sensors

Review
Towards Portable Nanophotonic Sensors
Abdul Shakoor 1, * , James Grant 2 , Marco Grande 3 and David. R. S. Cumming 2
1 Optoelectronics Research Centre, University of Southampton, Southampton SO17 1BJ, UK
2 School of Engineering, University of Glasgow, Glasgow G12 8LT, UK; james.grant@glasgow.ac.uk (J.G.);
david.cumming.2@glasgow.ac.uk (D.R.S.C.)
3 Dipartimento di Ingegneria Elettrica e dell’Informazione, Politecnico di Bari, 70125 Bari, Italy;
marco.grande@poliba.it
* Correspondence: shakabdul@gmail.com




Received: 15 March 2019; Accepted: 7 April 2019; Published: 10 April 2019


Abstract: A range of nanophotonic sensors composed of different materials and device configurations
have been developed over the past two decades. These sensors have achieved high performance
in terms of sensitivity and detection limit. The size of onchip nanophotonic sensors is also small
and they are regarded as a strong candidate to provide the next generation sensors for a range of
applications including chemical and biosensing for point-of-care diagnostics. However, the apparatus
used to perform measurements of nanophotonic sensor chips is bulky, expensive and requires experts
to operate them. Thus, although integrated nanophotonic sensors have shown high performance
and are compact themselves their practical applications are limited by the lack of a compact readout
system required for their measurements. To achieve the aim of using nanophotonic sensors in daily
life it is important to develop nanophotonic sensors which are not only themselves small, but their
readout system is also portable, compact and easy to operate. Recognizing the need to develop
compact readout systems for onchip nanophotonic sensors, different groups around the globe have
started to put efforts in this direction. This review article discusses different works carried out to
develop integrated nanophotonic sensors with compact readout systems, which are divided into
two categories; onchip nanophotonic sensors with monolithically integrated readout and onchip
nanophotonic sensors with separate but compact readout systems.

Keywords: optical chemical sensors; nanostructured materials; refractive index; biosensors; lab on
a chip

1. Introduction
The drive to improve healthcare has prompted researchers to develop high performance sensors to
enable diagnosis of diseases at an early stage. On-chip nanophotonic sensors are an excellent candidate
technology since they hold the potential to deliver high performance and compact sensors [1–21].
In particular, integrated nanophotonic optical sensors have shown great progress in achieving high
sensitivity and low detection limit, with values as good as 1000 nm/refractive index unit (RIU) [22,23]
and pg/mL [24,25] respectively, already reported. Nanophotonic sensors that are integrated on to
a single chip are composed of different materials such as metals [26–31], semiconductors [32–37],
dielectrics [38–40], or polymers [41,42], and consist of different device configurations such as an
array of nanostructures [43–46], cavities [47–52], waveguides [53–56], interferometers [12,57–59],
or gratings [60–64]. These sensors are mostly based on the phenomenon of refractive index sensing [65].
In these devices the signal output is altered by a change of the refractive index in close proximity
to the sensor that is induced by applying an analyte. The output signal can be either a shift in the
resonance wavelength for resonant based sensors [43–52] or a change in the transmission level for
waveguide [53–56] or interferometric devices [12,57–59]. Mostly, these sensing devices require external

Sensors 2019, 19, 1715; doi:10.3390/s19071715 www.mdpi.com/journal/sensors

Sensors 2019, 19, x FOR PEER REVIEW 25 of 25
Sensors 2019, 19, 1715 2 of 26

sensing devices require external bulky and expensive equipment such as external detectors or
spectrum
bulky andanalyzers
expensivetoequipment
measure the such output signals,
as external makingor
detectors their commercial
spectrum application
analyzers to measure limited,
the
especially where miniaturization would be an advantage. There are examples
output signals, making their commercial application limited, especially where miniaturization would of commercial sensor
systems
be that useThere
an advantage. nanophotonic
are examples structures, but their
of commercial sensoruse systems
is still limited
that use by the large size
nanophotonic of the
structures,
equipment used for their readout. Notable examples are Biacore [66], which
but their use is still limited by the large size of the equipment used for their readout. Notable examples is based on surface
plasmon
are Biacoreresonance
[66], which (SPR),
is basedandonGenalyte [67], which
surface plasmon uses ring
resonance (SPR), resonators.
and Genalyte Thus, although
[67], which uses the
nanophotonic sensing chips are themselves compact their readout requires
ring resonators. Thus, although the nanophotonic sensing chips are themselves compact their readout a laboratory setup that
makes the
requires use of nanophotonic
a laboratory setup that makessensorsthein use
everyday life impractical.
of nanophotonic sensors The need for large
in everyday laboratory
life impractical.
equipment
The need for gives
largeriselaboratory
to the so called “chip in
equipment a labrise
gives dilemma”
to the for nanophotonic
so called “chip insensors. To transform
a lab dilemma” for
nanophotonic sensors from laboratory-based demonstrations into
nanophotonic sensors. To transform nanophotonic sensors from laboratory-based demonstrations practical devices that can be
commercialized
into and used
practical devices easily
that can bein everyday life, itand
commercialized is necessary
used easily to in
develop
everydaya compact
life, it isnanophotonic
necessary to
develop a compact nanophotonic sensor system, where not only the sensor chip itself, but itsand
sensor system, where not only the sensor chip itself, but its readout system is also compact easy
readout
to operate by a non-expert. There have been several efforts to develop on-chip
system is also compact and easy to operate by a non-expert. There have been several efforts to develop nanophotonic sensors
with compact
on-chip readoutsensors
nanophotonic systemswith where researchers
compact readouthave systemstakenwheredifferent approaches
researchers have [68–78]. In this
taken different
article, we will give an overview of the work that has been done
approaches [68–78]. In this article, we will give an overview of the work that has been done to dateto date to develop on-chip
nanophotonic
to develop on-chipsensors with compact
nanophotonic readout
sensors withsystems.
compactThis readoutarticle is organized
systems. as follows;
This article first, the
is organized as
physical phenomena on which nanophotonic sensors operate along
follows; first, the physical phenomena on which nanophotonic sensors operate along with associated with associated performance
parameters will
performance be discussed;
parameters will beadiscussed;
brief summary
a brief of different
summary of types
differentof on-chip
types of nanophotonic
on-chip nanophotonic sensors
made using different materials such as metal (plasmonic), dielectric
sensors made using different materials such as metal (plasmonic), dielectric and semiconductor and semiconductor will thenwill
be
provided;
then and finally,
be provided; andanfinally,
overview of the efforts
an overview made
of the so farmade
efforts to miniaturize
so far to the readout system
miniaturize of the
the readout
nanophotonic sensors will be presented. In this review, the sensors having
system of the nanophotonic sensors will be presented. In this review, the sensors having compact compact readout system
are divided
readout systemintoaretwo categories,
divided into two namely: thosenamely:
categories, where those sensors wherehavesensors
a monolithically integrated
have a monolithically
readout system [68–76] and those where the readout system is compact
integrated readout system [68–76] and those where the readout system is compact but separate but separate to the sensor
to
the sensor chip [77,78]. The commonest transducer to capture signals into the electronic domainisis aa
chip [77,78]. The commonest transducer to capture signals into the electronic domain
semiconductor photodiode
semiconductor photodiode (PD). (PD). ToTo develop
develop nanophotonic
nanophotonic sensors sensors withwith aa monolithically
monolithically integrated
integrated
readout system, it is increasingly commonplace to use a complementary
readout system, it is increasingly commonplace to use a complementary metal oxide semiconductor metal oxide semiconductor
(CMOS), photodiode
(CMOS), photodiode devicedevice or or array,
array,andandthese
thesewill
willbebediscussed
discussedin inthis
thisreview.
review.

2. On
2. On Chip
Chip Nanophotonic
Nanophotonic Sensors
Sensors

Label free sensing is increasingly important in the implementation of portable and ready-to-use
optical sensors [79–86]. Refractive index sensing is therefore an ideal method since other established
techniques, such as fluorescence sensing require
require aa labelling
labelling technology
technology to to work
work [87,88].
[87,88]. In refractive
index sensing
index sensing the
the transmission/reflection
transmission/reflection signal
signal from
from the nanophotonic structures
the nanophotonic changes by
structures changes by
changing its localized or surrounding refractive index on introducing an analyte or binding aa
changing its localized or surrounding refractive index on introducing an analyte or binding
biological specie
biological specie [65].
[65]. Most
Most common
common nanophotonic
nanophotonic refractive
refractive index
index sensors
sensors are made of
are made of resonant
resonant
nanostructures [43–52],
nanostructures [43–52], whose
whose resonance
resonance wavelength
wavelength shifts
shifts due
due to
to aa change
change inin the
the refractive
refractive index
index on
on
applying any measurand such as a chemical or a biological specie, as shown
applying any measurand such as a chemical or a biological specie, as shown in Figure 1.in Figure 1.

Figure 1.1.Resonance
Figure Resonancewavelength
wavelengthshiftshift
due to change
due in the refractive
to change index. Reprinted
in the refractive index. with permission
Reprinted with
from [89]. Copyright © Elsevier (2012).
permission from [89]. Copyright © Elsevier (2012).
Sensors 2019, 19, 1715 3 of 26

The measurand is quantified from the magnitude of the resonance shift. Apart from
resonant nanophotonic sensors, there are other configurations available, including waveguide based
sensors [53–56], where the absorption of an analyte causes a change in the transmission intensity and
interferometric sensors, where a change in the localized refractive index of one arm of an interferometer,
changes the output signal of the interferometer [12,57–59]. In this review, we shall focus on label
free on-chip resonant refractive index sensors. The two main performance parameters of resonant
nanophotonic refractive index sensors are sensitivity and detection limit [65]. The sensitivity is defined
as a ratio of the magnitude of the resonance wavelength shift of the nanostructure to the induced
refractive index change and is expressed in the units of nm/refractive index unit (RIU). The optical
mode in the resonator decays evanescently into the surrounding analyte and the sensitivity depends
on the degree of the modal overlap with the analyte. The larger the overlap, the greater the sensitivity.
In addition to sensitivity, the detection limit is an important performance parameter for nanophotonic
sensors and is defined as the capability of the sensor to measure the least possible quantity of the
specie of interest. The value of the detection limit depends on the sensitivity of the sensor and the
resolution of the system used for the measurements [65].
In the following section, a brief overview of different state-of-the-art resonant nanophotonic
sensors composed of different materials such as metal, dielectric and semiconductor is presented.

2.1. Metal-Plasmonic Nanophotonic Sensors

Nanophotonic sensors made of metal exploit the phenomenon of surface plasmon resonance
(SPR) [90–93]. Surface plasmon resonance is a resonant oscillation of the metal’s conduction electrons
induced by light incident on its surface. Metal has a negative permittivity while its cladding such
as air has positive permittivity. The conduction electrons resonance induced by the incident light
generates plasmonic modes at the interface of the negative (metal) and positive (dielectric) permittivity
material, which can travel across the interface. The plasmon resonance causes enhancement of the
electric field at the interface of the metal and dielectric. When a biological species is bound to the metal,
it interacts with the high electric field intensity at the interface resulting in high sensitivity values.
However, SPR sensors require a prism-coupling scheme, which adds to additional complications in
the measuring setup. If the continuity of the metal is broken, such as in a nanoparticle, the plasmon
mode is localized at the interface with the air and is called localized surface plasmon resonance
(LPSR), which is exploited to develop high sensitivity sensors [94–98]. Another phenomenon called
extraordinary optical transmission (EOT) through an array of metallic holes is utilized to make high
performance optical sensors [4,5,31,43]. Plasmonic sensors based on metallic nanostructures that
give a Fano resonance response are also reported [99–104]. Fano resonance is a type of resonance
which has an asymmetric line shape and narrower linewidth compared to the standard Lorentzian
resonance and has the potential to develop high sensitivity plasmonic sensors. Fabricating an array
of metal nanostructures such as nanodiscs, nanoparticles or nanoholes generates an array of electric
field hotspots giving rise to a resonant transmission/reflection behavior, which is utilized for sensing.
The measurement of LSPR, EOT, or Fano resonance does not require prism coupling which simplifies
the measurement setup to some extent. However, these techniques still need an external spectrometer
or detector to record the resonant transmission/reflection response. Nanophotonic sensors exploiting
propagating [90–93] and localized SPR [94–98], EOT [4,5,31,43], and Fano resonance [99–104] are
reported, examples of which are provided in Figure 2. Plasmonic nanophotonic sensors can achieve
very high sensitivity values (few hundreds of nm/RIU) [43,98–111] and even higher (thousands of
nm/RIU) by metamaterial designs [23]. However, their readout requires external bulky equipment,
limiting their use to laboratory environments.
Sensors 2019,19,
Sensors2019, 19,1715
x FOR PEER REVIEW 4 of
25 of 26
25

(a) (b)

(c) (d)

(e)
Figure 2.
Figure 2. Schematic
Schematic of of plasmonic
plasmonic sensors.
sensors. (a)
(a) Surface
Surface plasmon resonance (SPR)
plasmon resonance (SPR) sensor
sensor requiring
requiring prism
prism
coupling. Reprinted
coupling. Reprintedfrom from[93]
[93] under
under CCCCBY BY3.0. 3.0. (b) Localized
(b) Localized surface
surface plasmon
plasmon resonance
resonance (LPSR)(LPSR)
based
based sensor
sensor composedcomposed of anofarray
of an array of metallic
metallic nanoparticles.
nanoparticles. Reprinted
Reprinted with permission
with permission fromunder
from [110] [110]
under CC BY-NC 3.0. Copyright © The Royal Society of Chemistry (RSC) (2014).
CC BY-NC 3.0. Copyright © The Royal Society of Chemistry (RSC) (2014). (c) An array of metallic (c) An array of
metallic nanoholes
nanoholes operating operating on the principle
on the principle of extraordinary
of extraordinary opticaloptical transmission
transmission (EOT).(EOT). Reprinted
Reprinted with
with permission
permission from [111].
from [111]. Copyright
Copyright © SPIE© (2010).
SPIE (2010). (d) Schematic
(d) Schematic of plasmonic
of plasmonic structures
structures havinghaving
Fano
Fano resonance.
resonance. (e) Fano(e) resonance
Fano resonance shift
shift by by change
change of refractive
of refractive indices.indices. (d,e) Reprinted
(d,e) Reprinted fromunder
from [103] [103]
under CC
CC BY 4.0. BY 4.0.
Sensors 2019, 19, 1715 5 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

2.2. On
2.2. On Chip
Chip Semiconductor/Dielectric
Semiconductor/Dielectric Nanophotonic
Nanophotonic Sensors
Sensors
Nanocavities made
Nanocavities made of of semiconductor
semiconductor or or dielectric
dielectric materials
materials suchsuch as
as silicon
silicon and
and silicon
silicon nitride
nitride
respectively, can achieve very narrow resonance linewidth, i.e., in the order
respectively, can achieve very narrow resonance linewidth, i.e., in the order of picometers [18,112]. of picometers [18,112].
This very
This verynarrow
narrow resonance
resonance response
response is exploited
is exploited to develop
to develop high performance
high performance sensors. The sensors.
most
The most notable onchip semiconductor cavity sensors are based
notable onchip semiconductor cavity sensors are based on ring resonators [19,35,47], disk on ring resonators [19,35,47],
disk resonators
resonators [48,49][48,49] and photonic
and photonic crystal crystal
cavitiescavities
[113–117].[113–117].
A specialAtypespecial typein
of cavity ofwhich
cavitythe
in optical
which
the optical
mode mode is
is confined in confined
the air slot in such
the air
asslot suchphotonic
slotted as slotted photonic
crystal cavitycrystal cavity [18,112,118,119]
[18,112,118,119] and slotted
and slotted ring resonator [17,120,121] is developed to enhance the overlap
ring resonator [17,120,121] is developed to enhance the overlap of the optical mode and the of the optical mode and
analyte
the analyte to increase the sensitivity. In addition to high Q-factor cavities,
to increase the sensitivity. In addition to high Q-factor cavities, grating designs having narrow grating designs having
narrow transmission/reflection
transmission/reflection responseresponse are utilized
are utilized for sensingfor sensing [60–64,122].
[60–64,122]. Nanocavities
Nanocavities or gratings
or gratings made
of silicon operate at sub-bandgap wavelengths (wavelengths larger than 1100 nm) hence to hence
made of silicon operate at sub-bandgap wavelengths (wavelengths larger than 1100 nm) performto
perform experiments
sensing sensing experiments in the range,
in the visible visiblenanocavities
range, nanocavities or gratings
or gratings made of made of silicon
silicon nitridenitride are
are used
used [17,38,64,123]. The main advantage of using semiconductor/dielectric
[17,38,64,123]. The main advantage of using semiconductor/dielectric nanocavities and gratings for nanocavities and gratings
for sensing
sensing is achieving
is achieving veryvery
highhigh detection
detection limit.limit. However,
However, to measure
to measure the resonance
the resonance wavelength
wavelength shift
shift which
which is in isthe
in the orders
orders of nano
of nano or or picometers,
picometers, costly
costly spectrometersare
spectrometers areneeded
neededwhich
which makes
makes the
the
sensors expensive and impractical. Schematic examples of high-performance
sensors expensive and impractical. Schematic examples of high-performance cavity based sensors is cavity based sensors is
shown in the Figure
shown in the Figure 3. 3.

(a)

(b) (c)
Figure 3.
3. Schematic
Schematicofofsemiconductor cavity-based
semiconductor sensors.
cavity-based (a) Ring
sensors. resonator
(a) Ring sensor.
resonator Reprinted
sensor. with
Reprinted
permission
with fromfrom
permission [89]. [89].
Copyright © Elsevier
Copyright (2012).
© Elsevier (b,c)
(2012). Slotted
(b,c) Slottedphotonic
photoniccrystal
crystalcavity
cavitysensor.
sensor.
Reprinted from [118] under CC BY 3.0. Both types of sensors require external measuring equipment
such as optical spectrum analyzers (OSA) to measure the small
small magnitudes
magnitudes ofof the
the wavelength
wavelength shift.
shift.
Sensors 2019, 19, 1715 6 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

3. Nanophotonic
3. Nanophotonic Sensors
Sensors with
with Compact
Compact Readout
Readout System
System
This section
This sectionprovides
providesananoverview
overview
of of different
different efforts
efforts donedone to develop
to develop nanophotonic
nanophotonic sensors
sensors with
with compact readout system. These works can be divided into two main categories; (i)
compact readout system. These works can be divided into two main categories; (i) nanophotonic nanophotonic
sensors having
sensors havingmonolithically
monolithically integrated
integrated readout
readout system
system and
and (ii) (ii) nanophotonic
nanophotonic sensorscompact
sensors having having
compact but separate readout
but separate readout system. system.

3.1. Nanophotonic Sensors having Monolithically Integrated

Integrated Readout
Readout System
System
One approach to to developing
developing aa portable
portable nanophotonic
nanophotonic sensor having a compact readout system system
to integrate
is to integrate nanophotonics
nanophotonics structures
structures monolithically
monolithically with the photodiodes
photodiodes (PDs)
(PDs) having
having high
high
responsivity in
responsivity inthe
theregion
regionofofinterest.
interest.By
Bydoing
doingso,
so,the
theresonance
resonance wavelength
wavelength shift
shift cancan
be be measured
measured as
as a change in the electrical output (current, voltage) of the PD as shown in the
a change in the electrical output (current, voltage) of the PD as shown in the Figure 4.Figure 4.

(a) (b)

Figure 4.4. (a)

(a) Resonance
Resonance wavelength
wavelength shift due to to change
change in in the
the refractive
refractive index.
index. Keeping
Keeping the
the incident
incident
wavelength fixed (red vertical
wavelength vertical arrow),
arrow),the theintensity
intensityofoflight
lightimpinging
impingingononthe thePDPDchanges
changes from
fromlevel
level1 to
1
level
to 2 resulting
level in in
2 resulting thethe
increase
increasein in
thethe
PDPDoutput
outputvoltage/current
voltage/current from level
from 1 to
level 2 as
1 to shown
2 as shownin in
(b).(b).

In contrast
contrast to tostandalone
standalonenanophotonic
nanophotonicsensorssensorswhere
whereperformance
performance is is
usually
usually quoted
quoted in in
terms
termsof
the resonance
of the resonance wavelength
wavelength shift in response
shift in responseof unit refractive
of unit index
refractive change,
index change,in the integrated
in the integrated system the
system
important parameter is not merely resonance wavelength shift but the
the important parameter is not merely resonance wavelength shift but the change in the optical change in the optical intensity
impinging on the PD on
intensity impinging duetheto the
PD wavelength shift. There are
due to the wavelength three
shift. parameters
There are threethat control the
parameters thatchange
controlin
the
the optical
changeintensity impinging
in the optical on theimpinging
intensity PD due to on wavelength
the PD due shift,toi.e. sensitivity, shift,
wavelength resonance linewidth
i.e. sensitivity,
and resonance
resonance depth, which
linewidth and isresonance
defined asdepth,
the difference
whichbetween
is definedthe transmission/reflection
as the difference between level of the
resonance dip/peak andlevel
transmission/reflection the background level. The
of the resonance higher and
dip/peak the sensitivity,
the background greaterlevel.
will beThe thehigher
resonancethe
shift per unit
sensitivity, refractive
greater index
will be the change
resonance causing a larger
shift per change in index
unit refractive the intensity. Similarly,
change causing the narrower
a larger change
the linewidth,
in the intensity.the greater will
Similarly, be the intensity
the narrower change the
the linewidth, for greater
certain willwavelength shift provided
be the intensity change the for
linewidth of the incident
certain wavelength shiftlight is smaller
provided the than the resonance
linewidth response
of the incident of the
light nanostructures.
is smaller than theInresonance
the same
way, the greater
response of the the resonance depth,
nanostructures. thesame
In the larger willthe
way, be the intensity
greater change induced
the resonance depth,by thethe wavelength
larger will be
shift. In integrating
the intensity change nanophotonic
induced by thestructures
wavelength withshift.
PDs,Initintegrating
is important to design and
nanophotonic optimizewith
structures the
nanophotonic
PDs, it is importantstructure in order
to design andto optimize
maximizethe thenanophotonic
intensity change for a in
structure certain
orderwavelength
to maximizeshift. the
Furthermore, the choice of nanophotonic structures for integrating with
intensity change for a certain wavelength shift. Furthermore, the choice of nanophotonic structures the PD depends on the
applications
for integrating andwithrequirements
the PD depends of the sensors. Plasmonic structures
on the applications offer highofsensitivity
and requirements the sensors. however due
Plasmonic
to high optical
structures offerlosses, have broadhowever
high sensitivity resonance linewidths.
due On the
to high optical otherhave
losses, hand,broad
semiconductor
resonanceor dielectric
linewidths.
structures
On the other such as cavities
hand, and gratings
semiconductor have moderate
or dielectric structuressensitivities compared
such as cavities to plasmonic
and gratings havestructures
moderate
however they
sensitivities have narrower
compared linewidths
to plasmonic and a greater
structures however resonance
they havedepth, resulting
narrower in a greater
linewidths and a change
greater
in the intensity impinging on the PD due to resonance wavelength shift.
resonance depth, resulting in a greater change in the intensity impinging on the PD due to resonance
wavelength shift.
3.1.1. Nanophotonic Sensors with Integrated Silicon Photodiode
3.1.1.An
Nanophotonic Sensors
initial effort in with Integrated
developing Silicon
nanophotonic Photodiode
sensors with compact readout system was presented
by Mazzotta et al. [68]. In this work, nano plasmonic
An initial effort in developing nanophotonic sensors structures (gold nanodisc
with compact readout array)
system were
was
presented by Mazzotta et al. [68]. In this work, nano plasmonic structures (gold nanodisc array) were
Sensors 2019, 19, 1715 7 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

monolithically
monolithically integrated
integrated with
with the
the bulk
bulksilicon
siliconphotodiode
photodiode(PD),
(PD),as
asshown
shownininFigure
Figure5.5. The
Thebest
best
results were obtained when the thickness and diameter of the gold nanodiscs were
results were obtained when the thickness and diameter of the gold nanodiscs were 20 nm and 11020 nm and 110 nm
respectively. TheseThese
nm respectively. parameters gave a gave
parameters resonance at 650 nm,
a resonance measured
at 650 by fabricating
nm, measured the gold nanodisc
by fabricating the gold
array on a array
nanodisc test silicon
on a nitride coated
test silicon glass coated
nitride slide. The optical
glass slide.sensitivity response
The optical was measured
sensitivity response wasby
applying different concentrations of glycerol as an analyte on the gold nanodisc array
measured by applying different concentrations of glycerol as an analyte on the gold nanodisc array fabricated on
the silicon nitride
fabricated on the coated
silicon glass
nitrideslide.
coated glass slide.

(a)

(b)

Figure 5. Schematic of the device detailed in Mazzotta et al. [68]. (a) Cross section of the photodiode
Figure 5. Schematic of the device detailed in Mazzotta et al. [68]. (a) Cross section of the photodiode
(PD) with integrated gold nanodiscs. (b) Schematic of the sensor chip having four PDs with dimensions
(PD) with integrated gold nanodiscs. (b) Schematic of the sensor chip having four PDs with
of 2 mm × 0.14 mm. Two PDs had gold nanodiscs fabricated on top while the other two PDs were
dimensions of 2 mm × 0.14 mm. Two PDs had gold nanodiscs fabricated on top while the other two
used as a reference. The total size of the sensor chip is 15 mm × 10 mm. Reprinted with permission
PDs were used as a reference. The total size of the sensor chip is 15 mm × 10 mm. Reprinted with
from [68]. Copyright © Elsevier (2010).
permission from [68]. Copyright © Elsevier (2010).
The resonance wavelength of the gold nanodisc array red-shifted by applying different
The resonance
concentrations wavelength
of glycerol. From the of the goldofnanodisc
redshift array wavelength,
the resonance red-shifted the by applying different
optical sensitivity
concentrations
value of the goldof glycerol.
nanodisc From
array wasthe redshift to
measured ofbethe133resonance
nm/RIU,wavelength,
which is a typical the optical sensitivity
sensitivity value
for these types of plasmonic structures. The gold nanodisc array having similar dimensions as invalue
value of the gold nanodisc array was measured to be 133 nm/RIU, which is a typical sensitivity the
for these types of plasmonic structures. The gold nanodisc array having similar
test sample was fabricated on top of silicon nitride coated bulk silicon photodiode (PD). The top silicon dimensions as in the
test sample was fabricated on top of silicon nitride coated bulk silicon photodiode
area was p-doped while rest of the bulk substrate was n-doped to create top and bottom metal contacts, (PD). The top
silicon area was
respectively. p-doped while rest
By monolithically of the bulk
integrating thesubstrate was n-doped
gold nanodisc array withto create top and
the silicon PD,bottom metal
its optical
contacts, respectively.
transmission response was By monolithically
converted to anintegrating the gold
electrical signal nanodisc
and hence the array
need for with the silicon
external PD, its
equipment
optical transmission response was converted to an electrical signal and hence
to measure the optical response was eliminated. When the resonance wavelength of the gold nanodisc the need for external
equipment
array to measure
red shifted due tothe opticalan
applying response
analyte,was
sucheliminated.
as glycerol,When the resonance
the optical intensity wavelength
incident on ofthe
the
gold nanodiscintegrated
monolithically array red PD shifted due to
changed applying
which in turnanchanged
analyte,thesuchPDas glycerol,
output the optical intensity
current.
incident on the monolithically integrated PD changed which in turn
The electrical sensitivity data was presented in terms of PD output current ratio, changed the PD output current.
as shown in
The electrical sensitivity data was presented in terms of PD output
Figure 6, which is defined as the PD output current when analyte is applied versus the PD output current ratio, as shown in
Figure 6, which is defined as the PD output current when analyte is applied
current with air as the cladding (reference diode). From the PD output current ratio, the photocurrent versus the PD output
current
ratio with air which
sensitivity, as the cladding
is defined(reference
as the ratiodiode).
of theFrom
change thein
PDtheoutput current ratio,
photocurrent ratio thewhenphotocurrent
analyte is
applied to the corresponding change in the refractive index was measured to be 0.01/RIU. analyte is
ratio sensitivity, which is defined as the ratio of the change in the photocurrent ratio when
applied
Fromtothe
thephotocurrent
corresponding change
ratio, in the refractive
the sensitivity in terms index was measured
of change to be 0.01/RIU.
in transmission or optical intensity
From the photocurrent ratio, the sensitivity in terms of change
was estimated to be −29%/RIU, which is less than a half compared to the change in transmission in transmission or optical
intensity was estimated to be −29%/RIU, which is less than a half compared to the change in
transmission measured on a test glass slide sample (−70% RIU). The negative sign indicates decrease
Sensors 2019, 19, 1715 8 of 26

Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

measured on a test glass slide sample (−70% RIU). The negative sign indicates decrease in transmission.
The difference was
in transmission. attributed
The to was
difference the possible
attributedvariation in plasmonic
to the possible properties
variation of theproperties
in plasmonic gold nanodisc
of the
array fabricated on the glass substrate and on the silicon PD and also to the difference
gold nanodisc array fabricated on the glass substrate and on the silicon PD and also to the difference in the
measurement setups. The capability of the integrated nanophotonic sensor to measure
in the measurement setups. The capability of the integrated nanophotonic sensor to measure the the specific
binding
specificof proteinofto
binding receptors
protein immobilized
to receptors on the gold
immobilized on the nanodisc surfacesurface
gold nanodisc was also
wasshown by theby
also shown
change in theinPD
the change theoutput signalsignal
PD output as presented in theinFigure
as presented 6d. 6d.
the Figure

(a) (b)

(d)
(c)

Figure6.6.Measurement
Figure Measurementresults resultsofofthe
thesensor
sensorchip
chipdetailed
detailed inin Mazzotta
Mazzotta et et al.
al. [68].
[68]. (a)
(a) The
The red red curve
curveis
the ratio between the reflection from the nanodiscs and the reference PD
is the ratio between the reflection from the nanodiscs and the reference PD showing the reflection showing the reflection
response
response ofofthe
thegold
goldnanodisc
nanodiscarray.
array.TheTheblue
bluecurve
curverepresents
representsthe thePDPDphotocurrent
photocurrentratio ratioforfordifferent
different
wavelengthsofofthe
wavelengths theincident
incidentlight.
light.(b)
(b)The
Thegraph
graphrepresents
representsthe thechange
changeininthethePDPDcurrent
currentratioratioversus
versus
changeininthe
change therefractive
refractivewhile
whilekeeping
keepingthe theincident
incidentlight
lightfixed
fixedatat
780780 nm.(c)(c)Graphical
nm. Graphicalillustration
illustrationofof
specificbinding
specific bindingofofneutravidin
neutravidinwithwithgold
goldnanodiscs.
nanodiscs.(d) (d)Normalized
Normalizedphotocurrent
photocurrentfrom fromreference
referencePD PD
(blue),PD
(blue), PDwith
withnanodisc
nanodiscarray
array(red)
(red)and
andthethe photocurrentratio
photocurrent ratio(green).
(green).The
Thecurves
curvesare arenormalized
normalized
withtheir
with theirinitial
initialvalues
valueswhich
whichwere
were1.679
1.679VVforforthe
thereference
reference(blue)
(blue)curve,
curve,0.693
0.693VVfor forthethePD PDwith
with
nanodiscs(red)
nanodiscs (red)andand0.413
0.413VVfor
forthe
thephotocurrent
photocurrentratio ratio(green).
(green).Reprinted
Reprintedwith withpermission
permissionfrom from[68].
[68].
Copyright©©Elsevier
Copyright Elsevier(2010).
(2010).

AAsimilar
similarapproach
approachwas taken
was by Guyot
taken by Guyotet al.et[69], where
al. [69], nanoplasmonic
where nanoplasmonic structures (array (array
structures of goldof
nanoholes) were monolithically
gold nanoholes) integratedintegrated
were monolithically with p-doped withsilicon substrate
p-doped thatsubstrate
silicon acted as athat
photodetector
acted as a
inphotodetector
the metal oxide in semiconductor
the metal oxide(MOS) configuration.
semiconductor (MOS) The array of nanoholes
configuration. The arrayacted
of as a top contact
nanoholes acted
while aluminum was deposited as a bottom metal contact, as shown in the Figure
as a top contact while aluminum was deposited as a bottom metal contact, as shown in the Figure 7a. Following the7a.
same principle
Following theas explained
same in Section
principle 3.1, theinwavelength
as explained Section 3.1,shift due to change
the wavelength in the
shift duerefractive
to changeindex
in the
was recorded
refractive as the
index waschange in theasintensity
recorded the changedetected
in thebyintensity
the photodetector.
detected by Inthe
thisphotodetector.
work, it was shown
In this
that the sensing performance is better when asymmetric nanohole arrays having
work, it was shown that the sensing performance is better when asymmetric nanohole arrays having different periods in
the orthogonal
different directions
periods in the [124] are used
orthogonal compared
directions to the
[124] aresymmetric
used comparedarray, as
to shown in the Figure
the symmetric array,7b.as
However, better sensing performance for the asymmetric nanohole array is
shown in the Figure 7b. However, better sensing performance for the asymmetric nanohole array isobtained by measuring
the signal by
obtained difference
measuringbetween orthogonal
the signal polarizations
difference and a self-referencing
between orthogonal polarizations and system to eliminate
a self-referencing
experimental noise. The
system to eliminate system requires
experimental a complicated
noise. The system requiressetupaand hence negates
complicated setup the
andusefulness
hence negatesof
the portable readout system. The sensing performance of the device was presented
the usefulness of the portable readout system. The sensing performance of the device was presented by measuring
the
bydetector
measuringsignal
the shift when
detector water
signal andwhen
shift different
waterconcentrations of ethanol are applied
and different concentrations to the
of ethanol aredevice.
applied
to the device. From Figure 7b, it can be seen that the 0.7% ethanol in water, which corresponds to
1.75 × 10−4 RIU change induced 0.07 mV and 0.15 mV signal shift for symmetric and asymmetric
nanoholes array, leading to the electrical sensitivity of 0.4 V/RIU and 0.8 V/RIU, respectively.
Sensors 2019, 19, 1715 9 of 26

From Figure 7b, it can be seen that the 0.7% ethanol in water, which corresponds to 1.75 × 10−4 RIU
change induced 0.07 mV and 0.15 mV signal shift for symmetric and asymmetric nanoholes array,
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25
leading to the electrical sensitivity of 0.4 V/RIU and 0.8 V/RIU, respectively.
The same group also integrated angle sensitive metallic nano gratings with the MOS silicon
The same group also integrated angle sensitive metallic nano gratings with the MOS silicon
photodetector and performed angular scanning of the incident light [70]. The integrated sensor was
photodetector and performed angular scanning of the incident light [70]. The integrated sensor was −5 .
able to distinguish between nitrogen and argon gases whose refractive index difference is 1.5 × 10−5
able to distinguish between nitrogen and argon gases whose refractive index difference is 1.5 × 10 .
Angle sensitive plasmonic nano gratings were also integrated with the bulk silicon photodetector
Angle sensitive plasmonic nano gratings were also integrated with the bulk silicon
in [71,72]. In [71], Perino et al. measured the sensitivity in terms of the change in the transmission
photodetector in [71,72]. In [71], Perino et al. measured the sensitivity in terms of the change in the
intensity of the zero-order diffracted ray of the functionalized and unfunctionalized grating and
transmission intensity of the zero-order diffracted ray of the functionalized and unfunctionalized
reported its value as 2.94/RIU, while the detection limit of the integrated sensor was reported to be
grating and reported its value as 2.94/RIU, while the detection limit of the integrated sensor was
2.2 × 10−4 RIU.
reported to be 2.2 × 10-4 RIU.

(a) (b)
7. (a)
Figure 7. (a) Schematic
Schematic of
of plasmonic
plasmonic nanostructures
nanostructures integrated
integrated with
with the
the silicon
silicon photodetector.
photodetector.
(b) Output of the sensor showing measurements for symmetric and asymmetric plasmonic nanohole
arrays when water and different concentrations of ethanol were applied.
applied. Reprinted with permission
from [69]. Copyright © The Optical Society (OSA) (2011).

In
In [72],
[72], Turker
Turker et
et al.,
al., deposited
deposited aa thin
thin silver
silver layer
layer on
on top
top of
of polymer
polymer gratings
gratings fabricated
fabricated on
on top
top
of the silicon photodetector to enable plasmonic coupling. The electrical sensitivity of the
of the silicon photodetector to enable plasmonic coupling. The electrical sensitivity of the gratings gratings
integrated
integrated silicon
silicon photodetector
photodetector sensor
sensor reported
reported inin [72]
[72] was
was 0.6
0.6 mA/RIU.
mA/RIU.

3.1.2. Nanophotonic Sensor

3.1.2. Nanophotonic Sensor with
with Integrated
Integrated Germanium
Germanium Pin Pin Photodiode
Photodiode
In
In order
order toto develop
develop aa nanophotonic
nanophotonic sensorsensor with
with compact
compact readout
readout system,
system, Augel
Augel et et al.
al. [73],
[73],
fabricated plasmonic nanohole arrays by etching nanoholes directly in the top
fabricated plasmonic nanohole arrays by etching nanoholes directly in the top aluminum metal aluminum metal contact
of the vertical
contact of thegermanium pin photodiode
vertical germanium (PD). Germanium
pin photodiode PDs were chosen
(PD). Germanium PDs instead of silicon
were chosen because
instead of
germanium has a higher absorption coefficient and offers a larger value of the
silicon because germanium has a higher absorption coefficient and offers a larger value of the generated photocurrent.
Furthermore, the operation
generated photocurrent. spectrum ofthe
Furthermore, germanium
operation extends
spectrum to of
thegermanium
near infrared regiontoand
extends thehence
near
allows to perform sensing experiments in the near infrared range in addition
infrared region and hence allows to perform sensing experiments in the near infrared range into the visible wavelengths.
The to
addition performance of the integrated sensing system was optimized by varying the germanium
the visible wavelengths.
layerThe
thickness to tune of
performance thethe
responsivity
integratedof the detector
sensing systemandwas byoptimized
controllingbythe resonance
varying response of
the germanium
the nanohole array by optimizing the diameter and periodicity of the nanoholes.
layer thickness to tune the responsivity of the detector and by controlling the resonance response The nanohole array
of
was designed to exhibit asymmetric Fano resonances that have narrower linewidths
the nanohole array by optimizing the diameter and periodicity of the nanoholes. The nanohole array compared to the
Lorentzian
was designed resonance response
to exhibit and promise
asymmetric higher sensitivity
Fano resonances that haveand lower detection
narrower linewidthslimit. The schematic
compared to the
of the device along with the cross section of the germanium pin PD
Lorentzian resonance response and promise higher sensitivity and lower detectionand the parameters of the limit.
plasmonic
The
nanohole array is shown in Figure 8.
schematic of the device along with the cross section of the germanium pin PD and the parameters of
the plasmonic nanohole array is shown in Figure 8.
Sensors 2019, 19, 1715 10 of 26

Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

(a) (b)

(d)
(c)

Figure8.8.(a)(a)Schematic
Figure Schematic illustration
illustration of device
of the the device presented
presented in Augel
in Augel et al.
et al. [73], [73], showing
showing the crossthe cross
section
ofsection of the germanium
the germanium PD and aluminum
PD and integrated integrated nanohole
aluminum nanohole
array arraycontact
in the metal in the area.
metal(b)contact area.
Schematic
(b) Schematic
showing the layersshowing
of the the layers ofPD
germanium thewhere
germanium PD where
the germanium thethickness
layer germanium is 780layer thickness
nm and 500 nmis
780sample
for nm andA500 andnm for sample A and
B respectively. B respectively.
(c) SEM (c) aluminum
image of the SEM imagenanohole
of the aluminum nanohole with
array integrated array
integrated
the germanium withPD.the(d)
germanium PD.parameters
The physical (d) The physical parameters
(hole diameter and(hole diameter
the pitch) and thenanohole
of various pitch) of
various
arrays nanohole
fabricated in arrays fabricated
the metal contact in
areatheofmetal contact area
the germanium PD.ofReprinted
the germanium PD. Reprinted
with permission with
from [73].
permission
Copyright © from [73]. Copyright
American © American
Chemical Society (ACS)Chemical
(2018). Society (ACS) (2018).

The
Thereadout of the of
performance integrated sensing
the integrated systemsystem
sensing was given in terms of the by
was demonstrated responsivity spectrum
changing the of
refractive
the germanium PD. The light transmitted from the nanohole array was incident on the monolithically
index of the surroundings of the nanohole array by adding DI water (n = 1.320), ethanol (n = 1.353),
integrated germanium
and isopropyl alcohol PD
(IPA)and(n its responsivity
= 1.369). As the spectrum
refractive was
indexmeasured. As canincreased,
of the solution be seen from the
the Fano
Figure 8, the responsivity spectrum of the germanium PD without the integrated nanohole
resonance of the nanohole array redshifted, which was read out as the redshift in the responsivity array is
flat while a Fano resonance peak is visible in the responsivity spectrum of the
spectrum of the integrated germanium PD, as shown in Figure 9. From the measurements, the plasmonic nanoholes
integrated
maximumPD. sensitivity for the most optimized parameters of the device estimated from the germanium
PD responsivity dataofwas
The performance the 1180
integrated
nm/RIU, sensing
whichsystem washigher
is even demonstrated
than theby changing the refractive
non-integrated plasmonic
index of the surroundings of the nanohole array by adding DI water (n = 1.320), ethanol (n = 1.353),
sensors.
and isopropyl alcohol (IPA) (n = 1.369). As the refractive index of the solution increased, the Fano
resonance of the nanohole array redshifted, which was read out as the redshift in the responsivity
spectrum of the integrated germanium PD, as shown in Figure 9. From the measurements,
the maximum sensitivity for the most optimized parameters of the device estimated from the
germanium PD responsivity data was 1180 nm/RIU, which is even higher than the non-integrated
plasmonic sensors.
Sensors 2019, 19, 1715 11 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

(a) (b) (c)

Figure 9. Experimental results detailed in Augel et al. [73]. (a) Experimental responsivity spectrum
Figure 9. Experimental results detailed in Augel et al. [73]. (a) Experimental responsivity spectrum of
of the device for different refractive indices of the surrounding medium. The physical parameters of
the device for different refractive indices of the surrounding medium. The physical parameters of the
the nanohole array were as follows; pitch 950 nm, hole diameter 480 nm, germanium layer thickness
nanohole array were as follows; pitch 950 nm, hole diameter 480 nm, germanium layer thickness
700 nm. (b) Simulation results for the responsivity of the device having parameters similar to (a).
700 nm. (b) Simulation results for the responsivity of the device having parameters similar to (a). The
The peak position of the responsivity red shifts as the refractive index increases. (c) Responsivity
peak position of the responsivity red shifts as the refractive index increases. (c) Responsivity peak
peak positions versus refractive indices for different combinations of the device physical parameters.
positions versus refractive indices for different combinations of the device physical parameters.
Reproduced with permission from [73]. Copyright © American Chemical Society (ACS) (2018).
Reproduced with permission from [73]. Copyright © American Chemical Society (ACS) (2018).
3.1.3. Nanophotonic Sensor Integrated with CMOS Technology
3.1.3. Nanophotonic Sensor Integrated with CMOS Technology
Complementary Metal Oxide Semiconductor (CMOS) technology has revolutionized the
Complementary
electronics Metal Oxide
industry especially Semiconductor (CMOS)
in telecommunications technology
and computing. The has
way revolutionized
CMOS technology the
electronics industry especially in telecommunications and computing.
has enabled widespread applications of electronic devices, it also holds promise to commercialize The way CMOS technology
has enabled widespread
nanophotonic sensors if applications of electronic
it can be integrated withdevices,
the CMOS it also holds promise
technology to commercialize
[125,126]. Integrating
nanophotonic sensors if it can be integrated with the CMOS technology
nanophotonic sensors with CMOS electronic technology combines the benefits of both nanophotonic [125,126]. Integrating
nanophotonic sensors with CMOS electronic technology combines the
sensors (high sensitivity and low detection limit) and the benefits of CMOS electronics such as benefits of both nanophotonic
sensors (highand
compactness sensitivity and low detection
ease of commercialization, limit)
thanks to and the benefits
the mature of CMOS
fabrication electronics
production lines ofsuch
CMOS as
compactness and ease of commercialization, thanks to the mature fabrication
foundries. Keeping this in view, Shakoor et al. [74–76], performed the first monolithic integration of production lines of
CMOS foundries.
nanophotonic sensorsKeeping
with the this in view, Shakoor
photodiodes (PD) made et byal. a[74–76], performed the first monolithic
CMOS foundry.
integration of nanophotonic sensors with the photodiodes
The CMOS PD integrated circuit was fabricated in a commercial CMOS (PD) made by a CMOS
foundry, foundry.
namely Austria
The CMOS PD integrated circuit was fabricated in a commercial
Microsystems using a 0.35 µm four metal layer high voltage CMOS technology. The dimensions CMOS foundry, namely Austria
of the
Microsystems using a 0.35 µm four metal layer high voltage CMOS
individual PDs were only 6 × 8 µm which is much smaller compared to the millimeter scale PDs usedtechnology. The dimensions of
the individual PDs were only 6 × 8 µm which is much smaller compared
in the works presented in Sections 3.1.1 and 3.1.2. Miniaturized PDs is one of the main advantages of to the millimeter scale PDs
used detectors
using in the works madepresented
by CMOS in Sections Depending
technology. 3.1.1 and 3.1.2. on theMiniaturized
applications of PDs is onenanophotonic
interest, of the main
advantages
sensors made of of
using detectors
different made and
materials by CMOS
designstechnology. Depending
can be fabricated on topon the applications
of the CMOS PDs. of interest,
In this
nanophotonic sensors made of different materials and designs can
work, plasmonic sensors composed of gold nano discs and dielectric sensors made of silicon be fabricated on top of the nitride
CMOS
PDs. In this
gratings werework, plasmonic
integrated with thesensors
CMOS composed
PDs. Theofnanophotonic
gold nano discs and dielectric
structures sensors in
were optimized made
termsof
silicon nitride gratings were integrated with the CMOS PDs. The
of its resonance line width, resonance depth and operating range which should match the maximum nanophotonic structures were
optimized inofterms
responsivity of to
the PD itsmake
resonance line width,
it suitable resonance
for integration depth
with and operating
the CMOS PDs. The range whichsensors
plasmonic should
matchgreater
offer the maximum
sensitivityresponsivity
compared of to the
the PD to make
dielectric it suitable
sensors, for integration
as discussed with 2,
in Section thehowever
CMOS PDs. due
to the high losses associated with the metal, the resonance linewidth of the plasmonic structures in
The plasmonic sensors offer greater sensitivity compared to the dielectric sensors, as discussed is
Sectionwhich
broad 2, however
reduces duethetomagnitude
the high lossesof theassociated
intensity with changetheinduced
metal, the byresonance
the resonance linewidth of the
shift when
plasmonic
an analyte isstructures
applied to is broad
the sensorwhich at reduces the magnitude
a fixed input wavelength. of the
Onintensity
the otherchange induced by the
hand, nanostructures
resonance shift when an analyte is applied to the sensor at a
exhibiting narrow resonance linewidths have limited dynamic range as the output signal fixed input wavelength. On saturates
the other
hand,just
with nanostructures
a small resonance exhibiting narrow
shift. Thus, forresonance
applications linewidths
where it ishave limited
required dynamiclarge
to measure range as the
changes
output signal saturates with just a small resonance shift. Thus, for applications
in refractive index, nanostructures having broad resonance linewidths are appropriate, while on where it is required
to measure large changes in refractive index, nanostructures having broad resonance linewidths are
appropriate, while on the other hand for measuring small changes in refractive index narrow band
Sensors 2019, 19, 1715 12 of 26

the other hand for measuring small changes in refractive index narrow band resonant structures
such as gratings or cavities are a better option. In this work, both broadband plasmonic and narrow
band dielectric structures were integrated with the CMOS PDs to demonstrate the potential of the
integration approach.
To integrate the nanophotonic sensors with the CMOS PDs, first a 500 nm thick layer of silica was
deposited on top of the CMOS chip. The main reason for depositing this layer was to replicate the
nanophotonic design optimized on a test glass slide sample. As the composition of the top passivation
layer of the CMOS chip is not fully known, using the same design for the nanophotonic sensors as
used in the test sample fabricated on the glass substrate could shift the resonance response if silica
layer was not deposited on top of the CMOS chip. The nanophotonic structures were fabricated on top
of the CMOS chip by standard e-beam lithography followed by lift off and etching processes for gold
nanodiscs and silicon nitride gratings, respectively. The microscopic images of the gold nanodiscs and
silicon nitride gratings fabricated monolithically on top of the CMOS chip along with the cross-section
schematic of the CMOS chip are given in Figure 10.
The total size of the chip was only 3.5 × 4.5 mm. The nanophotonic sensor integrated CMOS chip
was placed on a PGA-120 chip carrier, wire bonded to provide electrical connections and packaged
by using the EPO-TEK 302 epoxy to allow sensing experiments with aqueous solutions. A printed
circuit board controlled by a Labview program was used to power the chip. The Labview program
read the real time voltage signal from the PD in a synchronous manner. The electrical data from the
sensor system was recorded by computer by connecting it to the PCB via a USB cable. The system can
also be easily connected wirelessly to a smartphone or a tablet. A photograph of the integrated sensor
placed on a chip carrier and PCB is shown in Figure 10g.
The performance of the sensor system was evaluated by changing the refractive index of the
surroundings by introducing different concentrations of glycerol. As the glycerol concentration was
increased, the resonance peak red-shifted. The optical sensitivity values measured from test samples
for gold nanodisc arrays and silicon nitride gratings were 275 nm/RIU and 160 nm/RIU, respectively.
Keeping the wavelength of the input light fixed, the resonance-shift due to the change in refractive
index changed the intensity of light impinging the underlying active layer of the PD, which in turn
resulted in an increase or decrease of the PD output voltage. The change in the PD output voltage
when different concentrations of glycerol were applied on top of the gold nanodiscs and silicon nitride
gratings is shown in Figure 11. For the gold nanodisc integrated sensor, the change in PD output
voltage with change in refractive index is linear. On the other hand, for the silicon nitride grating sensor
the PD output voltage is not linear. This is because the resonance linewidth of the silicon nitride grating
is narrow, and the magnitude of the resonance shift for different concentrations of glycerol depends on
the chosen incidence wavelength. From the curve shown in Figure 11, the electrical sensitivity of the
CMOS PD integrated gold nanodisc array sensor was estimated to 5.6 V/RIU, while the maximum
sensitivity for silicon nitride grating was measured to be 6.75 V/RIU. The quoted electrical sensitivity
values depend highly on the design of the electronic readout circuitry and hence can vary among
different electronic readout systems. The estimated detection limit of the integrated detection system
was 0.003 RIU, which is lower compared to standalone resonant nanophotonic sensors measured
optically by high resolution spectrometers such as ring resonators. The main reason for lower detection
limit is that the nanophotonic sensors are integrated with the CMOS chip which has a thick passivation
layer and many layers of interlayer dielectrics. These layers can cause signal loss by back reflections
which compromises the performance of the device. The performance of the device can be improved by
removing the passivation layer and by carrying out improvements in the readout circuitry to reduce
the signal to noise ratio. In addition to glycerol, as a proof of concept, the electrical readout of 1 mg/mL
protein deposited on the gold nanodiscs was also shown in this work. Although the nanophotonic
sensors were integrated with the CMOS PD chip by post processing using electron beam lithography
in a non-CMOS clean room, it is a major step forward in developing a compact handheld nanophotonic
sensor system having an integrated readout system.
Sensors 2019, 19, 1715 13 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

(b) (d)
(a)
(f)

(c) (e)

(g)

Figure
Figure 10.Cross
10. (a) (a) Cross section
section schematic
schematic of the
of the complementarymetal
complementary metaloxide
oxidesemiconductor
semiconductor (CMOS)
(CMOS) PD PD
chip chip
with with integrated
integrated goldgold nanodisc
nanodisc array.
array. (b,c)(b,c) Microscopic
Microscopic images
images of theof CMOS
the CMOS PD chip.
PD chip. (b) with
(b) with and
and (c)integrated
(c) without without integrated gold arrays.
gold nanodisc nanodisc arrays.
The Theis PD
PD area area isinencircled
encircled both casesin and
bothhave
casesdimensions
and have
dimensions of only 6 × 8 µm. (d) SEM image of the gold nanodiscs integrated on
of only 6 × 8 µm. (d) SEM image of the gold nanodiscs integrated on top of the CMOS PD chip. (e) SEM top of the CMOS PD
image of the silicon nitride gratings fabricated on top of the CMOS PD chip. (f) Microscopic image(f)
chip. (e) SEM image of the silicon nitride gratings fabricated on top of the CMOS PD chip. of
Microscopic
the silicon nitrideimage of the
gratings silicon nitride
integrated with gratings
the CMOS integrated
PD chipwith the CMOS
having an arrayPDofchip
PDs.having an array
The four dark
of PDs. The four dark areas, one of which is encircled shows silicon nitride gratings. The PD pixels
areas, one of which is encircled shows silicon nitride gratings. The PD pixels between the silicon nitride
between the silicon nitride gratings were used as a reference. (g) Packaged sensor chip connected with
gratings were used as a reference. (g) Packaged sensor chip connected with the laptop with readout
the laptop with readout displayed on the laptop screen. (a–d) reprinted with permission from [74].
displayed on the laptop screen. (a–d) reprinted with permission from [74]. Copyright © American
Copyright © American Chemical Society (ACS) (2016). (e–g) reprinted with permission from [76].
Chemical Society (ACS) (2016). (e–g) reprinted with permission from [76]. Copyright © IEEE (2018).
Copyright © IEEE (2018).
Sensors 2019, 19, 1715 14 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

(a) (b)
Figure 11. Measured changes in the PD output voltage for various glycerol concentrations as detailed in
Figure 11.
Shakoor et Measured changes
al. [74,76]. The blackinstaircase
the PD output
curve isvoltage for various
the readout from the glycerol
PD withconcentrations as detailed
integrated nanophotonic
sensors while the flat red curve corresponds to the readout from the PD with no nanophotonic integrated
in Shakoor et al. [74,76]. The black staircase curve is the readout from the PD with structures.
nanophotonic
(a) Measured PD sensors
voltagewhile thegold
for the flatnanodisc
red curve corresponds
array sensor. (b)to the readout
Measured from the
PD voltage fromPD thewith no
silicon
nanophotonic
nitride grating structures.
sensor. In (a)(a)the
Measured PD PD
data for the voltage
outputforvoltage
the gold nanodisc array
is presented sensor.concentrations
for different (b) Measured
PDglycerol
of voltagewhile
frominthe silicon
(b) the datanitride grating
is presented sensor.
in terms In (a)
of the the data
refractive for the
indices PD output
of different voltage is
concentrations
presented
of glycerol.for
(a)different
reprintedconcentrations
with permission of glycerol
from [74].while in (b) the
Copyright data is presented
© American ChemicalinSociety
terms (ACS)
of the
refractive indices of different concentrations of glycerol.
(2016). (b) reprinted with permission from [76]. Copyright © IEEE (2018). (a) reprinted with permission from [74].
Copyright © American Chemical Society (ACS) (2016). (b) reprinted with permission from [76].
To enable ©real
Copyright IEEEcommercialization
(2018). the concept can be extended to fabricate the nanophotonic
sensors in the CMOS pilot line instead of post processing. Mass production in a CMOS foundry would
reduceTothe
enable real commercialization the concept can be extended to fabricate the nanophotonic
cost considerably.
sensors in the CMOS pilot line instead of post processing. Mass production in a CMOS foundry
3.2.
wouldNanophotonic
reduce theSensors with Compact but Separate Readout System
cost considerably.
Another approach adopted by researchers to develop sensors with compact readout system is
3.2.use
to Nanophotonic Sensors
imagers such with Compact
as CMOS or ChargebutCoupled
Separate Readout System imagers. Following this approach,
Device (CCD)
the need of expensive,
Another approachbulky andby
adopted external equipment
researchers such as
to develop spectrometers
sensors is eliminated.
with compact readout However,
system is
in these approaches the sensor chips and the imagers are separate and need housing
to use imagers such as CMOS or Charge Coupled Device (CCD) imagers. Following this approach, and alignment.
In
thethe following
need sections,
of expensive, an overview
bulky of different
and external efforts
equipment carried
such out to develop
as spectrometers nanophotonic
is eliminated. sensors
However,
with compact
in these readout
approaches system
the sensorbychips
using compact
and imagers
the imagers areisseparate
given. and need housing and alignment.
In the following sections, an overview of different efforts carried out to develop nanophotonic sensors
3.2.1. Nanophotonic Sensor Based on CMOS/CCD Imager for Readout
with compact readout system by using compact imagers is given.
To get rid of the bulky external equipment to measure nanophotonic sensor chips, Cetin et al.
used aNanophotonic
3.2.1. Sensor Based
lens free computational on CMOS/CCD
imaging Imagerthe
system to record fortransmission
Readout response of the plasmonic
nanostructures
To get rid of the bulky external equipment to measure nanophotonic record
[77]. In this work, CMOS/CCD imaging sensor was used to sensor the changes
chips, Cetininetthe
al.
diffraction patterns of the plasmonic nanohole array due to the optical resonance
used a lens free computational imaging system to record the transmission response of the plasmonic wavelength shift.
Following this approach,
nanostructures [77]. In thisa work,
handheld nanophotonic
CMOS/CCD sensing
imaging sensorsystem having
was used 7.5 cm
to record height
the andin60the
changes g
weight was demonstrated. The photograph of the packaged sensor developed in
diffraction patterns of the plasmonic nanohole array due to the optical resonance wavelength shift.this work is shown
in Figure 12a.
Following this The complete
approach, sensor system
a handheld consists sensing
nanophotonic of a battery, LED
system light source,
having plasmonic
7.5 cm height and chip
60 g
consisting of an array of nanoholes and an imager. The battery, LED and the
weight was demonstrated. The photograph of the packaged sensor developed in this work is shownimager are enclosed in
ainhousing while the plasmonic sensor chip is slid into the housing as shown in
Figure 12a. The complete sensor system consists of a battery, LED light source, plasmonic chipFigure 12b. An LED
is used as of
consisting ananexcitation source while
array of nanoholes andthe
an diffraction
imager. Thepatterns
battery,generated
LED and the by imager
the plasmonic modes
are enclosed in
of the nanoholes array are imaged by the CMOS/CCD imaging chip which
a housing while the plasmonic sensor chip is slid into the housing as shown in Figure 12b. An can be bought offLED
the
shelf.
is usedToasenable multiplexed
an excitation sourcemeasurements, an iterative
while the diffraction phasegenerated
patterns retrieval-based
by theimage reconstruction
plasmonic modes of
method
the nanoholes array are imaged by the CMOS/CCD imaging chip which can be boughtsimultaneous
was also employed to reconstruct the overlapped diffraction patterns from off the shelf.
measurements. The reconstructed
To enable multiplexed diffraction
measurements, an patterns
iterative are shown
phase in Figure 12f. image reconstruction
retrieval-based
method was also employed to reconstruct the overlapped diffraction patterns from simultaneous
measurements. The reconstructed diffraction patterns are shown in Figure 12f.
Sensors 2019, 19, 1715 15 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

(a) (b) (e)

(f)
(c) (d)

Figure
Figure12.12.(a)(a)Picture
Pictureofofthe thedeveloped
developed sensing device with
sensing device withsensor
sensorandandimaging
imagingchip chip placed
placed in in compact
compact
housing
housing as presented in Cetin et al. [77]. The total height of the device is only 7.5 cm and weighsweighs
as presented in Cetin et al. [77]. The total height of the device is only 7.5 cm and only
only
60 60
g. g.
(b)(b) Schematic
Schematic showing
showing thethe components
components of of
thethe sensor
sensor system.
system. (c) (c)
SEMSEM image
image of of
thethe metallic
metallic
nanohole
nanohole array.
array. (d)(d)Simulation
Simulationofofthe theplasmon
plasmonresonance
resonanceshowing
showingintense
intense electric
electric field
field at
at the
the edges
edges of
theofholes. (e) Illustration
the holes. (e) Illustration of the numerical
of the numericaltechnique
techniquefor forthe
the reconstruction
reconstruction of ofthe
thediffraction
diffraction patterns
patterns
of of
thethe
nanohole
nanoholearray arrayby byusing
usingthethephase
phase retrieval
retrieval method.
method. (f) (f)Recorded
Recordeddiffraction
diffraction patterns
patterns of of
sixsix
metallic
metallicnanohole
nanoholearrays arrays(top
(topline)
line) and
and the
the reconstructed diffractionimages
reconstructed diffraction imagesbybythe thephase
phase retrieval
retrieval
method
method (bottom
(bottomline). line).The
Thedistance
distancebetween
between the nanohole
nanoholearrayarrayandandthe
theimager
imageris is
2 mm2 mm andandnono lens
lens
waswasused
used to to
focus
focus thethepatterns.
patterns.Reprinted
Reprintedwithwith permission
permission fromfrom[77].
[77].Copyright
Copyright©©CIOMP CIOMP (2014).
(2014).

ToTo
showshowthethe
sensing
sensingperformance
performanceofofthe thedeveloped
developedsensor
sensorsystem,
system,mono
mono (M)(M) and
and bibi (B)
(B) layers
layers of
proteins were were
of proteins detected by recording
detected diffraction
by recording imageimage
diffraction of the of
plasmonic nanostructures.
the plasmonic The binding
nanostructures. The
of binding of 3 nm monolayer
3 nm monolayer induced induced
a 6 nm red a 6 nm
shiftred ofshift of the resonance
the resonance wavelength
wavelength whilewhile
an 11annm 11 nm bi
bi layer
layer
gave gave
a 17 nmashift
17 nm shift as measured
as measured by the spectrum
by the spectrum analyzer.
analyzer. As the
As the LED LED emission
emission was matched
was matched with the
with theresponse
resonance resonance response
of the of the
plasmonic plasmonic
nanoholes nanoholes
array, array, the
the diffraction diffraction
pattern pattern from
from unfunctionalized
unfunctionalized plasmonic array was bright, as the maximum
plasmonic array was bright, as the maximum intensity was recorded at resonance intensity was recorded at wavelength.
resonance
Thewavelength.
greater theThe greater the
resonance resonance
shift shift due to of
due to deposition deposition
the proteinof the protein
layer layer the
the darker thedarker the
diffraction
diffraction pattern gets, as shown in Figure 13b, where the diffraction pattern from
pattern gets, as shown in Figure 13b, where the diffraction pattern from bi layer is darker compared bi layer is darker
to compared
mono layer to mono
whichlayer which
in turn in turn is
is darker darker
than the than the unfunctionalized
unfunctionalized array. array. The quantification
The quantification of the
of the protein concentration was carried out by comparing the relative intensity change of the
protein concentration was carried out by comparing the relative intensity change of the diffraction
diffraction patterns with the optical resonance shift measured by an OSA. The optical sensitivity of
patterns with the optical resonance shift measured by an OSA. The optical sensitivity of the system
the system was measured to be 621 nm/RIU, while the minimum relative intensity of the diffraction
was measured to be 621 nm/RIU, while the minimum relative intensity of the diffraction pattern
pattern was estimated as 0.024 which corresponds to a 3 nm wavelength shift for the analyte
was estimated as 0.024 which corresponds to a 3 nm wavelength shift for the analyte concentration
concentration in the order of µg/mL. The demonstrated sensor system has the potential of
in improvement
the order of µg/mL. The demonstrated
in the detection limit by usingsensor system
a narrower has theincident
linewidth potential ofsource
light improvement
and a higher in the
detection limit by
performance CMOSusingimager.
a narrower
This linewidth
work usesincident
a smart light sourcetoand
technique a higher
record performance
the molecular CMOS
binding
imager. This work uses a smart technique to record the molecular binding instances.
instances. However, the quantification of the measured species still requires the comparison with the However,
theoptical
quantification
wavelength of the
shiftmeasured species
and therefore stilldependent
is still requires the comparison
on using externalwith
bulkythe optical wavelength
equipment.
shift and therefore is still dependent on using external bulky equipment.
Sensors 2019, 19, 1715 16 of 26
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25

(a) (b)

(c) (d)

Figure13.13.Experimental
Figure Experimentalresultsresultsdetailed
detailedininCetin
Cetinetetal.al.[77].
[77].(a)(a)Schematic
Schematicofofthe
theperformed
performedprotein
protein
assay.
assay.(b)
(b)Recorded
Recordedlenslensfree
freediffraction
diffractionpatterns
patternsofofthethebarebarenanohole
nanoholearray
array(top)
(top)and
andwhen
whenmono
mono
(0.5%
(0.5%v/v
v/vBSA)
BSA)and
andbibilayer
layerprotein
protein(0.5 mg/mL
(0.5 mg/mL protein
protein A/G A/G + +0.50.5mg/mL
mg/mLprotein
proteinIgG)
IgG)were
weredeposited
deposited
ononthe metallic
the nanoholes
metallic nanoholes array (bottom).
array (bottom). (c) (c)
Wavelength
Wavelength shiftshift
when monomono
when and biand
layers of protein
bi layers were
of protein
deposited on the metallic
were deposited on the nanohole array (measured
metallic nanohole by an OSA).
array (measured by(d)anPeak
OSA).wavelength shift estimated
(d) Peak wavelength shift
from the lens free diffraction image patterns by relating resonance wavelength shift
estimated from the lens free diffraction image patterns by relating resonance wavelength shift measured measured by the
OSA shown
by the OSAinshown
(c) andinrelative
(c) and intensity difference
relative intensity of the diffraction
difference patternspatterns
of the diffraction when mono whenandmonobi layer
and bi
proteins are deposited
layer proteins shown in
are deposited (b). Reprinted
shown with permission
in (b). Reprinted from [77].
with permission Copyright
from © CIOMP
[77]. Copyright © (2014).
CIOMP
(2014).
3.2.2. Self-Readout of Nanophotonic Sensor Based on Chirped Gratings and Camera
3.2.2.
ToSelf-Readout
develop a portableof Nanophotonic
nanophotonic Sensor Based
sensor, on Chirped
Triggs Gratings
et al., took a novel and Camera
route of utilizing chirped
resonant gratings [78]. The chirped resonant gratings were designed
To develop a portable nanophotonic sensor, Triggs et al., took a novel route of in such a way that they not
utilizing only
chirped
gave the resonance
resonant gratings response
[78]. Thebut also translated
chirped the generated
resonant gratings resonancein
were designed signal
suchinto
a wayspatial
that information,
they not only
which was read out by simple optical elements such as lens and a CCD
gave the resonance response but also translated the generated resonance signal into spatial camera.
On illuminating
information, which was the gratings
read out with polarized
by simple opticaland collimated
elements suchlight from
as lens thea top,
and CCDa camera.
guided mode
resonance was excited which
On illuminating gave rise
the gratings withto apolarized
reflectance/transmission
and collimated light peak from
at thethe
resonance wavelength
top, a guided mode
ofresonance
the designed was excited which gave rise to a reflectance/transmission peak at the change
structures. Similar to conventional gratings or resonant structures, the resonancein
the refractive of
wavelength index of the surrounding
the designed structures. owing
Similartotomolecular
conventional binding events
gratings induced astructures,
or resonant shift in the the
resonance
change in the refractive index of the surrounding owing to molecular binding events inducedina the
peak. However, in this work instead of using an external spectrometer, the change shift
resonance was measured
in the resonance by chirped
peak. However, in gratings
this workitself by making
instead of usingthe anresonance wavelength athe
external spectrometer, function
change
ofinthe
theexcitation
resonance area
was ofmeasured
the gratings. The gratings
by chirped wereitself
gratings chirped by tuning
by making thethe fill factor
resonance (FF) of the a
wavelength
gratings.
functionThe systematic
of the excitation tuning
area ofof the
the gratings.
FF was performed
The gratings by varying
were chirpedthe dose of the e-beam
by tuning the fill exposure
factor (FF)
during fabrication. The sensor was composed of a set of grating strips
of the gratings. The systematic tuning of the FF was performed by varying the dose of the e-beam each having dimensions of
µm × 500during
6 exposure µm. The chirped resonant
fabrication. The sensor gratings were designed
was composed of a andset fabricated
of grating on a 150
strips nm having
each thick
silicon nitride layer on a glass slide and had a period and fill factor of
dimensions of 6 µm × 500 µm. The chirped resonant gratings were designed and fabricated on a 150 560 nm and 0.7 respectively.
The
nmschematic of the
thick silicon chirped
nitride grating
layer on a sensor is shown
glass slide and in hadFigure 14. and fill factor of 560 nm and 0.7
a period
respectively. The schematic of the chirped grating sensor is shownpost
The estimation of the change in the refractive index involved processing
in Figure 14. of the measured
reflection image of the grating. On illuminating the chirped grating
The estimation of the change in the refractive index involved post processing array with monochromatic light,
of the measured
only a smallimage
reflection part ofof the
the horizontal
grating. Ongrating strip resonates
illuminating the chirped and thus reflection
grating array withoccurs from only that
monochromatic light,
localized region, whose intensity was recorded by the CCD camera.
only a small part of the horizontal grating strip resonates and thus reflection occurs from only that
localized region, whose intensity was recorded by the CCD camera.
Sensors 2019,19,
Sensors2019, 19,1715
x FOR PEER REVIEW 17
25of
of26
25
Sensors 2019, 19, x FOR PEER REVIEW 25 of 25
(a) (b)
(a) (b)

Figure 14. (a) Reflectance spectrum of standard rectangular gratings. (b) Schematic of chirped
Figure
Figure 14.
gratings. (a)
14.To Reflectance
(a)induce spectrum
chirping,
Reflectance of factor
the fill
spectrum standardwasrectangular
of standard changed gratings.
along
rectangular the (b)direction
Y Schematic
gratings. of chirped
which
(b) Schematic of gratings.
created a set of
chirped
To induce
rectangular
gratings. chirping, the
strips each
To induce fill factor
having
chirping, was changed
thedifferent fillwas
fill factor along
factors the Y direction
alongalong
changed which
the Y-direction. created a
Reprinted
the Y direction set
which fromof rectangular
created[78] under
a set of
strips
CC BY each
4.0.having
rectangular different
strips each havingfill factors
different along the Y-direction.
fill factors along theReprinted from
Y-direction. [78] under
Reprinted CC[78]
from BY 4.0.
under
CC BY 4.0.
The resonance position was then extracted by averaging and curve fitting to the measured
The resonance position was then extracted by averaging and curve fitting to the measured
intensity profile. A matlab code was used to perform the averaging and fitting operations. Any change
intensity profile. A position
The resonance matlab code was used
was then to perform
extracted the averaging
by averaging and curveandfitting
fittingtooperations.
the measuredAny
in the refractive index due to binding events at the grating was quantified by using only a camera to
change inprofile.
intensity the refractive
A matlabindex due
code to binding
was used to events
perform at the
the averaging
grating wasandquantified by using only
fitting operations. Anya
measure the reflection intensity, a simple monochromatic light source to excite the gratings and image
camerain
change to the
measure the reflection
refractive index due intensity, a simple
to binding eventsmonochromatic
at the grating light source to excite
was quantified the gratings
by using only a
post-processing algorithm. The reflection image from the gratings immersed in water and extraction of
and image
camera post-processing
to measure algorithm.
the reflection Theareflection
intensity, image from thelight
simple monochromatic gratings
sourceimmersed
to excite in
thewater and
gratings
the wavelength position by curve fitting is shown in Figure 15.
extraction
and of the wavelength
image post-processing position The
algorithm. by curve fitting
reflection is shown
image fromin Figure
the 15. immersed in water and
gratings
extraction of the wavelength position by curve fitting is shown in Figure 15.
(a) (b) (c) (d)
(a) (b) (c) (d)

Figure15.
Figure 15.Experimental
Experimentalresults
resultspresented
presentedin inTriggs
Triggsetetal. al.[78].
[78].(a)
(a)Resonance
Resonancewavelength
wavelengthmap mapwhen
when
waterisis
water
Figure 15.surrounding
surrounding
Experimental theresults
the gratings.
gratings. (b)Measured
(b) Measured
presented in Triggs brightfield
brightfield image
image
et al. [78]. ofthe
of thegratings
(a) Resonance gratings whenexcited
when
wavelength excited
map when byaa
by
monochromatic
monochromatic
water light
lightsource.
is surrounding source.
the (c)
(c)Intensity
gratings. Intensity profile
profileof
(b) Measured ofthe
themeasured
brightfield imageresonance
measured resonance brightfield
of the gratings whenimage
brightfield image shown
excitedshown
by a
in
in(b).
(b).The
Theintensity
monochromatic lightprofile
intensity profile
source. isis(c)
averaged
averaged
Intensityand
and normalized.
normalized.
profile The
Thechange
of the measured change in
inrefractive
resonancerefractive index
indexof
brightfield ofthe
thegrating
image grating
shown
cladding
in (b). Theinduces
cladding induces shift
intensityshift in
inthe
profile ispeak
the peak position
andof
position
averaged ofthe
theintensity
intensity
normalized. Theprofile.
profile.
change (d)inShift
(d) Shift in
inthe peak
peakposition
theindex
refractive position when
when
of the grating
the refractive
the refractive
cladding index
index
induces is
shift changed
is in
changed
the peak by introducing
byposition
introducing different
of thedifferent
intensity concentrations
concentrations of
profile. (d) Shift glycerol.
of glycerol.
in the peak Water
Water was added
was added
position when
after
after
the each
each concentration
refractive index is changedmeasurement,
measurement, whichmoved
which
by introducing movedthe
different the peak
peak position
position
concentrations back
back
of to the
to the
glycerol. original
original
Water value
value
was (0%
added
(0%
after glycerol).
glycerol). Reprinted
Reprinted
each concentration from from
[78][78] under
under
measurement, CC CC
BY BY
which 4.0. 4.0. the peak position back to the original value (0%
moved
glycerol). Reprinted from [78] under CC BY 4.0.
Since, this device works on measuring the spatial shift, the sensitivity value obtained by the
sensor system
Since, was quoted
this device worksinonterms of position
measuring shift/RIU
the spatial shift,rather than the value
the sensitivity resonance wavelength
obtained by the
shift/RIU.
sensor The sensitivity
system was quoted value in terms
in terms of of positionshift/RIU
position change per/RIU was reported
rather than to be 3469
the resonance µm/RIU,
wavelength
while the The
shift/RIU. limitsensitivity
of detection value
value was reported
in terms as 2.37
of position × 10per/RIU
change −4. was reported to be 3469 µm/RIU,
whileMicrofluidic channelsvalue
the limit of detection werewasfabricated
reportedtoasperform
2.37 × 10the
−4 . IgG binding assay. Two microfluidic
channels were created,
Microfluidic onewere
channels for the measurements
fabricated and the
to perform the other for the reference.
IgG binding assay. Two Themicrofluidic
shift in the
resonancewere
channels position as aone
created, function of measurements
for the time for both measurement
and the otherand for reference channels
the reference. is shown
The shift in
in the
resonance position as a function of time for both measurement and reference channels is shown in
Sensors 2019, 19, 1715 18 of 26

Since, this device works on measuring the spatial shift, the sensitivity value obtained by the sensor
system was quoted in terms of position shift/RIU rather than the resonance wavelength shift/RIU.
The sensitivity value in terms of position change per/RIU was reported to be 3469 µm/RIU, while the
limit of detection value was reported as 2.37 × 10−4 .
Microfluidic channels were fabricated to perform the IgG binding assay. Two microfluidic channels
Sensors 2019, 19, xone
were created, FORfor
PEER REVIEW
the 25 of 25
measurements and the other for the reference. The shift in the resonance
position as a function of time for both measurement and reference channels is shown in Figure 16.
Figure 16. From the experimental results, the detection limit for the IgG assay was estimated to be
From the experimental results, the detection limit for the IgG assay was estimated to be 40 ng/mL.
40 ng/mL. The estimated cost of the components used in this sensing system is relatively low at only
The estimated cost of the components used in this sensing system is relatively low at only U.S $10 and
U.S $10 and hence holds the potential of providing cheap portable sensors for point-of-care healthcare
hence holds the potential of providing cheap portable sensors for point-of-care healthcare applications.
applications.

Figure 16. Schematic of the microfluidic channels integrated with the guided mode resonance (GMR)
Figure 16. Schematic of the microfluidic channels integrated with the guided mode resonance (GMR)
chirped grating sensor to apply the analyte as presented in Triggs et al. [78]. Two channels were formed
chirped grating sensor to apply the analyte as presented in Triggs et al. [78]. Two channels were
which allowed introducing the analyte in one channel while second channel acted as a reference.
formed which allowed introducing the analyte in one channel while second channel acted as a
The graph shows the measurement results (shift in the resonance position versus time) for the IgG
reference. The graph shows the measurement results (shift in the resonance position versus time) for
assay performed on the GMR chirped grating sensors. Curves for both measurement (upper curve)
the IgG assay performed on the GMR chirped grating sensors. Curves for both measurement (upper
and the reference (lower curve) channels are given with each assay step indicated on the top of the
curve) and the reference (lower curve) channels are given with each assay step indicated on the top
graph. Reprinted from [78] under CC BY 4.0.
of the graph. Reprinted from [78] under CC BY 4.0.
4. Summary
4. Summary
The summary of the performance of the various onchip nanophotonic sensors having compact
Thesystem
readout summary of the performance
as discussed of the
in this article various
is given onchip
in Table 1. nanophotonic sensors having compact
readout system as discussed in this article is given in Table 1.
Sensors 2019, 19, 1715 19 of 26

Table 1. Summary of onchip nanophotonic sensors having compact readout system.

Output of Integrated Detection
References Device Integration Analyte Optical Sensitivity
System Limit
Mazzotta Gold nanodiscs integrated 0.008 V change between Ref
Monolithic Glycerol 133 nm/RIU 0.01 RIU
et al. [68] with bulk PD and analyte
Gold nanohole array
Guyot et al.
integrated with Si Monolithic Ethanol N.A 0.8 V/RIU 1.75 × 10−4
[69]
photodetector
Gold wire gratings
Perino et al.
integrated with Si Monolithic Dodecanethiol N.A 2.94 a.u/ RIU 2.2 × 10−4
[71]
photodetector
Turker et al. Silver coated polymer NaCl
Monolithic N.A 0.6 mA/RIU
[72] gratings Solution
Augel et al. Aluminum hole array DI, water,
Monolithic N.A 1180 nm/RIU N.A
[73] integrated with Ge PD IPA
Gold nanodiscs:
Gold nanodiscs and silicon Gold nanodiscs: 5.6 V/RIU,
Shakoor et al. Glycerol and 270nm /RIU,
nitride gratings integrated Monolithic Silicon nitride gratings: 6.75 3 × 10−3
[74,76] protein Silicon nitride
with CMOS PD V/RIU
gratings: 160 nm/RIU
0.024 relative intensity
Cetin et al. Gold nanohole array Not
Protein 621 nm/RIU change of diffraction 1 µg/mL
[77] readout with CMOS imager monolithic
pattern
Triggs et al. Chirped resonance gratings Not Glycerol and 3469 µm/RIU spatial shift 2.37 × 10−4 ,
137 nm/RIU
[78] read by camera monolithic IgG (not wavelength shift) 40 ng/mL

5. Conclusions and Outlook

In conclusion, integrated nanophotonic structures have shown their potential for developing
compact and high-performance sensors, i.e., which have high sensitivity and low detection limit,
demonstrated by proof of concept laboratory based experiments. These sensors are made of different
materials such as metals, semiconductors or dielectrics and generally require external bulky and
expensive equipment for their measurement. The lack of compact measuring systems for onchip
nanophotonic sensors has so far hindered their widespread application. In order, therefore, to transform
nanophotonic sensors from a laboratory-based research topic to practical devices usable in everyday
life, it is important to develop a compact and preferably integrated measurement system. Recognizing
the importance of the need of a compact readout system, the efforts to develop a miniaturized
measurement mechanism have been accelerated in the last few years with different approaches being
followed. One approach is to monolithically integrate nanophotonic sensors with the photodetectors
so that the resonance wavelength shift of the nanophotonic structures is read out as an electrical signal
which can be interfaced with a portable gadget such as smart phone or tablet. Research that is following
this approach has led to reports of integrating nanophotonic sensors with bulk silicon PDs, germanium
PDs, and miniaturized PDs made by the CMOS technology in commercial foundries. Owing to the
fact that CMOS technology has revolutionized the electronics and digital market, the monolithic
integration of nanophotonic sensors with the PDs made by CMOS technology holds great promise
for commercialization of nanophotonic sensors. In the reported work, the authors have integrated
nanophotonic sensors with the CMOS PDs as a post processing in non-CMOS clean room; but the
real commercialization opportunity lies in the complete fabrication of the sensor system in the CMOS
commercial foundry. The large-scale production of the integrated sensor system in CMOS foundries
will reduce the unit cost considerably. One major challenge to improving the performance of the
CMOS integrated nanophotonic sensors is to reduce the back-reflection of the signal arising from
different layers of the CMOS chip and to reduce the distance between the nanophotonic sensor and
the underlying PD layer. Another approach that has been adopted by different groups to develop a
compact readout mechanism for nanophotonic sensors is where a separate, yet small, imaging chip
is used to read the output signal from the nanophotonic structures. Using an imaging chip such as a
CMOS or CCD device to map the transmission response of the nanophotonic structures eliminates
the need of external bulky and expensive laboratory-based equipment. However, as opposed to the
monolithic integration approach, a housing is required to hold and align the nanophotonic sensor
chip and the imaging chip and also a rigorous and computationally demanding post processing
Sensors 2019, 19, 1715 20 of 26

algorithm is necessary to obtain meaningful results. A summary of the performance of the various
on-chip nanophotonic sensors that have a compact readout system is given in Table 1. The results
presented in various works discussed in this article are highly dependent on the device used for the
readout. For example, in the approach of monolithic integration of nanophotonic sensors with the
PDs, the output signal depends highly on the responsivity and noise of the PD and the gain of the
electronic readout circuitry. Similarly, in the approach, where separate CCD/CMOS imagers are used,
the results also depend on the performance of the imager. In essence, both approaches have eliminated
the need to use external and usually bulky equipment and therefore present a significant step towards
developing practical nanophotonic sensors, enabling their application in everyday life. The work
discussed in this review article has shown the sensing performance of several devices using basic
analytes such as different concentrations of solutions or basic protein functionalization. We confidently
expect that future design improvements to optimize the readout circuitry will improve performance
of the sensor systems to such an extent that it will be possible to address clinically relevant analytes.
By so doing, portable nanophotonic sensors will be used to target the diagnosis of many diseases
including cancers and Alzheimer disease.

Funding: This work was supported by the Engineering and Physical Sciences Research Council, U.K., under
Grant EP/K021966/1. The work of M. Grande was supported by Fondo di Sviluppo e Coesione 2007–2013–APQ
Ricerca Regione Puglia “Programma regionale a sostegno della specializzazione intelligente e della sostenibilita
sociale ed ambientale–FutureInResearch” (7K76VI3).
Conflicts of Interest: The authors declare no conflict of interests.

References
1. Tokel, O.; Inci, F.; Demirci, U. Advances in plasmonic technologies for point of care applications. Chem. Rev.
2014, 114, 5728–5752. [CrossRef]
2. Brolo, A.G. Plasmonics for future biosensors. Nat. Photonics 2012, 6, 709–713. [CrossRef]
3. Joshi, G.K.; Deitz-McElyea, S.; Johnson, M.; Mali, S.; Korc, M.; Sardar, R. Highly specific plasmonic biosensors
for ultrasensitive micro-RNA detection in plasma from pancreatic cancer patients. Nano Lett. 2014, 14,
6955–6963. [CrossRef] [PubMed]
4. Brolo, A.G.; Gordon, R.; Leathem, B.; Kavanagh, K.L. Surface plasmon sensor based on the enhanced light
transmission through arrays of nanoholes in gold films. Langmuir 2004, 20, 4813–4815. [CrossRef] [PubMed]
5. De Leebeeck, A.; Kumar, L.K.S.; de Lange, V.; Sinton, D.; Gordon, R.; Brolo, A.G. On-chip surface-based
detection with nanohole arrays. Anal. Chem. 2007, 79, 4094–4100. [CrossRef]
6. Lee, K.L.; Lee, C.W.; Wang, W.S.; Wei, P.K. Sensitive biosensor array using surface plasmon resonance on
metallic nanoslits. J. Biomed. Opt. 2007, 12, 044023. [CrossRef]
7. Sreekanth, K.V.; Alapan, Y.; ElKabbash, M.; Ilker, E.; Hinczewski, M.; Gurkan, U.A.; Luca, A.D.; Strangi, G.
Extreme sensitivity biosensing platform based on hyperbolic metamaterials. Nat. Mater. 2016, 15, 621–627.
[CrossRef]
8. Sreekanth, K.V.; Alapan, Y.; ElKabbash, M.; Wen, A.M.; Ilker, E.; Hinczewski, M.; Gurkan, U.A.;
Steinmetz, N.F.; Strangi, G. Enhancing the Angular Sensitivity of Plasmonic Sensors Using Hyperbolic
Metamaterials. Adv. Opt. Mater. 2016, 4, 1767–1772. [CrossRef]
9. Khanikev, A.B.; Wu, C.; Shevets, G. Fano-resonant metamaterials and their applications. Nanophotonics 2013,
2, 247–264. [CrossRef]
10. Luk’yanchuk, B.; Zheludev, N.I.; Maier, S.A.; Halas, N.J.; Nordlander, P.; Giessen, H.; Chong, C.T. The Fano
resonance in plasmonic nanostructures and metamaterials. Nat. Mater. 2010, 9, 707–715. [CrossRef] [PubMed]
11. Schipper, E.; Brugman, A.; Dominguez, C.; Lechuga, L.; Kooyman, R.; Greve, J. The realization of an
integrated Mach–Zehnder waveguide immunosensor in silicon technology. Sens. Actuators B Chem. 1997, 40,
147–153. [CrossRef]
12. Heideman, R.; Kooyman, R.; Greve, J. Performance of a highly sensitive optical waveguide Mach–Zehnder
interferometer immunosensor. Sens. Actuators B Chem. 1993, 10, 209–217. [CrossRef]
Sensors 2019, 19, 1715 21 of 26

13. Crespi, A.; Gu, Y.; Ngamsom, B.; Hoekstra, H.J.; Dongre, C.; Pollnau, M.; Ramponi, R.; van den Vlekkert, H.H.;
Watts, P.; Cerullo, G.; et al. Three-dimensional Mach–Zehnder interferometer in a microfluidic chip for
spatially-resolved label-free detection. Lab Chip 2010, 10, 1167–1173. [CrossRef] [PubMed]
14. Shew, B.; Cheng, Y.; Tsai, Y. Monolithic SU-8 micro-interferometer for biochemical detections. Sens. Actuators
A Phys. 2008, 141, 299–306. [CrossRef]
15. Baehr-Jones, T.; Hochberg, M.; Walker, C.; Scherer, A. High-Q optical resonators in silicon-on-insulator-based
slot waveguides. Appl. Phys. Lett. 2005, 86, 081101. [CrossRef]
16. Barrios, C.A.; Gylfason, K.B.; Sánchez, B.; Griol, A.; Sohlström, H.; Holgado, M.; Casquel, R. Slot-waveguide
biochemical sensor. Opt. Lett. 2007, 32, 3080–3082. [CrossRef] [PubMed]
17. Taniguchi, T.; Hirowatari, A.; Ikeda, T.; Fukuyama, M.; Amemiya, Y.; Kuroda, A.; Yokoyama, S. Detection of
antibody-antigen reaction by silicon nitride slot-ring biosensors using protein G. Opt. Commun. 2016, 365,
16–23. [CrossRef]
18. Di Falco, A.; O’faolain, L.; Krauss, T. Chemical sensing in slotted photonic crystal heterostructure cavities.
Appl. Phys. Lett. 2009, 94, 063503. [CrossRef]
19. Ksendzov, A.; Lin, Y. Integrated optics ring-resonator sensors for protein detection. Opt. Lett. 2005, 30,
3344–3346. [CrossRef]
20. Krioukov, E.; Klunder, D.; Driessen, A.; Greve, J.; Otto, C. Sensor based on an integrated optical microcavity.
Opt. Lett. 2002, 27, 512–514. [CrossRef]
21. Armani, A.M.; Vahala, K.J. Heavy water detection using ultra-high-Q microcavities. Opt. Lett. 2006, 31,
1896–1898. [CrossRef]
22. Wu, C.; Khanikaev, A.B.; Adato, R.; Arju, N.; Yanik, A.A.; Altug, H.; Shvets, G. Fano-resonant asymmetric
metamaterials for ultrasensitive spectroscopy and identification of molecular monolayers. Nat. Mater. 2012,
11, 69–75. [CrossRef]
23. Kabashin, A.V.; Evans, P.; Pastkovsky, S.; Hendren, W.; Wurtz, G.A.; Atkinson, R.; Pollard, R.; Podolskiy, V.A.;
Zayats, A.V. Plasmonic nanorod metamaterials for biosensing. Nat. Mater. 2009, 8, 867–871. [CrossRef]
24. Brandenburg, A.; Krauter, R.; Künzel, C.; Stefan, M.; Schulte, H. Interferometric sensor for detection of
surface-bound bioreactions. Appl. Opt. 2000, 39, 6396–6405. [CrossRef]
25. Schmitt, K.; Schirmer, B.; Hoffmann, C.; Brandenburg, A.; Meyrueis, P. Interferometric biosensor
based on planar optical waveguide sensor chips for label-free detection of surface bound bioreactions.
Biosens. Bioelectron. 2007, 22, 2591–2597. [CrossRef]
26. Im, H.; Shao, H.; Park, Y.I.; Peterson, V.M.; Castro, C.M.; Weissleder, R.; Lee, H. Label-free detection and
molecular profiling of exosomes with a nano-plasmonic sensor. Nat. Biotechnol. 2014, 32, 490–495. [CrossRef]
27. Fernández, F.; Hegnerová, K.; Piliarik, M.; Sanchez-Baeza, F.; Homola, J.; Marco, M.P. A label-free and
portable multichannel surface plasmon resonance immunosensor for on site analysis of antibiotics in milk
samples. Biosens. Bioelectron. 2010, 26, 1231–1238. [CrossRef]
28. Piliarik, M.; Bocková, M.; Homola, J. Surface plasmon resonance biosensor for parallelized detection of
protein biomarkers in diluted blood plasma. Biosens. Bioelectron. 2010, 26, 1656–1661. [CrossRef]
29. Haes, A.J.; Zou, S.; Zhao, J.; Schatz, G.C.; Van Duyne, R.P. Localized Surface Plasmon Resonance Spectroscopy
near Molecular Resonances. J. Am. Chem. Soc. 2006, 128, 10905–10914. [CrossRef]
30. Anker, J.N.; Hall, W.P.; Lyandres, O.; Shah, N.C.; Zhao, J.; Van Duyne, R.P. Biosensing with Plasmonic
Nanosensors. Nat. Mater. 2008, 7, 442–453. [CrossRef]
31. Lesuffleur, A.; Im, H.; Lindquist, N.C.; Lim, K.S.; Oh, S.H. Laser-illuminated nanohole arrays for multiplex
plasmonic microarray sensing. Opt. Express 2008, 16, 219–224. [CrossRef]
32. Fernández Gavela, A.; Grajales García, D.; Ramirez, J.; Lechuga, L. Last advances in silicon-based optical
biosensors. Sensors 2016, 16, 285. [CrossRef]
33. Zinoviev, K.E.; González-Guerrero, A.B.; Domínguez, C.; Lechuga, L.M. Integrated bimodal waveguide
interferometric biosensor for label-free analysis. J. Lightwave Technol. 2011, 29, 1926–1930. [CrossRef]
34. Densmore, A.; Xu, D.X.; Janz, S.; Waldron, P.; Mischki, T.; Lopinski, G.; Delâge, A.; Lapointe, J.;
Cheben, P.; Lamontagne, B.; et al. Spiral-path high-sensitivity silicon photonic wire molecular sensor
with temperature-independent response. Opt. Lett. 2008, 33, 596–598. [CrossRef]
35. De Vos, K.; Bartolozzi, I.; Schacht, E.; Bienstman, P.; Baets, R. Silicon-on-Insulator microring resonator for
sensitive and label-free biosensing. Opt. Express 2007, 15, 7610–7615. [CrossRef]
Sensors 2019, 19, 1715 22 of 26

36. Ciminelli, C.; Dell’Olio, F.; Conteduca, D.; Campanella, C.; Armenise, M. High performance SOI microring
resonator for biochemical sensing. Opt. Laser Technol. 2014, 59, 60–67. [CrossRef]
37. Lee, M.R.; Fauchet, P.M. Two-dimensional silicon photonic crystal based biosensing platform for protein
detection. Opt. Express 2007, 15, 4530–4535. [CrossRef]
38. Lee, S.; Eom, S.C.; Chang, J.S.; Huh, C.; Sung, G.Y.; Shin, J.H. Label-free optical biosensing using a horizontal
air-slot SiNx microdisk resonator. Opt. Express 2010, 18, 20638–20644. [CrossRef]
39. Tu, X.; Song, J.; Liow, T.Y.; Park, M.K.; Yiying, J.Q.; Kee, J.S.; Yu, M.; Lo, G.Q. Thermal independent
silicon-nitride slot waveguide biosensor with high sensitivity. Opt. Express 2012, 20, 2640–2648. [CrossRef]
40. Liu, Q.; Tu, X.; Kim, K.W.; Kee, J.S.; Shin, Y.; Han, K.; Yoon, Y.J.; Lo, G.Q.; Park, M.K. Highly sensitive
Mach-Zehnder interferometer biosensor based on silicon nitride slot waveguide. Sens. Actuators B Chem.
2013, 188, 681–688. [CrossRef]
41. Chao, C.Y.; Fung, W.; Guo, L.J. Polymer microring resonators for biochemical sensing applications. IEEE J.
Sel. Top. Quantum Electron. 2006, 12, 134–142. [CrossRef]
42. Girault, P.; Lorrain, N.; Poffo, L.; Guendouz, M.; Lemaitre, J.; Carré, C.; Gadonna, M.; Bosc, D.; Vignaud, G.
Integrated polymer micro-ring resonators for optical sensing applications. J. Appl. Phys. 2015, 117, 104504.
[CrossRef]
43. Tetz, K.A.; Pang, L.; Fainman, Y. High-resolution surface plasmon resonance sensor based on
linewidth-optimized nanohole array transmittance. Opt. Lett. 2006, 31, 1528–1530. [CrossRef]
44. Zafar, R.; Salim, M. Enhnaced figure of merit in Fano resonance-based plasmonic refractive index sensor.
IEEE Sens. J. 2015, 15, 6313–6316. [CrossRef]
45. Bao, K.; Mirin, N.A.; Nordlander, P. Fano resonances in planar silber nanosphere clusters. Appl. Phys. A 2010,
100, 333–339. [CrossRef]
46. Mirin, N.A.; Bao, K.; Nordlander, P. Fano resonances in plasmonic nanoparticle aggregates. J. Phys. Chem. A
2009, 113, 4028–4034. [CrossRef]
47. Luan, E.; Yun, H.; Laplatine, L.; Dattner, Y.; Ratner, D.M.; Cheung, K.; Chrostowski, L. Enhanced sensitivity
of sub-wavelength multi-box waveguide microring resonator label-free biosensor. IEEE J. Sel. Top. Quantum
Electron. 2019, 25, 1–11. [CrossRef]
48. Armani, A.M.; Kulkarni, R.P.; Fraser, S.E.; Flagan, R.C.; Vahala, K.J. Label-free, single-molecule detection
with optical microcavities. Science 2007, 317, 783–787. [CrossRef]
49. Grist, S.M.; Schmidt, S.A.; Flueckiger, J.; Donzella, V.; Shi, W.; Fard, S.T.; Kirk, J.T.; Ratner, D.M.; Cheung, K.C.;
Chrostowski, L. Silicon photonic micro-disk resonators for label-free biosensing. Opt. Express 2013, 21,
7994–8006. [CrossRef]
50. Zlatanovic, S.; Mirkarimi, L.W.; Sigalas, M.M.; Bynum, M.A.; Chow, E.; Robotti, K.M.; Burr, G.W.; Esener, S.;
Grot, A. Photonic crystal microcavity sensor for ultracompact monitoring of reaction kinetics and protein
concentration. Sens. Actuators B 2009, 141, 13–19. [CrossRef]
51. Dorfner, D.; Zabel, T.; Hurlimann, T.; Hauke, N.; Frandsen, L.; Rant, U.; Abstreiter, G.; Finley, J. Photonic
crystal nanostructures for optical biosensing applications. Biosens. Bioelectron. 2009, 24, 3688–3692. [CrossRef]
52. Mandal, S.; Serey, X.; Erickson, D. Nanomanipulation using silicon photonic crystal resonators. Nano Lett.
2009, 10, 99–104. [CrossRef]
53. Shi, Y.; Ma, K.; Dai, D. Sensitivity Enhancement in Si Nanophotonic Waveguides Used for Refractive Index
Sensing. Sensors 2016, 16, 324. [CrossRef]
54. Barrios, C.A. Optical Slot-Waveguide Based Biochemical Sensors. Sensors 2009, 9, 4751–4765. [CrossRef]
55. Mukundan, H.; Anderson, A.S.; Grace, W.K.; Grace, K.M.; Hartman, N.; Martinez, J.S.; Swanson, B.I.
Waveguide-Based Biosensors for Pathogen Detection. Sensors 2009, 9, 5783–5809. [CrossRef]
56. Dell’Olio, F.; Passaro, V.M. Optical Sensing by Optimized Silicon Slot Waveguides. Opt. Express 2007, 15,
4977. [CrossRef]
57. Gonzalez-Guerrero, A.B.; Osmond, J.; Zinoviev, K.; Sepulveda, B.; Dominguez, C.; Dante, S.; Duval, D.;
Lechuga, L.M. Towards a complete lab-on-chip system using integrated Mach-Zehnder interferometers.
Opt. Pure Appl. 2012, 45, 87–95.
58. Heideman, R.; Kooyman, R.; Greve, J. Development of an optical waveguide interferometric immunosensor.
Sens. Actuators B Chem. 1991, 4, 297–299. [CrossRef]
Sensors 2019, 19, 1715 23 of 26

59. Heideman, R.; Lambeck, P. Remote opto-chemical sensing with extreme sensitivity: Design, fabrication
and performance of a pigtailed integrated optical phase-modulated Mach–Zehnder interferometer system.
Sens. Actuators B Chem. 1999, 61, 100–127. [CrossRef]
60. Jugessur, A.; Dou, J.; Aitchison, J.; De La Rue, R.; Gnan, M. A photonic nano-Bragg grating device integrated
with microfluidic channels for bio-sensing applications. Microelectron. Eng. 2009, 86, 1488–1490. [CrossRef]
61. Prabhathan, P.; Murukeshan, V.; Jing, Z.; Ramana, P.V. Compact SOI nanowire refractive index sensor using
phase shifted Bragg grating. Opt. Express 2009, 17, 15330–15341. [CrossRef]
62. Schmid, J.H.; Sinclair, W.; García, J.; Janz, S.; Lapointe, J.; Poitras, D.; Li, Y.; Mischki, T.; Lopinski, G.;
Cheben, P.; et al. Silicon on-Insulator Guided Mode Resonant Grating for Evanescent Field Molecular
Sensing. Opt. Express 2009, 17, 18371. [CrossRef]
63. Sun, T.; Kan, S.; Marriott, G.; Chang-Hasnain, C. High-Contrast Grating Resonators for Label-Free Detection
of Disease Biomarkers. Sci. Rep. 2016, 6, 27482. [CrossRef]
64. Shakoor, A.; Grande, M.; Grant, J.; Cumming, D.R.S. One-dimensional silicon nitride grating refractive index
sensor suitable for integration with CMOS detectors. IEEE Photonics J. 2017, 9, 1–11. [CrossRef]
65. White, I.M.; Fan, X. On the Performance Quantification of Resonant Refractive Index Sensors. Opt. Express
2008, 16, 1020. [CrossRef]
66. GE Healhtcare. Biacore. 2006. Available online: https://www.biacore.com/lifesciences/index.html
(accessed on 14 March 2019).
67. Genalyte. Genalyte. 2009. Available online: https://www.genalyte.com (accessed on 14 March 2019).
68. Mazzotta, F.; Wang, G.; Hägglund, C.; Höök, F.; Jonsson, M.P. Nanoplasmonic biosensing with on-chip
electrical detection. Biosens. Bioelectron. 2010, 26, 1131–1136. [CrossRef]
69. Guyot, L.; Blanchard-Dionne, A.-P.; Patskovsky, S.; Meunier, M. Integrated silicon-based nanoplasmonic
sensor. Opt. Express 2011, 19, 9962–9967. [CrossRef]
70. Patskovsky, S.; Meunier, M. Integrated Si-based nanoplasmonic sensor with phase-sensitive angular
interrogation. Ann. Phys. 2013, 525, 431–436. [CrossRef]
71. Perino, M.; Pasqualotto, E.; De Toni, A.; Garoli, D.; Scaramuzza, M.; Zilio, P.; Ongarello, T.; Paccagnella, A.;
Romanato, F. Development of a complete plasmonic grating-based sensor and its application for
self-assembled monolayer detection. Appl. Opt. 2014, 53, 5969–5976. [CrossRef]
72. Turker, B.; Guner, H.; Ayas, S.; Ekiz, O.O.; Acar, H.; Guler, M.O.; Dâna, A. Grating coupler integrated
photodiodes for plasmon resonance based sensing. Lab Chip 2011, 11, 282–287. [CrossRef]
73. Augel, L.; Kawaguchi, Y.; Bechler, S.; Körner, R.; Schulze, J.; Uchida, H.; Fischer, I.A. Integrated Collinear
Refractive Index Sensor with Ge PIN Photodiodes. ACS Photonics 2018, 5, 4586–4593. [CrossRef]
74. Shakoor, A.; Cheah, B.C.; Hao, D.; Al-Rawhani, M.; Nagy, B.; Grant, J.; Dale, C.; Keegan, N.; McNeil, C.;
Cumming, D.R. Plasmonic sensor monolithically integrated with a CMOS photodiode. ACS Photonics 2016,
3, 1926–1933. [CrossRef]
75. Shakoor, A.; Cheah, B.C.; Hao, D.; Al-Rawhani, M.; Nagy, B.; Grant, J.; Dale, C.; Keegan, N.; McNeil, C.;
Cumming, D.R. Monolithic integration of a plasmonic sensor with CMOS technology. Proc. SPIE 2017, 10107,
101070F.
76. Shakoor, A.; Cheah, B.C.; Al-Rawhani, M.A.; Grande, M.; Grant, J.; Gouveia, L.C.; Cumming, D.R. CMOS
Nanophotonic Sensor With Integrated Readout System. IEEE Sens. J. 2018, 18, 9188–9194. [CrossRef]
77. Cetin, A.E.; Coskun, A.F.; Galarreta, B.C.; Huang, M.; Herman, D.; Ozcan, A.; Altug, H. Handheld
High-Throughput Plasmonic Biosensor Using Computational on-Chip Imaging. Light Sci. Appl. 2014,
3, e122. [CrossRef]
78. Triggs, G.J.; Wang, Y.; Reardon, C.P.; Fischer, M.; Evans, G.J.O.; Krauss, T.F. Chirped guided-mode resonance
biosensor. Optica 2017, 4, 229–234. [CrossRef]
79. Ray, S.; Mehta, G.; Srivastava, S. Label-free detection techniques for protein microarrays: Prospects, merits
and challenges. Proteomics 2010, 10, 731–748. [CrossRef]
80. Sang, S.; Wang, Y.; Feng, Q.; Wei, Y.; Ji, J.; Zhang, W. Progress of new label-free techniques for biosensors:
A review. Crit. Rev. Biotechnol. 2016, 36, 465–481. [CrossRef]
81. Gauglitz, G. Direct optical detection in bioanalysis: An update. Anal. Bioanal. Chem. 2010, 398, 2363–2372.
[CrossRef]
Sensors 2019, 19, 1715 24 of 26

82. Lavín, Á.; Casquel, R.; Sanza, F.J.; Laguna, M.F.; Holgado, M. Efficient design and optimization of
bio-photonic sensing cells (BICELLs) for label free biosensing. Sens. Actuators B Chem. 2013, 176, 753–760.
[CrossRef]
83. Salina, M.; Giavazzi, F.; Lanfranco, R.; Ceccarello, E.; Sola, L.; Chiari, M.; Chini, B.; Cerbino, R.; Bellini, T.;
Buscaglia, M. Multi-spot, label-free immunoassay on reflectionless glass. Biosens. Bioelectron. 2015, 74,
539–545. [CrossRef]
84. Coskun, A.F.; Cetin, A.E.; Galarreta, B.C.; Alvarez, D.A.; Altug, H.; Ozcan, A. Lensfree optofluidic plasmonic
sensor for real-time and label-free monitoring of molecular binding events over a wide field-of-view. Sci. Rep.
2014, 4, 6789. [CrossRef]
85. Holgado, M.; Barrios, C.A.; Ortega, F.J.; Sanza, F.J.; Casquel, R.; Laguna, M.F.; Banuls, M.J.; López-Romero, D.;
Puchades, R.; Maquieira, A. Label-free biosensing by means of periodic lattices of high aspect ratio SU-8
nanopillars. Biosens. Bioelectron. 2010, 25, 2553–2558. [CrossRef]
86. Vaisocherová, H.; Brynda, E.; Homola, J. Functionalizable lowfouling coatings for label-free biosensing in
complex biological media: Advances and applications. Anal. Bioanal. Chem. 2015, 407, 3927–3953.
87. Ligler, F.S. Fluorescence-Based Optical Biosensors. In Biophotonics. Biological and Medical Physics, Biomedical
Engineering; Pavesi, L., Fauchet, P.M., Eds.; Springer: Berlin/Heidelberg, Germany, 2008.
88. Strianese, M.; Staiano, M.; Ruggiero, G.; Labella, T.; Pellecchia, C.; D’Auria, S. Fluorescence-based biosensors.
Methods Mol. Biol. 2012, 875, 193–216.
89. Park, M.K.; Kee, J.S.; Quah, J.Y.; Netto, V.; Song, J.; Fang, Q.; Mouchel La Fosse, E.; Lo, G.-Q. Label-free
aptamer sensor based on silicon microring resonators. Sens. Actuators B 2013, 176, 552–559. [CrossRef]
90. Arima, Y.; Toda, M.; Iwata, H. Surface plasmon resonance in monitoring of complement activation on
biomaterials. Adv. Drug Deliv. Rev. 2011, 63, 988–999. [CrossRef]
91. Couture, M.; Zhao, S.S.; Masson, J.F. Modern surface plasmon resonance for bioanalytics and biophysics.
Phys. Chem. Chem. Phys. 2013, 15, 11190–11216. [CrossRef]
92. Šípová, H.; Homola, J. Surface plasmon resonance sensing of nucleic acids: A review. Anal. Chim. Acta 2013,
773, 9–23.
93. Roh, S.; Chung, T.; Lee, B. Overview of the characteristics of micro- and nano-structured surface plasmon
resonance sensors. Sensors 2011, 11, 1565–1588. [CrossRef]
94. Chung, T.; Lee, S.-Y.; Song, E.Y.; Chun, H.; Lee, B. Plasmonic nanostructures for nano-scale bio-sensing.
Sensors 2011, 11, 10907–10929. [CrossRef]
95. Raschke, G.; Kowarik, S.; Franzl, T.; Sonnichsen, C.; Klar, T.A.; Feldmann, J.; Nichtl, A.; Kurzinger, K.
Biomolecular Recognition Based on Single Gold Nanoparticle Light Scattering. Nano Lett. 2003, 3, 935.
[CrossRef]
96. Tam, F.; Moran, C.; Halas, N.J. Geometrical Parameters Controlling Sensitivity of Nanoshell Plasmon
Resonances to Changes in Dielectric Environment. J. Phys. Chem. B 2004, 108, 17290. [CrossRef]
97. Sun, Y.; Xia, Y. Increased Sensitivity of Surface Plasmon Resonance of Gold Nanoshells Compared to That of
Gold Solid Colloids in Response to Environmental Changes. Anal. Chem. 2002, 74, 5297. [CrossRef]
98. Raschke, G.; Brogl, S.; Susha, A.S.; Rogach, A.L.; Klar, T.A.; Feldmann, J.; Fieres, B.; Petkov, N.; Bein, T.;
Nichtl, A.; et al. Gold Nanoshells Improve Single Nanoparticle Molecular Sensors. Nano Lett. 2004, 4, 1853.
[CrossRef]
99. Zhan, Y.; Lei, D.Y.; Li, X.; Maier, S.A. Plasmonic Fano resonances in nanohole quadrumers for ultra-sensitive
refractive index sensing. Nanoscale 2014, 6, 4705–4715. [CrossRef]
100. Butet, J.; Martin, O.J.F. Refractive index sensing with Fano resonant plasmonic nanostructures: A symmetry
based nonlinear approach. Nanoscale 2014, 6, 15262–15270. [CrossRef]
101. Yanik, A.A.; Cetin, A.E.; Huang, M.; Artar, A.; Mousavi, S.H.; Khanikaev, A.; Connor, J.H.; Shvets, G.;
Altug, H. Seeing protein monolayers with naked eye through plasmonic Fano resonances. Proc. Natl. Acad.
Sci. USA 2011, 108, 11784–11789. [CrossRef]
102. Lee, K.-L.; Wu, S.-H.; Lee, C.-W.; Wei, P.-K. Sensitive biosensors using Fano resonance in single gold nanoslit
with periodic grooves. Opt. Express 2011, 19, 24530–24539. [CrossRef]
103. Lee, K.-L.; Huang, J.-B.; Chang, J.-W.; Wu, S.-H.; Wei, P.-K. Ultrasensitive biosensors using enhanced Fano
resonances in capped gold nanoslit arrays. Sci. Rep. 2015, 5, 8547. [CrossRef]
Sensors 2019, 19, 1715 25 of 26

104. Lee, K.-L.; Hsu, H.-Y.; You, M.-L.; Chang, C.-C.; Pan, M.-Y.; Shi, X.; Ueno, K.; Misawa, H.; Wei, P.-K. Highly
sensitive aluminum-based biosensors using tailorable Fano resonances in capped nanostructures. Sci. Rep.
2017, 7, 44104. [CrossRef]
105. Grande, M.; Vincenti, M.A.; Stomeo, T.; Morea, G.; Marani, R.; Marrocco, V.; Petruzzelli, V.; D’Orazio, A.;
Cingolani, R.; De Vittorio, M.; et al. Experimental demonstration of a novel bio-sensing platform via
plasmonic band gap formation in gold nano-patch arrays. Opt. Express 2011, 19, 21385–21395. [CrossRef]
106. Grande, M.; Marani, R.; Portincasa, F.; Morea, G.; Petruzzelli, V.; D’Orazio, A.; Marrocco, V.; de Ceglia, D.;
Vincenti, M.A. Asymmetric plasmonic grating for optical sensing of thin layers of organic materials. Sens.
Actuators B Chem. 2011, 160, 1056–1062. [CrossRef]
107. Xu, X.; Peng, B.; Li, D.; Zhang, J.; Wong, L.M.; Zhang, Q.; Wang, S.; Xiong, Q. Flexible visible-infrared
metamaterials and their applications in highly sensitive chemical and biological sensing. Nano Lett. 2011, 11,
3232–3238. [CrossRef]
108. Cao, C.; Zhang, J.; Wen, X.; Dodson, S.L.; Dao, N.T.; Wong, L.M.; Wang, S.; Li, S.; Phan, A.T.; Xiong, Q.
Metamaterials-based label-free nanosensor for conformation and affinity biosensing. ACS Nano 2013, 7,
7583–7591. [CrossRef]
109. Shen, Y.; Zhou, J.; Liu, T.; Tao, Y.; Jiang, R.; Liu, M.; Xiao, G.; Zhu, J.; Zhou, Z.-K.; Wang, X.; et al. Plasmonic
gold mushroom arrays with refractive index sensing figures of merit approaching the theoretical limit.
Nat. Commun. 2013, 4, 2381. [CrossRef]
110. Kazumaa, E.; Tatsuma, T. Localized surface plasmon resonance sensors based on wavelength-tunable spectral
dips. Nanoscale 2014, 6, 2397. [CrossRef]
111. Altug, H.; Yanik, A.A.; Huang, M.; Adato, R. Ultrasensitive plasmonic sensors mold the flow of light and
fluidics. SPIE Newsroom 2010. [CrossRef]
112. Jágerská, J.; Zhang, H.; Diao, Z.; Le Thomas, N.; Houdré, R. Refractive index sensing with an air-slot photonic
crystal nanocavity. Opt. Lett. 2010, 35, 2523–2525. [CrossRef]
113. Chow, E.; Grot, A.; Mirkarimi, L.; Sigalas, M.; Girolami, G. Ultracompact biochemical sensor built with
two-dimensional photonic crystal microcavity. Opt. Lett. 2004, 29, 1093–1095. [CrossRef]
114. Yang, D.; Tian, H.; Ji, Y. High-Q and high-sensitivity width-modulated photonic crystal single nanobeam
air-mode cavity for refractive index sensing. Appl. Opt. 2015, 54, 1–5. [CrossRef]
115. Pal, S.; Guillermain, E.; Sriram, R.; Miller, B.L.; Fauchet, P.M. Silicon photonic crystal nanocavity-coupled
waveguides for error-corrected optical biosensing. Biosens. Bioelectron. 2011, 26, 4024–4403. [CrossRef]
116. Zou, Y.; Chakravarty, S.; Zhu, L.; Chen, R.T. The role of group index engineering in series-connected photonic
crystal microcavities for high density sensor microarrays. Appl. Phys. Lett. 2014, 104, 141103. [CrossRef]
117. Zhang, L.; Fu, Z.; Sun, F.; Wang, C.; Tian, H. Highly sensitive one chip eight channel sensing of ultra-compact
parallel integrated photonic crystal cavities based on silicon-on-insulator platform. In Proceedings of the
Conference on Lasers and Electro-Optics Pacific Rim (CLEO-PR), Singapore, 31 July–4 August 2017; pp. 1–2.
118. Scullion, M.G.; Krauss, T.F.; Di Falco, A. Slotted Photonic Crystal Sensors. Sensors 2013, 13, 3675–3710.
[CrossRef]
119. Scullion, M.G.; Di Falco, A.; Krauss, T.F. Slotted photonic crystal cavities with integrated microfluidics for
biosensing applications. Biosens. Bioelectron. 2011, 27, 101–105. [CrossRef]
120. Carlborg, C.F.; Gylfason, K.B.; Ka´zmierczak, A.; Dortu, F.; Polo, M.B.; Catala, A.M.; Kresbach, G.M.;
Sohlström, H.; Moh, T.; Vivien, L.; et al. A packaged optical slot-waveguide ring resonator sensor array for
multiplex label-free assays in labs-on-chips. Lab Chip 2010, 10, 281–290. [CrossRef]
121. Claes, T.; Molera, J.G.; De Vos, K.; Schacht, E.; Baets, R.; Bienstman, P. Label-free biosensing with a
slot-waveguide-based ring resonator in silicon on insulator. IEEE Photonics J. 2009, 1, 197–204. [CrossRef]
122. Wangüemert-Pérez, J.G.; Cheben, P.; Ortega-Moñux, A.; Alonso-Ramos, C.; Pérez-Galacho, D.; Halir, R.;
Molina-Fernández, I.; Xu, D.X.; Schmid, J.H. Evanescent field waveguide sensing with subwavelength
grating structures in silicon-on-insulator. Opt. Lett. 2014, 39, 4442–4445. [CrossRef]
123. Zecca, D.; Qualtieri, A.; Magno, G.; Grande, M.; Petruzzelli, V.; Prieto-Simon, B.; D’Orazio, A.; De Vittorio, M.;
Voelcker, N.H.; Stomeo, T. Label-Free Si3 N4 Photonic Crystal Based Immunosensors for Diagnostic
Applications. IEEE Photonics J. 2014, 6, 1–7. [CrossRef]
124. Eftekhari, F.; Gordon, R.; Ferreira, J.; Brolo, A.G.; Sinton, D. Polarization-dependent sensing of a self
assembled monolayer using biaxial nanohole arrays. Appl. Phys. Lett. 2008, 92, 253103. [CrossRef]
Sensors 2019, 19, 1715 26 of 26

125. Iniewski, K. CMOS Biomicrosystems; Iniewski, K., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2011.
126. Ahmed, M.U.; Saaem, I.; Wu, P.C.; Brown, A.S. Personalized Diagnostics and Biosensors: A Review of
the Biology and Technology Needed for Personalized Medicine. Crit. Rev. Biotechnol. 2014, 34, 180–196.
[CrossRef]

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).