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Whispering-Gallery Mode Resonators for Detecting Cancer 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. Figure1 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]. Table1 shows the relations between the two systems. Sensors 2017, 17, 2095; doi:10.3390/s17092095 www.mdpi.com/journal/sensors Sensors 2017, 17, 2095 2 of 25 Sensors 2017, 17, 2095 2 of 24 FigureFigure 1.1. GraphsGraphs plotted plotted between between 5-year 5-year survival survival rate ratess versus versus stages stages of ofcancers. cancers. It is It clear is clear that that at the at theinitial initial stage stage of cancer of cancer development, development, patients patients have have significantly significantly larger larger chances chances of being of being cured. cured. (a) (Ovariana) Ovarian stromal stromal tumor tumor [5], [ 5(b],) ( Cervicalb) Cervical cancer cancer [6]. [ 6]. TableTable 1. 1.The The relationship relationship between between the the number number system system and and TNM TNM system system of cancerof cancer for cervicalfor cervical cancer cancer [7]. [7]. Number System TNM System Number System TNM System StageStage 0 0 Tis,Tis, N0, N0, M0 M0 Stage I T1, N0, M0 Stage I T1, N0, M0 Stage IA T1a, N0, M0 StageStage IB IA T1b,T1a, N0, N0, M0 M0 StageStage II IB T2,T1b, N0, M0N0, M0 StageStage IIA II T2a,T2, N0, N0, M0 M0 StageStage III IIA T3,T2a, N0, M0N0, M0 Stage IIIA T3a, N0, M0 StageStage IIIB III T3b, N0, M0 orT3, T1–T3, N0, M0 N1, M0 StageStage IV IIIA T3a, - N0, M0 StageStage IVA IIIB T3b, N0, T4, M0 N0, or M0 T1–T3, N1, M0 StageStage IVB IV T1–T3, N0–N3,- M1 Stage IVA T4, N0, M0 Even now, early diagnosesStage IVB for cancer are scarce. A qualitativeT1–T3, N0–N3, study M1 in 2015 asserted that late diagnosis is the result of difficulty in making appointments, worry regarding doctor availability, and unwillingnessEven now, to early learn ofdiagnoses the development for cancer of are cancer scarce. [8]. A Apart qualitative from the study emotional in 2015 concern asserted of scarringthat late fromdiagnosis unfortunate is the result discovery, of difficulty the findings in making reflect appointments, the difficulty inworry accessing regarding diagnostic doctor technologies availability, even and inunwillingness developed countries. to learn of Currently, the development cancer detection of cancer is [8]. still Apart based from on highlythe emotional invasive, concern time-consuming, of scarring andfrom costly unfortunate processes. discovery, the findings reflect the difficulty in accessing diagnostic technologies evenWhen in developed point-of-care countries. (POC) diagnosis Currently, was cancer introduced, detection the concept is still of based real-time, on orhighly at least invasive, shorter diagnosistime-consuming, time was and heralded costly processes. as the future of healthcare. The actual definition of POC diagnosis is testingWhen at or point-of-care near the site (POC) of patient diagnosis care wheneverwas introduced, medical the care concept is needed of real-time, [9]. The or firstat least biosensor shorter wasdiagnosis a glucose time meter was heralded that became as the popular future in of the healthcare. late 1980s The [10, 11actual]. However, definition POC of diagnosisPOC diagnosis is not is a newtesting concept. at or near At thethe dawnsite of of patien civilization,t care whenever doctors visitedmedical patients’ care is needed homes [9]. and The performed first biosensor diagnosis was anda glucose treatment meter without that became today’s popular centralized in the medicallate 1980s centers. [10,11]. The However, centralized POC medicaldiagnosis complex is not a wasnew introducedconcept. At in the the dawn early of 17th civilization, century [12 doctors], enhancing visited the patients’ mobility homes of technology and performed and knowledge. diagnosis Over and time,treatment and as without the world today’s population centralized increased medical exponentially, centers. moreThe patientscentralized have medical become dependentcomplex was on thisintroduced system. in The the demographic early 17th century growth [12], has resultedenhancing in anthe overwhelming mobility of technology demand forand healthcare knowledge. services. Over Thetime, diagnostic and as the and world treatment population capability increased are then expone limitedntially, by more the capacity patients of have the availablebecome dependent technology. on this Diagnosissystem. The requires demographic novel tools growth and instruments.has resulted in Based an overwhelming on the concept demand of reducing for diagnostichealthcare timesservices. and The steps, diagnostic modern and biosensors treatment have capability come to are play then an importantlimited by rolethe incapacity fulfilling of the ideologyavailable oftechnology. POC. Some cancers now can be detected at an early stage using less invasive and lower-cost proceduresDiagnosis [13– 15requires] through novel advancements tools and instruments. in sensor technologies Based on the such concept as electrochemical of reducing sensor diagnostic [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 SensorsSensors2017, 201717, 2095, 17, 2095 3 of 243 of 25 procedures [13–15] through advancements in sensor technologies such as electrochemical sensor [16], opticaloptical sensor, sensor, or piezoelectric or piezoelectric sensor sensor [14 [14].]. This This is thanks to to the the discovery discovery of cancer of cancer biomarkers biomarkers (cancer (cancer markers),markers), which which have have allowed allowed biosensor biosensor detection detection to be be more more specific specific [17]. [17 In]. particular, In particular, the optical the optical biosensorbiosensor has highhas high sensitivity sensitivity and and can can perform perform label-freelabel-free detection [17,18]. [17,18 One]. One technique technique gaining gaining the the attentionattention of biosensor of biosensor researchers researchers is is the the optical optical resonator.resonator. Figure Figure 22 shows shows the the publications publications on this on thistype type of opticalof optical sensor. sensor. FigureFigure 2. Figure 2. Figure shows shows how how the the number numberof of articlesarticles on fi fixx in in figure figure label label opti opticalcal resonators resonators evolved evolved betweenbetween 1999–2016. 1999–2016. The The graph graph shows shows increasing increasing trends in in this this area area of ofstudy. study. Remark: Remark: The Thedata datawere were gatheredgathered from from the the Web Web of Scienceof Science database database ((wwwwww.webofknowledge.com.web of knowledge.com) with) with the the keyword keyword “Optical “Optical Resonator”,Resonator”, and and then
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