Abstract
1. INTRODUCTION
The terahertz (THz) wave lies between microwave and infrared waves, and it normally refers to the electromagnetic waves covering the frequency of 0.1–10 THz () [1], corresponding to the wavelength range of 0.03–30 mm. It can be characterized by high penetration to non-polar dielectric materials [2], so it is very convenient to operate perspective detection of materials inside non-transparent packaging materials [3,4]. The THz wave is also coherent, and its spectrum contains both amplitude and phase information, which can effectively obtain the dielectric coefficient and attenuation characteristics of the analytes in the THz regime. Since THz waves have the characteristics of non-ionization and non-invasion, they will not do damage to the analytes and target samples, which opens a novel feasible way for THz label-free detection. In recent years, with the continuous development of THz technology, as well as the innovation of efficient emission sources and sensitive detectors suitable for THz frequency region, THz science and technology have entered a stage of rapid development. Commercial THz time-domain spectroscopy (THz-TDS) also helps bridge the THz gap in many applications related to the THz band. These advances have been widely used in the area of astronomy [5], communications [6], food safety [7], and defense [8]. Particularly, the quantitative and qualitative analysis of biomedical macromolecules can be achieved by utilizing the molecule THz fingerprint, combined with the amplitude of the fingerprint spectrum peak [9]. This is because the vibration caused by the vibration mode of many biological molecules, the photon modes of crystals, the skeleton vibration mode of organic molecules, and the weak intermolecular interactions (hydrogen bonding and van der Waals forces) usually falls in the THz regime (Fig. 1). It is helpful to reveal the composition of the substances, the structure of the molecules, and the relevant physicochemical properties. Therefore, the THz sensing technique established by THz waves as the signal source has developed into one of THz application technologies, and especially its unique advantages in biomedical molecule detection and analysis have aroused strong interest and widespread attention of researchers in related field.
Figure 1.THz gap in the electromagnetic spectrum and corresponding vibration mode of biological molecules.
THz-TDS is widely used in many applications related to the THz band. The detection principle of the THz-TDS system is that the amplitude and phase information of the electric field of the analytes in a certain frequency region can be obtained through time-domain signal acquisition and Fourier transform. Specifically, by acquiring the THz reference signal without analytes and the THz sample signal with analytes, and then performing the Fourier transform on them, respectively, the spectral information can be obtained, and furthermore, the absorption coefficient and refractive index of the analytes and other optical parameters can be calculated. The THz-TDS system can avoid the use of the complex Kramers-Kronig relationship to realize the effective extraction of the analytes’ absorption coefficient and refractive index, which has the characteristics of high signal-to-noise ratio, good stability, and rich acquisition of information [10]. Since the vibrational and rotational energy levels of many biomolecules are located in the THz regime, the use of THz-TDS for biomedical detection is advantageous. For instance, by tableting the analytes and then putting them in the THz-TDS, the analytes’ THz fingerprint and other parameters can be obtained. At present, the use of the characteristic fingerprint spectrum of the substance has been realized for the detection of pesticides [11], antibiotics [12], biotoxins [13], amino acids [14], sugars [15], and other biochemical molecules, supplemented with the density functional theory to analyze the vibration modes of molecules [16], which provides the basis of the qualitative detection of the analytes, and combined with the Beer–Lambert law they can be realized corresponding to the quantitative analysis of the substance. Since the macroscopic properties of substances are related to the composition and structure of substances, by analyzing the THz vibrational properties of target molecules, the relationship between the macroscopic spectral response parameters of targets and their microscopic composition, structure, and physicochemical properties can be constructed, which can be used to assist in the analysis of the biochemical functions of molecules.
The spectral signals obtained by THz fingerprint spectroscopy are derived from the interaction of the analytes with THz waves. However, conventional detection methods have the deficiency of poor detection results, sophisticated systems, and higher limit of detection (LoD). Thus, the THz sensing technology based on the absorption properties of analytes needs a sufficient number of samples to obtain reliable characteristic signals when used for biochemical molecular detection and property analysis, and it cannot realize the analysis of trace substances. There is an urgent need to introduce a physical mechanism that enhances the interaction of the material to be measured with electromagnetic waves in order to meet the real demand for trace detection.
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In parallel to rapid development of THz technology, metamaterials are the artificial materials that have been unearthed in left-handed materials [17]. This kind of artificial material can produce specialized properties that are not found in natural materials, such as a negative refractive index [18–22] and negative magnetic permeability [23], and has attracted extensive attention from scientists due to its special properties. These special electromagnetic phenomena act on and interact with special dielectric materials, which can produce more exotic electromagnetic phenomena. Metamaterials have a wide range of uses and can be applied to perfect absorption [24–26], electromagnetically induced transparency [27–29], and other directions of research. A metasurface is a two-dimensional planar structure possessing the properties of a three-dimensional metamaterial with a periodic arrangement of unit structures on a two-dimensional plane with a subwavelength thickness [30]. Due to the different arrangements and combinations of the periodic structures of the metasurface, it has the ability to manipulate light–matter interaction in both linear and non-linear regimes [31,32]. The nature of the structure of the metasurface is determined due to a combination of multiple factors, which are related to the size, shape, and arrangement pattern of the periodic arrangement of the metamaterial structure, in addition to the dielectric material that constitutes the metasurface itself. The flattened design of the metasurface structure makes it easier to be prepared for practical processing and greatly facilitates experimental work.
THz metamaterials consist of periodically and uniformly distributed subwavelength structural units that can flexibly and effectively manipulate the transmission and localization properties of THz waves [33–35]. In recent years, the development of THz technology has played an important role in the development of metamaterials technology and has now entered the “era of metasurface.” THz resonant devices represented by THz metamaterials are widely used in THz performance enhancement of sensing research (also called the metasensor) due to their flexible design, versatile functions, convenient operation, and obvious electric field enhancement effect. One of the most critical characteristics that determines the performance of the THz metasensor is the different target information and corresponding sensing principle. From the perspective of this, the THz metasensor can be divided into a target subject to a featureless refractive index-type sensor, which is not specific to the THz wave, and a target subject to a molecular information-type sensor, which is related to THz spectroscopic fingerprints or chirality, as shown in Fig. 2.
Figure 2.Principles of the metasensor for versatile THz detection techniques.
Specifically, when the THz fingerprint spectrum of the substance is not obvious or does not match the characteristic peaks of the THz metasensor, the refractive index of the substance can cause frequency drift and amplitude change, which can be analyzed and demonstrated from different localized resonant modes and specificity by material modification. When the THz fingerprint spectrum of the substance matches the characteristic peaks of the THz metasensor, it can cause a drastic change in amplitude in a high dielectric metasurface/plasmonic nanostructure or an absorption-induced transparency enhancement in a plasmonic metasurface. A broadband fingerprint spectrum of the trace analyses can be amplified by using the array multiplexing technique, in which a series of resonance peaks generated by multiple unit-structured metasurfaces of different sizes or incident wave angles are utilized to enhance the interaction between the THz wave and the analyte. The envelope is the boosting line shape of the absorption spectrum of the analyte. Finally, THz chiral spectroscopy and sensing technology show the importance of the identification and structural characterization of chiral molecules subject to chiral metamaterials. Figure 3 summarizes how several sensing principles of THz metasensors depend on different target information.
Figure 3.Diagram principle of THz trace detection for different target information by metasensors.
The primary strategy for metasensing is based on changes in refractive index contrast due to the lack of THz spectroscopic features, which exhibits a high resonance in the THz range. When a biochemical medium is intentionally introduced in the vicinity of the metasensor, the dielectric environment and electromagnetic boundary conditions are changed, resulting in a resonance shift. Such THz refractive index metasensing techniques have been widely discussed and can offer an excellent sensitivity. However, as Markelz and Mittleman mentioned in the review article [36], some related claims should be skeptical. For instance, specific recognition of different kinds of avian influenza viruses can be realized by a metasensor based on a nano slot-antenna array [37]. Featureless permittivity spectra cannot be distinguished with each other by measuring resonance values at resonant frequency. So the discussion and review of THz metasensors responses that can offer molecular specificity are extremely important to clarify the above unsubstantiated claims and skepticism. In addition, it is also vital to make a clear distinction between the featureless refractive index and molecular feature metasensing. We note that most past review articles have demonstrated THz metasensors in terms of their structures, applications, or materials [38–43]. Unlike other review articles, this review on metasensors will be driven by discriminating the real information (featureless refractive index or molecular information) in biochemical molecule detection. Table 1 summarizes different target information detections with THz metasensors, listing their highlights and concerns. For featureless refractive index metasensing, we see different resonant modes from metallic/dielectric metasensors with strong local electric field and high sensitivity. However, this scheme offers little specificity since the measured target information is the average refractive index at the resonant frequency of the metasensor. In addition, by using specific different assisted-material chemical modification techniques, such a modified metasensor can achieve enhanced specific detection of a given target. However, this approach is not specific to THz sensing, and so it is unclear if it offers greater improvement compared to other frequencies. To investigate molecular information, the primary method for enhanced responses is based on resonance matching between the structure and target analyte. In this case, stronger amplitude/frequency change can be observed compared with that of the mismatching case. Meanwhile, destructive interference between the broadband oscillations in the metasensor interacting with the narrowband oscillations of the analyte can also result in induced narrowband transparency within the broadband absorption phenomenon [or the absorption induced transparency (AIT) effect, in some work it was also called hybridization induced transparency]. The physical origin behind both effects is unclear. The primary explanation is that dramatic amplitude/frequency change is due to interaction of the narrowband metasurface with broadband absorption line of analyte and AIT is due to the coherent coupling of a broadband mode of the metasurface to a narrowband mode resonance of the analyte [44]. However, additional shifting of the metasurface resonance due to the nondispersive component (real permittivity) of the analyte and fabrication error make it difficult to match the metasurface resonance with the resonance frequency of the analyte covered system. To enhance broadband THz spectroscopic fingerprints, a multiplexing array can be used due to strong light–matter interaction between a series of narrowband resonant peaks of metasurfaces with broadband mode resonance of analytes. But metasensor fabrication/manipulation is complex. Particularly, to acquire chiral molecular information, chiral metamaterials and corresponding enhanced THz polarization/chiral spectrum techniques have emerged as an effective approach for the detection of chiral enantiomers of biochemical substances. In this case, the standard THz-TDS system is modified to the THz time domain polarization spectroscopy system to obtain polarization/chiral characteristics. We clarify the ideas and methods to achieve important technological breakthroughs at this stage and look forward to the future development of THz trace metasensor technology. Highlights and Concerns of Different Target Information Detections with THz MetasensorsAnalyte Information Principles Highlights Concerns Featureless Refractive index Sensitivity enhancement by different localized mode High sensitivity depending on high Without fingerprint spectrum information Specifically modified by different material Specific detection due to material-target binding Not specific to THz wave, lacking spectroscopic fingerprints Molecular structure Narrow fingerprint match Specific fingerprint detection for certain frequency Matching between the structure and target analyte Multiplexing Broadband fingerprint spectrum amplitude enhancement Complex metasensor fabrication/manipulation Chirality Specific circular dichroism/chiral spectrum by chiral metasensor Complex experiment setup, chiral molecule selectivity
2. THEORETICAL BACKGROUND OF METASENSORS
A. Sensitivity
The introduction of a biochemical medium in the vicinity of the metasensor can cause a resonance shift due to the changed dielectric environment, which can be stated by the perturbation theory. The electromagnetic boundary conditions are changed when a sample is intentionally introduced, and as a result the resonant frequency and the quality factors are changed [45]. The change in resonant frequency as a function of an average dielectric of the material is regularly used to quantify sensitivity (), which is defined by , where and denote the relevant resonant frequency shift and the refractive index variation, respectively. In order to get quantification of sensing capability, in some literatures a normalized sensitivity can also be defined as (, per refractive index unit), where is the resonant frequency [46]. More generally, sensitivity can also depend on parameters such as concentration or thickness. The reduction in amplitude is associated with the dielectric loss of the material [47]. In some occasions, the parameter used for sensing is the change in the amplitude of a peak or a dip in the spectrum, and the sensor quality is measured with the amplitude sensitivity. Quality factor () is also associated with the dielectric loss and can be expressed as , where FWHM is the full width at half-maximum of the resonance peak. High does not ensure a high sensitivity, which depends on whether the mostly confined electromagnetic fields are fully overlapped with the analyte. A figure of merit (FoM) defined by the ratio of the sensitivity to the FWHM of the resonance is usually used to evaluate the actual device performance ().
For metasensors combined with a waveguide cavity system, the effective index change of the mode in the waveguide is related to the electric field intensity with the following equation [48]:
B. LoD
The LoD is defined as the smallest concentration of an analyte that can be reliably detected, where reliable detection means the sensor response should be different from that of blank/reference [50]. Analytical LoD can be calculated according to 3s/m method [51]:
For the nonlinear calibration/fitting curve, the Hill model was used to fit the relationship between biomolecular concentration and resonance frequency shift. The Hill model can be described as [53,54]
C. Complex Dielectric Constant
The Lorentz model explains much of classical optics via a physical picture borrowed from mechanics. The starting point is the description of electrons connected to nuclei. Thus, the incident electric field displaces the electrons with a restoring force tethering them to the nucleus. The Lorentz model can explain much of dielectric constant of the target materials. The Lorentz dispersion model is expressed by [55]
3. METASENSORS BASED ON FEATURELESS REFRACTIVE INDEX CHANGE
As we cover the analyte with a specific dielectric constant on the metasensor when the resonance peaks do not match the fingerprint spectrum or the analytes do not show obvious THz fingerprint spectrum, the detection using THz metasensors is mainly based on the change of the equivalent dielectric constant of the target on the surface of the metasensor, i.e., the refractive index of the target mainly changes the frequency of the resonance peaks whereas the extinction coefficient mainly changes the intensity of the resonance peaks. The detection focuses on the change of the frequency of single or multiple resonance peaks of the metasensor to realize the sensitive perception of the refractive index information of the substance at the point of resonance frequency. When the metasensor is used for substance detection and analysis, it can significantly enhance the interaction of THz waves with the substance at the resonance frequency and improve the sensitivity of detection. In the last decade, researchers have carried out a lot of work to improve the sensitivity and selectivity of THz metasensors in terms of optimizing the stronger localized resonant modes and material (receptor) assisted specific recognition. In this section, we introduce the enhanced THz metasensor technology induced by featureless refractive index change from the above two perspectives.
A. Stronger Localized Resonant Modes
THz metasurfaces are developed as a promising device to boost the interaction between targeted samples and THz waves, thus improving the sensitivity. Depending on the mechanism of resonance generation, metallic metasurfaces can be classified into several types due to different excited modes: inductor−capacitor (LC) [56,57], spoof localized surface plasmons [58–60], surface plasmons [61,62], lattice [63], toroidal modes [64–66], electromagnetically induced transparency (EIT) [67], Fano mode [68,69], anapole [70,71], quasi-bound states in the continuum [72,73], exceptional points due to parity-time symmetry [74], etc. For instance, Xu
Figure 4.(a) Microscopic image of dual-torus toroidal metasensor and experimentally measured transmission spectra of mixed ethanol-water [64]. (b) Schematic model of the engineered cross-polarization four-arrowhead plasmonic nanostructure and transmittance spectra of a coronavirus-infected patient with a CT value of 21 [56]. (c) Schematic diagram of THz all dielectric metamaterial absorber and transmission spectra of chlorpyrifos with different concentration [75]. (d) Schematic diagram of the metasurface metal-insulator-metal (MIM) waveguide structure and experimental reflection spectra under refractive index variations [46]. (a) Reprinted with permission from Ref. [64], copyright 2021, John Wiley; (b) reprinted with permission from Ref. [56], copyright 2022, American Chemical Society; (c) reprinted with permission from Ref. [75], copyright 2020, Elsevier.
B. Material (Receptor) Assisted THz-Specific Chemical Modification Techniques
In order to enhance the specificity, THz metasensors can be combined with other functional materials, which can enhance the detection specificity toward biochemical molecules. Some functional materials produce extremely high specificity through modification. For instance, molecule-specific THz metamaterials can be realized by decorating antibodies or aptamers on their interfaces or by using functionalized nanoparticles with a high refractive index. Aptamers endow hydrogels with the ability of highly specific human -thrombin (-TB) molecular recognition owing to high affinity for -TB molecules. In this section, we show how the materials modified on the surface of metasensors can achieve detection specificity for a given target.
1. Metallic Nanoparticles (AuNPs)
THz metasensors coupled with nanoparticles were developed for detecting RNA and protein [87–90]. As shown in Fig. 5(a), when metamaterials are linked to a large refractive index metallic nanoparticle, remarkable frequency shifts are produced [87]. Such nanoparticle-Trigger miRNA complexes were formed when Trigger miRNA molecules were subsequently conjugated to metallic nanoparticles (AuNPs). The THz metasensor presents good detection sensitivity with a limit of detection of 14.54 aM (). In addition, the frequency shift of the target miRNA and Mix B (including miRNA) sample was significantly greater than those of other RNA, demonstrating good specificity for detecting miRNA-21 in the presence of potential interferences, as shown in Fig. 5(a). A similar approach has been used for the sensitive, specific detection of the neo-coronavirus SARS-CoV-2 spike protein, and the LoD can reach 4.2 fM [88].
Figure 5.Strategy and specificity of employing different materials modified with metasensor to achieve analyte-specific binding: (a) metal nanoparticle [87]; (b) graphene [91]; (c) antibody [92]; (d) hydrogel [93]; (e) MIP [94]. (a) Reprinted with permission from Ref. [87], copyright 2021, Elsevier; (b) reprinted with permission from Ref. [91], copyright 2021, Elsevier; (c) reprinted with permission from Ref. [92], copyright 2022, Elsevier; (d) reprinted with permission from Ref. [93], copyright 2021, American Chemical Society; (e) reprinted with permission from Ref. [94], copyright 2023, Elsevier.
2. Graphene
As a special two-dimensional nanomaterial, graphene can not only efficiently identify trace chemical elements but also achieve specific recognition through surface modification [91,95–99]. Different substances have different chemical doping effects on graphene, and the off-domain -electrons on the surface of graphene can interact strongly with molecules with large -bonds [95]. As shown in Fig. 5(b), graphene-functionalized THz complementary asymmetry split ring metamaterials may sensitively reveal trace DNA molecule-induced variations through stacking between them. The LoD of 100 nM DNA short sequences can be successfully realized. The comparative tests for other kinds of DNA also verified that this method can be used to specifically recognize target DNA sequences of E. coli O157:H7 with high selectivity. Xu
3. Antibody
The functionalization of the metamaterial surface also enables the sensor to carry out specific immune detection [92,100–102]. For example, an antibody modified on a THz metasensor [Fig. 5(c)] consisting of square and circle split-ring-resonators array was proposed to detect cancer biomarkers (CA125). The sensitivity modified by Anti-CA125 was 4.526 GHz/lg (U/mL), and the LoD reached 0.01 U/mL [92]. The functional modification steps are shown in Fig. 5(c). Experimental results verify that the sensor modified by Anti-CA125 had a specific recognition for CA125. In 2021, they also proposed an antibody modified THz metamaterial biosensor to detect the concentration of carcinoembryonic antigen (CEA) [100]. The sensitivity can achieve 76.5 GHz/RIU, and the LoD can reach 0.1 ng/mL. A similar method can also be pioneered to achieve specific detection of the target virus (ZIKV envelope protein) by using the immune binding effect between antibodies and viruses [101]. More recently, experiment results showed that halloysite nanotubes (HNTs) can selectively adsorb biomolecules and exhibit good biocompatibility. The HNTs can improve the sensitivity of the sensor and have specific sensing ability after the addition of antibodies [102].
4. Hydrogel
A molecular-specific THz metasensor was presented by functionalized aptamer hydrogels [shown in Fig. 5(d)], which are three-dimensional hydrophilic and insoluble polymeric networks [93,103]. The binding reaction between -TB and hydrogels alters the crosslinking density of aptamer hydrogels and enriches -TB molecules in the hydrogel matrix. The sensing performance (LoD) of this biosensor can reach 0.21 pM [93]. Then, the specificity was investigated by comparing the signal variation of -TB with other samples. The method is promising for developing a molecule-specific THz biosensor applicable to aqueous environments. Similarly, to avoid aqueous solvents (blood serum) interference, THz hydrogel-functionalized metamaterial was used to specifically detect the glucose in water with a sensitivity of 0.0446 dL mg−1 and a detection limit of 1.64 mg dL−1, as well as glucose in human serum and in human sweat, which has a potential application in wearable devices [103].
5. Molecularly Imprinted Polymers
As the final example, a rapid detection method based on molecularly imprinted polymers (MIPs) was developed for detecting the -propanol gas, which has been paid attention to in environmental monitoring and exhalation of lung cancer patients [94,104]. The MIP modified metasensor was placed in the closed testing chamber and installed in the THz-TDS system. When -propanol MIP is contacted with -propanol gas, the –CHO group of -propanol is linked to the –COOH group of MIPs through hydrogen bonds, causing free -propanol gas to bind to the MIP. Since the MIP adsorbed with -propanol changes the dielectric environment of the sensor, the resonance frequency of the sensor also changes. The experimental results showed that the sensor can effectively detect the -propanol concentration in the range of 50–500 ppm (parts per million). In addition, the non-imprinted polymer (NIP)-modified sensor has a small response to all gases and cannot differentiate between them. However, the MIP modified sensor was only more responsive to -propanol and less to other gases, demonstrating the specificity of the MIP and providing a new idea and method for the sensitive and specific detection of -propanol gas.
For other specific applications, Seto
C. Discussion
The THz refractive index metasensor is mainly based on the change of the equivalent dielectric constant of the target on the surface of the metamaterial, i.e., the refractive index of the target mainly changes the frequency of the resonance peaks while the extinction coefficient mainly changes the intensity of the resonance peaks. The detection focuses on the change of the frequency of single or multiple resonance peaks of metamaterials in order to realize the sensitive perception of the refractive index information of the substance at the resonance frequency points. However, due to the small refractive index difference of substances in the limited THz frequency band and the influence of the refractive index change brought by non-targets, this sensitive detection loses the information of the THz fingerprint spectrum of substances, resulting in poor detection specificity and great challenges when used for the detection of a mixture of substances. Material modified molecular methods can realize specific sensitive detection, but the detection specificity is completely determined by the functional material, which is unable to respond to the characteristic absorption information of the substance to be tested in the THz frequency band, and the sample processing is complicated.
4. METASENSORS BASED ON RESONANCE MATCHING BETWEEN THE STRUCTURE AND TARGET ANALYTE
If the design of the resonance mode realizes an effective match with the absorption resonance mode of the target molecule, the ability to perceive the characteristic absorption of the substance can be enhanced. The phenomena either dramatically change the peak intensity or frequency shift of the resonance or AIT. In this section, we discuss these two phenomena in more detail.
A. Amplitude/Frequency Change Enhancement
Recently, the high dielectric metasurface or plasmonic nanostructure has significantly enhanced the absorption cross-section of the substance, improved the detection specificity, and enhanced the ability to recognize the substance. For a plasmonic nanostructure, Lee
Figure 6.Significant amplitude/frequency shift change induced by fingerprint. (a) Schematic diagram of sugar molecules using the nano-antenna array-based metamaterial and THz transmission spectra for
Dramatic resonant frequency shift of the metasensors has also been observed experimentally to specifically identify substances through correlating the substance fingerprint peak with the resonance of metasensors [109]. Figure 6(c) shows the fingerprint peaks of three pesticides around 0.92 THz and their deviations from the resonant peak of the metasensor (structure1, 0.92 THz). The difference between the closest fingerprint peak of chlorothalonil (0.74 THz) and 0.92 THz is 180 GHz. Accordingly, the maximum frequency shift is 5.7 GHz. The difference between the closest fingerprint peak of pyraclostrobin (0.95 THz) and 0.92 THz is about 30 GHz, and the maximum frequency shift is about 11.9 GHz. The resonance peak of the metasensor is nearly completely matching with the fingerprint peak of deltamethrin. The obtained corresponding maximum frequency shift is about 17.1 GHz, as shown in Fig. 6(c). The better the fingerprint peak matches the sensor resonance peak, the greater the shift of the sensor resonance peak. Through this method, the fingerprint peak positions of the unknown substances can be deduced through the frequency shifts of the sensor. This study provides a new idea for the specific identification of the substances by the metasensor.
B. AIT Effect
For THz plasmonic metasensor, the specificity can also be improved by further optimizing the THz resonance modes and exploring the use of the physical effects of the THz band to exploit effects such as AIT [111]. Similar to a hybrid of electromagnetically induced transparency [112] and plasmon induced transparency [27], AIT describes the possibility of realizing induced transparency in a system that contains a combination of plasmonic and atomic structures [111,113]. A transparent formant can be observed at the original absorption peak of the substance, that is, at the position of the fingerprint spectrum of the substance. The design of the plasmonic resonance modes enables effective coupling with the absorption resonance modes of the target molecules during measurements, which enhances the perception of the characteristic absorption of the substance and improves the detection specificity. The condition of AIT excitation needs to be satisfied: the broad spectrum formant of the AIT chip matches the narrow spectrum absorption peak of the object.
We established the equivalent AIT model based on the three-level atomic system scheme and equivalent resonance oscillator model, as shown in Figs. 7(a) and 7(b). Resonance oscillator 1 can strongly couple the THz wave from the outside. Resonance oscillator 2 can be equivalent to a molecular model, which has weak ability to couple the THz wave from the outside. The vibration amplitudes of the resonance oscillators 1 and 2 are represented by and , respectively. The coupling amplitudes of the two oscillators satisfy the following differential equation:
Figure 7.Equivalent AIT model. (a) Level scheme of a hybrid system composed of a cross slot metamaterial and molecular medium. (b) Equivalent resonance oscillator model [111].
Through calculating the power transmission spectrum of the system from the equation , the AIT effect can be clearly observed. In 2011, Weis
Figure 8.THz metasensing specificity based on the AIT effect: (a) schematic diagram of vibrations detection of
The physical origin behind both effects is unclear. The primary explanation is that dramatic amplitude/frequency change is due to interaction of the narrowband metasurface with a broadband absorption line of analyte, and AIT is due to the coherent coupling of a broadband mode of the metasurface to a narrowband mode resonance of analyte [44]. Despite that fingerprint detection can be achieved in the detection methods described in Sections 4.A and 4.B, they can only be used at narrowband fingerprint frequencies. The real part of the refractive index of the object will synchronously change the resonance frequency of the metamaterial, which affects the accurate judgment of the frequency match subject to the characteristic fingerprint of the object.
5. METASENSORS BASED ON MULTIPLEXING TECHNOLOGY
Due to the strong interaction of surface plasmon resonances with analytes, there have been many studies on AIT sensors for fingerprint spectroscopy based on plasmonic metasensors. However, plasmonic metasensors will introduce a certain amount of background absorption noise, which will bring different degrees of negative impact on the subsequent signal processing and detection evaluation especially for the trace detection. Due to the small dose of the sample, the THz response of the sample is weak, which makes the negative effect of the noise more significant.
Parameter-based multiplexed metasurfaces can utilize a series of resonance peaks generated by multiple metasurfaces with different size cell structures or multiple incident wave angles to enhance the interaction between the wave and the material, especially when the peak values of these resonances change with the absorption spectrum of the analytes. The envelope is consistent with the shape of the characteristic absorption spectrum of the analytes, while the amplitude is substantially higher than that of the unenhanced absorption spectrum. This multiplexing mechanism can directly and significantly enhance the fingerprint absorption spectra of trace substances. The fingerprint absorption spectrum of the trace object to be measured thus has great application value. In 2018, Tittl
Zhu
Figure 9.THz metamaterial multiplexing sensing experiment: (a) experimental angle-multiplexed fingerprint metasensing scheme and the maximum enhancement is up to 98 times for thin film
6. THz CHIRAL MOLECULAR SPECTRUM TECHNIQUES BASED ON CHIRAL METAMATERIALS
Chirality of substance is defined in that its mirror image cannot overlap with itself through basic rotations and translations. Chiral isomers have the same chemical composition but may have completely different chemical properties. Chiral characteristics significantly affect the function of biochemical substances. Some chiral molecules for diseases are therapeutic, but their isomers are toxic. The THz chiral spectrum has been successfully employed to acquire molecular chiral information because chiral molecules exhibit different spectral responses with respect to different chiral light fields, and enhanced chiral light fields can be excited by chiral metamaterials to strengthen the interaction between chiral molecules and chiral light fields [121–130]. In this section, unique THz chiral spectroscopy and sensing techniques combined with different chiral metamaterials are introduced in the identification and analysis of chiral enantiomers.
A new THz sensing method based on THz chiral spectroscopy and a chiral metasensor was proposed, as shown in Fig. 10(a). The strong chiral response of a spiral metasurface by oblique incidence can enforce the strong interaction subject to chiral enantiomers of proline acid aqueous solution. The - and -enantiomers can be qualitatively distinguished by the significant difference in THz polarization parameters [polarization ellipsoid angle (PEA), polarization rotation angle (PRA), circular dichroism (CD), and optical activity (OA)] at the characteristic frequency. The polarization ellipses of output THz waves of - and -proline also show great difference at 0.55 THz. The sensing accuracies are in the order of to , and the minimum value reaches . This method is not only suitable for amino acid aqueous solutions but also other chiral biochemical solutions. Therefore, THz polarization spectroscopy and chiral metasurface sensors have great potential for highly-sensitive quantitative detection and chirality identification in the analysis of biochemical materials [121].
Figure 10.(a) Geometry of spiral chiral metasensor: the PEA, PRA, CD and OA spectra differences of
In another work, the advantage of metasurface to identify chiral amino acid isomers was fully demonstrated by Zhang
7. EXPERIMENTAL SYSTEM
THz-TDS is the primary method and provides a powerful tool for THz spectroscopy and metasensing applications. Figures 11(a) and 11(b) show the typical THz-TDS setup with electro-optic (EO) sampling measurements [61,131]. The femtosecond laser pulse is split into two parts: a strong pump light and a weak probe light. The pump light illuminates the GaAs metal-intrinsic-n-type (m-i-n) diode and radiates the THz beam. Then, the THz beam is radiated on an EO ZnTe crystal. A delay line is mechanically moved to vary the time domain delay between the THz/probe pulses. The THz signal in the time domain field can be measured by scanning the time delay. The principle of this sampling method is that THz signals are obtained by sampling and using the femtosecond probe pulse. To increase the signal-to-noise ratio (SNR), the pump light passes through a chopper with modulation. The THz signal can be extracted by a lock-in amplifier. A linearly polarized THz pulse can also be emitted when a femtosecond laser is incident on the photoconductive antenna. Time traces of the transmitted THz electric field were measured by varying the time delay between the probe beam and the THz pulse. To make the system flexible and portable, the fiber-coupled THz-TDS was also developed independently. The typical optical fiber THz-TDS has a spectral range of 0.2–3.5 THz, and the spectral resolution is less than 3.5 GHz. The resolution can reach 1 GHz by increasing the delay line and then going through a fast Fourier transform [115]. To obtain THz chiral/polarization spectrum, the standard THz-TDS system should be modified to the THz time domain polarization spectroscopy system, in which two THz polarizers are added to control the polarization direction of the incident wave and detect the complete polarization state of the output wave [129].
Figure 11.(a), (b) Experimental setup for free space EO sampling [61]. (c), (d) Schematic of THz coherent photomixing spectrometer setup [56] and (e), (f) reflective mode angle-multiplexed THz-TDS system [119]. (a), (c), (e) Optical path diagram and configuration. (b), (d), (f) Corresponding photograph of the measuring platform. (a), (b) Reprinted with permission from Ref. [61], copyright 2019, Springer Nature; (c), (d) reprinted with permission from Ref. [56], copyright 2022, American Chemical Society; (e), (f) reprinted with permission from Ref. [119], copyright 2023, IEEE.
In some particular application scenarios such as screening coronavirus carriers, the frequency resolution should be improved [56]. Then a linearly polarized continuous wave THz spectroscopy system is utilized to record the transmittance spectra, as shown in Figs. 11(c) and 11(d). This spectrometer has two fiber-coupled InGaAs photomixers with a metal-insulator-metal heterostructure architecture [132]. Two temperature-controlled 1550 nm distributed-feedback (DFB) lasers operated with a minute difference in wavelength. Such two laser beams from two different DFB lasers were mixed in a fiber combiner to obtain the envelope of the interference spectrum (laser beat) in the THz domain. This spectrometer works with a coherent detection scheme, where the second photomixer acts as the THz receiver. The incoming THz wave generates a voltage in the antenna, while the laser beat modulates the conductivity of the photomixer. Consequently, the photocurrent generated was proportional to the THz electric field amplitude. The difference frequency could be steadily tuned on the MHz level by controlling the temperature accurately. The spectrum is obtained by sweeping the single-frequency THz transmission photomixer over a specified frequency range from 0.05 to 2.0 THz with an instantaneous line width in MHz magnitude [133].
The reflection THz-TDS system has the same optical components as the transmission THz-TDS system except for the optical path. The reflection THz-TDS system can be divided into vertical incidence [134], oblique incidence [135], and attenuated total reflection [136]. Compared with the transmission THz-TDS system, the reflection THz-TDS system has higher requirements for the experiment device because the position of the reflector and sample should keep consistent when measuring the reference signal and the small changes of optical path will greatly affect the output signal. The reflection mode has its special characteristic for use in a liquid environment. In some situations, such as angle-multiplexed measurement, a reflection-mode angle-multiplexed platform is used to obtain the spectra of samples, as shown in Figs. 11(e) and 11(f), where two sets of the photoconductive antenna (PCA) are applied [119]. Such a reflection-mode angle-multiplexed platform can also be achieve by applying a transmitter (TX) and a receiver (RX). For instance, at the TX side, a vector signal generator is used to generate the intermediate frequency (IF) signal. For the frequency extender, it multiplies a local oscillator (LO) signal generated by a signal generator. Then, the IF signal is mixed with the LO signal and extended up into the THz range. A horn antenna with high gain is used to transmit the THz signal channel. At the RX side, the transmitted signal is received by a horn antenna and then is downconverted into the IF signal through a frequency extender. A spectrum analyzer is utilized to demodulate the IF signal [137].
We note that the computational cost related to the data processing includes the calibration curve cost (determination of the concentration of analyte in an unknown specimen by comparing unknown to a set of reference samples having known concentration), the cost for removing interference from external noise or degradation of metasensor response, and the repeatability cost of measurements. The computational time is very short for metasensor detection. For instance, the total computational time of THz COVID-19 breath screening method by using metasensors is less than 1 min [56].
8. FABRICATION OF THE THz METASENSOR
In this section, some common fabrication techniques for terahertz metasensors are reviewed. The discussion focuses on the most frequently used techniques for the fabrication of the metasensor platform, especially fabrication on a large scale.
Currently, most manufacturing processes are based on the photolithography technique. Figure 12(a) shows the processing flowchart of photolithography [52]. The first step was that the silicon, quartz, or polyimide substrate substrates were coated with photoresist. A prebaking process was then performed to evaporate the solvent in the photoresist. Next, the coated substrates were exposed by an ultraviolet (UV) photolithographer, which was a laser direct writing system. After photolithography, the exposed part was washed away with a developer solution, and the photoresist with the desired structural pattern was left as a mask. Thin gold film was deposited on the coated substrates by magnetron sputtering. Finally, a lift-off process was performed to wash out the photoresist, and a complete metamaterial structure was obtained. When depositing the gold film, it is common to predeposit a layer of Cr or Ti with several nanometers to increase the adhesion of gold on the substrate. For all dielectric (for example, silicon) metasurface fabrication, after removing photoresist, a silicon substrate was etched with inductively coupled plasma (ICP) using copper film as a mask. Then copper film was removed with a copper corrosion solution. The silicon wafer was thinned to the target thickness by dry etching, and finally a metasurface was obtained [53].
Figure 12.(a) Flow chart of metamaterial sensor processing and preparation by photolithography [52]. (b) Schematic view of fabrication flow of 3D printing with stereolithography. In the first approach (first row in the figure), the top surface of mushroom MEGO was coated with conductive paste (stamping method). In the second approach (second row in the figure), metal was sputtered on the whole 3D printed device. The device was submerged in etchant to etch away the existing metal on the pedestal and the substrate [138]. (c) Left side, the schematic of the ps laser micromachining system; right side, the metamaterial fabrication steps [109].
With increasing resolutions, 3D printing technologies have also been used to realize 2D and 3D metamaterials with complex geometries and large scales [138,139]. Sadeqi
Recently, free-standing all metal metasensors have received more attention due to low dispersion and losses [69,109,140]. The fabrication approach is also cheaper than photolithography. This metasensor is realized by laser beam machining, as shown on the left side of Fig. 12(c). The schematic of laser beam machining consists of a picosecond (ps) laser, a beam expander, a scanning galvanometer, a field lens, a control system, and a mobile platform [109]. The laser generates ps pulses with the wavelength of 355 nm, the repetition frequency of 200 to 500 kHz, the pulse width of 15 ps, and the maximum power of 30 W. The laser is incident on the scanning galvanometer through the beam expander and three mirrors, and the spot diameter on the sample surface is focused by the field lens. The scanning galvanometer controls the scanning path of the light spot on the sample surface. The maximum scanning area is . The fabrication process of metamaterials is shown on the right side of Fig. 12(c), including three steps: sample preparing, ps laser etching, and metamaterial cleaning.
9. FUTURE PERSPECTIVES AND CONCLUSION
The THz molecule information is unique and should be completely used for the quantitative and qualitative analysis of biomedical macromolecules. However, recent review articles about the “metasensor” topic focus more on structures and topology, materials, or applications. Few articles mention the sensing principle, especially THz molecular detection. This is because THz molecular information is hard to be found, especially for trace detection. Fortunately, the recent development of metasensors generally permeates the molecular information to specific detection in the metasensor platform, for instance, the AIT technology, parameter multiplexing, and chiral spectrum. So summarization of these new technologies is necessary. This is very important because, unlike the featureless refractive index, molecular information is indeed the unique feature that cannot be found in the optical, infrared, and microwave frequency range. By summarizing and combining the progress of the THz metasensor application above, the development of THz metasensor technology can be roughly divided into the following aspects. (1) THz featureless refractive index metasensors, which can be described by the following perspectives: (i) the sensitivity enhancement is significant due to excitation of stronger localized resonant mode, but the specificity is poor, mainly manifested as the featureless refractive index sensor at one particular frequency; (ii) THz metamaterials are combined with functional materials for specificity improvement. The selectivity of the functional materials to biochemical molecules can strengthen the detection specificity and sensitivity, but the functional material and binding reaction does not have THz fingerprint spectral information, manifesting as the specific material binding induced refractive index sensor. (2) THz molecular metasensors, which can be described by the following perspectives. (i) THz specific fingerprint metasensing through resonance matching between the structure and target analyte to realize either specific amplitude/frequency shift variation enhancement or AIT effect. This method has some drawbacks. The operation frequency range is narrow and cannot reflect the broadband fingerprint spectral information, being regarded as a specific narrowband fingerprint metasensing. (ii) Metasurface multiplexing that can amplify the broadband fingerprint spectra of the molecule. The combination of these molecular fingerprint spectra at broadband frequency range gives a clear molecular fingerprint that can be used to identify different samples. (iii) The THz chiral spectrum combined with chiral metasensors can quantitatively and selectively analyze chiral molecules and can be applicable to aqueous environments. Table 2 summarizes the selected works and recent applications of THz metasensors based on the above-mentioned sensing principles. Comparison of Selected Works Representing the Advances in THz Metasensors Development Based on Different PrinciplesTechnique Principles Metasensor Resonant Frequencies Analytes Sensitivity/ Timeline References Featureless refractive index Sensitivity enhancement by different localized mode 0.55 THz (toroidal) Ethanol-water solution 124.3 GHz/RIU (experiment) 2021 [ 0.81 THz (LC) COVID-19 45 GHz 2022 [ 0.93 THz (cylindrical SPPs/bound mode) Chlorpyrifos 0.1 mg/L (LoD) (experiment) 2020 [ 0.76 THz and 1.28 THz (dipole & F-P mode) Bovine serum albumin (BSA) 0.47/RIU and 2019 [ 0.51/RIU (experiment) Specific modification by different material 0.735 THz (gold-nanoparticles) miRNA 14.54 aM (LoD) (experiment) 2020 [ 0.46 THz and 0.76 THz (graphene) Escherichia coli O157:H7 0.1 mg/L (experiment) 2021 [ 0.754 THz (protein antibody) CA125 and CA199 4.2 fM (LoD) (experiment) 2022 [ 0.912 THz (hydrogel) Human 0.40 pM (LoD) (experiment) 2021 [ 0.849 THz (molecularly imprinted polymer) 50–500 ppm (LoD) (experiment) 2023 [ Molecular structure Narrow fingerprint match 1.4 THz (resonance matching) 10 mg/dL (glucose) (experiment) 2015 [ Fructose Sucrose 529.2 GHz (resonance matching) Lactose 31 times (theory) 2019 [ 0.92 THz (resonance matching) Chlorothalonil 5.7 GHz/(g/L) 2022 [ Pyraclostrobin 11.9 GHz/(g/L) Deltamethrin 17.1 GHz/(g/L) (experiment) 1.14 THz (AIT) 4.5 dB (experiment) 2018 [ 0.53 THz (AIT) Lactose 7.6 (transmission) 13 (reflection) (theory) 2019 [ 0.53 THz, 0.64 THz, 0.82 THz, and 1.17 THz (AIT) 8.61 mg/mL, 6.96 mg/mL, 7.54 mg/mL, and 8.35 mg/mL (LoD) (experiment) 2024 [ Multiplexing 0.5–0.55 THz (angle multiplexing) 98 times (experiment) 2023 [ 0.9–2 THz (geometry multiplexing) D-/L-carnitine 7 times (experiment) 2023 [ Chirality 0.58 THz (metallic chiral metasensor) D-/L-proline 2021 [ 0.97 THz, 1.37 THz, and 1.63 THz (dielectric chiral metasensor) D-/L-tyrosine D-/L-arginine D-/L-cysteine 11.4 times (experiment) 2022 [
Due to the strong absorption of polar solutions in the THz frequency band, the ability of THz sensing technology to capture effective information in solution samples has also been improved by functionalizing hydrogel on molecule-specific THz metasensors or utilizing chiral/polarization measurement by chiral metasensors in aqueous environments. Another approach to reduce the strong absorption of the polar liquid analytes is using microfluidic devices to minimize the effective depth of interaction between the THz signal and the solution sample. For instance, Ng
In recent years, the metasensor for dynamic modulation of THz signals has made some progress. Through mechanical, thermal, optical, or electrical stimuli, the parameters of metamaterials are changed to realize the dynamic modulation of the resonance intensity/frequency/phase [145–148]. Therefore, the dynamic modulation of resonance performance of THz metamaterials can be used in the metasensing analysis of substances, which is expected to break through the bottleneck of conventional metamaterials that can only realize the detection of targets at a limited number of frequency points and realize the sensing of THz fingerprint information of measured substances in a broad frequency band. For instance, as shown in Fig. 13(a), Sun
Figure 13.(a) Enhanced absorption fingerprint spectrum based on THz graphene assisted frequency-agile metasurface; the absorptance is improved as much as nearly 5 times [149]. (b) The reconfigurable multiplexed metasensor by angle and thickness multiplexing; broadband absorbance enhancement factor is 79 times [150]. (c) Molecular fingerprint detection using THz metasurface array;
For fingerprint metasensor based on resonance matching between the structure and target analyte, it is a challenge that additional shifting of the metasurface resonance due to the nondispersive component (real permittivity) of the analyte and fabrication error make it difficult to match the metasurface resonance with the resonance frequency of the analyte covered system. Recently, an innovative approach was showcased by seamlessly incorporating a metasurface array onto a THz chip, as depicted in Fig. 13(c) [151]. Such a metasensor array with scaled structural parameters encompasses a wide frequency range spanning from 1.15 THz to 2.69 THz. This extended frequency range presents a valuable opportunity to effectively capture the vibrational fingerprint signals of molecules by the AIT effect, which exhibits good robustness. The successful identification of -glutamate has been experimentally achieved through the utilization of the broadband metasensor array design and confirmed through transmission-absorption spectroscopy. Parallel, Lyu
Another perspective for metasensors is to combine the THz metasensor with a machine learning algorithm. A machine learning algorithm imitates human intelligence by learning about its surroundings to automatically improve computer performance. Machine learning is widely used to analyze data in a variety of fields, such as optics [158], near-infrared [159], and Raman spectroscopy [160]. Such an algorithm can help metasensors to accurately extract valid information from spectra at low signal-to-noise ratios and improve the recognition accuracy [161]. For instance, Fu
Wearable biosensors are important due to their flexible and versatile features. More recently, a graphene-based THz cavity sensor with user-designed patterns was presented. External molecules can strongly interact with electrons in graphene. The multilayer structure can provide cavity resonance for sensing. Pesticide molecules of a concentration of 0.60 mg/L were successfully observed on the surface of an apple, as shown in Fig. 13(e) [153]. Another work replaced graphene with covalent organic frameworks (COFs), which show good biosorption ability for pesticide molecules. Such a flexible sensor can also measure the pesticide residue on the surface of apple for practical application, as depicted in Fig. 13(f) [154]. It is interesting to see applications of this kind of metasensor in wearable scenarios.
So far, THz metasensors have had a certain accumulation in the design of feature units, optimization of sensing performance, and investigation of the basic sensing mechanism, which provides a theoretical basis and technical support for the use of THz metamaterials to achieve higher performance sensing applications. Metasensors should be both sensitive and selective to a desired target medium in a mixture of chemical samples and will be developed to make up for the lack of sensitive information at specific frequency points, realize the sensitive material for THz fingerprint information, and promote the formation of a new generation of THz sensing technology for analytes with broadband and narrowband fingerprints. In the future, for THz metasensors with the analysis of complex composition samples, the problems of weak characteristic signals and serious signal interference will be run into, so it is urgent to strengthen the complex signal processing and the depth of effective information data mining and analysis.
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