Wang 

et al. Nanoscale Res Lett (2021) 16:109

https://doi.org/10.1186/s11671-021-03566-3

NANO EXPRESS Open Access

All‑metal terahertz metamaterial biosensor

for protein detection
Gangqi Wang1  , Fengjie Zhu2*, Tingting Lang1, Jianjun Liu3, Zhi Hong3 and Jianyuan Qin4 

Abstract 
In this paper, a terahertz (THz) biosensor based on all-metal metamaterial is theoretically investigated and experimen-
tally verified. This THz metamaterial biosensor uses stainless steel materials that are manufactured via laser-drilling
technology. The simulation results show that the maximum refractive index sensitivity and the figure of merit of this
metamaterial sensor are 294.95 GHz/RIU and 4.03, respectively. Then, bovine serum albumin was chosen as the detec-
tion substance to assess this biosensor’s effectiveness. The experiment results show that the detection sensitivity is
72.81 GHz/(ng/mm2) and the limit of detection is 0.035 mg/mL. This THz metamaterial biosensor is simple, cost-effec-
tive, easy to fabricate, and has great potential in various biosensing applications.
Keywords:  Bovine serum albumin, All-metal metamaterials, Terahertz, Biosensors

Introduction biosensors is of considerable significance and quite in

Nowadays, doctors usually collect serum from patients demand.
in the hospital for various examinations. Such as tumor The THz wave is between the microwave and infrared
detection [1–3] and virus detection [4–6] etc. The pre- optical wave and in the transition region from electron-
liminary method for tumor detection is protein detec- ics to photonics. Compared with light waves, the energy
tion, because proteins are the components of many tumor of photons in this band is very low. This means that tera-
markers, and these biomolecules with a lot of informa- hertz waves will not cause radiation ionization damage to
tion exist in the serum. Serum albumins are the most biological molecules. Many biological macromolecules
abundant (52–62%) total water-soluble fraction proteins also have unique fingerprints in the terahertz band [12–
in the blood plasma [7, 8]. Furthermore, nutritional and 15]. Therefore, terahertz waves have received consider-
physiological functions of serum albumins make them able attention in the field of biosensing [16, 17].
as essential bio-macromolecules. As one of the most Metamaterials are artificial electromagnetic materi-
popular serum albumins, bovine serum albumin (BSA) als composed of subwavelength structures. Their unique
is used in a lot of research fields. Therefore, the research electromagnetic resonance has many characteristics, such
on the detection of BSA is quite important. There are as a negative RI [18, 19], electromagnetically induced
many methods for detecting and determining the con- transparency [20, 21], and extreme environmental sensi-
centration of BSA, including electrochemical impedance tivity [22, 23]. Metamaterials sensitive to the surrounding
spectroscopy [9], capillary electrophoresis [10], and light environment, especially those composed of subwave-
scattering techniques [11]. But they all have some disad- length metal structures [24–26], have been widely used
vantages, such as complicated procedures, poor repro- to detect various biomolecules. The combination of tera-
ducibility or time-consuming. Therefore, developing new hertz waves and metamaterials provides a new detection
method for the biomedical molecules, which cannot only
achieve label-free detection, but also refresh the resolu-
*Correspondence: [email protected] tion limit of existing sensors. In addition, detection can
2
Zhejiang Chinese Medical University, Hangzhou, China
Full list of author information is available at the end of the article

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Wang et al. Nanoscale Res Lett (2021) 16:109 Page 2 of 10

be completed simply and rapidly using a small amount of the refractive index sensitivity was calculated. Then this
analyte with no chemical reagents. THz metamaterial biosensor was fabricated and meas-
At THz frequencies, metamaterial production usually ured. The experiments confirmed the high sensitivity of
relies on micron-level processing methods. Photolithog- this senor to external environment. BSA was chosen as
raphy [27] or electron beam lithography [28] is mainly the detection substance to assess the biosensor’s effec-
used to transfer micro-nano patterns from the photore- tiveness. The Hill formula was used to fit the experimen-
sistor to the surface of the functional materials, and then tal data. A detection sensitivity of 72.81  GHz/(ng/mm2)
wet [29, 30] or dry etching [31, 32] is required to com- and the limit of detection (LOD) of 0.035  mg/mL were
plete the final processing of the metamaterials. Through obtained. The measurements were repeated three times
the above steps, the construction of fine graphics can to verify the biosensor’s reliability.
be achieved, but unfortunately, most of these methods
demand expensive processing equipment, high standard Design
operation environments, and cumbersome processing Figure  1a shows the structure of the proposed all-metal
procedures. Laser drilling [33, 34] is the first practical metamaterial terahertz biosensor. A hollow dumbbell
laser processing technology, and it is also one of the main pattern with a periodic arrangement along the x and y
application fields of laser processing. The laser beam is directions was formed on a 50  μm thick stainless-steel
highly concentrated in space and time. By focusing with plate (conductivity of 1.4 × ­106 S/m). The period sizes
a lens, the spot diameter can be reduced to micron level, Px and Py of the unit structure are 500 μm and 300 μm,
and the laser power density of 1 ­ 05–1015  W/cm2 can be respectively. The hollow dumbbell’s length L and gap H
obtained. With such a high-power density, laser drilling are 294 μm and 60 μm, respectively. The radius R of cir-
can be carried out in almost any material. To the best of cles at both ends of the hollow dumbbell is 60  μm. The
our knowledge, this is the first time to apply laser-drilling biosensor had an all-metal structural design and no tra-
technology in the fabrication of metamaterial biosen- ditional dielectric substrate. The terahertz wave is per-
sors, which can significantly reduce the processing cost pendicular incident to the surface of the metamaterial
of metamaterial biosensors and promote their practical biosensor.
applications.
In this study, a highly sensitive terahertz biosensor for Methods and simulation
protein detections based on all-metal metamaterial was Then the three-dimensional full wave electromagnetic
proposed, theoretically simulated and experimentally field simulation via the finite integral method (Commer-
demonstrated. The device was simple to manufacture, cial software CST) was used for the following simula-
cost-effective and quite stable. It was composed of stain- tions. Periodic boundary conditions were applied in the
less-steel material and manufactured using laser-drilling x and y directions, and the perfectly matched layer was
technology. At first, this metamaterial sensor was simu- used in the wave propagation direction of z. As shown in
lated and analyzed using the finite integral method, and the upper right corner of Fig. 1a, the wave vector of the

Fig. 1  a Three-dimensional array diagram and cell structure diagram of the biosensor. The structural parameters are Px = 500 μm, Py = 300 μm,
L = 294 μm, H = 60 μm, R = 60 μm. b Simulated transmission of the biosensor
 Wang et al. Nanoscale Res Lett (2021) 16:109 Page 3 of 10

incident electromagnetic field kz was a plane wave propa- metamaterial biosensor by adjusting the length of the
gating in the z-axis, and the electric and magnetic fields hollow dumbbell L and the gap of the hollow dumbbell
were polarized along the y-axis and x-axis, respectively. H.
As shown in Fig.  1b, there was a transmission peak at It is also very important to study the influence of the
0.48 THz. incident angle and the polarization angle on the trans-
To study the physical mechanism of this resonance mission spectra. The electromagnetic wave was vertically
peak’s generation, the biosensor’s surface current and incident, and then the incident and polarization angles
magnetic field at the resonance peak frequency were were changed. The definition of these angles is shown
simulated. As shown on the left side of Fig.  2, the inci- in Fig. 4a. The incident angle means θi in the y–z plane,
dent electromagnetic waves were polarized along the and the polarization is θp in the x–y plane. As shown in
y axis, inducing charge oscillations at both ends of the Fig. 4b, when the incident angle changed from 0° to 15°,
opening, resulting in an electric dipole. The charge oscil- the difference of the resonance peak’s frequency was only
lations were accompanied by counter-rotating current 9 GHz. As shown in Fig. 4c, when the polarization angle
oscillations along the rims of the two circular holes that increased from 0° to 15°, the difference in resonance peak
comprised the apertures. This led to a pair of counter- frequency was almost 0  GHz, but the resonance peak
oriented out-of-plane magnetic dipoles. As shown on the amplitude decreased by about 0.1. This showed that the
right side of Fig. 2, there was a pair of obvious opposite biosensor was almost insensitive to changes in the inci-
magnetic dipoles in the z axis connected end to end to dent and polarization angles, which is beneficial for prac-
form a toroidal dipole. Therefore, the metamaterial’s tical biosensor applications.
response was dominated by a combination of electric and To explore the biosensor’s sensing performance, a 120-
toroidal dipoles. μm thin layer of analyte was added to this metamaterial
Because the performances of the sensor are affected biosensor as shown in Fig.  5a, then different transmis-
by the structure parameters, it is necessary to optimize sion spectra of this metamaterial biosensor was simu-
the structural parameters during the design procedure. lated when the refractive index of the analyte changed as
Figure 3 shows the effect of the structural size changes shown in Fig. 5b. The RI sensitivity S was defined as the
on the transmission spectra. As shown in Fig. 3a, when ratio of the variations in the transmission peak position
the length of the hollow dumbbell increased from 290 to the RI unit (S = Δf/Δn). As the analyte’s RI increased,
to 298  μm, the peak frequency of the transmission the resonance peak frequency red-shifted. Then the res-
spectra red-shifted from 0.48 THz. As shown in Fig. 3b, onance peak frequency shift corresponding to each RI
when the gap of the hollow dumbbell increased from 56 was collected. Good linearity was observed. The fitting
to 64 μm, the peak frequency of the transmission spec- result in Fig.  5c shows that the sensitivity to the RI was
tra blue-shifted from 0.48 THz. As L and H increased, 294.95 GHz/RIU.
the resonance peak started to move toward the low The sensing performance was also quantified using the
frequency and high frequency, respectively. When the figure of merit (FOM), which was defined as:
circle’s radius varied from 56 to 64  μm and the thick-
S
ness of the stainless-steel varied from 40 to 60 μm, the FOM = (1)
position of the resonance peak slightly changed. There- FWHM
fore, it is easier to adjust the resonant frequency of the

Fig. 2  Simulated surface current distribution diagram and magnetic distribution diagram (y = 0 μm) at 0.48 THz
Wang et al. Nanoscale Res Lett (2021) 16:109 Page 4 of 10

Fig. 3  Transmission spectra of a different length L, b gap H, c radius R, and d stainless steel plate thickness

where S is the sensitivity and FHWM is the full width at To further investigate the biosensor’s sensing principle,
half maximum of the resonance peak. The FOM of this the electric field distribution diagrams were simulated, as
biosensor was 4.03. shown in Fig. 7. The top and side views of the simulated
For most metamaterial structures, they usually use die- electric field distribution demonstrated that the electric
lectric materials as the substrates. However, this metama- field energy was mainly concentrated in part of the stain-
terial biosensor proposed in this paper was based on an less-steel holes. Therefore, it is crucial to make sure that
all-metal metamaterial with an all stainless-steel design the analyte was added into the holes.
and the air was used as the substrate. Compared with tra- Table 1 summarized the proposed sensor’s RI sensitiv-
ditional dielectric materials, such as polyethylene tereph- ity and FOM, and compared them with other reported
thalate (PET), quartz, and silicon, the air has the lowest studies [35–37]. The other THz sensors are all based
RI. To evaluate the role of the substrate, these metamate- on traditional photolithography processes. It can be
rial biosensors were simulated again using different sub- seen that the stainless-steel metamaterial biosensor we
strates, and the refractive index sensitivities and FOM designed had excellent sensing performance using cheap
values were calculated subsequently. As shown in Fig. 6, laser-drilling technology.
as the RI of the substrate increased, the sensor’s RI sen-
sitivity and FOM began to decrease. This result indicated
that the biosensor with a lower substrate RI had a better
sensing performance.
 Wang et al. Nanoscale Res Lett (2021) 16:109 Page 5 of 10

Fig. 4  a Schematic diagram of changing incident angle θi and polarization angle θp. Transmission spectra versus b the incident angle and c the
polarization angle

Experiment process of adding and drying the protein. As shown in

Materials and sample preparation Fig.  9a, the stainless steel sheet was clean, and then as
Then in order to demonstrate the biosensing ability of the shown in Fig. 9b, the BSA solution of one concentration
proposed THz mmetamaterial sensor, protein detection was added to the stainless-steel sheet’s surface, and the
was performed in the experiment. BSA and PBS buffer solution stayed on this biosensor’s surface and did not
were both purchased from Sigma-Aldrich. The BSA solu- pass through the holes due to the effect of water surface
tion was formulated in PBS buffer (pH = 7.4). tension. After heating and drying, a thin layer of the BSA
A microscope image of the fabricated metamaterial film was formed as shown in Fig. 9c.
biosensor is shown in Fig. 8. The overall size of the meta- In order to observe the situation inside the stainless-
material biosensor was 12 mm × 12 mm. steel’s holes, one side of the stainless-steel was cut off,
The concentrations of the formulated BSA solution so that one side of the holes was revealed and observed
were 0.2  mg/mL, 0.5  mg/mL, 2.0  mg/mL, and 4.0  mg/ with a microscope. As shown in Fig. 9d–g, when the BSA
mL. The analyte was added to the biosensor surface by solution was dripped and dried, a thin layer of the BSA
liquid deposition method. Each time, 150 μL BSA solu- was added into the stainless-steel’s holes, which is mainly
tion was transferred to the biosensor surface with a because the diameter of the holes is much larger than the
pipette gun, and the biosensor was dried on a 40 ℃ heat- size of the BSA proteins. This proves that the analyte to
ing table. When the biosensor was heated at 40 ℃, the be detected can enter the detection sensitive region of
protein film formed faster and more uniformly. Each time our biosensor, which can greatly increase the sensitivity
before changing different concentrations of BSA solution, of this metamaterial biosensor.
the stainless-steel sheet was put into deionized water
and vibrated in an ultrasonic vibrator to ensure that the Spectral measurements
protein film from the previous process is cleared and the All the spectral measurements were conducted using a
surface of this mmetamaterial biosensor is clean. Figure 9 continuous-wave THz spectroscopy system (TeraScan
showed the pictures and the microscopy pictures of the 1550, Toptica Photonics AG). The system consisted of
Wang et al. Nanoscale Res Lett (2021) 16:109 Page 6 of 10

Fig. 5  a Cross-sectional view and top view of the metamaterial biosensor model diagram with a 120-μm thin layer of analyte. b Influence of the
changes in the analyte’s RI on the biosensor’s transmission spectra. c Corresponding linear fit of the peak’s frequency shift with the corresponding RI

shown in Fig. 10. THz waves were collimated and focused

on the sample through the 90° off-axis parabolic mir-
rors. All transmission spectra were obtained by scanning
between 50 and 1220 GHz in step sizes of 40 MHz with
an integration time of 10  ms operating in the fast scan
mode to reduce the scanning time. The polarization of
the terahertz wave was along the dumbbell ring’s opening
direction.

Experiment results and discussion

The protein detection experiments of the metamaterial
biosensor were carried out with four concentrations of
the BSA solutions. Throughout the experiments, each
group of BSA solutions was added in order from low to
Fig. 6  The sensitivities and FOMs when different substrates are used high. All the measurements were repeated three times.
As shown in Fig. 11a, as the concentration of the BSA
solutions increased, the resonance peak frequency red-
shifted. This trend is consistent with the simulation
dual-laser control (DLC) smart electronics, two distrib- results. The decrease in the intensity of the resonance
uted feedback (DFB) lasers, two fibre-coupled InGaAs was due to the absorption of the terahertz wave by the
photomixers, and four 90° off-axis parabolic mirrors as BSA protein.
 Wang et al. Nanoscale Res Lett (2021) 16:109 Page 7 of 10

Fig. 7  Simulated electric field distributions. a Top view, b side view (y = 0 μm)

Table 1  Comparison of various terahertz sensors [BSA]n

f = fmax ·   (2)
Sensitivity Wavelength FOM RI range of References KD + [BSA]n
(GHz/RIU) band (THz) analyte
where the maximum peak frequency shift Δfmax is the
182 0.6–1.2 – 1.0–1.5 [35]
saturation value, [BSA] is the concentration of the BSA
76.5 0.4–1.2 1.67 1.0–2.0 [36]
solution, n is the Hill coefficient, and KD is the dissocia-
74 0.2–1.0 1.23 1.0–2.0 [37]
tion constant.
294.95 0.2–0.7 4.03 1.0–1.4 This paper
Using the fitting curve as shown in Fig.  11b, the Hill
coefficient n was calculated to be 0.83, and the disso-
ciation constant KD was calculated to be 2.87  mg/mL.
Furthermore, Δfmax was approximately 166  GHz, which
indicated the maximum peak frequency shift at the
saturation concentration. The Hill fitting results of the
resonant frequency peak confirmed the experiment’s reli-
ability and accuracy.
The biosensor’s sensitivity S was deduced as follows
[41]:
�fmax
S= (3)
δmax
where Δfmax is 166 GHz and δmax is the BSA’s surface den-
sity. δmax was determined by [41]:
MBSA
δmax = 2 (4)
NA × PBSA
Fig. 8  Micrograph of the fabricated biosensor sample
where MBSA = 66,430  g/mol is the estimated molecular
mass of BSA [42], NA = 6.02 × ­1023  ­mol−1 is Avogadro’s
number, and PBSA = 6.96 nm [43] is the average length of
The relationship between the frequency shift and the one BSA molecule. δmax was 2.28 ng/mm2 and the biosen-
concentration of the BSA solutions is not linear, which sor’s BSA detection sensitivity was 72.81 GHz/(ng/mm2).
is common in biological experiments [38, 39]. The Hill KD obtained using the Hill model showed that the dis-
model can characterize the binding ability between our sociation constant was strongly related to the BSA, and
metamaterial biosensor and biomolecules. Therefore, the limit of detection (LOD) Clim of the BSA was calcu-
the Hill model [40] was used to fit the experimental data, lated using the following equation [44]:
as shown in Fig.  11b. The Hill equation is described as Sf
follows: Clim = KD × (5)
fmax − Sf
Wang et al. Nanoscale Res Lett (2021) 16:109 Page 8 of 10

Fig. 9  Pictures of the stainless-steel in different testing steps: the metamaterial biosensor after a ultrasonic cleaning and drying, b adding 150 μL
BSA solution (0.2 mg/mL), and c drying; Microscope photos of the stainless-steel sheet’s d sidewall and e surface before adding BSA; Microscope
photos of the stainless-steel sheet’s f sidewall and g surface after adding and drying the BSA solution (0.2 mg/mL)

was obtained. Compared with Refs. [45–47], a relatively

higher frequency change was achieved at the same BSA
concentration. The Hill’s formula was applied to analyze
the metamaterial biosensor’s data. The calculated LOD
of 0.035 mg/ml was significantly better than that in Ref.
[45]. All these predict that our proposed all-metal THz
metamaterial biosensor will have excellent performance
in many biological and chemical applications.
Based on the excellent sensing performance of stain-
less steel biosensor, the stainless steel biosensor can be
modified with specific antibody to achieve specific anti-
gen detection in the future. And the thickness of stainless
steel biosensor is only 50  μm. With the development of
Fig. 10  Schematic diagram of the continuous-wave THz microfluidics technology and terahertz spectroscopy, it
spectrometer used in our experiments
is hopeful to apply real-time measurement in vivo in the
future.

where Sf is the spectral resolution of 2 GHz. Equation (5)

shows that smaller dissociation constant resulted in Conclusion
a lower detection limit. Thus, Clim was calculated to be In conclusion, a terahertz biosensor based on an all-
0.035 mg/mL. metal metamaterial was used to measure protein con-
Table  2 shows our biosensor’s BSA sensing perfor- centrations. The biosensor was made of stainless-steel
mance compared with those reported studies. In the and prepared via laser-drilling technology. The maximum
experiment, the lowest concentration of the BSA solu- RI sensitivity and FOM calculated using CST electro-
tion was 0.2 mg/mL and a frequency change of 10.8 GHz magnetic simulation software are 294.95  GHz/RIU and
 Wang et al. Nanoscale Res Lett (2021) 16:109 Page 9 of 10

Fig. 11  a Measured spectra with different BSA concentrations. b Hill fit of the BSA experiment

Table 2  Comparison of various biosensors for detecting BSA

BSA detection sensitivity Frequency shift (GHz)/lowest Limit of detection (mg/ Wavelength band References
concentration (mg/mL) mL) (THz)

1.43 GHz/(mg/ml) 50/49.8 1.18 1.0–1.7 [45]

– 2/0.1 – 0.6–1.0 [46]
– 300, 400/9 – 0.1–1.4 [47]
72.81 GHz/(ng/mm2) 10.8/0.2 0.035 0.2–0.7 This work

4.03, respectively. The sample was characterized using the authors reviewed the manuscript. All authors read and approved the final
manuscript.
a continuous-wave THz spectrometer. The experimen-
tal results showed that, for the BSA analyte solution, the Funding
detection sensitivity and detection limit are 72.81  GHz/ This work was supported by the National Natural Science Foundation of China
(61875251, 61875179), the Fundamental Research Funds for the Provincial
(ng/mm2) and 0.035  mg/mL, respectively. This biosen- Universities of Zhejiang (2020YW08) and the Outstanding Student Achieve-
sor has advantages of small shape, high detection sensi- ment Cultivation Program of China Jiliang University (2019YW27).
tivity, low detection limits, reusability, easy to fabricate
Availability of data and materials
and cost-effective. These research results are of consider- All data are fully available without restriction.
able significance for future applications in biomolecular
detection and disease diagnosis. Declaration

Competing interests
The authors declare that they have no competing interests.
Abbreviations
THz: Terahertz; RI: Refractive index; FOM: Figure of merit; BSA: Bovine serum
Author details
albumin; PET: Polyethylene terephthalate; DLC: Dual-laser control; DFB: Distrib- 1
 Institute of Optoelectronic Technology, China Jiliang University, Hang-
uted feedback; LOD: Limit of detection.
zhou 310018, China. 2 Zhejiang Chinese Medical University, Hangzhou, China.
3
 Centre for THz Research, China Jiliang University, Hangzhou 310018, China.
Acknowledgements 4
 Lab of Terahertz Photonics, China Jiliang University, Hangzhou 310018, China.
We thank the Centre for THz Research, China Jiliang University for the use of
their equipment.
Received: 23 March 2021 Accepted: 21 June 2021
Authors’ contributions
FZ conceived the research and supervised the whole work, GW conducted
simulations, experiment and analyses, and wrote the draft of the manuscript.
TL and ZH assisted in the analysis and revised the manuscript. JL and JQ
assisted in fabrication of metamaterials and experimental measurement. All
Wang et al. Nanoscale Res Lett (2021) 16:109 Page 10 of 10

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