Current Applied Physics 15 (2015) 402e411

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Current Applied Physics

journal homepage: www.elsevier.com/locate/cap

Overview of CMOS image sensor use in molecular diagnostics

Jasmine Pramila Devadhasan a, In Sang Yoo b, Sanghyo Kim a, c, *
a
Department of Bionanotechnology, Gachon University, Sungnam 461-701, Republic of Korea
b
Department of Chemical and Biochemical Engineering, Gachon University, Sungnam 461-701, Republic of Korea
c
Gachon Medical Research Institute, Gil Medical Center, Incheon 405-760, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: CMOS sensors comprise an important tool in bioscientic applications. This review focuses on CMOS
Received 14 August 2014 sensor-based molecular diagnostics of DNA, protein, and metabolic molecules. Herein, gene sequencing,
Received in revised form DNAeDNA hybridization, single nucleotide polymorphisms (SNP), protein interactions, peptide in-
9 January 2015
teractions, antigeneantibody (AgeAb) interactions, as well as glucose and cholesterol monitoring using
Accepted 9 January 2015
Available online 14 January 2015
CMOS sensors are discussed along with existing experimental outcomes. CMOS sensor based electro-
chemical, optical, impedance, dual, continuous, and label-free analysis and their related integration
techniques are explained. Moreover, we describe the utilization of a CMOS chip in microarray fabrication,
Keywords:
CMOS image sensor
assay platform development, and transducer incorporation for molecular diagnostics. Furthermore,
Molecular diagnostics CMOS sensor-based point-of-care (POC) applications, other biological analyses, and the role of nano-
Point-of-care diagnosis particles in biomolecular sensing are discussed. Future directions include information about the novel
Biochemical detection integration of CMOS sensor-based molecular diagnostic devices with a central focus towards enhance-
Biochip ment of POC approaches. This review is helpful in creating highly sensitive, cheaper, and user-friendly
Nanoparticles biomedical devices with modern dimensions.
2015 Elsevier B.V. All rights reserved.

1. Introduction
In modern times, biosensors play an important role in biosci-
entic applications, and modern sensors are expected to replace
the conventional bioanalytical systems due to their improved ef-
ciency, sensitivity, and user-friendliness. CMOS sensors have shown
potential in various elds, including biomedical, chemical, indus-
trial, food-safety, national-security, and environmental applica-
tions [1e3]. Generally, CMOS sensors are known as electronic
devices useful for image-sensing elements, micro processors, and
storage devices [4]. In addition, the CMOS sensors can be incor-
porated into implantable biomedical devices or portable clinical
diagnostic devices [5]. Actually, the CMOS sensors are working with
basic physics and semiconducting technology. The CMOS sensors
are made up of silicon comprised a photosensitive diode array. Each
CMOS sensor contains photodiode to absorb the photons and
accumulated as electrical energy. The electrical energy is converted
into digital images or digital numbers with aid of an analog-to-
digital converter (ADC) [6]. Further, CMOS active pixel sensor
* Corresponding author. Department of Bionanotechnology, Gachon University,
Sungnam 461-701, Republic of Korea.
E-mail address: samkim@gachon.ac.kr (S. Kim).
(APS) amplied the signal and reduced the noise. Moreover, the
sensor can be integrated with hardware and software electronic
circuit to create a new kind of sensor [7]. Nowadays, CMOS tech-
nology plays a considerable role in biosensing applications due to
their transducer implementation, reduced power consumption,
high signal-to-noise ratio, camera-on-chip integration, miniaturi-
zation, user-friendliness, and availability in mobile phone cameras
[8]. In that respect, integration of CMOS sensors with bioanalytical
techniques has resulted in the formation of highly sensitive bio-
analytical sensors used in optical bioimagery [9], digital monitoring
[10], nanoscopy [11], and uorescence microscopy [12,13] as well as
electrochemical sensors of ISFET [14] and BioFET [15], conduction
or impedance sensors [16,17], and MOSFET sensors [18]. Among its
several applications, CMOS sensor-based molecular diagnostics
have received great attention due to its extraordinary sensitivity,
specicity, and label-free detection [19].
CMOS sensors have been identied as one of the most powerful
tools in molecular diagnostics at present, as they do not require any
expensive tools, highly trained staff, or several hours of work like
conventional molecular diagnostic methods [20]. Moreover, this
review attempts to summarize CMOS sensor-based molecular
diagnostic techniques focused on DNA analysis [21], protein in-
teractions [22], and monitoring of metabolic molecules [23,24]

http://dx.doi.org/10.1016/j.cap.2015.01.009
1567-1739/ 2015 Elsevier B.V. All rights reserved.
 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411 403

with a central focus towards enhancement of a point-of-care (POC)
monitoring system. CMOS sensor chips have been established to
develop DNA chips [25], protein microarrays [22], and photo sensor
arrays [8], which are applied to DNA and RNA hybridization, anti-
geneantibody (AgeAb) interactions, bioimaging, and luminescence
detection, etc. [26,27]. Furthermore, nanoparticles, nanowires,
nanotubes, nanoribbons, and nanopores are enhanced the sensi-
tivity and use of CMOS sensor-based molecular diagnostics. Addi-
tionally, nanoparticles are utilized for multi-target detection with
high-sensitivity [28].
This review continues with a detailed discussion of the basic
principles of CMOS sensors in biomolecular diagnostics, DNAeDNA
hybridization, gene sequencing, gene amplication, protein in-
teractions, AgeAb interactions, as well as glucose and cholesterol
level monitoring with a POC sensing approach. Various sensing
platforms for molecular interactions as well as the importance of
POC applications are described in detail. This review on CMOS
sensor-based molecular diagnostics aims to prove that CMOS sen-
sors constitute a genuine approach for molecular diagnostic
applications.
2. Basic principles of CMOS sensor in molecular diagnostics
Generally, biosensors consist of three main parts, the bio-
receptor, transducer, and signal processing system [29]. Addition-
ally, an ideal biosensor must be characterized by selectivity,
sensitivity, and resolution, short response time, repeatability,
longevity, compact size, low cost, low power consumption, porta-
bility, and compatibility [30,31]. Similarly, a CMOS sensor integrates
the bioreceptor, transducer, and signal processor, and attains ideal
sensor qualications. CMOS sensor-based biorecognition is medi-
ated by fabrication of a microarray or assay platform to immobilize
receptor molecules. Transduction of a CMOS sensor results in an
electrochemical, optical, microcantilever, and conductometric
sensor based on transducer integration. A CMOS sensor-based
signal processing system is capable of converting the trans-
duction signal into an electrical signal, which can be displayed as
digital units or images that can be stored, displayed, and trans-
mitted. Based on its sensing principles and circuit integrity, CMOS
technology could be used to create a powerful molecular diagnostic
system. Fig. 1 shows several examples of CMOS sensor applications
in biomolecular diagnostics with various sensing approaches.
3. Time dependent evolution of CMOS based molecular
diagnostics
The CMOS sensor technology has introduced in the late of 1960s.
After realization of the possibilities in integration techniques and
surface modication approaches with CMOS sensor, created a high
impact in various elds such as electrical, biological, environ-
mental, etc., Also, the sensor established the revolutionary effect in
biomolecular diagnostics. Initially, the CMOS sensor chip has been
used to develop the DNA microarray substrate; then the sensor was
implemented as electronic DNA sensor array chip with fully elec-
tronic read out method [40]. Further, the CMOS sensor employed
for various kinds of DNA analysis, such as bioluminescence based
DNA sequencing [41], electrochemical assay for quantitative and
specic DNA hybridization [42], spectrally-multiplexed uorescent
contact imaging for POC DNA diagnostics [43], cantilever based
label-free HBV DNA detection [44], uorescence spectroscopy for
target DNA or RNA analysis [45]. And different types of uorescence
imaging method for DNA diagnostics have achieved by CMOS
sensor [46]. Currently, the CMOS based DNA analysis has reached at
POC diagnosis with a minimal amount of sample, cheaper, portable
and less time. On the other hand, CMOS sensors proved the ef-
ciency in protein analysis, which includes CMOS compatible
nanowire for label-free immunodetection [47], surface-acoustic-
wave integrated CMOS for cancer biomarker detection [48],

Fig. 1. CMOS sensor based various biomolecular diagnoses are carried out with different sensing principles on various sensing platforms and the sensor can be incorporated into the
smartphone, laptop, computer or other portable clinical diagnostic devices. CMOS sensor involved in: protein array development for protein diagnosis [32], uorescence detection
for protein and peptide diagnosis [4], CMOS based detection of AgeAb interaction on nanoparticle substrate [6], chemiluminescence analysis for AgeAb diagnosis [33], microarray
platform development for DNA, RNA hybridization [16], DNA array development for DNA analysis [34], integrated program for sequence analysis [35], PCR approach for DNA
amplication [7], integrated platform for gas sensing [36] optical sensing imager for the bio-molecule detection [37], microscopic approach for biomarker detection [38], and color
density analysis for blood glucose monitoring [39].
404 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411

detection of various AgeAb interactions such as interferon gamma
[49], C-reactive protein (CRP) [50], Troponin I [51], HIV [28], and
hepatitis B (HBV) [52] and label free electrical detection of hTSH
[53]. Also, number of CMOS based cell sensors accomplished the
cell monitoring with POC approach [54]. Moreover, surface modi-
cations and integration approaches are important to improve the
molecular diagnostics in various dimensions. Fig. 2 shows the
various surface modication approaches for DNA and protein
analysis.
4. Development of DNAeDNA hybridization on CMOS sensor
DNAeDNA hybridization is a fundamental gene analysis tech-
nique that is used to identify genes of interest based on sequence
similarity. Conventional southern hybridization is powerful tech-
niques with multiple assay steps, including DNA isolation, ampli-
cation, probe identication, probe labeling, blotting, and
hybridization, aimed at identifying genes of interest over several
hours. In addition, a highly skilled person is required to perform the
analysis. Microarray techniques have been developed to perform
DNA and RNA hybridization with smaller sample amounts, minimal
waste, and shorter duration. The single-stranded target DNA can be
labeled with a uorescent reporter. Probe and complementary DNA
strands bind together and form DNAeDNA complex. The DNAeDNA
complex can be read under monochromatic light using the micro-
array reader. Fluorescence emission reveals successful hybridiza-
tion. However, the requirement for an expensive array reader limits
this tool. Instead, a CMOS image sensor has been as an optical

Fig. 2. Different surface modication approaches for DNA and protein analysis: (a) ultra-sensitive dopamine detection on APTES functionalized surface [55], (b) label free DNA
detection on slinanized surface [56], (c) DNA, protein and glucose detection on polymer coated surface [57], (d) nucleic acid and antigen detection of magnetic sensing platform [58]
(e) protein interaction on silanized surface [59], (f) protein interaction on polymer coated substrate [60], (g) protein detection on microelectronics integrated substrate [53].
 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411
reader to identify DNA hybridization [61]. In addition, DNA
microarray chips are typically made from a glass or polymer ma-
terial [62e66]. Pre-labeled single-stranded DNA probes are
immobilized on the array chip using micro spotters at a sub-
nanoliter range sample volume. CMOS sensor with an integrated
silicon chip has been developed as a carrier material to construct a
silicon-based DNA microarray chip [67,68]. This was the rst step
towards CMOS sensor-based DNAeDNA hybridization. At present,
commercialized semiconductor-based DNA sequencing systems
(Ion torrent Systems) are a promising tool for biomedical applica-
tions [35]. Further, numerous sensors have been proposed for
DNAeDNA hybridization [69], gene amplication [70], and gene
sequencing [71]. Efciency of CMOS sensor enables data storage
and transfer, high sensitivity, transducer incorporation, quantita-
tive and qualitative analysis, user friendliness, portability, high
speed, reduced labor, cost effectiveness, and multiple analyses.
4.1. CMOS sensor-based DNA amplication and gene sequencing
CMOS sensor chip-based DNA hybridization array has been
available since the last decade. Various DNA analyses are available,
some of which include in situ hybridization, restriction fragment
length polymorphisms (RFLP), single nucleotide polymorphisms
(SNP), gene sequencing, and mutational screening. Han et al. has
suggested a CMOS sensor-integrated DNA microarray for the
detection of DNA hybridization [72]. CMOS sensors monitor DNA
hybridization by a highly sensitive giant magnetoresistive (GMR)
sensing approach. Hybridized DNA alters the sensor resistance and
generates an electrical signal on the CMOS sensor due to the ab-
sorption of magnetic nanoparticles. The study demonstrated that
the chip can be applied to other biomolecular (e.g. protein assay)
recognition processes using different surface modication
methods. In another study, Swanson and colleagues reported a
multiplexed CMOS sensor chip-based DNA hybridization and
sequencing method [73]. Herein, CMOS chip was modied with 400
or more reaction sites, and each site was controlled by a hardware
and software electronic circuit called a eld-programmable gate
array (FPGA). On the other hand, an agarose permeation
membrane-coated chip was attached to biotinylated DNA probes
for electronic hybridization assay. Two kinds of genes, such as
D13S317 and THO1 were used; here, oligonucleotides targets were
synthesized for D13S317 and TIO1 gene targets were amplied in
PCR. Further, hybridization detected the amplied gene (THO1) and
sequenced gene (D13S317) by uorescence emission, which was
captured by a CCD camera. In this study, CMOS sensor chip was
used to develop the array and carry out DNA hybridization without
affecting the chip by electrochemical harmfulness. Further, the
electronic circuit controlled FPGA involved in gene hybridization.
And the CCD camera captured the uorescent emission. Moreover,
they suggested that the CMOS array chip had been potential in
genetic identication analysis, infectious and genetic disease di-
agnostics, microbial analysis, and drug screening. However, the
level of contamination could not be measured by this detection
system. In addition, an integrated CMOS sensor chip performed
DNA hybridization and immunoassay as electric eld driven
techniques.
As an advanced approach, integrated CMOS sensor was devel-
oped for real-time DNA amplication and detection [7]. CMOS
sensor modied with integrated circuits was containing an ion-
sensitive eld effects transistors (ISFET) sensor, temperature sen-
sors, resistive heating, and a signal processing and control system in
a platform silicon nitride (Si3N4) insulating layer, which was used as
the sensing layer. And two types of DNA amplication techniques
have established that is PCR and loop mediated isothermal ampli-
cation (LAMP) to determine the DNA amplication. The pH-ISFET
405
sensor system measured the DNA amplication based upon the
quantity of released hydrogen ions. Therefore, the amplication
system called as pH-PCR and pH-LAMP that amplied the pUC19
plasmid DNA and CYP2C9 gene, respectively. For the pH-PCR
amplication, the reaction mixture, including KCl, MgCl2, dNTP,
reverse primers and taq DNA polymerase was prepared and
adjusted the pH to 8e8.5. Then pUC19 plasmid and genomic DNA
were applied to the reaction mixture. Then the integrated CMOS
thermocycling process carried out the PCR reaction, which was 50
cycles of 95
C for 2 min, 95
C for 15 s and 70
C for 15 s. Then
hydrogen ions have been released during thermocycling process
and were measured by ISFET sensor; and no hydrogen ions released
if there is no complementary sequence for amplication process.
Further, the amplication yield was quantied by Qubit & Quant-iT
HS Kit. The amplication signals captured by the CMOS-based ISFET
sensor and the analog signals were converted into digital units.
Moreover, both reactions could detect as few as 10 genomic copies
at a time. Further, this study carried out the DNA amplications
with various genomic DNA templates and suggested that the pH-
PCR can be used to analyze the SNP detection since the sensor is
more sensitive than pH-LAMP. And, the both sensors are performed
under low buffering capacity. This kind of semiconductor archi-
tecture can be applied to any current analytical techniques,
including gene sequencing, microarray analysis, digital PCR, gene
amplication at the POC approach. In addition, integrated CMOS
sensor has successfully accomplished the gene sequencing [35]. The
integrated circuits contained large array sensor elements, and ISFET
was connected with oating gate. For sequencing, 3.5 mm diameter
well was formed and 3 mm dielectric layer formed over the sensor.
And bacterial genome with 270 megabase sequence used for gene
sequencing and pyrosequencing method was followed to accom-
plish the sequencing. Hydrogen ion was released during the
nucleotide incorporations and was measured by the CMOS inte-
grated ISFET sensor.
4.2. CMOS sensor array as electronic chip for label-free DNA
detection
Labeling is one of the most common techniques in DNA analysis.
It is applicable to clinical or research laboratory analysis for highly
sensitive detection. However, additional time that is required for
labeling, highly complex labeling detection, and high cost are all
limitations of uorescent labeling and detection. Moreover, re-
quirements for light sources and a controlled atmosphere (xenon
arc lamps or mercury vapor lamps, high-power LEDs) make the
system unsuitable for POC use. CMOS sensor-based label-free
DNAeDNA hybridization is an appropriate solution for new-
generation molecular diagnostic devices. As such, cantilever-
based fully integrated CMOS DNA diagnosis system-on-chip can
be used to perform label-free DNA detection with high sensitivity.
CMOS DNA cantilever sensor was embedded with a physical
transducer of a polysilicon piezoresistor [74]. These compact,
inexpensive, and high stability systems are known as a CMOS Bio-
Micro electromechanical systems (CMOS Bio-MEMS) platform.
Moreover, the same group carried out HBV DNA diagnosis by the
same mechanism with a minimal concentration of 10 fM DNA.
10 mM thiol-modied single-stranded DNA probe
(50 eSHeCCGATCCATACTGCGGAAC-30 ) have been immobilized on a
chip surface. Various concentrations (10 nM, 100 pM, 1 pM, 10 fM)
of complementary DNA strands were added to the chip. Hybridi-
zation induced surface stress led to mechanical bending of the
cantilever, which altered the resistance of the piezoresistor. Vari-
ations in resistances were detected by using a readout circuit as
digital units. Moreover, the mismatch target DNA (50 -
GTTCCGTAGTATGGATCGG-30 ) was identied by frequency
406 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411
decrements of 60%. The single base pair mismatch and match DNA
could be identied based on frequency changes, suggesting CMOS
Bio-MEMS had the capability of a POC system with clinical diag-
nostic applications. Further, this system can be used to elucidate
non-specic binding, multiple DNA sequences, accurate measure-
ment times, recommended buffers, and suitable temperatures, and
its sensitivity and accuracy make it useful for real-time monitoring.
Generally, the microarray detection principle is based on uo-
rescence emission following the same mechanism as CMOS-based
DNA hybridization. Label-free microarray was developed on a
CMOS chip with 128 sensing sites by Stagni et al. [19]. This CMOS
chip array consists of two interdigitated gold electrodes and an
incorporated measurement circuit. In this method, thiolated DNA
probes were immobilized onto reaction sites and hybridized with
the complementary DNA strand, leading to reduction of capaci-
tance at the electrode. The output signal of the capacitive mea-
surement was then detected and converted into digital units with
the help of analog-to-digital converter circuits. The hybridization
level on chip was measured and compared with reference elec-
trodes. Furthermore, another group developed a label-free CMOS
DNA microarray for the detection of DNAeDNA hybridization as
well as additionally sequencing of short DNA segments based on
the charge sensing method [75]. The CMOS sensor chip was fabri-
cated by sensing electrodes. To attach the single-stranded DNA
probes, a thin polymer layer was applied over the die electrode.
dNTP solutions were added onto the chip to achieve complete
polymerization with the second strand, and the output voltage was
then recorded. A labView program then checked and compared the
electrode signals with and without hybridized DNA. The output
signal of the hybridized DNA increased to 150 mV above the initial
value. Label-free CMOS DNA hybridization and sequence sensing
was thus successfully demonstrated.
4.3. CMOS sensor-based DNAeDNA hybridization with optical
imaging
Apart from this, CMOS image sensors have been used for the
detection of DNA hybridization based on images and voltage shifts.
A bioanalytical CMOS image senor consisting of a scanning circuit,
electrolyte, and external reference electrode was constructed pre-
viously [76]. Therein, the CMOS image sensor chip was silanized to
introduce amino-linked single-stranded DNA probe. The integrated
electrode displayed the output voltage shift before and after
DNAeDNA hybridization. Moreover, the sensor showed the voltage
shifts for the immobilized strand, mismatched DNA, and reference
eld for easy comparison of the data. Negative charges in the DNA
induced potential changes over the semiconductor chip, and sur-
face potential decreased upon DNA hybridization. In addition, pH
buffer solutions displayed color differences on the chip based on
their hybridized and non-hybridized areas. The captured 2D images
showed color differences for reference, probe immobilization, hy-
bridization, and mismatched zones, and DNA hybridization was
easy to detect using this portable, label-free, and inexpensive
method. Thus, the non-uniformity of silanization, noise ratio, and
charge transfer induced uctuations and affected the output data,
which limits the sensing system as a POC or real-time approach.
Improvements will make the sensor an efcient device.
5. CMOS image sensor in protein interactions
Protein, peptide, and AgeAb interactions are some of the most
important assays in life science technologies. Generally, conven-
tional ELISA techniques can safely and quantitatively detect many
targets within the minimum diagnosis range of 1e10 ng/ml [6].
However, it is a time-consuming process that requires a highly
trained staff and expensive tools [77]. Additionally, expensive
analytical systems such as FTIR, SPR, XRD, uorescence, and
chemiluminescence are utilized instead for conventional immu-
nodiagnostics. Recently, protein microarray and bio barcode assay
have been developed as sensitive diagnostic tools requiring a
minimal amount of sample. However, their expensive instrumental
costs make them feasible only in urbanized areas, and less expen-
sive hand-held instruments for on-site monitoring are the most
effective way to reach remote areas anyway. As a result, CMOS
sensors are mainly used for analyzing protein interactions as a
standard laboratory analytical tool and POC monitoring system [8].
Moreover, CMOS sensor-based immunoassays are capable of
providing results within 15 min by the direct optical detection
method with high sensitivity and a smaller amount of sample [78].
CMOS sensor-based protein interactions were detailed by Stadler
et al., who used a surface-modied CMOS sensor chip for protein
interactions as well as to overcome non-specic interactions [4].
The CMOS sensor chip was surface-modied by poly (ethylene
glycol) methacrylate (PEGMA) polymer, which provided high-
loading functional groups and a chemically stable microarray. The
chip was then spotted with hemagglutinin (HA) and FLAG
(DYKDDDDK) epitope protein. Subsequently, respective primary
antibodies (anti-HA and anti-FLAG) and uorophore-conjugated
secondary antibodies were added onto the chip and incubated.
The chip was analyzed by uorescence microscopy, which dis-
played red and green emission spots over the chip. Additionally, the
chip was incubated with other proteins such as BSA and lysozyme
in order to conrm non-specicity. Moreover, a labView virtual
instrument was used to check the microelectronic functions of the
CMOS chip. The chip input data corresponded with the output data,
proving the CMOS chip was very stable after chemical exposure and
surface modication. This CMOS sensor chip-based protein method
is similar to microarray techniques. However, conventional tools for
uorescence microcopy and XPS were needed to conrm the pro-
tein interaction. Besides, the study was able to provide information
about CMOS chip surface modication, protein immobilization, and
array fabrication in order to study the next level of AgeAb inter-
action and detection. Additionally, Table 1 shows some immuno-
assay methods carried out by CMOS sensor and sensor integrated
mobile phones with various detection principles.
Table 1
CMOS sensor based immunodiagnostics approach.
Assay method Diagnosis method Performance
of CMOS
sensor
Sandwich immunoassay on C-reactive protein (CRP) detection RGB color
microtiter plate by colorimetric readout detection [79]
Sandwich immunoassay on a1 acid glycoprotein, the plant CMOS based
microarray lectin ricin, M13 phage, Bacillus CombiMatix
globigii spores, and uorescein chip [80]
detection by electrochemical
method
Gold nanoparticle labeled Human IgG and anti-human IgG Image
immunoassay in detection by silver staining captured [81]
microuidic chip enhancement
Lateral ow immunoassay Thyroid stimulating hormone Light intensity
with (TSH) for point-of-care approach detection [82]
immunochromatography
strips
Lateral ow immunoassay Malaria, TB and HIV detection by Color intensity
with rapid diagnostic measurement detection [83]
immunochromatography
platform.
 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411
5.1. Immobilization of proteins on CMOS sensor chip
Generally, CMOS sensor surface modication can be prepared by
various methods such as silanization, esterication, phosphoriza-
tion, hydroxysilylation by using APTES, APDMES, APMS, and SiO2
[84]. And the modied surfaces have been capable of immobilizing
the proteins and other biomolecules. Miniaturized microarrays are
useful tools in immunoassay applications. However, the immobi-
lization of protein, peptides, and desired analytes is a challenging
task in microarray generation. Generally, glass slides are used to
develop an array. To construct a sensitive microarray platform,
CombiMatrix was developed as a CMOS sensor-based microarray
with 1024 microelectrodes with a diameter of 100 mm [85]. Previ-
ously, CombiMatrix has been applied to DNA hybridization and
diagnosis [86]. Recently, multiplexed immunochemical assays were
carried out using respective biochips with effective immobilization.
For this, a porous reaction layer material was coated onto the
microelectrode array to modify it for bioanalytical applications.
Further, the chip was placed into acetonitrile/methanol containing
biotineNehydroxysuccinimide (beNHS) and various electrolytes
in order to promote biotin linkage within the porous reaction layer,
and materials allowed immobilization of biomolecules on the mi-
croelectrodes. Further, competitive immunoassay for bacillus glo-
bigii (BG) spore) and sandwich immunoassay with saxitoxin were
carried out on the chip and epiuorescence microscopy captured
the uorescence emission of the BG spore AgeAb interaction about
50 spores. Moreover, integrated video capture cards in the Com-
biMatrix sensor were able to develop images of the protein in-
teractions [85]. Thus, the developed microarrays were capable of
monitoring biomarkers, genetic expression, proteineprotein in-
teractions, and drug discovery. In addition, Fig. 2ceg shows the
various surface modication approaches for protein
immobilization.
5.2. CMOS sensor as uorescence microscope
The Fluorescence microscopy has been applied to measure
levels of proteins and AgeAb interactions. Alternatively, commer-
cially available CMOS imaging sensors can distinguish among
AgeAb interactions by the white LED emission method. Shen and
colleagues developed a CMOS image sensor-based portable multi-
color uorescence detection system for analyzing microparticles
by polarization signal isolation [32]. Three kinds of microparticles,
green, orange, and non-uorescent polystyrene particles were
used. The CMOS sensor monitored the mixture of the particles
under white LED light with a high-contrast background; the uo-
rescence emission could be differentiated and the particles moni-
tored easily. Microparticles with different emissions could be
excited and detected simultaneously, leading to ~98% accuracy in
particle counting and ~97% accuracy in size measurement. The
spectral resolution distinguished different uorescent-labeled
particles, even of the same size. Also, aim of the detection system
is uorescence based AgeAb diagnosis. Thus, this method could
eradicate the need for conventional microscopic analysis and may
lead to mobile phone-camera based AgeAb interactions for real-
time monitoring. Another method carried out real-time uores-
cence monitoring by mobile phone [87]. The CMOS sensor utilized
orescence microscopy and ow cytometry. A simple external de-
vice was developed as an analyzing platform containing a LED light;
the uorescent-tagged cells owed on the sample platform and
were captured by the mobile phone by continuous monitoring. This
study proved that mobile phone-based uorescence monitoring is
possible to analyze blood cells, demonstrating a potential for HIV
monitoring with POC applications. Extensive literature sources
have demonstrated that the CMOS sensor is a potential tool in
407
immunodiagnostics.
5.3. Label free AgeAb interactions by CMOS image sensor
Advanced real-time diagnosis does not require any labeling
probes for immunodetection. Label-free analysis reduces the
complexity of detection and eliminates the requirement for
expensive analytical tools. Thus, a highly sensitive enzymatic
immunoassay method could incorporate a CMOS sensor. Indeed,
CMOS sensors are possible tools for the detection of AgeAb in-
teractions by sandwich and indirect immunoassay methods. Label
free holographic imaging has been carried out by CMOS image
sensor for immunoassay diagnosis [88,89]. Devadhasan et al.
demonstrated CMOS image sensor-based label-free AgeAb in-
teractions with sandwich and indirect ELISA by simple photon
count variations [28,50e52]. Various concentration (100 mg/ml,
10 mg/ml, 100 ng/ml, 10 ng/ml, 100 pg/ml, 100 fg/ml, and 10 fg/ml) of
desired Ab (10 ml) immobilized onto the various thickness
(10 nme100 nm) of indium nanoparticle (InNP) substrate, and
recognition sites of the Ab identied the suitable Ag and formed the
AgeAb complex. Importantly, the CMOS image sensor could di-
agnose the AgeAb concentration upto10 fg/ml. Qualitative or semi-
quantitative analysis was made possible by spot density. The
AgeAb interacted area would be darker than the non-interactive
area. Applying high concentration of protein makes darker spot
and high density on the InNP substrate [66]; similarly, the least
concentration (10 fg/ml) of protein showed the minimal dark spot
and less density. For the quantication, an InNP chip was exposed
on the CMOS image sensor; the sensor absorbed the photons
passing through the substrate and converted them into digital
numbers with the aid of an ADC converter. The high concentration
protein with darker density spots allowed passing less photon
when exposed on the CMOS sensor. And less concentration of
protein allowed more photons through the InNP substrate which
observed by CMOS image sensor and provide the quantitative
detection as a photon number variation. Indeed, this method was
shown to be simple, cheaper, and sensitive for AgeAb interactions.
Further, this method could be performed without any expensive
analytical tools, within a reasonable time, without multiple steps,
and with minimal amount of sample. In addition, this group carried
out the CMOS image sensor based detection of AgeAb interactions
for cardiovascular markers of C-reactive protein, Troponin I [51],
and infectious diseases such as HIV [28] and hepatitis B [52] with
high sensitivity and specicity. The optical sensing method showed
results as a digital number for easy read-out. Moreover, this group
demonstrated the methodology for CMOS image sensor-based
AgeAb interactions based on refractive index changes [51].
AgeAb layers inuenced the direction of light and the refractive
index has decreased when protein layers increased on the sub-
strate. Further, the InNP substrates were measured by ellipsometry.
The thickness has increased after subsequent interaction of protein
on the substrate. Furthermore, thermally evaporated semi-
conducting metal of InNP substrate showed the high dielectric
constant and the dielectric constant has decreased with subsequent
protein adsorption. In addition, this detection system requires no
signal amplication. Whole blood immunoassay can be imple-
mented in the detection system with a proper chip model that will
extend the sensitive detection system for POC immunodiagnostics.
6. CMOS image sensor for the detection of metabolic
molecules
CMOS sensor-based glucose and cholesterol monitoring is a
highly sensitive and user-friendly method. Glucose and cholesterol
sensors have become increasingly available to meet the demands of
408 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411
diabetic and cardiovascular disease (CVD) patients. Further, glyce-
mic patients are at higher risk of CVD. Electrochemical, enzymatic,
hydrogel, and nanoparticle-based glucose analyses are struggling to
achieve 100% accuracy. A previous report stated that accurate
glucose meters are produced only 63% of acceptable values [90].
However, precise diagnostics could secure a patient's health and
lead to the proper treatment with minimal side effects. CMOS
sensors have the ability to monitor blood glucose and cholesterol
levels [39,91]. According to a patient's needs, CMOS glucose sensors
have been designed as continuous monitors, wearable sensors,
amperometric sensors, or optical strip sensors to achieve sensitive
detection. Continuous or multiple monitoring is an effective
approach to control the glucose level. Thereby, CMOS sensor-based
continuous and optical glucose monitoring has been achieved by
various groups [92e95]. In addition, CMOS sensor-based dual
monitoring is one among the most prospective methods for dia-
betic and CVD patients.
6.1. Efcient glucose monitoring by CMOS image sensor
A previous report demonstrated that the enzyme kinetic
method is an effective technique for measuring the glucose level
and could eradicate non-specic enzyme interactions [96,97].
Therein, Devadhasan and colleagues developed a CMOS image
sensor-based glucose monitoring technique by simple photon
count variation. Sensitive enzyme kinetic analysis was carried out
to develop the assay. Previously, the group developed a glucose
assay with various concentrations of aqueous glucose [93], and
later used mouse serum [39]. A successful outcome led them to
continue their study for whole blood-glucose analysis. In the whole
blood-glucose assay, a simple polyethylene terephthalate (PET) lm
chip was designed to lter out plasma from whole blood, and the
assay reagents were adsorbed onto amine functionalized silica
(AFSiO2) nanoparticles and immobilized onto the reaction area of
the chip. Filtered plasma reacted with assay reagent and produced a
color based on the glucose concentration. A high concentration of
glucose produced high color density, whereas low glucose con-
centration produced less color density. Furthermore, the chip was
analyzed by a CMOS image sensor and produced a photon number
based on the glucose concentration. The analog-to-digital con-
verter absorbed the photons and converted them into a digital
number. Moreover, the sensing method was compared with a
commercially available glucose sensor and GM9 glucose sensor, and
the data proved that CMOS sensor-based glucose monitoring was
almost equal to that of the commercial sensor. This optical-based
sensing method was thus shown to be highly accurate as a poten-
tial POC approach. This CMOS image sensor-based glucose moni-
toring method required no expensive hand-held instrumentation,
as the sensor was available as a mobile phone camera. As 90% of
people worldwide have a mobile phone, no money needs to be
spent to carry an additional device. Further, enzymatic-based
continuous glucose monitoring is made possible by the CMOS
sensor [95]. Turbidimetric assay was carried out for glucose level
monitoring, and CMOS sensor captured images of different in-
tensities of turbidities indicated the glucose concentration level.
Additionally, CMOS integrated contact lens has performed as
wireless glucose sensor that can be utilized for continuous glucose
monitoring [98]. Therein, CMOS sensor monitored the tears con-
taining glucose through the contact lens. The CMOS sensor wire-
lessly connected with contact lens and performed energy storage
capacitor. The fully integrated contact lens system continuously
monitors the glucose level. And in a different work, hydrogel
implantable glucose sensor is controlled by CMOS sensor [99]. The
implemented circuit in CMOS sensor can act as remote controller
and wireless read out system. According to the reports, the CMOS
sensor can be utilized as enzymatic glucose sensor, implantable
glucose sensor, electrochemical glucose sensor and continuous
glucose sensor for real time monitoring.
6.2. CMOS sensor-based cholesterol monitoring
A CMOS sensor-based enzyme-free amperometric nanosensor
was previously used for the detection of the cholesterol level [24].
The CMOS chip was fabricated from nanoporous platinum (Pt) for
the working and counter electrodes by electroplating technique as
well as silver (Ag) for the reference electrode. Then, various con-
centrations (10 mMe8 mM) of cholesterol were dissolved with
Triton-X 100 surfactant, and 2-propanaol solution were applied
onto the sensor surface and analyzed in terms of electron transfer
force. The surface-modied CMOS chip showed highly sensitive
current responses based on the cholesterol concentration. To
conrm the limit of detection, 10 mM, 20 mM, and 50 mM has
analyzed on the sensor; a concentration of 50 mM showed more
responses than other concentrations with excellent electrocatalytic
activity. Thus, CMOS chip-based cholesterol detection can be used
as a POC approach. However, the sensing system has to be proven to
be reproducible and sensitive with real samples. The respective
study provided highly sensitive results at high concentrations of
cholesterol only, and thus improvement is required to obtain sen-
sitive results at all concentrations of cholesterol. Another group
developed a CMOS-based dual sensor for glucose and cholesterol
sensing [91]. The dual sensor could read-out the glucose and
cholesterol levels within 11 and 20 s, respectively. FPGA carried out
the assay as an electrochemical method and captured electrons
with the integrated circuit. In addition, CMOS sensor consisting of
ADC converted the analog values into numerical numbers, which
are easier to nd on an LCD screen. Further, the dual sensing is
rapid, accurate, and consumes less power. The system carried out
the assay with a glucose solution and can improve the sensing
system by using blood-glucose analysis.
7. Bio scientic applications by CMOS sensor
Various bioscientic applications have been carried out by
CMOS sensors. CMOS image sensor-based bioimaging has been
applied instead of light microscopy in the clinical laboratory to
identify P. falciparum-infected sickle red blood cells (RBC) and
M. tuberculosis-infected sputum samples with LED excitation [100].
Further, a mobile phone camera containing a CMOS sensor was
used for bacillus and RBC cell counts, prototype identication, and
morphological structural comparison of microbes, and was shown
to be portable, low-cost, and a simple image analysis system [101].
This analytical method is an important tool in disease diagnosis and
screening applications. Live-dead cell detection was carried out
using a CMOS image sensor. HeLa cells were harvested and treated
with trypan blue. Damaged cells could uptake the dye into their cell
membranes, and cells were analyzed on the CMOS sensor well. The
sensor captured images and showed live and dead cells were blue
and white colored, respectively. Moreover, the sensor could capture
chemiluminescence signals, which could legitimize the system for
real-time cell analysis study [102]. In addition, a mobile phone-
based imaging cytometer measured the density of human white
blood cells, and the data provided decent matches with a laboratory
hematology analyzer [87]. This study was able to perform POC
monitoring of HIV patients, malaria diagnosis, and screening of
water quality [103]. Further, the CMOS sensor was utilized for
bioimpedance applications, which include electrical cell-substrate
spectroscopy [104], immobilization of bacteriophages and micro-
bial responses. Therein, 2-D cell culture images and their imped-
ance measurement were captured by CMOS circuit integrated 88
 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411
Fig. 3. Importance or need of POC devices in disease diagnosis: The POC devices enable to get rid of the multiple and complicated laboratory procedure in a single device.
electrode array sensor. Less concentration of epithelial breast can-
cer cells was cultured on the sensor surface. CMOS sensor detects
the cell location and electrode array sensing the electrical simula-
tion. The electrical current decreases when cells are present in the
electrode that showed in waveforms. Further, 2D images represent
the availability of the cells on the electrode; white color displayed
the absence of cells on the pixel and the black color displayed the
presence of cells on the pixel [104]. Thus, this approach performs
portable, inexpensive, and on-site monitoring with high sensitivity.
8. Future perspectives
There are a number of methods and analytical tools used for
biomolecular diagnostics, which includes lab-on-chip, lateral ow
strips, bio barcode assay, and gene chip. Usually, molecular diag-
nostic is a costly procedure. A research report previously demon-
strated the capability of CMOS sensor-based molecular diagnostics
[28,35,94]. Indeed, CMOS sensors constitute a suitable device for
POC applications due to their availability in mobile phone cameras
and user-friendliness. Thus, CMOS sensor-based molecular di-
agnostics should be modied for POC use by implementing or
integrating effective techniques and disposable chips. Additionally,
this detection system will probably make it possible to detect all
stages of relevant diseases. This detection method can be improved
as a self-monitoring technique by using CMOS sensors. Above all,
this method is cheaper, and detection will be at the molecular level
in every POC test. The importance of POC sensors has been
demonstrated in Fig. 3. Further, the gure demonstrates that mul-
tiple expensive laboratory procedures can be eliminated by POC
devices. Integrated CMOS sensor-based molecular diagnostics can
be widely used not only for disease diagnosis but also for all bio-
logical applications such as enzymeesubstrate interactions in
physiological buffers [105] unlabeled single molecule protein
detection [106] and nucleic acid sequence detection in a liquid
sample [45]. The ultimate purpose of CMOS sensor-based molec-
ular diagnostics is enhancement of POC monitoring. Prevention or
early diagnosis is the best solutions to reduce the mortality and
morbidity rates of cancer, HBV, malaria, etc. However, self-
diagnosis could improve human health care and awareness.
Recently, lateral ow immunoassay was made available for the
detection of HBV, TB, etc. with POC approach.
9. Summary
This review describes CMOS sensor based molecular di-
agnostics. CMOS sensor represents promising analytical tool
409
applicable in DNA analysis, protein interactions, AgeAb in-
teractions and metabolic molecule analysis. And, the sensor per-
formed as optical, electrochemical, impedance, dual and label free
sensor in biomolecular diagnosis. Various nanoparticles including,
magnetic nanoparticles, InNP substrate, AFSiO2 nanoparticles and
platinum nanoporous were played an important role in the bio-
molecular analysis. Besides, different nanomaterials utilized to
microarray generation, microelectrode development, biomolecule
immobilization and sensing platform development and were
applied to CMOS sensor based POC diagnostic applications. This
review envisioned CMOS sensor-based molecular diagnostics as an
innovative diagnostic tool. Future directions will attempt to create
an integrated system to achieve real-time molecular diagnosis. This
advanced sensor will potentially be a common and sensitive tool for
all biological techniques.
Acknowledgment
This research was supported by the R&D Program for Society of
the National Research Foundation (NRF) funded by the Ministry of
Science, ICT & Future Planning (2013M3C8A3078806 and
2013M3C1A8A01072922).
References
[1] F. Huang, T.M. Hartwich, F.E. Rivera-Molina, Y. Lin, W.C. Duim, J.J. Long,
P.D. Uchil, J.R. Myers, M.A. Baird, W. Mothes, M.W. Davidson, D. Toomre,
J. Bewersdorf, Video-rate nanoscopy using sCMOS camera-specic single-
molecule localization algorithms, Nat. Methods 10 (2013) 653e658.
[2] E.K. Bolton, G.S. Sayler, D.E. Nivens, J.M. Rochelle, S. Ripp, M.L. Simpson, In-
tegrated CMOS photodetectors and signal processing for very low-level
chemical sensing with the bioluminescent bioreporter integrated circuit,
Sens. Actuators B Chem. 85 (2002) 179e185.
[3] K. Narsaiah, S.N. Jha, R. Bhardwaj, R. Sharma, R. Kumar, Optical biosensors for
food quality and safety assurance-a review, J. Food Sci. Technol. 49 (2012)
383e406.
[4] V. Stadler, M. Beyer, K. Konig, A. Nesterov, G. Torralba, V. Lindenstruth,
M. Hausmann, F.R. Bischoff, F. Breitling, Multifunctional CMOS microchip
coatings for protein and peptide arrays, J. Proteome Res. 6 (2007)
3197e3202.
[5] J. Ohta, T. Tokuda, K. Sasagawa, T. Noda, Implantable CMOS biomedical de-
vices, Sensors (Basel, Switz.) 9 (2009) 9073e9093.
[6] K. Kandasamy, M. Marimuthu, G.Y. Sung, C.G. Ahn, S. Kim, Complementary
metal-oxide semiconductor (CMOS) image sensor: an insight as a point-of-
care label-free immunosensor, Anal. Sci. 26 (2010) 1215e1217.
[7] C. Toumazou, L.M. Shepherd, S.C. Reed, G.I. Chen, A. Patel, D.M. Garner,
C.J. Wang, C.P. Ou, K. Amin-Desai, P. Athanasiou, H. Bai, I.M. Brizido,
B. Caldwell, D. Coomber-Alford, P. Georgiou, K.S. Jordan, J.C. Joyce, M. La
Mura, D. Morley, S. Sathyavruthan, S. Temelso, R.E. Thomas, L. Zhang,
Simultaneous DNA amplication and detection using a pH-sensing semi-
conductor system, Nat. Methods 10 (2013) 641e646.
[8] Y. Adiguzel, H. Kulah, CMOS cell sensors for point-of-care diagnostics, Sen-
sors (Basel) 12 (2012) 10042e10066.
410 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411
[9] D.X.D. Yang, B. Fowler, A.E. Gamal, A Nyquist rate pixel level ADC for CMOS
image sensors, in: Custom Integrated Circuits Conference, 1998. Proceedings
of the IEEE 1998, 1998, pp. 237e240.
[10] E.R. Fossum, CMOS image sensors: electronic camera-on-a-chip, IEEE Trans.
Electron. Devices 44 (1997) 1689e1698.
[11] Y.J. Huang, C.W. Huang, T.H. Lin, C.T. Lin, L.G. Chen, P.Y. Hsiao, B.R. Wu,
H.T. Hsueh, B.J. Kuo, H.H. Tsai, H.H. Liao, Y.Z. Juang, C.K. Wang, A CMOS
cantilever-based label-free DNA SoC with improved sensitivity for hepatitis B
virus detection, IEEE Trans. Biomed. Circuits Syst. 7 (2013) 820e831.
[12] Y. Ardeshirpour, M.J. Deen, S. Shirani, 2-D CMOS based image sensor system
for uorescent detection, in: Electrical and Computer Engineering, 2004.
Canadian Conference on, vol. 1443, 2004, pp. 1441e1444.
[13] M. Barbaro, A. Bonglio, L. Raffo, A charge-modulated FET for detection of
biomolecular processes: conception, modeling, and simulation, Electron
Devices, IEEE Trans. 53 (2006) 158e166.
[14] V.P. Chodavarapu, R.M. Bukowski, S.J. Kim, A.H. Titus, A.N. Cartwright,
F.V. Bright, Multi-sensor system based on phase detection, an LED array, and
luminophore-doped xerogels, Electron. Lett. 41 (2005) 1031e1033.
[15] U. Brand, B. Reinhardt, F. Rther, T. Scheper, K. Schgerl, Bio-eld-effect
transistors for process control in biotechnology, Sens. Actuators B Chem. 4
(1991) 315e318.
[16] J. Li, M. Xue, Z.H. Lu, Z.K. Zhang, C. Feng, M. Chan, High-density conduction-
based micro-DNA identication array fabricated with a CMOS compatible
process, IEEE Trans. Electron. Devices 50 (2003) 2165e2170.
[17] Y.-T. Cheng, C.-C. Pun, C.-Y. Tsai, P.-H. Chen, An array-based CMOS biochip for
electrical detection of DNA with multilayer self-assembly gold nanoparticles,
Sens. Actuators B Chem. 109 (2005) 249e255.
[18] E. Nebling, T. Grunwald, J. Albers, P. Schafer, R. Hintsche, Electrical detection
of viral DNA using ultra microelectrode arrays, Anal. Chem. 76 (2004)
689e696.
[19] C. Stagni, C. Guiducci, L. Benini, B. Ricco, S. Carrara, B. Samori, C. Paulus,
M. Schienle, M. Augustyniak, R. Thewes, CMOS DNA sensor array with in-
tegrated A/D conversion based on label-free capacitance measurement, IEEE
J. Solid-State Circuits 41 (2006) 2956e2964.
[20] O. Mudanyali, D. Tseng, C. Oh, S.O. Isikman, I. Sencan, W. Bishara, C. Oztoprak,
S. Seo, B. Khademhosseini, A. Ozcan, Compact, light-weight and cost-
effective microscope based on lens less incoherent holography for tele-
medicine applications, Lab. Chip 10 (2010) 1417e1428.
[21] S. Choi, M. Goryll, L. Sin, P. Wong, J. Chae, Microuidic-based biosensors
toward point-of-care detection of nucleic acids and proteins, Microuid
Nanouid 10 (2011) 231e247.
[22] B.C. Jacquot, N. Munoz, D.W. Branch, E.C. Kan, Non-Faradaic electrochemical
detection of protein interactions by integrated neuromorphic CMOS sensors,
Biosens. Bioelectron. 23 (2008) 1503e1511.
[23] J. Luo, P. Luo, M. Xie, K. Du, B. Zhao, F. Pan, P. Fan, F. Zeng, D. Zhang, Z. Zheng,
G. Liang, A new type of glucose biosensor based on surface acoustic wave
resonator using Mn-doped ZnO multilayer structure, Biosens. Bioelectron. 49
(2013) 512e518.
[24] Y.J. Lee, D.D. Kim, J.Y. Park, CMOS-integrable enzyme-free amperometric
cholesterol nano-biosensor for U-health and POC applications, J. Korean
Phys. Soc. 54 (2009) 1769e1773.
[25] P. Kruppa, A. Frey, I. Kuehne, M. Schienle, N. Persike, T. Kratzmueller,
G. Hartwich, D. Schmitt-Landsiedel, A digital CMOS-based 2416 sensor
array platform for fully automatic electrochemical DNA detection, Biosens.
Bioelectron. 26 (2010) 1414e1419.
[26] F. Mallard, G. Marchand, F. Ginot, R. Campagnolo, Opto-electronic DNA chip:
high performance chip reading with an all-electric interface, Biosens. Bio-
electron. 20 (2005) 1813e1820.
[27] H. Eltoukhy, K. Salama, A. El Gamal, A 0.18-mm CMOS bioluminescence
detection lab-on-chip, IEEE J. Solid-State Circuits 41 (2006) 651e662.
[28] J. Devadhasan, S. Kim, CMOS image sensor based HIV diagnosis: a smart
system for point-of-care approach, BioChip J. 7 (2013) 258e266.
[29] V. Perumal, U. Hashim, Advances in biosensors: principle, architecture and
applications, J. Appl. Biomed. 12 (2014) 1e15.
[30] R. Rego, N.d. Caetano, A. Mendes, Development of a new gas sensor for bi-
nary mixtures based on the permselectivity of polymeric membranes:
application to carbon dioxide/methane and carbon dioxide/helium mixtures,
Anal. Chim. Acta 511 (2004) 215e221.
[31] N.F. Atta, A. Galal, E.H. El-Ads, Smart electrochemical morphine sensor using
poly (3,4-ethylene-dioxythiophene)/gold-nanoparticles composite in pres-
ence of surfactant, Int. J. Electrochem. Sci. 9 (2014) 2113e2131.
[32] L. Shen, M. Ratterman, D. Klotzkin, I. Papautsky, Portable multi-color uo-
rescent detection for point-of-care, in: 15th International Conference on
Miniaturized Systems for Chemistry and Life Sciences, 2011, 978-0-
9798064-4-5/mTAS.
[33] C.C. Lin, F.H. Ko, C.C. Chen, Y.S. Yang, F.C. Chang, C.S. Wu, Miniaturized metal
semiconductor metal photocurrent system for biomolecular sensing via
chemiluminescence, Electrophoresis 30 (2009) 3189e3197.
[34] T. Tokuda, T. Noda, K. Sasagawa, J. Ohta, Optical and electric multifunctional
CMOS image sensors for on-chip biosensing applications, Materials 4 (2010)
84e102.
[35] J.M. Rothberg, W. Hinz, T.M. Rearick, J. Schultz, W. Mileski, M. Davey,
J.H. Leamon, K. Johnson, M.J. Milgrew, M. Edwards, J. Hoon, J.F. Simons,
D. Marran, J.W. Myers, J.F. Davidson, A. Branting, J.R. Nobile, B.P. Puc, D. Light,
T.A. Clark, M. Huber, J.T. Branciforte, I.B. Stoner, S.E. Cawley, M. Lyons, Y. Fu,
N. Homer, M. Sedova, X. Miao, B. Reed, J. Sabina, E. Feierstein, M. Schorn,
M. Alanjary, E. Dimalanta, D. Dressman, R. Kasinskas, T. Sokolsky, J.A. Fidanza,
E. Namsaraev, K.J. McKernan, A. Williams, G.T. Roth, J. Bustillo, An integrated
semiconductor device enabling non-optical genome sequencing, Nature 475
(2011) 348e352.
[36] L. Shen, M. Ratterman, D. Klotzkin, I. Papautsky, A CMOS optical detection
system for point-of-use luminescent oxygen sensing, Sensors Actuators B
Chem. 155 (2011) 430e435.
[37] T. Tokuda, A. Yamamoto, K. Kagawa, M. Nunoshita, J. Ohta, A CMOS image
sensor with optical and potential dual imaging function for on-chip biosci-
entic applications, Sensors Actuators A Phys. 125 (2006) 273e280.
[38] H. Lee, L. Xu, D. Koh, N. Nyayapathi, K.W. Oh, Various on-chip sensors with
microuidics for biological applications, Sensors (Basel) 14 (2014)
17008e17036.
[39] J.P. Devadhasan, S. Kim, C.S. Choi, CMOS image sensors as an efcient plat-
form for glucose monitoring, Analyst 138 (2013) 5679e5684.
[40] R. Thewes, F. Hofmann, A. Frey, M. Schienle, C. Paulus, P. Schindler-Bauer,
B. Holzapf, CMOS-based DNA Sensor Arrays, Advanced Micro and Nano-
systems, vol. 1, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2004.
[41] H. Eltoukhy, K. Salama, A. El Gamal, A 0.18-mm CMOS bioluminescence
detection lab-on-chip, Solid-State Circuits, IEEE J. 41 (2006) 651e662.
[42] P.M. Levine, P. Gong, R. Levicky, K.L. Shepard, Active CMOS sensor array for
electrochemical biomolecular detection, Solid-State Circuits, IEEE J. 43
(2008) 1859e1871.
[43] D. Ho, M.O. Noor, U.J. Krull, G. Gulak, R. Genov, CMOS spectrally-multiplexed
FRET-on-a-chip for DNA analysis, IEEE Trans. Biomed. Circuits Syst. 7 (2013)
643e654.
[44] H. Yu-Jie, H. Che-Wei, L. Tsung-Hsien, L. Chih-Ting, C. Li-Guang, H. Po-Yun,
W. Bi-Ru, H. Hsiao-Ting, K. Bing-Jye, T. Hann-Huei, L. Hsin-Hao, J. Ying-Zong,
W. Chorng-Kuang, L. Shey-Shi, A CMOS cantilever-based label-free DNA SoC
with improved sensitivity for hepatitis B virus detection, IEEE Trans. Biomed.
Circuits Syst. 7 (2013) 820e831.
[45] H. Yu, Y. Tan, B.T. Cunningham, Smartphone uorescence spectroscopy, Anal.
Chem. 86 (2014) 8805e8813.
[46] N. Guo, K.W. Cheung, H. Wong, D. Ho, CMOS time-Resolved, contact, and
multispectral uorescence imaging for DNA molecular diagnostics, Sensors
14 (2014) 20602e20619.
[47] E. Stern, J.F. Klemic, D.A. Routenberg, P.N. Wyrembak, D.B. Turner-Evans,
A.D. Hamilton, D.A. LaVan, T.M. Fahmy, M.A. Reed, Label-free immunode-
tection with CMOS-compatible semiconducting nanowires, Nature 445
(2007) 519e522.
[48] O. Tigli, L. Bivona, P. Berg, M.E. Zaghloul, Fabrication and characterization of a
surface-acoustic-wave biosensor in CMOS technology for cancer biomarker
detection, IEEE Trans. Biomed. Circuits. Syst. 4 (2010) 62e73.
[49] M. Marimuthu, K. Kandasamy, C.G. Ahn, G.Y. Sung, M.G. Kim, S. Kim, CMOS
image sensor for detection of interferon gamma protein interaction as a
point-of-care approach, Anal. Bioanal. Chem. 401 (2011) 1641e1649.
[50] J.P. Devadhasan, M. Marimuthu, S. Kim, M.G. Kim, A CMOS image sensor to
recognize the cardiovascular disease markers troponin I and C-reactive
protein, Anal. Bioanal. Chem. 402 (2012) 813e821.
[51] J.P. Devadhasan, S. Kim, CMOS image sensor-based immunodetection by
refractive-index change, Anal. Sci. 28 (2012) 875e880.
[52] J.P. Devadhasan, S. Kim, Label free quantitative immunoassay for hepatitis B,
J. Nanosci. Nanotechnol. 15 (2015) 85e92, http://dx.doi.org/10.1166/
jnn.2015.9253.
[53] N. Lu, P. Dai, A. Gao, J. Valiaho, P. Kallio, Y. Wang, T. Li, Label-free and rapid
electrical detection of hTSH with CMOS-compatible silicon nanowire tran-
sistor arrays, ACS Appl. Mater. Inter. (2014), http://dx.doi.org/10.1021/
am505915y.
[54] T. Saeki, M. Hosokawa, T.-k. Lim, M. Harada, T. Matsunaga, T. Tanaka, Digital
cell counting device integrated with a single-cell array, PLoS One 9 (2014)
e89011.
[55] L. Dong-Che, Y. Po-Hung, M.S.C. Lu, CMOS open-gate ion-sensitive eld-
effect transistors for ultrasensitive dopamine detection, IEEE T. Electron.
Dev. 57 (2010) 2761e2767.
[56] W.-A. Lai, C.-H. Lin, Y.-S. Yang, M.S.C. Lu, Ultrasensitive and label-free
detection of pathogenic avian inuenza DNA by using CMOS impedimetric
sensors, Biosen. Bioelectron. 35 (2012) 456e460.
[57] S. Minnikanti, A. Gangopadhyay, D. Reyes, Polyelectrolyte multilayers in
microuidic systems for biological applications, Polymers 6 (2014)
2100e2115.
[58] A. Pai, A. Khachaturian, S. Chapman, A. Hu, H. Wang, A. Hajimiri, A handheld
magnetic sensing platform for antigen and nucleic acid detection, Analyst
139 (2014) 1403e1411.
[59] S. Lenci, L. Tedeschi, F. Pieri, C. Domenici, UV lithography-based protein
patterning on silicon: towards the integration of bioactive surfaces and
CMOS electronics, Appl. Surf. Sci. 257 (2011) 8413e8419.
[60] W. Franks, F. Heer, S. Tosatti, S. Hazovic, P. Seif, M. Textor, A. Hierlemann,
CMOS biosensor with guided cell growth, in: Sensors, 2004. Proceedings of
IEEE, vol. 1012, 2004, pp. 1014e1017.
[61] M. Bigas, E. Cabruja, J. Forest, J. Salvi, Review of CMOS image sensors,
Microelectr. J. 37 (2006) 433e451.
[62] M. Schena (Ed.), DNA Microarrays: a Practical Approach, Oxford University
Press, Oxford, 2000.
[63] M. Schena (Ed.), Microarray Biochip Technology, Eaton Publishing, Natick,
 J.P. Devadhasan et al. / Current Applied Physics 15 (2015) 402e411
MA, 2000.
[64] D. Meldrum, Automation for genomics, part two: sequencers, microarrays,
and future trends, Genome Res. 10 (2000) 1288e1303.
[65] T. Vo-Dinh, B. Cullum, Biosensors and biochips: advances in biological and
medical diagnostics, Fresenius J. Anal. Chem. 366 (2000) 540e551.
[66] P. Hegde, R. Qi, K. Abernathy, C. Gay, S. Dharap, R. Gaspard, J.E. Hughes,
E. Snesrud, N. Lee, J. Quackenbush, A concise guide to cDNA microarray
analysis, Biotechniques 29 (2000) 548e550.
[67] B.J. Cheek, A.B. Steel, M.P. Torres, Y.Y. Yu, H. Yang, Chemiluminescence
detection for hybridization assays on the ow-thru chip, a three-dimensional
microchannel biochip, Anal. Chem. 73 (2001) 5777e5783.
[68] A. Steel, M. Torres, J. Hartwell, Y. Yu, N. Ting, G. Hoke, H. Yang, in: M. Schena
(Ed.), Microarray Biochip Technology, Eaton Publishing, Natick, MA, 2000, pp.
87e117.
[69] Y. Hu, F. Li, X. Bai, D. Li, S. Hua, K. Wang, L. Niu, Label-free electrochemical
impedance sensing of DNA hybridization based on functionalized graphene
sheets, Chem. Commun. 47 (2011) 1743e1745.
[70] J. Pen~ a, S.C. Ricke, C.L. Shermer, T. Gibbs, S.D. Pillai, A gene amplication
hybridization sensor based methodology to rapidly screen aerosol samples
for specic bacterial gene sequences, J. Environ. Sci. Heal. A 34 (1999)
529e556.
[71] P.H. Bolivar, M. Nagel, F. Richter, M. Brucherseifer, H. Kurz, A. Bosserhoff,
R. Buttner, Label-free THz sensing of genetic sequences: towards THz bio-
chips, Philos. Trans. A Math. Phys. Eng. Sci. 362 (2004) 323e333.
[72] S.J. Han, L. Xu, H. Yu, R.J. Wilson, R.L. White, N. Pourmand, S.X. Wang, CMOS
integrated DNA microarray based on GMR sensors, in: International Electron
Devices Meeting, IEDM, 2006, pp. 1e4.
[73] P. Swanson, R. Gelbart, E. Atlas, L. Yang, T. Grogan, W.F. Butler, D.E. Ackley,
E. Sheldon, A fully multiplexed CMOS biochip for DNA analysis, Sens. Actu-
ators B Chem. 64 (2000) 22e30.
[74] C.W. Huang, Y.J. Huang, P.W. Yen, H.H. Tsai, H.H. Liao, Y.Z. Juang, S.S. Lu,
C.T. Lin, A CMOS wireless biomolecular sensing system-on-chip based on
polysilicon nanowire technology, Lab. Chip 13 (2013) 4451e4459.
[75] E. Anderson, J. Daniels, H. Yu, T. Lee, N. Pourmand, A label-free CMOS DNA
microarray based on charge sensing, in: Instrumentation and Measurement
Technology Conference Proceedings, 2008. IMTC 2008, IEEE, 2008, pp.
1631e1636.
[76] Y. Maruyama, S. Terao, K. Sawada, Label free CMOS DNA image sensor based
on the charge transfer technique, Biosens. Bioelectron. 24 (2009)
3108e3112.
[77] P. Jahanshahi, E. Zalnezhad, S.D. Sekaran, F.R. Adikan, Rapid immunoglobulin
M-based dengue diagnostic test using surface plasmon resonance biosensor,
Sci. Rep. 4 (2014) 3851.
[78] I. Giouroudi, F. Keplinger, Microuidic biosensing systems using magnetic
nanoparticles, Int. J. Mol. Sci. 14 (2013) 18535e18556.
[79] C.M. McGeough, S. O'Driscoll, Camera phone-based quantitative analysis of
C-reactive protein ELISA, IEEE Trans. Biomed. Circ. Syst. 7 (2013) 655e659.
[80] K. Dill, D.D. Montgomery, A.L. Ghindilis, K.R. Schwarzkopf, S.R. Ragsdale,
A.V. Oleinikov, Immunoassays based on electrochemical detection using
microelectrode arrays, Biosens. Bioelectron. 20 (2004) 736e742.
[81] Y. Lu, S. Shi, J. Qin, B. Lin, Low cost, portable detection of gold nanoparticle-
labeled microuidic immunoassay with camera cell phone, Electrophoresis
30 (2009) 579e582.
[82] D.J. You, T.S. Park, J.-Y. Yoon, Cell-phone-based measurement of TSH using
Mie scatter 83. optimized lateral ow assays, Biosens. Bioelectron. 40 (2013)
180e185.
[83] O. Mudanyali, S. Dimitrov, U. Sikora, S. Padmanabhan, I. Navruz, A. Ozcan,
Integrated rapid-diagnostic-test reader platform on a cellphone, Lab. Chip 12
(2012) 2678e2686.
[84] L.C.P.M. de Smet, D. Ullien, M. Mescher, E.J.R. Sudho lter, Organic Surface
Modication of Silicon Nanowire-based Sensor Devices, Abbass Hashim,
Intech, 2011, http://dx.doi.org/10.5772/23861.
[85] K. Dill, D.D. Montgomery, W. Wang, J.C. Tsai, Antigen detection using
microelectrode array microchips, Anal. Chim. Acta 444 (2001) 69e78.
411
[86] K. Maurer, J. Cooper, M. Caraballo, J. Crye, D. Suciu, A. Ghindilis, J.A. Leonetti,
W. Wang, F.M. Rossi, A.G. Sto ver, C. Larson, H. Gao, K. Dill, A. McShea,
Electrochemically generated acid and its containment to 100 Micron reaction
areas for the production of DNA microarrays, PLoS One 1 (2006) e34.
[87] H. Zhu, S. Mavandadi, A.F. Coskun, O. Yaglidere, A. Ozcan, Optouidic uo-
rescent imaging cytometry on a cell phone, Anal. Chem. 83 (2011)
6641e6647.
[88] G. Stybayeva, O. Mudanyali, S. Seo, J. Silangcruz, M. Macal, E. Ramanculov,
S. Dandekar, A. Erlinger, A. Ozcan, A. Revzin, Lensfree holographic imaging of
antibody microarrays for high-throughput detection of leukocyte numbers
and function, Anal. Chem. 82 (2010) 3736e3744.
[89] J.M. Yang, J. Bell, Y. Huang, M. Tirado, D. Thomas, A.H. Forster, R.W. Haigis,
P.D. Swanson, R.B. Wallace, B. Martinsons, M. Krihak, An integrated, stacked
microlaboratory for biological agent detection with DNA and immunoassays,
Biosens. Bioelectron. 17 (2002) 605e618.
[90] B.H. Ginsberg, Factors affecting blood glucose monitoring: sources of errors
in measurement, J. Diabetes Sci. Technol. 3 (2009) 903e913.
[91] T. Lesmana, C. Wen-Yaw, C. Shih-Lun, H. Lu-Chiang, Dual glucose/cholesterol
meter applications based on FPGA platform, in: Next-generation Electronics
(ISNE), 2013 IEEE International Symposium on, 2013, pp. 17e20.
[92] R.A. Croce Jr., S. Vaddiraju, J. Kondo, Y. Wang, L. Zuo, K. Zhu, S.K. Islam,
D.J. Burgess, F. Papadimitrakopoulos, F.C. Jain, A miniaturized transcutaneous
system for continuous glucose monitoring, Biomed. Microdevices 15 (2013)
151e160.
[93] J.P. Devadhasan, S. Kim, Toward CMOS image sensor based glucose moni-
toring, Analyst 137 (2012) 3917e3920.
[94] T.D. O'Sullivan, R.T. Heitz, N. Parashurama, D.B. Barkin, B.A. Wooley,
S.S. Gambhir, J.S. Harris, O. Levi, Real-time, continuous, uorescence sensing
in a freely-moving subject with an implanted hybrid VCSEL/CMOS biosensor,
Biomed. Opt. Express 4 (2013) 1332e1341.
[95] A.J. Rosenbloom, H.R. Gandhi, G.L. Subrebost, Microdialysis coupled with an
embedded systems controller and CMOS image sensor, in: Conf. Proc. IEEE
Eng. Med. Biol. Soc. 2009, 2009, pp. 1230e1233.
[96] A. Heller, B. Feldman, Electrochemical glucose sensors and their applications
in diabetes management, Chem. Rev. 108 (2008) 2482e2505.
[97] S.B. Bankar, M.V. Bule, R.S. Singhal, L. Ananthanarayan, Glucose oxidase d An
overview, Biotechnol. Adv. 27 (2009) 489e501.
[98] Y.T. Liao, F. Yao, A. Lingley, B. Parviz, B.P. Otis, A 3-mu W CMOS glucose
sensor for wireless contact-lens tear glucose monitoring, IEEE J. Solid-State
Circuits 47 (2012) 335e344.
[99] P.H. Kuo, S.S. Lu, J.C. Kuo, Y.J. Yang, T. Wang, Y.L. Ho, M.F. Chen, A hydrogel-
based implantable wireless CMOS glucose sensor SoC, in: IEEE International
Symposium on Circuits and Systems (ISCAS), 2012, pp. 994e997.
[100] D.N. Breslauer, R.N. Maamari, N.A. Switz, W.A. Lam, D.A. Fletcher, Mobile
phone based clinical microscopy for global health applications, PLoS One 4
(2009) e6320.
[101] S. Seo, T.W. Su, D.K. Tseng, A. Erlinger, A. Ozcan, Lensfree holographic im-
aging for on-chip cytometry and diagnostics, Lab. Chip 9 (2009) 777e787.
[102] T. Tanaka, T. Saeki, Y. Sunaga, T. Matsunaga, High-content analysis of single
cells directly assembled on CMOS sensor based on color imaging, Biosens.
Bioelectron. 26 (2010) 1460e1465.
[103] H. Zhu, A. Ozcan, Wide-eld uorescent microscopy and uorescent imaging
ow cytometry on a cell-phone, J. Vis. Exp. 74 (2013) 1e7.
[104] A. Yufera, A. Rueda, A CMOS bio-impedance measurement system, in: Design
and Diagnostics of Electronic Circuits & Systems, 2009. DDECS'09. 12th In-
ternational Symposium on, 2009, pp. 252e257.
[105] L. Mu, I.A. Droujinine, N.K. Rajan, S.D. Sawtelle, M.A. Reed, Direct, rapid, and
label-free detection of enzyme-substrate interactions in physiological
buffers using CMOS-compatible nanoribbon sensors, Nano. Lett. 14 (2014)
5315e5322.
[106] M. Piliarik, V. Sandoghdar, Direct optical sensing of single unlabelled pro-
teins and super-resolution imaging of their binding sites, Nat. Commun. 5
(2014), http://dx.doi.org/10.1038/ncomms5495.