This article has been accepted for publication in IEEE Sensors Journal.

This is the author's version which has not been fully edited and
content may change prior to final publication. Citation information: DOI 10.1109/JSEN.2023.3341620

IEEE SENSORS JOURNAL, VOL. XX, NO. XX, MONTH X, XXXX 1

Highly sensitive and selective detection of

cortisol using a novel SPR-aptamer sensor
modified by gold nanoparticles
Liyun Ding*,a,b, Shenghu Weia, Tian Wub, Yumei Zhangb, Fei Ma*,a, Jue Zhaoa, Xingdong
Jianga, Juanjuan Zuo*,c

Abstract—Cortisol is an indicator of
adrenocortical function in humans, and its
concentration detection is significant for the
early identification and diagnosis of
Addison’s disease and Cushing's syndrome.
A novel, simple and low-cost surface
plasmon resonance (SPR) aptamer biosensor
was constructed for rapid and sensitive
detection of cortisol. In order to further
improve the sensitivity of the SPR effect, this
study immobilized gold nanoparticles
(AuNPs) on the surface of an Au film, and
increased the sensitivity of the SPR effect through the plasmonic coupling between the AuNPs and the Au film. The
optimal particle size of the AuNPs used was 40 nm, and the RI sensitivity of the sensor increased by 45% when the
incubation time was 20 min. The sensor functionalized by the aptamer can detect cortisol at concentrations between 0.1
- 1000nM with excellent selectivity.

Index Terms—Au film, aptamer, cortisol, gold nanoparticles, SPR

I. INTRODUCTION chromatography [6], liquid chromatography [7], fluorescence

C
analysis [8] and mass spectrometry (MS) [9] et al. These
ORTISOL plays an important role in regulating central
methods generally have the disadvantages of expensive
nervous and peripheral physiological functions, involving
equipment, long time consuming and high requirements for
many stress-related diseases. Transient concentrations of
operators.
cortisol can reflect the level of stress response in the body [1],
In 1982, Liedberg et al. [10] applied surface plasmon
and long-term changes in its secretion cncentration are
resonance (SPR) sensing technology to biosensors for the first
associated with an increased risk of somatic and psychiatric
time. SPR sensors are very powerful label-free biosensors
disorders [2]. As a consequence, cortisol not only influences the
because they are highly sensitive to changes in refractive index
physiological and pathological processes in the body, but also
(RI), and the interaction between the target and the
is highly correlated with the level of stress [3]. Highly sensitive
biorecognition molecule can occur in an electromagnetic field
cortisol assays are of great significance for disease diagnosis
close to the detection surface [11]. When a bioreceptor is
and basic life science research. Currently, the commonly used
immobilized on a metal surface, analytes present in the liquid
detection methods for cortisol in the world include ELISA [4],
sample are selectively recognized and captured, producing a
electrochemiluminescence immunoassay [5], gas
local increase in the refractive index of the gold surface [12].
The change of refractive index of the medium around SPR
This work was supported by the National Natural Science Foundation sensor will lead to the change of resonance wavelength or
of China (No. 51878524), Hubei Provincial Natural Science Foundation
of China (No. 2021CFA041), the Fundamental Research Funds for the
intensity. SPR biosensors have been widely used in the field of
Central Universities (WUT:2021Ш028JC). sensors due to their advantages of high sensitivity, no labeling,
a
School of Physical Science and Technology, Lanzhou University, and real-time monitoring [13]. At present, SPR sensing
Lanzhou, 730000, China technology has been widely used in cortisol detection. Richard
b
National Engineering Research Center of Fiber Optic Sensing
Technology and Networks, Wuhan University of Technology, Wuhan et al. proposed a mobile SPR sensor based on AuNPs [14].
430070, China Cátia et al. designed SPR sensors based on AuPd and tilted
c
Tongji Hospital Affiliated to Tongji Medical College HUST, Wuhan fiber Bragg grating successively [15,16]. In the detection of
430030, China
Liyun Ding is currently a professor at the College of Physical Science cortisol, these SPR sensors have some problems such as narrow
and Technology, Lanzhou University (e-mail: dingly@lzu.edu.cn). detection range and poor linear relationship.
Fei Ma is currently an associate professor at the College of Physical In recent years, with the rapid development of
Science and Technology, Lanzhou University (e-mail: maf@lzu.edu.cn).
nanotechnology, local surface plasmon resonance (LSPR)

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 This article has been accepted for publication in IEEE Sensors Journal. This is the author's version which has not been fully edited and
content may change prior to final publication. Citation information: DOI 10.1109/JSEN.2023.3341620
8 IEEE SENSORS JOURNAL, VOL. XX, NO. XX, MONTH X, XXXX
generated by gold nanoparticles (AuNPs) has been used to
improve the sensitivity of SPR sensors [17]. When light
interacts with nanoparticles, the electromagnetic field from the
light causes charge separation between free electrons and
ionized metal nuclei. The presence of Coulomb repulsion
between free electrons will act as a restoring force, causing
collective oscillations of the electrons [18]. The principle of
signal amplification lies in the strong coupling between AuNPs
and Au film [19]. Due to the inductive coupling between
AuNPs and the Au film of the sensor, the refractive index of
SPR increases, and the extent of this increase is related to the
particle size of AuNPs and the distance between AuNPs and the
Au film [20]. The form commonly used to improve the
sensitivity of the sensor is sandwich detection, that is the
structure of Au film/biological analytes/AuNPs [21,22]. AuNPs
can be functionalized with a variety of biomolecules to
recognize and bind to specific targets. AuNPs have unique
optical properties, such as their distinctive plasma bands, which
give AuNP solutions their vibrant red color, as well as their
extremely high extinction coefficients, which allow for the
detection of AuNPs with the naked eye even at low
concentrations [23].
Aptamers are single-stranded nucleic acids with the
advantage of easy modification of various functional groups
suitable for coupling and high stability even under
non-physiological conditions [24]. They represent the next
frontier of biorecognition elements in biosensors [25]. In this
study, we developed a novel AuNPs coupled enhanced SPR
adapter sensor for the detection of cortisol concentration in the
target solution. The effects of the size and incubation time of
gold nanoparticles on the performance of SPR sensor were
studied. The optimum preparation conditions were determined
by analyzing the RI sensitivity of the sensor. Then we used
sulfhydryl groups to bind cortisol aptamers to the surface of
AuNPs, forming an Au film/AuNPs/aptamer structure. Cortisol
can be detected without additional markers or indicators. It is
worth mentioning that this is the first time that an
AuNPs-enhanced SPR sensor is used for label-free detection of
cortisol.
II. EXPERIMENTAL SECTION
A. Materials
Trisodium citrate (TSC), gold (III) chloride trihydrate
(HAuCl4), 1,6-Hexanedithiol, Tris (2-carboxyethyl) phosphine
hydrochloride (TCEP) and sodium dodecyl sulfate (SDS) were
purchased from Aladdin Industrial Co. Ethanol absolute,
sodium phosphate dibasic dehydrate (Na2HPO4·2H2O), sodium
dihydrogen phosphate anhydrous (NaH2PO4), HNO3 (68%),
HCl (38%) and glycerol were bought from Sinopharm
Chemical Reagent Beijing Co. Ltd. All the chemicals are
analytical grade. All procedures were performed at ambient
temperature if not specifically noted. Ultra-pure (U-P) water
was produced by the Hitech-Kflow water purification system.
Cortisol aptamer with a 5`-thiol modification was purchased
from Shanghai Sangon Biotechnology Co. Ltd. and purified via
High Performance Liquid Chromatography (HPLC). The
sequence of the cortisol aptamer was:
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5'- GGA ATG GAT CCA CAT CCA TGG ATG GGC AAT
GCG GGG TGG AGA ATG GTT GCC GCA CTT CGG CTT
CAC TGC AGA CTT GAC GAA GCT T -3' [26].
B. Principle of AuNPs Enhanced SPR Cortisol Sensors
The SPR reflection spectrum was detected by Kretschmann
prism SPR sensor [27] in angle modulation mode. The sensing
platform is composed of a light source, a photodetector, a
hemispherical prism, a sample grass, two symmetrical driving
arms, and a computer. The light source is monochromatic light
with a wavelength of 650 nm. Two symmetrical driving arms
fix the light source and photodetector respectively. Fig. 1(a)
shows the detection principle of the SPR cortisol aptamer
sensor enhanced by AuNPs. After activation, cortisol aptamer
with sulfhydryl group is combined with AuNPs on Au film
through Au-S bond. When cortisol solution was added to the
reaction cell, the aptamer on the AuNPs surface combined with
cortisol, which changed the refractive index of the local
environment around the Au film. As a result, the position of the
SPR reflection peak of the Au film will shift. Due to the
different concentration of cortisol solution, the change of
refractive index is different, and the deviation of SPR reflection
peak is different. With the specificity of the cortisol aptamer,
the sensor can selectively recognize cortisol in solution
independent of other steroid hormones.
Fig. 1. (a) Schematic diagram of the prism-based SPR sensor. (b) Cell
survival rate at different times
C. Preparation of AuNPs
Following a previous method [28], AuNPs with different
sizes were prepared. The specific steps are shown in Fig. 2.
Firstly, 30 mL of TSC (2.2 mM) was heated to boiling with
magnetic stirring, and the condensation tube was used to
prevent solvent volatilization. After reflux, 200 μL HAuCl4 (25
mM) was added. Stop heating after the solution reaction is
complete. Keep the temperature at 90 ℃ and add 200 μL
HAuCl4. After 30 min of reaction, repeat the operation once.
Secondly, 11 mL of the reaction solution was taken out and
diluted with 10.6 mL of ultrapure water. Then add 400 μL TSC
(60 mM) and 200 μL HAuCl4. After 30 min of reaction, 200 μL
HAuCl4 was added to react for another 30 min again. The size
of AuNPs can be increased by continuously diluting the
reaction solution. Finally, AuNPs of 20 nm, 40 nm, 55 nm, and
70 nm were prepared, corresponding to g0, g1, g2 and g3 in Fig.
2.
The glass instruments used in the above experimental
process were soaked in aqua regia (V hydrochloric acid: V nitric acid =
 This article has been accepted for publication in IEEE Sensors Journal. This is the author's version which has not been fully edited and
content may change prior to final publication. Citation information: DOI 10.1109/JSEN.2023.3341620
8 IEEE SENSORS JOURNAL, VOL. XX, NO. XX, MONTH X, XXXX
3:1), then washed with deionized water and dried in an oven.
Fig. 2. Schematic of the synthesis of AuNPs prepared by the crystal
seeding method.
D. Preparation of AuNPs enhanced SPR sensor
A 50 nm Au film magnetron sputtered on a square glass sheet
(18 mm×18 mm×0.20 mm) was prepared using a BESTECH
machine from Germany.
In order to modify AuNPs in the sensing region, we
improved the method described in the literature [29]. First, the
surface of the Au film was cleaned by absolute ethanol. Second,
15 mmol·L-1 1,6-hexanediol was prepared with absolute ethanol
as solvent, to soak the Au film completely. After sealed at
ambient temperature for 24 hours, the Au film was taken out,
washed with absolute ethanol and deionized water three times,
and dried. Third, AuNPs solution (0.01% SDS) was added
dropwise onto the Au film. After incubation for a period of time,
the Au film was taken out washed with deionized water several
times, and dried at the ambient temperature.
Cortisol aptamer was treated with TCEP solution for 1 hour,
the loading ratio was TCEP: aptamer = 1000:1, and the
sulfhydryl group at the top of the aptamer was activated. After
that, the activated cortisol aptamer was added to the AuNPs
modified Au film and incubated at the ambient temperature for
12 hours. At last, the Au film surface was washed with ethanol
and deionized water, and dried at the ambient temperature.
E. SPR Detection of cortisol
Prepared a series of cortisol standard solutions (phosphate
buffer, pH=7) with different concentrations (0, 0.1 nM, 1 nM,
10 nM, 50 nM, 100 nM, 500 nM, 1000 nM). Then it was added
to the sample cell, and the response sensitivity to cortisol was
determined by detecting the angle change of SPR reflection
peak of the sensor.
F. Determination of the sensor selectivity
The selectivity of the sensor is a key property for its ability to
be used in practical assays. Steroid hormones with similar
structure to cortisol were selected, and cortisol, cortisone,
progesterone and triamcinolone were added to the sample cell
of the system at a concentration of 1000 nM, and a blank PBS
buffer was used as a control, and the sensor was used to detect
the drift of their SPR resonance angles, so as to determine the
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selectivity of the prepared sensors.
III. RESULTS AND DISCUSSION
A. Cytotoxicity of AuNPs-Apt Probe
It is well known that the biocompatibility of a sensor is
crucial for its practical application. Here, we performed a
cytotoxicity test of AuNPs-Apt couplings to assess their
biocompatibility. The biocompatibility test of AuNPs-Apt was
mainly carried out by utilizing a cell counting kit (Cell
Counting Kit-8, CCK-8) with SY5Y as the cultured cell.
The absorbance of the sample was recorded with a
microplate meter to calculate the survival rate of the cells
(Equation 1).
(1)
where Ds, Db, and Dc correspond to the absorbance of the
experimental group, blank group, and control group.
It can be seen from Fig. 1(b) that the cell survival rate in the
experiment was higher than 100%. In the same incubation time,
the cell survival rate of high-concentration conjugates was
higher than that of low-concentration conjugates. At the same
concentration, the cell survival rate of the conjugated
compound with an incubation time of 24 h was higher than that
of 16 h. This indicates that AuNPs-Apt conjugation is not toxic
to cells, but promotes cell growth. This is due to the nature of
the aptamer is a five-carbon ring, which provides nutrients for
cell growth. This confirmed the excellent biocompatibility of
AuNPs-Apt conjugation enabling it to be used in biosensors.
B. Optical Properties and Morphology of AuNPs
Modified Au films
The refractive index sensitivity of the sensor is used to
characterize its performance of the sensor. We prepared
glycerol solutions with different concentrations (0, 10%, 20%,
30%, 40%, 50%), and their refractive index was measured by
the Abbe refractometer. Fig. 3 shows the refractive index
sensing performance of pure Au film without fixed AuNPs. As
can be seen from Fig. 3(a), the SPR resonance angle of the Au
film drifts to a larger angle and its intensity decreases as the
refractive index of the Au film solution increases continuously.
Fig. 3(b) shows the relationship between the resonance angle
and the refractive index of the solution. The slope of the
linearly fitted line was the RI sensitivity of 72.639°·RIU-1 for
the Au film sensor.
Fig. 3. (a) SPR reflectance spectra of Au film at different concentrations
of glycerol. (b) The relationship between the position of SPR functional
resonance angle of Au film and the refractive index of solution.
 This article has been accepted for publication in IEEE Sensors Journal. This is the author's version which has not been fully edited and
content may change prior to final publication. Citation information: DOI 10.1109/JSEN.2023.3341620
8 IEEE SENSORS JOURNAL, VOL. XX, NO. XX, MONTH X, XXXX
Fig. 4(a) is the SEM image of the Au film modified by
AuNPs with the incubation time of 20 min. As seen from SEM
images, AuNPs are evenly distributed on the Au film with
strong dispersion with a particle size of 20 nm. From the SPR
reflection spectrum in Fig. 4(b), the SPR resonance angle of the
Au film modified by AuNPs moves to a smaller Angle and its
intensity decreases. Both of these results proved that AuNPs
successfully modified the Au film.
Fig. 4. (a) SEM images of AuNPs modified Au film. (b) SPR reflectance
spectra of Au films in pure water before and after AuNPs modification.
C. Optimization of the Experimental Conditions
1) Effect of incubation time of AuNPs
According to the principle of the sensor, the refractive index
sensitivity of the sensor is used to characterize the performance
of the sensor. We prepared glycerol solutions with different
concentrations (0, 10%, 20%, 30%, 40%, 50%), and their
refractive index was measured by the Abbe refractometer. The
results of the refractive index sensing performance of Au film
without AuNPs are shown in Fig. 2. As the concentration of
glycerol on the surface of the gold film increases, which means
that the refractive index of the solution increases, the SPR
resonance Angle of the gold film shifts to a large Angle and the
intensity decreases. Fig. 3(b) shows the refractive index
sensitivity of the sensor. The RI sensitivity of Au film is
72.639 °·RIU-1.
Fig. 5(a) shows the SPR spectra of the sensor with different
incubation time of AuNPs (0, 10 min, 20 min, 30 min, 60 min).
With the prolongation of AuNPs incubation time, the position
of SPR reflection peak shifted to a smaller angle and the
intensity decreased. Different concentrations of glycerol were
detected by AuNPs modified Au films with different incubation
times, and their RI sensitivity was obtained as shown in Fig.
5(b). When incubation time is not enough, the amount of
AuNPs on the Au film is low, so that the improvement of RI
sensitivity is subtle. When incubation time is too much, AuNPs
may agglomerate, which also leads to the decrease of
sensitivity. Since the surface plasma wave decays
exponentially on the metal surface, and the clustered and
overlapping AuNPs increase the distance between the target
and the sensor surface, thus causing a decrease in the sensitivity
to the target. On the other hand, the LSPR resonance frequency
generated when the AuNPs overlap clusters does not match
well with the resonance frequency of the SPR, and the
plasmonic coupling between the AuNPs and the Au film is
weakened, leading to a decrease in sensitivity. Therefore, the
optimal incubation time for AuNPs is set to 20 minutes based
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on the relationship between RI sensitivity and incubation time.
Fig. 5. (a) SPR reflection spectra of Au films with different AuNPs
incubation time. (b) RI sensitivity of Au films with different AuNPs
incubation time.
2) Effect of the size of AuNPs
AuNPs with particle sizes of 20 nm, 40 nm, 50 nm and 70 nm
were prepared by seeded-growth method. The Au film was
modified by AuNPs with different particle sizes and incubated
for 20 min. The distribution of AuNPs on the Au film is shown
in Fig. 6. As can be seen from the figure, the uniformity and
density of AuNPs with different particle sizes are not the same.
When the density of AuNPs exceeds a certain value, the more
obvious the agglomeration phenomenon is and the worse the
uniformity is. This is because the stability of larger AuNPs is
poor, and their growth route differ in the preparation process
[30].
Fig. 6. SEM images of AuNPs with different particle sizes on Au film. (a)
20nm. (b) 40nm. (c) 55nm. (d) 70nm. (e) RI sensitivity of AuNPs
modified Au films with different particle sizes.
Au films modified by AuNPs with different particle sizes
were used to measure the SPR reflection peak of glycerol
solutions with different concentrations. The RI sensitivity
dependence with diameter of AuNPs is shown in Fig. 6(e).
When the particle size of AuNPs increases to 40 nm, the RI
sensitivity of Au film sensor is maximized. However, when the
size of AuNPs increases further, the stability and uniformity of
large-size AuNPs decrease, resulting in the weakening of their
electric field enhancement ability. Therefore, when 40 nm
AuNPs is used to modify Au film and the incubation time is 20
min, the RI sensitivity of the sensor is 104.687 °· RIU-1.
Compared with the unmodified Au film, the refractive index
sensitivity is increased by 45%.
D. Quantitative Assay of Cortisol Using the AuNPs
Enhanced SPR Sensors
After optimizing the SPR sensor, the cortisol detection
efficiency was studied. Fig. 7(a) shows the SPR reflection
 This article has been accepted for publication in IEEE Sensors Journal. This is the author's version which has not been fully edited and
content may change prior to final publication. Citation information: DOI 10.1109/JSEN.2023.3341620
8 IEEE SENSORS JOURNAL, VOL. XX, NO. XX, MONTH X, XXXX
spectra with different cortisol solution concentration of
0.1-1000 nM. The angle of SPR reflection peak of phosphate
buffer with 0 cortisol was set as a blank reference. When the
sensor detects different concentrations of cortisol solution, the
angle difference of SPR reflection peak relative to the blank
reference is known as ΔIncident angle.
Fig. 7. The sensor was used to detect cortisol at different concentrations
(0.1-1000 nM). (a) SPR reflection spectrum. (b) Δ Incident angle change
corresponding to the cortisol solutions in the concentration range of
0.1-1000 nM.
Fig. 7(b) shows the relationship between ΔIncident angle and
log concentration of cortisol solution. By linear fitting, the
relationship between the drift of sensor SPR reflection peak and
cortisol concentration (C) was obtained: ΔIncident angle=0.364
log10(C) + 0.510, and the linear relationship is well (R2 = 0.988).
The detection range of the sensor is 0.1-1000 nM.
E. Selectivity of the AuNPs Enhanced SPR Sensors
We evaluated the selectivity of the sensor by comparing the
shifts of the reflection peaks of the sensor in response to 1000
nM cortisol, cortisone, progesterone and triamcinolone. All of
these steroid hormones are structurally similar to cortisol [31].
It can be seen from Fig. 8 that the interfering molecules have
little impact on the detection of cortisol, which indicates the
superior selectivity to cortisol of the AuNPs Enhanced SPR
sensor.
Fig. 8. Selectivity of SPR aptamer sensor.
IV. CONCLUSION
In this paper, a novel and sensitive SPR cortisol aptamer sensor
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based on AuNPs and Au film coupling effect is proposed. The
experimental results show that when the particle size of AuNPs
is 40 nm and the incubation time is 20 min, the RI sensitivity of
Au film sensor is maximized (104.687 °·RIU-1), which is about
1.4 times higher than that of Au film sensor without AuNPs.
The sensor can detect the lowest concentration of cortisol at 0.1
nM, which meets the current practical application requirements
of cortisol detection. In addition, the sensor is unresponsive to
steroids other than cortisol and has excellent selectivity. The
novel SPR cortisol sensor overcomes the drawback of the
labeling required to enhance the SPR effect with AuNPs
coupling. The sensor is simple to operate and low cost,
allowing further development of portable SPR cortisol sensor
technology.
ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (No. 51878524),
Hubei Provincial Natural Science Foundation of China (No.
2021CFA041), the Fundamental Research Funds for the
Central Universities (WUT:2021Ш028JC).
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AUTHOR INFORMATION
Liyun Ding received her Ph. D in materials science from Wuhan
University of Technology, Wuhan, in 2007. She is now a professor at
the School of Physical Science and Technology, Lanzhou University.
Her research interest is in field of the optical fiber chemical and
biosensors.
Shenghu Wei received his B.S. degree in physics from Xiamen
University in 2022. He is now a graduate student at the School of
Physical Science and Technology, Lanzhou University. His research
interest is optical fiber chemical biosensor.
Tian Wu received her B.Eng. degree from China university of
Geoscience, Wuhan, in 2015. She is now a graduate student in
Wuhan University of Technology, Wuhan. Her research interest is in
SPR sensors and optical fiber chemical biosensors.
Yumei Zhang received her B.Eng. degree from Henan University of
Science and Technology, Wuhan, in 2013 and graduated from
Changchun University of Technology in 2019. She is now a graduate
student in Wuhan University of Technology, Wuhan. Her research
interest is in optical fiber biosensors.
Fei Ma received his Ph. D in material physics and chemistry from
Lanzhou University, Lanzhou, in 2008. He is now an associate
professor in the School of Physical Science and Technology of
Lanzhou University. His research interest is in field of the functional
nanomaterials.
Jue Zhao received her Bachelor's degree in materials physics from
Lanzhou University in 2002. She is now a lecturer at the School of
Physical Science and Technology, Lanzhou University. Her research
interest is in field of electromagnetic and optical experimental
Measurements
Xingdong Jiang received his Ph.D. in particle physics and nuclear
physics from Lanzhou University in 2019. He is now an engineer at the
School of Physical Science and Technology, Lanzhou University. His
research interests are in the ion irradiation effect of functional
materials and the preparation and characterization of materials.
Juanjuan Zuo, a nurse with a bachelor's degree in nursing, works
as a clinical nurse in surgery and assists with drug trial enrollment data
collection and laparoscopic robotic coordination.