (b)(b) Cervical cancer [6].[6]. (a) Ovarian stromal tumor Cervical cancer Table1.1.The Therelationship relationshipbetween betweenthe the number system and TNM system of cancer for cervical cancer Table number system and TNM system of cancer for cervical cancer [7]. [7]. Number System
TNM System
Number System TNM System Stage 0 0 Tis,Tis, N0, N0, M0 M0 Stage Stage I T1, N0, M0 Stage I T1, N0, M0 Stage IA T1a, N0, M0 Stage IA T1a, Stage IB T1b, N0, N0, M0 M0 Stage N0, M0 Stage II IB T2,T1b, N0, M0 Stage IIA II T2a,T2, N0,N0, M0 M0 Stage Stage III T3, N0, M0 Stage IIA T2a, N0, M0 Stage IIIA T3a, N0, M0 Stage T3,T1–T3, N0, M0 Stage IIIB III T3b, N0, M0 or N1, M0 Stage T3a, Stage IVIIIA - N0, M0 Stage IVAIIIB T4,M0 N0,or M0T1–T3, N1, M0 Stage T3b, N0, Stage IVB T1–T3, N0–N3, - M1 Stage IV Stage IVA T4, N0, M0 Stage IVB T1–T3, N0–N3, Even now, early diagnoses for cancer are scarce. A qualitative studyM1 in 2015 asserted that late diagnosis is the result of difficulty in making appointments, worry regarding doctor availability, and Even now, diagnoses for cancerofare scarce. qualitative study in 2015 asserted that late unwillingness to early learn of the development cancer [8]. A Apart from the emotional concern of scarring diagnosis is the result of difficulty in making worry regarding doctor availability,even and from unfortunate discovery, the findings reflectappointments, the difficulty in accessing diagnostic technologies unwillingness to learn ofCurrently, the development of canceris[8]. Apart from the emotional concern of scarring in developed countries. cancer detection still based on highly invasive, time-consuming, fromcostly unfortunate discovery, the findings reflect the difficulty in accessing diagnostic technologies and processes. evenWhen in developed countries. Currently, detection is stillof based on or highly point-of-care (POC) diagnosis wascancer introduced, the concept real-time, at leastinvasive, shorter time-consuming, and costly processes. diagnosis time was heralded as the future of healthcare. The actual definition of POC diagnosis is When diagnosis was introduced, thecare concept of real-time, or first at least shorter testing at orpoint-of-care near the site(POC) of patient care whenever medical is needed [9]. The biosensor diagnosis timemeter was heralded as the futureinof actual definition of diagnosis POC diagnosis was a glucose that became popular thehealthcare. late 1980sThe [10,11]. However, POC is not is a testing at or near thedawn site ofof patient care whenever medicalpatients’ care is needed first biosensor was new concept. At the civilization, doctors visited homes[9]. andThe performed diagnosis a glucose meterwithout that became popular in the medical late 1980s [10,11].The However, POC medical diagnosiscomplex is not a was new and treatment today’s centralized centers. centralized concept. Atinthe civilization, doctors visitedthe patients’ and performed diagnosisOver and introduced thedawn early of 17th century [12], enhancing mobilityhomes of technology and knowledge. treatment without today’s centralized medical centers. The centralized medical complex was time, and as the world population increased exponentially, more patients have become dependent on introduced the early 17th century enhancing theoverwhelming mobility of technology andhealthcare knowledge. Over this system. in The demographic growth[12], has resulted in an demand for services. time, and as theand world population increased exponentially, patientsofhave become dependent on The diagnostic treatment capability are then limited by more the capacity the available technology. this Diagnosis system. The demographic growth has resulted in an overwhelming demand for healthcare requires novel tools and instruments. Based on the concept of reducing diagnostic services. diagnostic treatment capability limited byrole the in capacity of the ideology available times andThe steps, modernand biosensors have come to are playthen an important fulfilling technology. of POC. Some cancers now can be detected at an early stage using less invasive and lower-cost Diagnosis requires novel tools and instruments. Based on the of reducingsensor diagnostic procedures [13–15] through advancements in sensor technologies suchconcept as electrochemical [16], times and steps, modern biosensors have come to play an important role in fulfilling the ideology of POC. Some cancers now can be detected at an early stage using less invasive and lower-cost
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procedures [13–15] through advancements in sensor technologies such as electrochemical sensor [16],
optical sensor, or piezoelectric sensor [14]. thankstotothe thediscovery discovery of cancer biomarkers (cancer optical sensor, or piezoelectric sensor [14].This This is is thanks of cancer biomarkers (cancer markers), which have allowed biosensor detection to be more specific [17]. In particular, the optical markers), which have allowed biosensor detection to be more specific [17]. In particular, the optical biosensor has high sensitivity and can detection[17,18]. [17,18]. One technique gaining biosensor has high sensitivity and canperform performlabel-free label-free detection One technique gaining the the attention of biosensor researchers theoptical optical resonator. resonator. Figure thethe publications on this attention of biosensor researchers is is the Figure2 2shows shows publications on type this type of optical sensor. of optical sensor.
Figure 2. Figure shows how numberof ofarticles articles on optical resonators evolved Figure 2. Figure shows how thethe number on fix fixin infigure figurelabel label optical resonators evolved between 1999–2016. graph showsincreasing increasing trends trends in study. Remark: TheThe datadata werewere between 1999–2016. TheThe graph shows inthis thisarea areaofof study. Remark: Web of Sciencedatabase database(www.webofknowledge.com) (www.web of knowledge.com) with thethe keyword “Optical gathered gathered fromfrom the the Web of Science with keyword “Optical Resonator”, and then the category filter “Optics” was applied [19]. Resonator”, and then the category filter “Optics” was applied [19].
Optical resonators enhance light guide properties for detection in the environment. The sensors
Optical resonators lightinguide properties for detection theresonators, environment. The sensors are based on light enhance confinement waveguide structures, such as in ring Fabry-Perot are based on lightwhispering-gallery confinement in waveguide structures, such as(WGR) ring resonators, Fabry-Perot resonators, resonators, mode (WGM) resonators and high-contrast gratings. whispering-gallery resonators (WGR)research and high-contrast gratings. Currently, there is Currently, there mode is high(WGM) growth in optical resonator because of their promising properties, such as high sensitivity, low response time, compactness, and immunity to electromagnetic high growth in optical resonator research because of their promising properties, such as high sensitivity, interference [17,18,20,21], whichand are unlike other to waveguide sensors orinterference fiber sensors,[17,18,20,21], in which sensor low response time, compactness, immunity electromagnetic which dimension light–matter interaction. resonators determine the interaction length by the are unlike otherlimits waveguide sensors or fiberOptical sensors, in which sensor dimension limits light–matter quality (Q) factor [22], the dimensionless of temporal confinement light resonating inside interaction. Optical resonators determinequantity the interaction length by the of quality (Q) factor [22], the the sensor [23]. WGR and ring resonators are emerging cancer detection technologies known for their dimensionless quantity of temporal confinement of light resonating inside the sensor [23]. WGR and easy fabrication and high performance. These aspects allow the sensors to perform early detection ring resonators are emerging cancer detection technologies known for their easy fabrication and high when cancer biomarker concentrations are still low. This is the first review of such technologies for performance. These aspects allow the sensors to perform early detection when cancer biomarker cancer detection. concentrations stillsensors, low. This first review of such technologies cancer detection. Unlikeare other suchisasthe electrochemical sensors, which usuallyfor require probe labeling or Unlike sensors, such as electrochemical sensors, whichmodification usually require labeling analyte other modification [24], optical resonators require no chemical of theprobe analyte [21]. or Optical resonators[24], can optical diagnoseresonators different cancer in amodification short time [17,25–27]. These [21]. analyte modification requirebiomarkers no chemical of the analyte properties also can match the concept of POC diagnosis. Opticalin resonators have[17,25–27]. wide-ranging Optical resonators diagnose different cancer biomarkers a short time These applications. As label-free biosensors, most optical resonators eliminate the pre-detection procedures properties also match the concept of POC diagnosis. Optical resonators have wide-ranging applications. by removing, or at least shortening, sample preparation time. label-based sensing, the biological As label-free biosensors, most optical resonators eliminate theFor pre-detection procedures by removing, sample must undergo analyte marking, for example, with a fluorescent dye or radio marker. This not or at least shortening, sample preparation time. For label-based sensing, the biological sample must only requires extra cost for the labeling material, but also causes undesirable delay between sample undergo analyte marking, for example, with a fluorescent dye or radio marker. This not only requires collection and analysis. This delay and labeling approach can result in changes in both the physical extraand costchemical for the labeling but also causes undesirable delay between sample collection and propertiesmaterial, of the analyte [17,25,28–30]. analysis. In This and approach can resultofinoptical changes in bothand theevaluate physicalthe and chemical thisdelay review, welabeling introduce the fundamentals resonators various properties of and the analyte sensors, describe [17,25,28–30]. WGR and ring resonators in more detail. Then, we provide an overview of In this fabrication review, weand introduce the fundamentals of optical resonators and and evaluate thetheir various sensor preparation. We briefly introduce cancer biomarkers discuss sensors, and describe WGR and ring resonators in more detail. Then, we provide an overview of sensor fabrication and preparation. We briefly introduce cancer biomarkers and discuss their detection. We then review recent works on the application of optical resonators in cancer biomarker detection focused on early stage detection. We also discuss how the high sensitivity of the optical resonators
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plays an important role in the early stage cancer diagnosis and how these optical technologies can potentially save lots of lives. 2. Fundamentals of Optical Resonators 2.1. Performance Parameters of Optical Resonators Similar to other biomedical sensors, optical resonators are defined by sensitivity, limit of detection (LOD), resolution, dynamic range, and selectivity. Sensitivity describes the change in output upon a change in the physical properties of the sensor. For optical resonators, sensitivity is the ability to transduce the change (binding) on the resonator surface into an output, i.e., spectral shift. This can be described as the shift of resonant wavelength (δλ) or the difference of light intensity (δI) at a particular wavelength when the analyte is bound to the surface. The units are usually given as nm/RIU (wavelength shift over refractive index unit) and W/(m2· RIU) [31]. LOD is the minimum quantity of analyte to be detected by the sensor in the actual detection environment. The LOD is limited by noise source, efficiency of the optical detector in the optical system, and the amount of light that can be detected [32]. Optical system noise can come from: (1) thermal noise, (2) microphone vibrations (3) dark current of the detector and (4) shot noise of the optical detector and loss due to material defects. These amounts of noise will introduce losses in the optical resonator [33–35]. The LOD for optical resonators is normally defined by two parameters: First, the RIU and surface coverage, given as pg/mm2 , or it can be described as sample concentration in the molar unit. Label-free sensors are normally described by RIU, while surface coverage/sample concentration are used in both labeled and label-free sensors [36]. RIU can be converted to other physical parameter of analyte by using response unit. In optical sensors, it has been well established and validated over a wide range of different proteins that one response unit of 10−6 RIU is equivalent to 1 pg/mm2 . By knowing the sensing area size, the mass on the sensor can be determined. Similarly, with a known molecular weight, one can determine the number of molecules on the sensor [32]. Selectivity describes the ability to distinguish between the desired analyte and others in the environment. Whenever the analyte does not specifically bind to the sensor, it results in errors to the output signal. Biosensors are now equipped with biologically selective species such as antibody-antigen [37] or enzyme-substrate [38]. However, synthetic substances have also been developed; aptamer is one such example [39]. The process of introducing the binding material to the resonator surface to optimize selectivity is termed surface functionalization. Unlike other sensors, biomedical sensor development aims to reduce the sample volume, especially when the analyte requires invasive extraction procedures from a patient, such as a blood sample. The other parameter is the Q-factor, introduced earlier as the basic parameter for determination of the lifetime of light resonating in the waveguided resonator. The Q-factor can be defined as: Q = ω0 τ = 2πv0 τ =
ω0 ∆ω FW HM
(1)
where ω 0 is the angular frequency. The linear frequency of the mode is described by v0 . τ is the time for the field intensity to decay by the factor of e, the so-called cavity ring down lifetime. According to the equation, ∆wFWHM is inversely proportional to τ and determines the line width: the uncertainty of the frequency of resonance in angular frequency; FWHM stands for full width at half-maximum. The highest Q-value reported so far is 2 × 1010 on the spheroidal crystalline WGMR with a resonant wavelength of 1300 nm [40]. For amorphous material, it is 8 × 109 with a 633 nm resonant wavelength [41]. 2.2. Light Coupling Light coupling is commonly referred to as evanescent wave coupling in optical resonator research. It can be described as inducing light on another medium without contact. As two optical guide
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2.2. Light Coupling Light are coupling commonly referred to distance, as evanescent wave coupling in optical resonator components placediswithin evanescent zone light is coupled into the resonant structure research. It can be described as inducing light on another medium without contact. As two optical aided by a phase-matched evanescent field. A tunable laser source is commonly used for input; the guide components are placed within evanescent zone distance, light is coupled into the resonant wavelength of the source can be adjusted. At the matching wavelength, the intensity dip can be structure aided by a phase-matched evanescent field. A tunable laser source is commonly used for observed using a photodetector. As mentioned earlier, the optical resonator interaction length is the input; the wavelength of the source can be adjusted. At the matching wavelength, the intensity dip effect of a Q-factor. The length is described by: can be observed using a photodetector. As mentioned earlier, the optical resonator interaction length is the effect of a Q-factor. The length is described by: Qλ (2) Le f f = Q λ2πn Leff = (2) 2π n From Equation (1), L is the effective interaction length and n is the refractive index of the eff
the resonators effective interaction length and refractive index of thethe From Equationof(1), Leff isring resonator. Q-factors typical range from 104 to 10n9 . isλ the is resonant wavelength; 4 resonator. Q-factors is of determined typical ring by resonators rangecondition: from 10 to 109. λ is resonant wavelength; the matching wavelength the resonant matching wavelength is determined by the resonant condition: 2πrne f f λm = 2π rneff for m = 1, 2, 3, . . . (3) m for m = 1, 2, 3, … λm = (3) m where r describes the outer radius of the ring resonator; neff refers to the effective refractive index, where r describes the outer radius of the ring resonator; neff refers to the effective refractive index, which is sensitive to the binding event on the surface; m is the mode number; λm is the resonant which is sensitive to the binding event on the surface; m is the mode number; λm is the resonant freefree-space wavelength of the tunable laser. space wavelength of the tunable laser. Optical resonators mostly structures:the thefirst firstserves serves the system Optical resonators mostlyconsist consistof oftwo twooptical optical waveguide waveguide structures: the system as as anan input wherelight light enters and signal is detected the end. other end. inputand andoutput output waveguide, waveguide, where enters and thethe signal is detected at theat other The Theother other structure is the resonator structure, which confines the light propagated from the first structure is the resonator structure, which confines the light propagated from the first structure. structure. There are various techniques for coupling the light, the most common being tapered coupling. There are various techniques for coupling the light, the most common being tapered coupling. Examples of of methods (Figure3)3)include includetapered tapered coupling [42], Examples methodsfor forilluminating illuminatingresonator resonator structures structures (Figure coupling [42], prism coupling [43], angled waveguideside sidecoupling coupling[39,45,46], [39,45,46], free-space prism coupling [43], angledfiber fibercoupling coupling[44], [44], planar planar waveguide free-space coupling or or direct illumination coupler[49]. [49]. coupling direct illumination[47,48], [47,48],and andpolished polished half-block half-block coupler
Figure 3. Various types of optical coupling. (a) Tapered; (b) prism; (c) angled fiber; (d) planar Figure 3. Various types of optical coupling. (a) Tapered; (b) prism; (c) angled fiber; (d) planar waveguide side; (e) free-space; (f) polished half-block coupler. waveguide side; (e) free-space; (f) polished half-block coupler.
Tapered coupling has 99.8% coupling efficiency [50]; the losses are the result of material Tapered coupling has 99.8% coupling [50]; the Comparable losses are theefficiency result of material absorption, scattering, and bending lossesefficiency from fiber stress. has been absorption, reported scattering, and bending losses[49]. fromExperimental fiber stress. Comparable has prism been reported for the half-block coupler studies have efficiency shown that coupling for hasthe half-block coupler80% [49]. Experimental have shown prism coupling hasasapproximately 80% approximately efficiency [51,52].studies Angle-polished fiberthat coupling, also known “pigtailing,” has efficiency [51,52]. Angle-polished fiber coupling, also known as “pigtailing,” has 60% efficiency [44]. Tapered coupling has the advantages of not only higher coupling efficiency but also ease of fabrication
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and preparation. Despite theircoupling lower coupling efficiency, the other coupling methodsefficiency are of research 60% efficiency [44]. Tapered has the advantages of not only higher coupling but interest, as they can provide more robustness [18]. also ease of fabrication and preparation. Despite their lower coupling efficiency, the other coupling methods are of research interest, as they can provide more robustness [18]. 2.3. Whispering-Gallery Mode 2.3.Lord Whispering-Gallery Mode WGM in 1878, as he whispered on one side of the curved wall inside Rayleigh discovered St. Paul’s Cathedral UK). Hisinvoice be heard 40 away This demonstrated Lord Rayleigh(London, discovered WGM 1878,could as he whispered onmone side[53,54]. of the curved wall inside theSt.phenomena of the(London, acousticUK). wave which could40travel along the This edgedemonstrated of the gallerythe hall Paul’s Cathedral His(sound), voice could be heard m away [53,54]. with negligible loss. As he observed this phenomenon, he also proposed that electromagnetic waves phenomena of the acoustic wave (sound), which could travel along the edge of the gallery hall with could travel loss. withAsthis mode. Inthis 1961, the WGMheofalso optical lightthat waselectromagnetic first reported waves in a spherical negligible he observed phenomenon, proposed could microstructure [55].mode. Instead of thethe curved whispered voice, the light entirely travel with this In 1961, WGMwall-guided of optical light was first reported in awas spherical internally reflected in Instead a confined cavity. Later on, WGMswhispered in liquid voice, were also studied. microstructure [55]. of the curved wall-guided the light was Following entirely Lord Rayleigh’s discovery, Debye and Later Mie published two important theoretical works. Lord Debye internally reflected in a confined cavity. on, WGMs in liquid were also studied. Following Rayleigh’sthe discovery, and Mie published two important theoretical works. Debye determined resonantDebye eigenfrequencies for dielectric and metallic spheres in 1909 [56].determined Mie studied the resonant wave eigenfrequencies dielectric and spheres in 1909 [56]. Mie studied electromagnetic scattering infor microspheres [57].metallic These later became widely discussed in both electromagnetic wave scattering in microspheres [57]. These later became widely discussed in both theoretical and experimental works [53]. theoretical and experimental works [53]. was discovered in a microsphere resonator. Crystalline Optical WGM, as mentioned earlier, Optical WGM, as mentioned earlier, discovered in a microsphere resonator.inCrystalline calcium fluoride (CaF2 ) was fabricated as thewas resonator. A pulsed laser was illuminated a tangential calcium fluoride (CaF 2) was fabricated as the resonator. A pulsed laser was illuminated in a tangential direction to the sphere. The detected output laser showed transient oscillation instead of spikes from to the sphere. detected instead ofwas spikes from thedirection input, confirming theThe presence ofoutput WGM laser [55]. showed In 1981,transient WGM inoscillation liquid resonators observed the input, confirming the presence of WGM [55]. In 1981, WGM in liquid resonators was observed for the first time. In the experiment, a liquid droplet was optically levitated by a laser beam, and the for the first time. In the experiment, a liquid droplet was optically levitated by a laser beam, and the scattered light was detected [58]. WGR have many optics and optoelectronics applications and are scattered light was detected [58]. WGR have many optics and optoelectronics applications and are studied in both passive and active mode [59]. The previous applications for passive mode include studied in both passive and active mode [59]. The previous applications for passive mode include optical and photonic single resonator filters [60,61], high-order filter or cascade resonators [62,63], optical and photonic single resonator filters [60,61], high-order filter or cascade resonators [62,63], tunable filters [64], WGM filters in optoelectronic oscillator (OEO) [65,66], and sensors, which can tunable filters [64], WGM filters in optoelectronic oscillator (OEO) [65,66], and sensors, which can be be biological, biological,chemical, chemical, mechanical [67–70]. active-mode is commonly as a oror mechanical [67–70]. The The active-mode WGMWGM is commonly utilizedutilized as a laser laser source, and involves wave mixing devices such as continuous-wave (CW)-WGM laser, i.e., source, and involves wave mixing devices such as continuous-wave (CW)-WGM laser, i.e., thethe miniature laser [55,71], [72], switches switchesand andmodulators modulators [73], OEO [74], miniature laser [55,71],resonator-modified resonator-modified scattering scattering [72], [73], OEO [74], pulse propagation andand generation, andand wave-mixing oscillator [59].[59]. TheThe comparison of WGM of sound pulse propagation generation, wave-mixing oscillator comparison of WGM of and optical light is shown Figurein4.Figure 4. sound and optical light isinshown
Figure Comparisonofofmechanical mechanicalwave wave and and electromagnetic electromagnetic wave shows how Figure 4. 4. Comparison waveWGM. WGM.(a) (a)Diagram Diagram shows how WGM occurs: sound travels from one side of the gallery to another in the structure of St. Paul’s WGM occurs: sound travels from one side of the gallery to another in the structure of St. Paul’s Cathedral where WGM was first observed; (b) WGM of light: light is totally internally reflected within Cathedral where WGM was first observed; (b) WGM of light: light is totally internally reflected within the small curved cavity [54,75]. The phenomenon can be observed as light trapped inside the spherical the small curved cavity [54,75]. The phenomenon can be observed as light trapped inside the spherical structure [76]. structure [76].
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2.4. Detection Mechanism Total generates an anevanescent evanescentwave waveononthe theresonator resonator surface. This allows Total internal reflection generates surface. This allows the the resonator to detect any analyte the environment with the resonator. Fundamentally, resonator to detect any analyte in theinenvironment boundbound with the resonator. Fundamentally, optical optical resonators are sensitive to the refractive index. The analyte molecules to the resonator resonators are sensitive to the refractive index. The analyte molecules bindingbinding to the resonator surface surface a shift in the effective refractive [33,77]. The measurement is processed by plotting cause acause shift in the effective refractive indexindex [33,77]. The measurement is processed by plotting the the graph between light intensity versuswavelength, wavelength,i.e., i.e.,the the so-called so-called spectral spectral shift. The surface graph between light intensity versus surface molecule density is related to the the spectral spectral shift shift and and can can be be described described by by the the first-order first-order perturbation perturbation theory [68,78,79]. [68,78,79].
α exσαex σ δλ δλ == 2 2 2 − n− )rf f er )r λλ ε 0ε(0n(ring nring n2bu buffer
(4) (4)
Equation (3) reveals reveals the the relationship relationship between between molecule molecule surface surface density density (σ) (σ) and spectral spectral of of microring resonator, where whereλλisisresonant resonantwavelength wavelength and is the of resonant wavelength; and δλ δλ is the shiftshift of resonant wavelength; ε0 is εconstant vacuum permittivity, polarizability for molecules; nbuffer are the vacuum permittivity, αex is α excess polarizability for molecules; nring andnnring bufferand are the refractive ex is excess 0 is constant refractive index of the microsphere resonator and buffer solution, respectively, r is the ring index of the microsphere resonator and buffer solution, respectively, while r is the while ring radius. Figure radius. Figure 5 depicts the optical resonator system. 5 depicts the optical resonator system.
Figure 5. 5. Diagram Diagram shows shows the the optical optical resonator resonator system system and and analysis. analysis. (a) (a) Optical Optical resonator resonator system: system: the the Figure resonator. The detector is equipped to measure the the laser guided by a coupling waveguide excites the resonator. intensity dip of the resonant wavelength at the end of the coupling waveguide (Detector 1) or intensity dip of the resonant wavelength at the end of the coupling waveguide (Detector 1) or scattered Graph the of absence light at resonant wavelength. When the scattered light (Detector 2). (b) light (Detector 2). (b) Graph shows theshows absence light atofresonant wavelength. When the analyte analyte on the surface, a wavelength can be observed by both modes. binds onbinds the surface, it causesitacauses wavelength shift thatshift can that be observed by both modes.
3. Optical 3. Optical Resonator Resonator Types Types Optical resonator resonatortypes types defined by geometries their geometries and materials. The of examples of Optical are are defined by their and materials. The examples geometries geometries range from the heavily used mirroring [37,67,80–82] to microspheres [27,83–85], range from the heavily used mirroring [37,67,80–82] to microspheres [27,83–85], microgoblets [86], microgoblets [86], disks [21,80,87], microtoroids and bottles [20]. disks [21,80,87], microbubbles [88,89],microbubbles microtoroids [88,89], [90], and bottles [20].[90], Resonators generally Resonators generally utilize dielectric material. However, in recent research, there is increasing utilize dielectric material. However, in recent research, there is increasing interest in polymer-based interest in polymer-based structures. Polymers are usedoptions to expand materials options with that might structures. Polymers are used to expand the materials that the might be compatible other be compatible with other systems such as electronics, and polymers can be manufactured more easily systems such as electronics, and polymers can be manufactured more easily than typical silicon-based than typical silicon-based structures [80,82,91]. resonators canbiosensing also integrate with other structures [80,82,91]. Optical resonators can alsoOptical integrate with other systems such as biosensing systems as microfluidics lab-on-a-chip [92].inThe main types studied in microfluidics [81] orsuch lab-on-a-chip (LOC)[81] [92].orThe main types(LOC) studied biomedical applications, biomedicalfor applications, especially for cancer detection, configurations basedand on microring especially cancer detection, are configurations based are on microring [17,92–95] spherical [17,92– optical 95] and spherical optical resonators [27]. resonators [27]. Optical resonators evanescent wave-based sensors [36],[36], which can Optical resonators or oroptical opticalresonant resonantsensors sensorsare are evanescent wave-based sensors which be fabricated as a microstructure with different geometries. The sensors trap light inside their can be fabricated as a microstructure with different geometries. The sensors trap light inside their microcavities, allowing allowing the the optical optical rays rays to to resonate resonate in in the the confined confined space space aided aided by by light light coupling coupling via via microcavities, optical waveguides. waveguides. Optical resonators are are used used not not only only for for biomedical biomedical detection detection [21,96,97] [21,96,97] but but also also optical Optical resonators for gas detection [98], environmental control [87], toxin detection [99], temperature detection [70,100], microforce detection [67], single protein detection [90] and even nanoparticle detection [101,102].
of the optical fiber, which will melt the fiber. The molten material soon forms a spherical shape with the aid of surface tension. The sphere has low surface roughness, helping the sensor achieve dramatically high Q-factors in the range of 106 to 109. The sensor has a very low LOD: 10−8 to 10−9 RIU [68,78]. The configuration is utilized in miniature scale detection, down to the single molecule. Figure 6 depicts Sensors 2017,the 17, setup. 2095 8 of 25 Unlike ring resonators, the 3D geometry of a microsphere resonator means it has various methods for coupling, i.e., tapered coupling, prism coupling, angled fiber coupling or even direct for gas detection [98],coupling environmental control [87], toxin have detection [99], temperature detectionmultiple [70,100], illumination. Prism and half-block coupling the advantage of illuminating microforce detection [67], single protein detection [90] and even nanoparticle detection [101,102]. microsphere resonators simultaneously [27]. Microsphere resonators are also considered easy to fabricate. As mentioned above, the principle 3.1. WGM Microsphere Resonators is based on melting a waveguide fiber and allowing the surface tension to reform the material into a These (3D) introducing heat to one of sphere. Thethree-dimensional heat applied to the tipresonators of fiber canare betypically flame orfabricated an electricby arc. The melted fiber, e.g.,end silica the optical fiber, which will melt the fiber. The molten material soon forms a spherical shape with the (SiO2), will need to retain a minimum value of surface energy, forming a sphere. Then, the material aid of surface The sphereishas low surface roughness, helpingof thethe sensor achieve microsphere dramatically solidifies aftertension. the heat source removed. Despite the simplicity fabrication, 8 to 10−9 RIU [68,78]. The high Q-factors the range of 106 to 109The . Thefused sensorfiber has aisvery lowsensitive LOD: 10−to formation hasinlow reproducibility. very the environment and configuration utilized in miniature scale down to the single molecule. 6 depicts contamination.isAlthough the sphere size candetection, be adjusted by selecting the desired size Figure of the preheated the setup. fiber, some errors still occur during experiments [103].
Figure 6. Example Example of of microsphere microsphere configuration. Shown is an example of a microsphere with tapered coupling. The microsphere utilizes the WGM principle to resonate light inside its cavity. The analyte onthe the microsphere surface causes the change in the refractive The resonant binding on microsphere surface causes the change in the refractive index. Theindex. resonant wavelength wavelength is as also shifted as a result. is also shifted a result.
3.2. Ring Resonators Unlike ring resonators, the 3D geometry of a microsphere resonator means it has various methods for coupling, i.e., tapered coupling, prism coupling, angled fiber coupling or even direct illumination. 3.2.1. Microring and Microtoroid Optical Resonators Prism coupling and half-block coupling have the advantage of illuminating multiple microsphere The term “microring resonator” often refers to a planar ring resonator, the configuration being resonators simultaneously [27]. a microscale waveguide in a circular This resonator has the advantage ease of Microsphere resonators are also geometry considered(Figure easy to7).fabricate. As mentioned above, the of principle fabrication Silicon or siliconfiber nitride commonly utilizedtension as the toresonating The is based on [82]. melting a waveguide and is allowing the surface reform thestructure. material into resonator waveguide can theelectric same substrate, meaning all a sphere. and The coupling heat applied to the tip of also fiberbe canfabricated be flame on or an arc. The melted fiber, structures on same chip. The ring diameters value range of 10 surface μm to 10energy, mm [78,87,92,99,104]. Microring e.g., silica are (SiO will need to retain a minimum forming a sphere. Then, 2 ),the resonator arrays can also bethe fabricated and is have been commercialized. Genalyteof(San CA, the material solidifies after heat source removed. Despite the simplicity the Diego, fabrication, USA) manufactures microring that can 128 is tests within 15 min [105]. There are microsphere formation has lowresonators reproducibility. Theperform fused fiber very sensitive to the environment threecontamination. main approaches to the fabrication process. The is deepbyultraviolet lithography, and Although the sphere size can befirst adjusted selecting (DUV) the desired size of the main fabrication technique metal-oxide[103]. semiconductor (CMOS). The resolution preheated fiber, some errorsfor stillcomplementary occur during experiments is comparably rough to other techniques (100 nm). The UV wavelength is 248 nm or 193 nm. The 3.2. Ringmethod, Resonators second electron beam lithography (EBL), has higher resolution in the range of 10 nm. This method creates fewer flaws than DUV, the trade-off being the longer fabrication time. Lastly, 3.2.1. Microring and Microtoroid Optical Resonators The term “microring resonator” often refers to a planar ring resonator, the configuration being a microscale waveguide in a circular geometry (Figure 7). This resonator has the advantage of ease of fabrication [82]. Silicon or silicon nitride is commonly utilized as the resonating structure. The resonator and coupling waveguide can also be fabricated on the same substrate, meaning all structures are on the same chip. The ring diameters range 10 µm to 10 mm [78,87,92,99,104]. Microring resonator arrays can also be fabricated and have been commercialized. Genalyte (San Diego, CA, USA) manufactures
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microring resonators that can perform 128 tests within 15 min [105]. There are three main approaches to the fabrication process. The first is deep ultraviolet (DUV) lithography, the main fabrication technique for complementary metal-oxide semiconductor (CMOS). The resolution is comparably rough to other techniques (100 nm). The UV wavelength is 248 nm or 193 nm. The second method, electron beam lithography Sensors 2017, 17,(EBL), 2095 has higher resolution in the range of 10 nm. This method creates fewer flaws 9than of 24 DUV, the trade-off being the longer fabrication time. Lastly, nanoimprinting lithography (NIL) requires nanoimprintingfrom lithography requires pre-processing from the to earlier twoand techniques. pre-processing the earlier(NIL) two techniques. The polymer is applied a mold, then curedThe to polymer is applied to a mold, and then cured to solidify. The mold is later utilized to create the replica solidify. The mold is later utilized to create the replica of the structure with waveguide materials. The of the structure withcan waveguide materials. The polymer mold itself can also be the resonator [106]. polymer mold itself also be the resonator [106].
Figure Diagramshows showsan anexample examplecommon commonmicroring microringoptical opticalresonator resonatorsetting. setting.A A tunable tunable laser laser Figure 7. 7.Diagram sourceprovides providesthe theoptical opticalinput inputthrough throughthe thecoupling couplingwaveguide. waveguide.The The coupling coupling illuminates illuminates the the source Thecoupling couplingwavelength wavelengthcan canbe beobserved observedusing usingaaphotodetector photodetectorand andan an analytic analytic resonator structure.The resonator structure. instrument such instrument suchasasa acomputer. computer.The Thewavelength wavelengthshifts shiftswhen whenthe theresonator resonatoris is bound bound with with the analyte, altering the refractive index. altering the refractive index.
The resulting resulting Q-factor Q-factor of of ring ring resonators resonators use use to to be be comparably comparably low low (10 (1044)) [62,107] [62,107] against against The microsphere and microtoroid configurations. This is the result of residual flaws during the microsphere and microtoroid configurations. This is the result of residual flaws during the microfabrication. The other reason is because optical wave leakage occurs as the resonator is microfabrication. The other reason is because optical wave leakage occurs as the resonator is connected connected to the[58]. substrate [58]. The surface of roughness of isthe device is oftenduring generated during the to the substrate The surface roughness the device often generated the fabrication fabrication process. This considered as defect which lead generate noise, resulting in lowering process. This considered as defect which lead generate noise, resulting in lowering the quantitythe of quantity of Q-factor as discuss in previous session. However, ultra-high Q ring resonator was Q-factor as discuss in previous session. However, ultra-high Q ring resonator was discovered later. discovered later. The modification of the direction coupling to the resonator instead of a The modification of the direction coupling waveguide to the waveguide resonator instead of a traditional single traditional single straight bus waveguide [108,109]. straight bus waveguide [108,109]. Microtoroids, on on the the other other hand, hand, were were invented invented to to address address the the signal signal lost lost problems problems of of ring ring Microtoroids, resonator. Even though, microtoroids are WGM-based optical resonator, the device is fabricated resonator. Even though, microtoroids are WGM-based optical resonator, the device is fabricated onon a a chip like microringresonator resonatorfabrication. fabrication.The Themicrotoroid microtoroidstructure structureisisraised raisedabove abovethe the substrate substrate chip like inin microring by the the post, post, preventing preventing any any leak leak from from evanescent evanescent scattering scattering to to the the substrate substrate [110]. [110]. As As aa result, result, aa high high by 8 [23]. Microtoroids can be fabricated using lithography, Q-factor can be observed, with values up to 10 8 Q-factor can be observed, with values up to 10 [23]. Microtoroids can be fabricated using lithography, reactive ion ion etching, etching, and and xenon xenon difluoride difluoride (XeF (XeF2)) etching. etching. Hence, array of of microtoroids microtoroids can can be be reactive Hence, an an array 2 fabricated. The fabrication process is as follows: The resonator substrate, SiO 2, is deposited on a fabricated. The fabrication process is as follows: The resonator substrate, SiO2 , is deposited on a silicon silicon substrate. Then, etching is create used to 2 disk. The post is created by removing the substrate. Then, etching is used to thecreate SiO2 the disk.SiO The post is created by removing the substrate substrate below the disk via XeF 2 isotropic etching. Finally, the CO2 laser illuminates the structure, below the disk via XeF2 isotropic etching. Finally, the CO2 laser illuminates the structure, and the edge and the edge of the disk melts and forms a smooth aidedtension by surface tension [29,111,112] of the disk melts and forms a smooth toroid aided toroid by surface [29,111,112] (Figure 8). (Figure 8). The smoother surface generates less noise due to the surface roughness. However, microtoroid has a difficulty of coupling since the resonators are perched atop of silicon pillar, resulting in difficulty of coupling alignment [113,114]. In addition, during the process of CO2 laser illumination melt the resonators, the diameter of microtoroid is shrink. This lead to difficulty of monolithically integration for a micortoroid resonant cavity with an on-chip waveguide [113,115].
Figure 8. Microtoroid resonator fabrication process. (1) SiO2 is deposited on a silicon wafer; (2)
reactive ion etching, and xenon difluoride (XeF2) etching. Hence, an array of microtoroids can be fabricated. The fabrication process is as follows: The resonator substrate, SiO2, is deposited on a silicon substrate. Then, etching is used to create the SiO2 disk. The post is created by removing the substrate below the disk via XeF2 isotropic etching. Finally, the CO2 laser illuminates the structure, and the edge of 2095 the disk melts and forms a smooth toroid aided by surface tension [29,111,112] (Figure Sensors 2017, 17, 10 of 25 8).
Figure Microtoroid resonator fabrication process. (1) SiO is deposited on a silicon wafer; (2) Figure8. 8. Microtoroid resonator fabrication process. (1)2 SiO 2 is deposited on a silicon wafer; Hydrofluoric acid etching is applied to create the disk structure on top of the wafer; (3)wafer; XeF2 etching (2) Hydrofluoric acid etching is applied to create the disk structure on top of the (3) XeF2 illuminates the structure to smoothen the toroidthe is etching used to iscreate structure; (4) CO2 laser used atopost create a post structure; (4) CO laser illuminates the structure to smoothen 2 structure. toroid structure.
3.2.2. Optofluidic Ring Resonator (OFRR) OFRR is also a ring resonator configuration. The resonator is used to overcome the disadvantage of low Q-factor in microring resonators and the low reproducibility of microsphere resonators [116]. The OFRR uses a microscale SiO2 capillary with a diameter in the range of hundreds of micrometers. However, the wall thickness can be thin, i.e.,
