Sensor technology has become increasingly crucial in medical research and clinical diagnostics to directly detect small numbers of low-molecular-weight biomolecules relevant for lethal diseases. In recent years, various technologies have been developed, a number of them becoming core label-free technologies for detection of cancer biomarkers and viruses. However, to radically improve early disease diagnostics, tracking of disease progression and evaluation of treatments, today’s biosensing techniques still require a radical innovation to deliver high sensitivity, specificity, diffusion-limited transport, and accuracy for both nucleic acids and proteins. In this review, we discuss both scientific and technological aspects of hyperbolic dispersion metasurfaces for molecular biosensing. Optical metasurfaces have offered the tantalizing opportunity to engineer wavefronts while its intrinsic nanoscale patterns promote tremendous molecular interactions and selective binding. Hyperbolic dispersion metasurfaces support high-k modes that proved to be extremely sensitive to minute concentrations of ultralow-molecular-weight proteins and nucleic acids.
In recent years, a great interest has been spurred by the tremendous technological potential of optically thin nanopatterned surfaces, better known as metasurfaces , , , , , , , , , , , . Metasurfaces allow wavefront engineering, local phase and amplitude control of light along the surface by using dielectric or plasmonic resonators , , , , , , , , , . Plasmonic materials are next-generation nanomaterials with enormous potential to transform health care by providing advanced sensors , , , , imaging devices , , and therapies , , , , as well as to advance energy-relevant materials, such as bio-antennae and light-harvesting systems , , . One promising target for plasmonic sensing technologies is the isolation and detection of circulating tumor cells (CTCs), which have received much attention as novel biomarkers in clinical trials of translational cancer research , , . Because CTCs and other cancer-related biomarkers are present in the blood of many patients with cancer, the detection of CTCs can be considered as a real-time liquid biopsy. It has recently been reported that CTCs can leave primary tumors and enter the circulation at a relatively early stage of tumor growth. Therefore, the detection of CTCs is particularly important to study the mechanism of cancer metastasis , . The quantification and analysis of CTCs and other cancer-related biomarkers in clinical specimens provide a foundation for the development of future noninvasive liquid biopsy techniques , , , .
Another class of promising biomarkers is exosomes, which could be useful in early diagnosis of various diseases including cancer, and also for the monitoring of cancer progression through noninvasive or minimally invasive procedures , , . Exosomes are nanoscale (30–150 nm) vesicles released by most cells, including cancer cells, and are found in bodily fluids such as blood, urine, and saliva. Exosomes can transfer their cargo containing proteins, lipids, RNA, and DNA to recipient cells and play a key role in different biological process including intercellular signaling, coagulation, inflammation, and cellular homeostasis , . With respect to exosomes, the main requirements for next-generation sensors are (i) high levels of specificity to isolate exosomes, (ii) the ability to detect low counts of exosomes (100 target cells per 109 blood cells), and (iii) the ability to detect in patient whole blood samples. In this direction, a plasmonic-based, label-free, high-throughput exosome detection approach has been proposed, allowing detection of low counts of exosomes , , , . However, label-free detection and quantification of such nanosized objects remains challenging and cumbersome due to the lack of highly sensitive, reproducible, and cost-effective techniques. In particular, the sensitivities of existing optical and plasmonic sensors are not high enough to detect dilute analytes of low molecular weights or low surface coverage of exceedingly small bound molecules , .
New sensing platforms are needed to address these concerns. To circumvent the limits of plasmonic sensing with traditional materials, research in metamaterials has intensified in the past decade. Metamaterials are a class of engineered materials that do not exist in nature and exhibit exotic and unusual electromagnetic properties that make them attractive for applications in bioengineering and biosensing , , . In particular, metamaterials that show hyperbolic dispersion such as 3D hyperbolic metamaterials (HMMs) and 2D hyperbolic metasurfaces (HMs) have shown extreme sensitivity for low concentrations of smaller bioanalytes , , , .
HMMs are a class of artificial anisotropic materials, which originates from the concept of optics of crystals. HMM shows hyperbolic dispersion ,  because the out-of-plane dielectric component has an opposite sign to the in-plane dielectric components . As is well known, homogenous isotropic materials exhibit elliptical dispersion, with the dispersion relation . However, uniaxial anisotropic materials such as HMMs have a hyperbolic dispersion relation , where the dielectric response is given by the tensor , , . This hyperbolic dispersion allows these materials to support waves with infinitely large momentum (bulk plasmon polaritons, BPPs) in the effective medium limit. These waves can propagate inside HMMs, but are evanescent and decay away exponentially in the superstrate . Because the BPP modes are nonradiative with high momentum, they can only be excited using a momentum coupler such as a prism  or grating , just like in the case of surface plasmon polaritons. It has been shown that the BPP modes of both type I (, ) and type II (, ) HMMs can be excited using either coupling technique and the excited modes showed high quality (Q) factor resonances . Because HMMs support high Q-factor multimode BPP resonances, they can be used to develop ultrasensitive multimode biosensors . In recent times, various HMM-based ultrasensitive biosensors using different interrogation schemes have been proposed for noninvasive liquid biopsies , , , , .
Kabashin et al. first proposed to use type I HMM, such as gold nanorods electrochemically grown into a substrate, in biosensing . This plasmonic nanorod HMM excited a bulk guided mode in the near-infrared (NIR) wavelength range using prism coupling and exhibited a record bulk refractive index (RI) sensitivity of 32,000 nm per refractive index unit (RIU). They also demonstrated the real-time binding of small biomolecules such as biotin at a concentration as low as 1 μM. Sreekanth et al. developed a compact multimode biosensor by exciting the BPP modes of an Au/Al2O3 HMM using a grating coupling approach . This miniaturized multimode sensor exhibited extreme bulk RI sensitivity with a record figure of merit (FOM) and detected biotin concentrations as low as 10 pM. Since then different hyperbolic dispersion metamaterials have been proposed for sensitivity enhancement purposes , , , , , , , , , , .
One avenue for exploration is using alternative techniques for interrogating the sensor, such as the Goos–Hanchen shift. This has shown to improve the detection limit for small molecules on a 2D hyperbolic metasurface . Another avenue is the development of HMMs free of noble metals, which would also improve the small molecule detection limit because the performance of plasmonic sensors in the visible frequency range is significantly limited by inherent losses in the metallic components. In this direction, a TiN/Sb2S3 multilayered HMM-based reconfigurable biosensor has been recently proposed . Plasmonic sensors are also hampered by the limitations of the biomolecular receptors used to target analytes. The receptors can bind to parasitic molecules that cannot be easily distinguished from the targets, which results in a false positive signal. One way around this issue is the use of multiplex detection, realized by developing HMM-based multimode sensors  and reconfigurable sensors , . In particular, the sensitivity of these sensors can be tuned from maximum to minimum, so that different molecular weight biomolecules including parasitic molecules can be recognized. However, algorithms to analyze proper logic functions based on this concept must be implemented through deep learning or artificial intelligence .
In short, significant progress has been made in real-time label-free biosensing of nanoscale targets – such as small molecules and exosomes – at lower concentrations using HMM-based plasmonic biosensor platforms. These in turn can be used to develop cost-effective, noninvasive liquid biopsies for point-of-care (POC) clinical evaluation, early cancer screening and real-time diagnosis of diseases. This review highlights the recent advances in hyperbolic dispersion metasurfaces–based biosensor technology, and in particular discusses biosensors involving metal/dielectric multilayered HMMs. This includes biosensors using different coupling mechanisms and interrogation schemes. We also discuss reconfigurable sensors based on tunable HMMs, localized surface plasmon resonance (LSPR) sensors based on type I HMMs, and biosensing applications of multifunctional hyperbolic nanocavities.
2 Enabling highly tunable engineering of the optical density of states in multifunctional hyperbolic nanocavities for biosensing applications
HMMs of either type I or type II have been investigated in confined in-plane geometries for a variety of applications. In particular, miniaturized optical cavities made of metal-dielectric multilayers have been shown to enable radical increases in the photon density of states. They thus represent an ideal platform to enhance light–matter interactions for applications in optical nanotechnologies . In 2012, Yang et al. reported on nanostructured optical cavities made of indefinite metal-dielectric multilayers that confine the electromagnetic field down to λ/12 and with ultrahigh (up to 17.4) optical refractive indices  (Figure 1).
Their experiments also revealed that these types of cavities display anomalous scaling laws. For instance, cavities with different sizes can be resonant at the same frequency, and higher-order resonant modes oscillate at lower frequencies. These archetypical structures were also proposed to enhance the quantum yield and spontaneous emission of quantum emitters. In 2014, Guclu et al. proposed a radiative emission enhancement mechanism based on the use of hyperbolic nanostructures . In particular, they showed that hyperbolic metamaterial resonators behave like nanoantennas and, owing to their very large density of states, can lead to a 100-fold enhancement of the radiative emission of quantum emitters placed in their vicinity. The same year, Lu et al. demonstrated experimentally enhanced spontaneous emission rates of molecules by using nanopatterned multilayered hyperbolic metamaterials  (Figure 2).
They showed that by nanopatterning an HMM of type II made of Ag and Si multilayers, the spontaneous emission rate of rhodamine dye molecules is enhanced 76-fold at tunable frequencies and the emission intensity of the dye increases by a factor 80 compared with the same HMM without nanostructuring. The same group has also reported a 160-fold enhancement of the spontaneous carrier recombination rates in InGaN/GaN quantum wells thanks to the excitation of hyperbolic modes supported by stacking Ag–Si multilayers, which enable a high tunability in the plasmonic density of states for enhancing light emission at various wavelengths . This approach led to the realization of ultrafast and bright quantum well-based LEDs with a 3-dB modulation bandwidth beyond 100 GHz. More recently, Indukuri et al. proposed nanostructured hyperbolic antennas with an engineered optical density of states and a very large quality-factor/modal volume ratio. Their architecture can enable applications in cavity quantum electrodynamics, nonlinear optics, and biosensors . From a more fundamental point of view, research have been recently focused on layered metal-dielectric HMMs, which support a wide landscape of surface plasmon polaritons and Bloch-like gap-plasmon polaritons with high modal confinement. Light can excite only a subset of these modes, and typically within a limited energy/momentum range if compared with the large set of high-k modes supported by hyperbolic dispersion media, and coupling with gratings , ,  or local excitation  is necessary. Isoniemi et al. recently used electron energy loss spectroscopy (EELS) to achieve a nm-scale local excitation and mapping of the spatial field distribution of bright and dark modes in multilayered type II HMM nanostructures, such as HMM pillars and HMM slot cavities  (Figure 3). In particular, as recently demonstrated by Maccaferri et al., HMM nanoantennas can enable a full control of absorption and scattering channels .
By varying the geometry of the nanoantennas, the ratio of scattering and absorption and their relative enhancement/quenching can be tuned over a broad spectral range from visible to NIR. Notably, both radiative and nonradiative modes supported by this type of architecture can be excited directly with far-field radiation, even when the radiative channels are almost totally suppressed. Similarly, Song and Zhou showed that multiresonant composite nanoantennas made of vertically stacked building blocks of metal-insulator loop nanoantennas can support multiple nanolocalized modes at different resonant wavelengths, and are thus suitable for multiband operations, such as multiphoton processes, broadband solar energy conversion, and wavelength multiplexing  (Figure 4).
Furthermore, these hyperbolic nanoantennas have proven to possess both angular and polarization-independent structural integrity, unlocking promising applications as solvable nanostructures. In this framework, Wang et al. experimentally synthetized and measured the optical properties of hyperbolic nanoparticles made with either Au or dielectric nanoobjects coated with alternating SiO2 and Au multishells . These soluble nanoparticles enable highly tunable optical modes covering a broad wavelength range. Moreover, they exhibit high local field intensity enhancement, thus opening excellent opportunities in plasmon-enhanced spectroscopy, nanolasers, design of nonlinear phenomena, photothermal conversions, and hot-electron generation. It is worth mentioning here that nanostructured HMMs have also been proposed to achieve a near-perfect absorption of light. Zhou et al. have proposed a broadband absorber based on a tapered a hyperbolic metamaterial, made of alternating metal-dielectric multilayers and working in the visible and NIR ranges  (Figure 5).
They demonstrated that light couples into the tapered structure most strongly due to the hyperbolic dispersion phase-matching conditions. Moreover, they obtain a broad absorption band thanks to the broadening of the resonances from an array of coupled HMM tapered structures. Similarly, Sakhdari et al. theoretically propose a vertically integrated hot-electron device based on a nanostructured HMMs that can efficiently couple plasmonic excitations into electron flows, with an external quantum efficiency approaching the physical limit . Their metamaterial-based architecture displays a broadband and omnidirectional response at infrared and visible wavelengths, thus representing a promising platform for energy-efficient photodetection and energy harvesting beyond the bandgap spectral limit. More recently, Abdelatif et al. proposed a funnel-shaped anisotropic metamaterial absorber made of periodic array of nickel–germanium (Ni/Ge) enabling enhanced broadband absorption (up to 96%) due to the excitation of multiple orders of slow-light modes over a wavelength range from the ultraviolet to NIR range . In 2017, Riley et al. have synthetized transferrable hyperbolic metamaterial particles showing broadband, selective, omnidirectional, perfect absorption. Their system is made of hyperbolic nanotubes (HNTs) on a silicon substrate that exhibit near-perfect absorption at telecommunication wavelengths even after being transferred to a mechanically flexible, visibly transparent polymer, which is a more desirable substrate in view of mechanically flexible and low-cost applications  (Figure 6).
Finally, Caligiuri et al. presented an approach to achieve super-absorption capabilities based on resonant gain singularities. The proposed mechanism enables a huge amplification of the emitted photons resonantly interacting with a multilayered hyperbolic system. In particular, they theoretically demonstrated that metal/doped-dielectric multishell nanostructures can be used as self-enhanced loss compensated devices, being a favorable scenario for low-threshold SPASER action .
3 Extreme sensitivity biosensing platform based on HMMs
Hyperbolic metamaterials support both radiative and nonradiative modes. The radiative modes such as Ferrell–Berreman ,  and Brewster modes ,  can be excited from free space. However, a momentum-matching condition must be satisfied to excite HMM nonradiative modes, such as SPP and BPP modes. A phase-sensitive HMM-based biosensor can be developed by exciting the Brewster mode of the HMM because a sudden phase jump occurs at the Brewster angle. In this scheme, the phase shift at the Brewster angle due to the change in RI arising from the presence of the analyte can be recorded as the sensing parameter . However, extreme sensitivity biosensing is only possible by exciting the BPP modes of the HMM. A type II HMM supports only high-k BPP modes, whereas a type I HMM supports both high-k and low-k BPP modes. In the following sections, we discuss the development of multilayered HMM-based biosensors based on metasurface grating and prism coupling excitation schemes.
3.1 Grating-coupled HMM-based multimode biosensor
In this section, the excitation of BPP modes of type II HMMs using grating coupling and its application for the development of biosensors with differential sensitivity is reported. Wavelength and angular interrogation schemes to demonstrate the extreme sensitivity of the biosensor for small molecule detection at low analyte concentrations have been investigated , . The HMM-based plasmonic biosensor platform, with integrated microfluidics, is illustrated in Figure 7a and b. As can be seen, it is a combination of a plasmonic metasurface and an HMM. The HMM consists of 16 alternating thin layers of gold and aluminum dioxide (Al2O3) with thickness 16 and 30 nm, respectively. The fabricated multilayer is a type II HMM, which shows hyperbolic dispersion at λ ≥ 520 nm, where the real parts of parallel and perpendicular permittivity components are negative and positive, respectively (Figure 7c). To excite the BPP modes of Au–Al2O3 HMM, the grating coupling technique has been used , , . For this purpose, a 2D subwavelength Au diffraction grating with period 500 nm and hole dimeter 160 nm was integrated with the HMM (inset of Figure 7a). Au has been considered because it is the most popular plasmonic material for biosensing applications because of its low oxidation rate and high biocompatibility.
The principle behind grating coupling is that the surface plasmons supported by a metasurface grating can be excited when the parallel wavevectors of the surface plasmons are comparable with the wavevector of the light. Grating diffraction orders are no longer propagating waves when this condition is satisfied, but they are evanescent fields. The enhanced wavevector of the evanescent field is responsible for the coupling of incident light to the surface plasmon modes , . The proposed metasurface grating-coupled HMM (GC-HMM)-based sensor works based on the coupling condition between the metasurface grating modes and BPP modes. The coupling condition alters when the RI of the surrounding medium changes, which allows measuring a change in resonance wavelength and resonance angle. Explicitly, the grating coupling condition is given by , where θ is the incident grazing angle, n0 is the RI of surrounding medium, k0 = 2π/λ is the vacuum wavevector, m is the grating diffraction order, and is the grating wavevector with being the grating period.
To show the BPP modes of the Au–Al2O3 HMM, the reflectance spectra of the GC-HMM with varying incidence angle, have been acquired using a variable angle high-resolution spectroscopic ellipsometer. The Q factors of these modes are remarkably high because of strong mode confinement and large modal indices. In Figure 7d, the spectral response of the fabricated sensor at different angles of incidence has been shown. The narrow modes recorded at wavelengths above 500 nm represent highly confined fundamental and higher-order BPP modes of the HMM. The Q-factors of the modes measured at resonance wavelengths 1120, 755, and 580 nm are 29.5, 26, and 23, respectively. The sensor supports many modes with different Q-factors, which increases with increasing mode resonance wavelength.
The performance of the HMM-based sensor using spectral and angular interrogation schemes has been analyzed. The detection limit of the sensor has been first determined by injecting different weight ratios of aqueous solutions of glycerol into the sensor microchannel (sample volume = 1.4 μl). In Figure 7e and f, the reflectance spectra of the sensor with varying concentrations of glycerol in distilled water (0.1–0.5% w/v) have been shown, using spectral and angular scans, respectively. It is evident from Figure 7e that the resonance wavelength corresponding to each BPP mode red shifts and the quality factor of each mode declines with increasing glycerol concentration. In the angular scan, a positive angular shift is obtained when the glycerol weight ratio is increased (Figure 7f). The sensor can record extremely small RI changes of glycerol concentrations in both scans. For example, a significant shift of 12 nm is obtained at 1300 nm even with 0.1% w/v glycerol concentration. It should be noted that the shift increases when the spectral position of the BPP mode varies from visible to NIR wavelengths because the transverse decay of the field in the superstrate strongly varies from one mode to another. Thus the sensor provides different sensitivities as the resonance wavelength increases from visible to NIR wavelengths due to the differential response of the BPP modes. The measured maximum bulk RI sensitivity for the longest wavelength BPP mode in spectral and angular scans is around 30,000 nm/RIU and 2500°/RIU, respectively. The minimum sensitivity is recorded at the shortest wavelength BPP mode, which is 13,333 nm/RIU and 2333°/RIU for spectral and angular scans, respectively. In addition, the sensor exhibits different FOM for each BPP mode, which are 206, 357, 535 and 590 at 550, 660, 880, and 1300 nm, respectively. It is worth noting that the recorded FOMs of the proposed multilayered HMM-based sensor are much higher than existing plasmonic biosensors. An interesting characteristic of the proposed sensor is the flexibility in the selection of a mode for the identification of specific biomolecules since it provides differential sensitivities.
To demonstrate the capabilities of the proposed sensor device for the detection of smaller biomolecules, biotin (molecular weight, 244 Da) has been selected as the analyte because it is a model system for small molecule compounds such as vitamins, cancer-specific proteins, hormones, therapeutics, or contaminants such as pesticides or toxins. To selectively detect biotin, the sensor surface has been immobilized with streptavidin biomolecules and the sensor monitors the wavelength or angular shifts due to the RI change caused by the capture of biotin at the streptavidin sites. The sensor performance is monitored by injecting different concentrations (10 pM–10 μM) of biotin prepared in PBS into the sensor microchannel. The reflectance spectra of the sensor have been recorded after a reaction time of 40 min for each concentration of biotin. PBS was introduced into the microchannel to remove the unbound and weakly attached biotin molecules before each injection of a new concentration of biotin. In Figure 8a and b, the responses of the device during the detection of different concentrations of biotin in spectral and angular scans have been plotted respectively. One can see that an increase in spectral and angular shift is obtained with increasing biotin concentrations. It reflects the increase in RI change due to the capture of biotin molecules on the streptavidin sites. Moreover, a nonlinear variation in shift with increase in biotin concentration is observed in both scans. In Figure 8c, the real-time binding kinetics by injecting 10 pM biotin has been shown, where a red shift has been observed and discrete steps in resonance wavelength over time, which is due to the 0.2 nm discreteness in the wavelength sensitivity. Variability in the step size was observed, which is due to statistical fluctuations in which larger or smaller numbers of binding events can occur. Finally, the sensitivity of the wavelength and angular shift to the number of adsorbed biotin molecules on the sensor surface have been investigated. The saturation values of the wavelength () and angular () shift for each concentration c of biotin in PBS were considered. Because the shift of the resonance wavelength and angle depends on the number of bound molecules, it is possible to reliably estimate an upper bound Nmax (c) based on the sensor parameters. In Figure 8d and e, the number of adsorbed biotin molecules with corresponding shifts in wavelength and angle has been plotted, respectively. This behavior is accurately reproduced using a phenomenological double-exponential fitting function . In contrast to type I HMM-based sensor , the proposed multilayered type II HMM-based sensor demonstrates the detection of 10 pM biotin in PBS, which shows that sensitivity is increased by six orders of magnitude.
3.2 Biomolecular sensing at the interface between chiral metasurfaces and HMMs
The interface between a chiral metasurface and hyperbolic metamaterials can enable both high sensitivity and specificity for low-molecular-weight nucleic acids and proteins , , , , . Interestingly, an adapted out-of-plane chiral metasurface enables three key functionalities of the HMM sensor: (i) an efficient diffractive element to excite surface and bulk plasmon polaritons , ; (ii) an increase in the total sensing surface enabled via out-of-plane binding, improving diffusion-limited detection of small analyte concentrations; and (iii) additional biorecognition assays via circular dichroism (CD) and chiral selectivity that can be optimally tailored to amplify the chiral–chiral interactions between the metamaterial inclusions and the molecules, enabling high-sensitivity handedness detection of enantiomers , , , , .
A sketch of a chiral metasurface hypergrating (CMH), consisting of a periodic array of right-handed Au helices on a type II HMM composed by indium tin oxide (ITO – 20 nm) and silver (Ag – 20 nm) is shown in Figure 9a. From top to bottom, the geometry consists of a superstrate containing the Au helices, the multilayer system (gray stack of ITO/Ag), and the glass substrate. The reflectance and transmittance curves are calculated for a transverse magnetic (TM) wave and an incident angle θi = 50° with respect to the helix axes. This is done by solving the frequency-domain partial differential equation that governs the E and H fields associated with the electromagnetic wave propagating through the structure . As shown in Figure 9b, for the calculated reflectance for the CMH–HMM, it is possible to distinguish three minima at 635 (mode A), 710 (mode B), and 890 nm (mode C), corresponding to different BPP modes of the underlying HMM, whereas the transmittance remains zero in the entire spectral region.
The sensitivity of the sensing platform can be evaluated as a function of the analyte concentration binding at the chiral metasurface. To this end, different molar fractions of an aqueous solution of 1,2,3-propantriol, characterized by an ultralow molecular weight (C3H8O3 ≈ 60 Da) , have been considered. Figure 9b shows the calculated reflection spectra of the CMH–HMM sensor in measuring 1,2,3-propantriol solutions with different concentrations. As expected, the calculated reflectance minima (mode dips) of the coupled system linearly shift toward longer wavelengths with the increase of RI – from 1.333 (water) to 1.401 (molar fraction of C3H8O3 of about 17%). The corresponding limit of detection (LOD) is equal to 1.5 × 10−4 RIU.
An important aspect of the 3D chiral metasurface is the significant increase of the out-of-plane sensing surface because the specific binding of the analytes can occur on the entire helical surface. At the same time, a chiral structure can modify the fluid dynamics around it, inducing an increase of the probability of specific binding.
Clearly, the wavelength shift of BPP modes is strongly related to the quantity of molecules that bind selectively on the surface of the helices. It is possible to quantify this effect by considering different surface coverage of the helix, by considering the maximum RI change equals to 0.068. Coverage was varied from 0 to 100%, where in the latter case the whole surface of the helix is totally covered by molecules; here a maximum spectral shift of 15 nm for mode A, 21 nm for mode B, and 31 nm for mode C have been obtained, as seen in Figure 9c. The minimum detectable surface coverage, necessary to have an appreciable shift of all three modes, is about 16%, whereas for the most sensitive mode (C) alone, it is approximately 12%.
The sensitivity of the CMH–HMM sensor is also strongly affected by the distance of the bond analyte from the HMM surface. In particular, the local change of RI in a small disk surrounding the helix produces appreciable shifts even when the binding is confined exclusively to the upper region of the helix, which represents the maximum distance from the HMM. In Figure 9d a small disk, with n = 1.401 and corresponding to an adsorbed surface of 20%, is positioned at different distances (D) with respect to the surface of the HMM. By plotting the resonance shift of the three modes A, B, and C as a function of the distance D normalized to the helix height (h) it is possible to see that the proposed biosensing platform is able to detect a shift of the considered modes even in the worst case (D/h = 1). For this case, the shift is about 1.3 nm for the mode A, 4.0 nm for the mode B, and 4.5 nm for the mode C, as reported in Figure 9d. These results highlight the advantages of having a metasurface to promote the detection of target analytes away from the surface of the HMM, exploiting the increased surface/volume ratio of the 3D CMH exposed to the analytes.
On the other hand, considering the intrinsic chirality of the nanohelices, CMH could excite new BPP modes of the HMM by coupling with their circular polarization-dependent plasmon modes. Indeed, as reported in Figure 10b, different reflectance dips are obtained for left-handed circular polarized (LCP) and right-handed circular polarized (RCP) light. In particular, the reflectance dips obtained for LCP light, indicated in the figure as BPP3 to BPP6, are strongly related to a coupling between the plasmonic modes of the gold helix array and the HMM as reported in Figure 10c.
From the chiroptical response of the CMH, it is possible to calculate the CD signal, such as bipolar peaks and crossing points, as seen in Figure 10d. These signatures allow for increased sensitivity and accuracy when monitoring RI changes due to the analyte absorption. This sensing modality offers strong optical contrast even in the presence of highly achiral absorbing media, increasing the signal-to-noise CD measurements of a chiral analyte, relevant for complex biological media with limited transmission . For this purpose, the reflectance curves obtained for LCP and RCP light at θi = 75° are used to calculate the reflectance circular dichroism (RCD) spectra, which characterizes the reflectance difference between LCP and RCP light, leading to an RCD amplitude (RCD = RLCP − RRCP). As expected, the RCD spectra for the CMH–HMM exhibit multiple features: different maxima, minima, and crossing points (Figure 10d) that are strongly affected by the RI variation (from 1.333 to 1.401).
It is possible to distinguish in the range 700–900 nm a minimum (λm), a crossing point (λ0) and a maximum (λM), respectively, at 797, 816, and 852 nm which significantly shift and modify their intensity as the RI changes. These signals show a chiral plasmon (CP) sensitivity of 412 nm/RIU for λm, 485 nm/RIU for λ0 and 471 nm/RIU for λM, respectively. After extracting the classical full-width at half-maximum (FWHM) for the λm and λM modes and the FWHM in the |RCD| spectrum for λ0, the FOM, defined as FOM = SCP/FWHM , has been calculated. The corresponding FOM values are 18, 20, and 30. The scientific significance of chiral metasurfaces coupled with HMM nanostructures for biosensing lies in the synergistic functionalities which arise from chiral geometries and optical selectivity. This will have important implication in developing next-generation biosensors for gene–protein recognition.
4 Type I HMM-based biosensor
4.1 Type I HMMs: gold nanopillars for high-sensitivity LSPR sensors
Kabashin et al. demonstrated an improvement in biosensing technology using a plasmonic metamaterial that is capable of supporting a guided mode in a porous nanorod layer . Benefiting from a substantial overlap between the probing field and the active biological substance incorporated between the nanorods and a strong plasmon-mediated energy confinement inside the layer, this type I metamaterial (Figure 11c) provides an enhanced sensitivity to RI variations of the medium between the rods (more than 30,000 nm/RIU). They focused on newly emerging plasmonic metamaterials, composite structures consisting of subwavelength-size components, and designed a sensor-oriented metamaterial that is capable of supporting similar or more sensitive guiding modes than SPPs. In particular, they reported on the experimental realization of such a metamaterial-based transducer using an array of parallel gold nanorods oriented normal to a glass substrate (Figure 11a and b). When the distance between the nanorods is smaller than the wavelength, this metamaterial layer supports a guided mode with the field distribution inside the layer determined by plasmon-mediated interaction between the nanorods. This anisotropic guided mode has resonant excitation conditions similar to the SPP mode of a smooth metal film and a large probe depth (500 nm). The structural parameters can be controlled by altering the fabrication conditions – typical ranges span rod lengths of 20–700 nm, rod diameters 10–50 nm, and separations 40–70 nm – thus achieving a nanorod areal density of approximately 1010–1011 cm−2. The lateral size and separations between the nanorods are much smaller than the wavelength of light used in the experiments, so only average values of nanorod assembly parameters are important, and individual nanorod size deviations have no influence on the optical properties that are well described by effective medium theory . The nanorod structures’ sensing properties were characterized in both direct transmission and attenuated total internal reflection (ATR) geometries using spectrometric and ellipsometric platforms.
In the direct-transmission geometry, the extinction spectra of the nanorod array in an air environment show two pronounced peaks at 520 and 720 nm. These resonances correspond to the transverse and longitudinal modes of plasmonic excitations in the assembly , , . The transverse mode is related to the electron motion perpendicular to the nanorod long axes and can be excited with light having an electric-field component perpendicular to it, whereas the longitudinal mode is related to the electron oscillations along the nanorod axes and requires p-polarized light to be excited with a component of the incident electric field along the nanorods. The electric-field distribution associated with the longitudinal mode has an intensity maximum in the middle of the nanorods and results from a strong dipole-dipole interaction between the plasmons of individual nanorods in the array and is, therefore, not sensitive to the presence of the superstrate , , , . Under oblique incidence and with p-polarized light, the electric field couples to both the transverse and longitudinal modes with the metamaterial slab showing extreme anisotropy of dielectric permittivity similar to that of a uniaxial crystal . The illumination of the same nanorod structure in the ATR geometry reveals the new guided mode in the NIR spectral range which is excited only with p-polarized light and dominates the optical response of the assembly.
The metamaterial works similar to a conventional SPP-based sensor, showing a red shift of the resonance in response to an increase in the RI (Figure 11d and e). Furthermore, a change of the RI by 10−4 RIU causes a shift of the resonance by 3.2 nm even without any optimization of the structure (Figure 11f). The corresponding minimum estimation of sensitivity of 32,000 nm/RIU exceeds the sensitivity of localized plasmon-based schemes by two orders of magnitude , , ,  and an FOM value of 330 is achieved.
4.2 Prism-coupled HMM-based tunable biosensor
In this section, Sreekanth et al. demonstrated the development of a tunable type I HMM and excitation of BPP modes via prism coupling. By using the Goos–Hänchen (G–H) shift interrogation scheme, reconfigurable sensing with extreme sensitivity biosensing for small molecules has been shown . The G–H shift describes the lateral displacement of the reflected beam from the interface of two media when the angles of incidence are close to the coupling angle .
As shown in Figure 12a, to develop a low-loss tunable HMM, 10 alternating thin layers of a low-loss plasmonic material such as TiN (16 nm) and a low-loss phase change material such as Sb2S3 (25 nm) are deposited on a cleaned glass substrate. The optical properties of the developed HMM can be tuned by switching the structural phase of Sb2S3 from amorphous to crystalline. In Figure 12b, the EMT-derived uniaxial permittivity components of Sb2S3–TiN HMM have been shown when Sb2S3 is in amorphous and crystalline phases. As can be seen, Sb2S3–TiN HMM exhibits type I hyperbolic dispersion at λ > 580 nm when Sb2S3 is in amorphous phase, where and . However, the operating wavelength of type I region is slightly blue shifted to 564 nm after the crystallization of Sb2S33 layers in the HMM.
To excite the BPP modes of Sb2S3–TiN HMM through prism coupling, a He–Ne laser (632.8 nm) with p-polarized light was used as the excitation source. This wavelength belongs to the hyperbolic region of the HMM and the effective index of HMM is less than that of the used BK7 prism index (1.5), so that the momentum matching condition can be satisfied. In Figure 12c, the excited BPP mode of Sb2S3–TiN HMM have been plotted, when Sb2S3 is in both phases. After switching the phase of Sb2S3 from amorphous to crystalline state, the effective index of the HMM decreased, as a result (i) the minimum reflected intensity at the resonance angle declined, (ii) the linewidth of the reflection spectrum decreased, and (iii) the coupling angle slightly shifted. Figure 12d shows the calculated dispersion diagram of fundamental BPP mode of the Sb2S3–TiN HMM. Note that the experimentally determined parallel wavevector at 632.8 nm is exactly on the BPP dispersion curve of HMM. Then the Poynting vector (Sx) of the HMM guided mode at 632.8 nm has been calculated (Figure 12e). It shows that the excited mode is a propagating wave inside the HMM, decays exponentially at HMM–water (air) interface, and is leaky in the prism. These are the basic characteristics of a typical BPP mode of an HMM. At resonance, the estimated propagating mode nearest in momentum is 13.08 μm−1 with a propagation length of 177 nm. It appears that the excited mode is the fundamental BPP mode of Sb2S3–TiN HMM, but it is a low-k mode. It is known that the phase difference between TM- and TE-polarized light experiences a sharp singularity at the coupling angle . Thus, as shown in Figure 12f, this phase difference can be actively tuned by switching the phase of Sb2S3 from amorphous to crystalline.
Because the phase derivative at the coupling angle determines the magnitude of the G–H shift, an enhanced and tunable G–H shift at the BPP mode excitation angle can be realized using the Sb2S3–TiN HMM. As shown in Figure 13a, the maximum G–H shift is obtained at the coupling angle, where there is a sharp change of phase difference. In addition, a tunable G–H shift is possible by switching the phase of Sb2S3 in the HMM from amorphous to crystalline. To validate this tunable behavior experimentally, RI sensing has been performed because the G–H shift strongly depends on the superstrate RI. A differential phase-sensitive setup to record the GH shifts has been used , , . In the experiments, the G–H shifts have been monitored, by injecting different weight ratios (1–10% w/v) of aqueous solutions of glycerol with known refractive indices into sensor channel. The real-time RI sensing data are presented in Figure 13b, where measured G–H shift change with time due to the RI change of glycerol solutions has been report. It is evident that a clear step function in G–H shift by varying the glycerol concentration is obtained. More importantly, a tunable G–H shift is obtained by switching the Sb2S3 structural phase from amorphous to crystalline. It is clear from both calculations and experimental data that the maximum G–H shift is possible when Sb2S3 in the HMM is in the crystalline phase because the crystalline phase provides a higher phase change at the coupling angle. Therefore, the obtained maximum RI sensitivity for the crystalline phase of HMM results to be 13.4 × 10−7 RIU/nm. The minimum sensitivity obtained for the amorphous phase of HMM is 16.3 × 10−7 RIU/nm. Because the sensor shows tunable sensitivity, a reconfigurable sensor device can be developed for future intelligent sensing applications. Although the obtained tunable range is small, the G–H shift tunability can be further improved using longer wavelength sources and higher RI prisms.
Because enhanced RI sensitivity is possible with the G–H shift interrogation scheme, it can be used to detect small biomolecules at extremely low concentrations. To demonstrate this, it was first sputtered a 10-nm film of gold on top of the crystalline HMM sample. Then the streptavidin–biotin affinity model protocol has been followed for the capture of biotin and the RI change caused by the capture of biotin on the sensor surface was recorded by measuring the G–H shift. By injecting different concentrations (10 fM to 1 μM) of biotin prepared in PBS into the sensor channel with a sample volume of 98 μl and the corresponding G–H shift with increasing concentration was recorded. For biotin concentrations from 10 fM to 1 μM, the response of the sensor with time was analyzed by calculating the marginal G–H shifts (). Figure 13c shows the recorded marginal G–H shifts after a reaction time of 40 min and an increase in marginal G–H shifts with increasing biotin concentration is obtained. To confirm the specific binding of biotin on streptavidin sites, the marginal G–H shift change of a single measurement as the biotin molecules accumulate on the sensor surface over time has been recorded, as shown in Figure 13d. A clear step in G–H shift due to the binding of biotin molecules to streptavidin sites is observed. By considering the experimental noise level, it was possible to quantify that the detection limit of the sensor device is less than 1 pM. The detection of ultralow-molecular-weight biomolecules such as biotin at a low concentration of 1 pM is occurred due to the extreme RI sensitivity of the sensor, which is achieved through the G–H shift interrogation scheme. To conclude, it is possible to envision that small molecules such as exosomes can be detected even from bodily fluids using the proposed HMM-based plasmonic platform.
In this review, it has been reported the state of the art of hyperbolic dispersion metasurfaces and metamaterials and their applications in the field of molecular biosensing. We started by highlighting the physical aspects characterizing hyperbolic dispersion materials, followed by a review of some relevant designs and properties of HMM that have been proposed by different groups worldwide. HMMs have demonstrated to support extremely sensitive optical modes that can be used to develop cost-effective, noninvasive liquid biopsies for POC clinical evaluation, early cancer screening and real-time diagnosis of diseases. This review highlights the recent advances in hyperbolic dispersion metasurface–based biosensor technology, and in particular discusses biosensors involving metal/dielectric multilayered HMMs. This includes biosensors using different coupling mechanisms and interrogation schemes. We also discuss reconfigurable sensors based on tunable HMMs, LSPR sensors based on type I HMMs and biosensing applications of multifunctional hyperbolic nanocavities. The diagnostic platforms discussed here would call for radical changes in clinical diagnosis and treatment decisions, with the outcomes of lower capital costs, higher accuracy, and specificity. The development of optical devices based on radically new metasurfaces holds the promise to deliver an unprecedented detection limit (areal mass sensitivity at a level of fg/mm) with an optimal dynamic range for proteomic-genomic tests.
Funding source: AIM: Attraction and International Mobility
Award Identifier / Grant number: PON R&I 2014-2020
Funding source: Luxembourg National Research Fund
Award Identifier / Grant number: C19/MS/13624497
Funding source: FEDER Program
Award Identifier / Grant number: 2017-03-022-19
G.P. acknowledges support from the “AIM: Attraction and International Mobility” – PON R&I 2014-2020 Calabria.
Author contribution: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: N.M. acknowledges support from the Luxembourg National Research Fund (CORE Grant No. C19/MS/13624497 “ULTRON”) and from the FEDER Program (Grant No. 2017-03-022-19 “Lux-Ultra-Fast”).
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
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