Low-dimensional van der Waals (vdW) materials can harness tightly confined polaritonic waves to deliver unique advantages for nanophotonic biosensing. The reduced dimensionality of vdW materials, as in the case of two-dimensional graphene, can greatly enhance plasmonic field confinement, boosting sensitivity and efficiency compared to conventional nanophotonic devices that rely on surface plasmon resonance in metallic films. Furthermore, the reduction of dielectric screening in vdW materials enables electrostatic tunability of different polariton modes, including plasmons, excitons, and phonons. One-dimensional vdW materials, particularly single-walled carbon nanotubes, possess unique form factors with confined excitons to enable single-molecule detection as well as in vivo biosensing. We discuss basic sensing principles based on vdW materials, followed by technological challenges such as surface chemistry, integration, and toxicity. Finally, we highlight progress in harnessing vdW materials to demonstrate new sensing functionalities that are difficult to perform with conventional metal/dielectric sensors. This review presents an overview of scenarios where van der Waals (vdW) materials provide unique advantages for nanophotonic biosensing applications. The authors discuss basic sensing principles based on vdW materials, advantages of the reduced dimensionality as well as technological challenges. The real-time, label-free sensing capability of this modality has been critical for the functional and quantitative characterization of antibodies3, drugs, aptamers, target-drug interactions4, and virus-host-cell receptor interactions5. SPR generates invaluable time-resolved kinetics data that cannot be obtained with conventional end-point binding assays that employ target labelings, such as enzyme-linked immunosorbent assays (ELISA) or radioimmunoassays. State-of-the-art SPR instruments can achieve limits of detection (LOD) that are comparable to ELISA and they are increasingly being applied toward the clinical analysis of patient biofluids to detect proteins, microRNAs, drugs, and small molecules associated with various disease conditions6. The refractive index (RI)-sensing transduction mechanism of SPR eliminates the need for labeling and washing steps, provides real-time kinetic information and is fast, which can be advantageous for clinical applications. Furthermore, SPR is useful for characterizing low-affinity analytes, which in equilibrium ELISA assays would require larger sample volumes and cause unwanted dissociation of weakly-bound analytes during wash steps6.Photonic biosensors are indispensable tools for life sciences and medical diagnostics. For example, commercial surface plasmon resonance (SPR)9. While nanoplasmonic structures add fabrication complexity and costs, they can improve multiplexing capacity, miniaturization, and sensitivity while also offering considerable design flexibility. Early demonstrations focused on enhancing the performance of conventional SPR by reducing the footprint of the sensing area to provide portability for point-of-care (POC) applications and/or increase parallel detection for high-throughput screening. For example, the widely used gold nanohole arrays11 can be excited with simple collinear optics compatible with a standard microscope, while simultaneously enabling array-based sensing via parallel imaging techniques12. The challenge of producing large-scale patterns with ease and low cost has been addressed using interference lithography13, replication from templates14, and photolithography15.To miniaturize and further improve the performance of SPR sensors, researchers have leveraged both top-down lithography and bottom-up synthesis to build “nanoplasmonic” sensors by engineering the flat gold films of conventional SPR into nanoparticles, nanoholes, or collections of sub-wavelength unit cells called “metasurfaces” of various shapes. Such nanostructures and metasurfaces can extend resonances to broader frequency ranges , and exhibit optical phenomena such as localized surface plasmon resonance (LSPR), radiative coupling, and extraordinary optical transmission18. By taking advantage of the nanohole geometry, which can selectively localize receptor molecules or biological nanoparticles, researchers have shown unique sensing functions utilizing nanovesicles11  single-walled carbon nanotubes (SWNTs) and two-dimensional (2D) graphene—have already demonstrated novel sensing capabilities that are inaccessible to metal/dielectric nanophotonic sensors. For example, SWNTs have been used for single-molecule detection27  materialsons Fig.  for new n27 Fig.  and in v 28 Fig.  via excig29 Fig. , moleculg29 Fig. , on-chip 30 Fig. , and nan 31 Fig. .Fig. 2LoIn this review, we explore the potentials of vdW materials for nanophotonic biosensing Fig. . We starQ) factor, and are of high contrast. When these conditions are met, analyte molecules can result in large intensity changes in the photodetector  may not be enough to characterize the LOD of disparate biosensors. A more fundamental quantity for nanophotonic structures is the evanescent field decay length of the resonant field into the sensing medium , of bound receptor-analyte pairs by subtracting the rate of dissociation from the rate of association:In this illustrative example, receptor molecules  SARS-Cov and (b) SARS-Cov2) are immobilized on the gold SPR sensor surface and their binding interactions with the target analytes (human ACE2 protein) are measured at different concentrations. A standard equation for 1:1 binding kinetics calculates the change in the normalized surface coverage, ca is the analyte concentration in solution, kon (mol−1 L s−1) is the association rate and koff is the dissociation rate. The equilibrium dissociation constant Kd = koff/kon (M) measures binding affinity (lower Kd means higher binding strength) and the equilibrium surface coverage is Kd) than SARS-CoV (a and b were plotted using the 1:1 binding kinetics equation and parameters from ref. 5), providing quantitative clues to its more infectious nature. (d) An example of reflectance vs. wavelength obtained from a conventional prism-based SPR setup. Conventional prism-based SPR has relatively broad resonance and typically the quality-factor  is on the order of 10. Resonance shift in SPR is measured by either bulk sensitivity (shift per RI change of the bulk solution), or the more biologically relevant thin-film sensitivity (shift per adsorbed film thickness). Conventional prism-based SPR setups exhibit very high bulk sensitivity of up to ~10,000 nm/RIU, or ~100°/RIU2. Resolution is defined as the minimum detectable RI change. This depends on multiple factors such as instrumentation technique, resonator design, and environmental control156. Despite relatively low Q’s, with external controls, robust curve-fitting algorithms, and schemes to reduce photodetector shot noise and source fluctuation, state-of-the-art SPR can resolve spectral shifts as small as 0.001 nm from a resonance dip156, which equates to a resolution of (0.001 nm)// = 10−7 RIU. However, bulk sensitivity does not always correlate with sensitivity to the molecular binding. For example, while nanoplasmonic sensors  (e) typically show lower bulk sensitivity (~700 nm/RIU in this example) than conventional SPR, they utilize more tightly localized evanescent fields and could show similar performance for detecting surface-bound molecules. Conversely, long-range SPPs show higher bulk sensitivity 158 than conventional SPR, but their molecular LOD is similar. A good sensitivity metric for surface-bound molecules can be estimated in terms of picograms/cm2, and thin-film sensitivity (shown in (f)), as measured by resonance shifts with deposited Al2O3 film thickness on gold nanodisks/nanoholes34 is a practical parameter for predicting detection limits159. Using new degrees of freedom available with nanostructures, researchers have engineered high-Q resonances. The figure-of-merit (FOM), defined as (bulk sensitivity)/(linewidth) considers intrinsic/extrinsic plasmon damping mechanisms and can serve as another useful metric. In particular, when an intensity-based sensing scheme is used , a narrower peak results in a greater intensity change at a fixed wavelength per RI change. The FOM can be increased by engineering structural resonances  to reduce the resonant linewidths. However, such changes also tend to reduce the intensity of the resonance, thereby degrading the overall sensitivity of detection. Likewise, arguments based on Q or FOM alone would favor high-Q dielectric resonators over metal plasmonics, but their molecular detection sensitivities are relatively similar. This is due in part to the low contrast in signal, determined by the relative magnitude of the resonant peaks. For continuous monitoring of binding kinetics at high temporal resolution (~millisecond acquisition time), it is essential to deliver high photon flux at the photodetector, which requires that the resonance dip or peak should be large in magnitude .where 5 and the 1:1 binding kinetics equation. (d) Example of SPR reflection spectrum from a prism-based setup. (e) Resonance shift measured for a high-quality-factor subradiant SPP mode with changing NaCl concentration. Reprinted with permission from ref. 157. (f) The resonance shift vs. ALD-grown Al2O3 film thickness was measured from which one can obtain the LSPR field decay length. Adapted with permission from ref. 34.Illustrative examples of SPR binding kinetics for purified recombinant receptor-binding domains of viral spike protein from (a) SARS-CoV and (b) SARS-CoV2, against human ACE2 protein plotted using (c) association and dissociation rates from ref. 37. While the surface of gold SPR sensors is commonly functionalized via a self-assembled monolayer of alkanethiols, the surface of graphene or other vdW materials requires different strategies for functionalization, which presents challenges as well as new opportunities. Graphene surfaces can be modified by attaching some molecules via π-stacking or other functional groups . However, the ease of attachment via π-stacking also implies increased nonspecific binding of interferents from biological samples, necessitating a proper blocking procedure. Xue et al. used antimonene-modified gold SPR chips to detect microRNA hybridization events31. Density functional theory energetic calculations predicted that antimonene surfaces have a higher affinity for single-stranded (ss) DNA than double-stranded (ds) DNA. By using gold nanorods to further boost SPR signals, they were able to detect ssDNA-microRNA hybridization events. vdW materials can also protect the surfaces of reactive metals—especially copper and silver—which is necessary for SPR biosensing applications38. Wu et al. characterized the potential of layer materials  to protect the chemical and optical properties of plasmonic metals39 At a wavelength of ~1 µm, they achieved bulk RI sensitivity of ~10,000 nm/RIU, which is comparable to the sensitivity of conventional spectroscopic techniques.Building on the mature capabilities of prism-coupled gold-film SPR instruments, researchers have explored the benefits of coating the gold film with various 2D materials. Groups have reported improved SPR sensitivity from graphene-coated gold surfaces, which was attributed to enhancement of the surface electric fields provided by an added charge transferred from graphene to goldWhile these studies demonstrate impressive LOD for molecules in buffer, the response of hybrid vdW-metal surfaces in biofluids for practical biosensing applications  needs to be characterized to ensure whether the same low LOD can be maintained. Also, instead of single-channel measurements, reference-channel measurements, as well as temperature stabilization, will be essential for ultrasensitive detection.40. However, the large-area growth and transfer of vdW materials atop metal films add complexity, labor, and costs. As such, in order to justify their use in practical biosensing applications, the benefits need to go beyond incremental gains in sensitivity and enhanced surface adsorption of analytes. Ideally, vdW nanophotonic biosensors should be used in tandem with other sensing modalities, such as electrical or electrochemical detection, or to enable novel functionalities such as vibrational fingerprinting with spectroscopy.As shown in these examples, the applications of vdW materials for conventional SPR or other nanophotonic RI sensors are rapidly expandingRefractometric sensors made with metals, dielectrics, and metal-vdW hybrids have shown impressive performance metrics, but cannot identify bound analyte molecules. Vibrational spectroscopy techniques like infrared (IR) absorption spectroscopy and Raman scattering complement SPR and enable such “fingerprinting” functions for molecules, viruses, extracellular vesicles, and cells. With their electrically tunable doping and ultra confined mid-IR and terahertz (THz) plasmons, graphene and other 2D vdW materials are especially promising for these applications.−1). IR spectroscopy taps into this so-called fingerprint region and is used in numerous scientific fields  and in the industry . However, the large mismatch between micrometer IR wavelengths and nanometer-sized molecules leads to low sensitivity, limiting the use of IR spectroscopy for measuring trace amounts of samples. Nanophotonics can bridge this gap by producing strong, tightly localized near-fields in the vicinity of resonant optical nanostructures. This approach is called SEIRA  typically exhibit lower enhancement factors (EF) of ~10nts Fig. , which dses Fig. . They sh 50 Fig. .Fig. 3De51. For instance, while metals can support strong plasmonic responses due to their high electron concentration, they suffer from high loss and provide resonators with low Q-factors . In contrast, Mie resonances in low-loss and high-index dielectric metasurfaces can achieve several orders of magnitude higher Q-factors. Tittl et al. used CMOS-compatible high-Q-factor (>100) silicon resonators in a sensing approach that can convert mid-IR molecular fingerprints into chemical-specific barcode-like images while eliminating the need for bulky IR spectroscopy instruments52. Leitis et al. used germanium metasurfaces to expand the spectral coverage of resonant SEIRA over 1000 cm−1 wavenumber and extracted vibrational signatures of different molecules in a multi-step assay53.To date, SEIRA has mostly employed metal-based plasmonic resonators with engineered nanostructures in various shapes and array configurations. However, this landscape is changing rapidly, with novel nanomaterials that can address the intrinsic shortcomings of metals54. The unique optoelectronic properties of graphene enable external control over plasmonic resonance frequency by changing its carrier density  with electrostatic biasing57. Such active tuning is used to realize dynamically configurable IR sensors tuned to specific molecular vibrational modes. Rodrigo et al. showed the first graphene-based tunable mid-IR biosensor and its potential for quantitative chemical-specific detection26. They measured plasmon resonance spectral shifts accompanied by narrow dips corresponding to the surface-enhanced molecular vibration bands of a protein analyte over a broad spectrum . Graphene nanoribbons can provide up to two orders of magnitude higher field confinement than metallic plasmonic dipole antennas, and thus enable unprecedentedly strong overlap of light with nanometric biosamples26  is typically used to synthesize large-area graphene, and the resulting grain boundaries, impurities and defects result in lower quality graphene, as shown by its reduced carrier mobility (~1000 cm2 V−1 s−1). Furthermore, nanopatterning of graphene with small structures  is often required to excite mid-IR plasmons, but the rough edges induced by the nanofabrication process lead to additional loss and further deteriorate the quality of the resonators. Limited plasmon lifetimes (~50 fs) and inelastic scattering with optical phonons have also been reported in graphene nanoribbons67. However, further effort is needed towards the development of high-quality 2D vdW materials that can be scalably manufactured for real-world applications. Observation of low-loss graphene from the encapsulation of exfoliated samples with hexagonal boron nitride (hBN)68 and recent advances in CVD graphene transfer involving proper cleaning and encapsulation, which result in room-temperature mobility in excess of 10,000 cm2 V−1 s−1, demonstrate some of the important ongoing progress in materials development69.Graphene can achieve high Q-factors, which can lead to increased sensitivity due to longer interaction time between the probing IR light and the analytes. In theory, Q-factors well over 100 can be expected with exfoliated grapheneEf), but this requires some care in terms of fabrication and design. In the past, devices typically relied on a thick dielectric spacer between the graphene and the gating layer. This leads to low capacitance values, and hence requires the application of high bias voltages (tens of volts). However, recent research shows that incorporation of a field-effect transistor (FET) device architecture and suitable spacer films as a substrate can greatly reduce the bias voltage while enabling high-speed operation and incorporation of imaging70. A related issue stems from the dependence of the graphene response on the optical properties of the spacer layer. Graphene plasmons can strongly couple with the phonon modes of the substrate, and this hybridization can produce complex spectral features and limit the operating spectral window. Hu et al. incorporated CaF2 nanofilms as spacers; since CaF2 has no phonons in the relevant range, it eliminates this problem and allows the use of SEIRA over a broader spectral range59.Dynamic tuning of graphene plasmons see Box  is achie71, integration with photonic cavities 72, and hybrid substrates incorporating plasmonic nanostructures73 , which is not practical for device applications. The coupling efficiency is further hampered by the low carrier density and the weak oscillator strength of graphene plasmons. In order to excite stronger plasmonic responses, recent works have used multi-layer stackss73 Fig. . Strong s73 Fig.  can also74. Because the field intensity decays exponentially from the plasmonic substrate surface with a decay length of ~100 nm, one can selectively probe surface-adsorbed molecules and minimize interference from water molecules in the sample. In contrast, graphene resonances are extracted from either the extinction spectra in the transmission configuration or the absorption spectra obtained in the reflection configuration with an optically thick metal layer, which make in situ measurements not possible. Recent work has combined graphene with attenuated total reflection (ATR) prisms for in situ studies, but these approaches involve inherently bulky instrumentation and are not suitable to exploit tunable and strongly confined plasmonic resonances76. Graphene and other liquid-impermeable vdW materials offer alternative routes to avoid water absorption by trapping water in nanometric volumes. This approach has been successfully demonstrated with tip-enhanced IR absorption spectroscopy using a graphene liquid cell50, and in graphene-based nanofluidics77.To benefit from these additional functions, graphene-based SEIRA devices need to be compatible with in-solution measurements and microfluidics. To this date, most SEIRA experiments have been conducted in a dry medium due to the high absorption of water and polymers used for microfluidics in the IR spectrum. These constraints are circumvented for metal-based SEIRA by utilizing strong plasmonic confinement and performing plasmon excitation and signal collection in the reflection configuration with an IR-transparent substrate81. The resonances of hBN, however, are spectrally limited in biosensing applications due to the fixed Reststrahlen bands—where the energy band between the longitudinal and transverse optic phonon frequencies Re(ε) is negative and surface phonon polaritons can be excited—which are not aligned with the amide absorption bands of proteins. However, recent work has shown that the Reststrahlen band of MoO3 can be tuned82, which may be useful for chemical sensing applications, although such tuning is not suitable for biomolecules such as proteins and nucleic acids.Besides graphene plasmons, phonon-polaritons in hBN have been utilized for confining mid-IR lightBox 2. Surface-enhanced infrared absorption spectroscopy (SEIRA)Raman scattering and IR absorption are commonly used to obtain molecular structural information. Raman spectroscopy is based on the inelastic scattering through which a molecule either gains energy from (Stokes process) or loses energy to (anti-Stokes process) incident photons. Transitions involved in IR absorption versus Raman scattering processes are subject to different selection rules. Thus, the measured spectra show different and complementary sets of peaks, and their utility depends on the specific application.6–1010 photons striking a molecule are scattered inelastically. Typical non-resonant Raman scattering cross-sections (σRaman) are 10−31~10−29 cm2/molecule—much smaller than for IR absorption (~10−20 cm2/molecule). However, a key advantage of Raman spectroscopy for biosensing is the small scattering cross-section of the water, which minimizes unwanted background in aqueous samples. In contrast, absorption of mid-IR radiation in water can obscure absorption signals from analytes.Raman scattering is extremely weak, as only 1 in 10E| is roughly |E|4, plus a chemical EF of 10–100-fold due to the modified polarizability of molecules on a metal surface, whereas SEIRA increases only with |E|2. In most SERS substrates, the spatial distribution of intense “hotspots” are random, thus the location of these spots cannot be easily predicted for continuous activation. In contrast, SEIRA EFs, while lower, can be more uniformly distributed and predictable. Importantly, the utility of SERS diminishes for probing large biomacromolecules or complexes, because SERS EF drops rapidly over a few nanometers from the metal surface. In addition, intrinsic SERS detection of protein molecules or changes in their orientation/conformation is difficult for large proteins. Autofluorescence can also easily mask weak Raman signals. Resonantly-excited plasmons in SEIRA substrates typically exhibit lower EFs but provide a wider probing range suitable for sensing the adsorption of larger targets.The scaling factor for electromagnetic enhancement for SERS as a function of electromagnetic near-field amplitude |ADev and A0 denote measured optical absorption from a SEIRA substrate and reference device, respectively, with VDev and V0 being the effective volumes where optical fields and target molecules overlap. Infrared reflection-absorption spectroscopy (IRRAS) is a common method to obtain reference signals from a thin film of target biomolecules. In this case, SEIRA EF can be rewritten as:AIRRAS and θ are measured absorption from IRRAS and the incident angle of IR radiation, respectively. The oblique incidence of IR radiation and the dipole-mirror effect is accounted for by ADev is calculated from the power dissipation by integrating The performance of a SEIRA substrate is represented by the EF, which measures the ratio of absorption from a substrate to that of a reference sample when normalized to an effective volume. This performance metric is given as:Box 3. Characteristics of tunable graphene plasmonsGraphene plasmons offer the unique advantages of tight field confinement as well as electrical tunability of plasmon resonances. Plasmons in 2D vdW materials represent the ultimate limit in terms of sub-diffraction field confinement. As shown in the left panel, graphene plasmons can be conceptualized as an extension of short-range SPP waves in a metal film with symmetric charges across the film, and these plasmons are further squeezed as the film is thinned down. The dispersion of conventional graphene plasmons scales as EF is the graphene Fermi level, εeff is the effective dielectric constant of the environment, and q is the momentum. By placing graphene in proximity to a metal plate, mirror image charges are created that modify the plasmon field distribution. The dispersion for the resulting acoustic graphene plasmon now becomes linear . On the other hand, the plasmon resonances of metallic nanostructures are fixed upon fabrication due to the high carrier concentration  for noble metals. The 2D semi-metallic nature of graphene allows for electrical tunability that is not possible with conventional metals. Free carriers in graphene obtained through electrical doping can number 0.001–0.01 per atom, and the corresponding graphene plasmon resonance resides in the mid-IR (3–20 µm wavelength) and THz frequency ranges, which are ideally suited for reconfigurable vibrational spectroscopy with dynamically tunable resonances26.These dispersions assume the same graphene doping with Box 4. vdW materials for trapping of biomolecules via DEP161 DEP, a radiofrequency (kHz–MHz) analog of the optical trapping process, has been used to manipulate biological particles and can be useful in the context of vdW materials. With a relatively simple apparatus (electrodes and a function generator), DEP can be employed to attract, trap, or repel neutral particles based upon their polarizability. When a particle of radius R and complex permittivity 162.Rapid transport of target analytes to the nanophotonic sensor is critical for detecting low-concentration analytes. Nanophotonic sensors typically exhibit small detection areas, and active transport and concentration of analytes can greatly improve the detection speed and overall sensitivity.dx, it is possible to boost its magnitude by shrinking the critical dimensions of the system  without using high bias voltages or electric fields that are detrimental to biological systems (a). Sharp tips163, nanometric gaps, or nanopores164 in metal films have been used for a wide range of DEP applications such as particle filtering, sorting, trapping, levitation, and rotation162. Atomically sharp vdW materials are uniquely capable of creating ultra-strong DEP forces in the context of (b) sharp electrode tips realized with SWNTs166 and (c) graphene-edge DEP169. Barik et al. showed that patterned edges of monolayer graphene can generate high-gradient fields to trap nanoscale objects and molecules with enhanced trapping forces168. Such edge-trapping DEP devices can be made from graphene or other conductive vdW materials patterned over a metal electrode, separated by a thin insulator. Using this setup, polystyrene particles were trapped on the edges of graphene at voltages as low as 0.5 V. Furthermore, both long (10 kb) and short (500 bp) DNA strands were trappable at low voltages (~2–3 V).where The ultra-strong gradient forces at nanoscale distances in graphene-edge DEP have the potential for nanophotonic as well as nanoelectronic biosensing applications, where analytes such as antibodies, proteins, viruses, nanoparticles, or cells could be trapped rapidly using relatively low (~1 V) bias voltages. Furthermore, the electrical readout capabilities of some vdW materials could also enable a path toward hybrid optical/electrical DEP-enhanced sensors. Surface functionalization of the sensor could be utilized to further enhance detection selectivity. DEP can also be combined with rapidly advancing nanopore sensing technologies (d) based on vdW materials, as discussed in the Supplementary Information.(a) Dielectrophoresis is a scalable particle trapping mechanism. Smaller electrode separation and sharper electrode tip can boost field gradients. (b) Carbon nanotube electrodes (adapted from ref. 166 with permission), (c) graphene edge electrodes (adapted with permission from ref. 168), and (d), metallic nanopores (adapted from ref. 164 with permission), can generate high gradient fields at relatively low trapping voltages toward trapping nanoparticles and biomolecules.83. Initially, using metal plasmonic elements, researchers have already addressed some of the challenges. Schwarz et al. demonstrated a compact mid-IR chemical sensing platform84, which monolithically integrates a bi-functional quantum cascade laser/detector coupled to a dielectric-loaded gold SPP waveguide  waveguide-integrated black phosphorous detectors93, and heterogeneously-integrated Si waveguides on mid-infrared compatible substrates, which could extend the detection limit out to 8 μm94. These advancements in miniaturization due to waveguide-mediated delivery of light onto the vdW sensor, could eventually eliminate the need for expensive and bulky FTIR spectrometers as well as laborious alignment of free-space optics via moving mechanical parts.Tightly-confined excitons in graphene and other vdW materials offer additional exciting opportunities for nanophotonic biosensing. One long-term vision shared by many researchers is to realize compact nanophotonic “lab-on-a-chip” devices that integrate light sources, low-loss dielectric waveguides, nanophotonic sensors, and on-chip photodetectors, as illustrated in Fig. ide Fig. . Waveguiide Fig. 85. Incorrus Fig. 87, have 96 can address an entirely new set of problems—such as in vivo nanophotonic sensing and bioimaging. Shortly after the discovery of SWNTs’ near-infrared (NIR) fluorescence, this phenomenon was recognized as ideal for optical imaging and sensing97. The unique electronic properties of SWNTs that result in their bandgap fluorescence have been reviewed by Weisman98. Briefly, SWNTs can be thought of as single sheets of graphene rolled into cylindrical geometries. Their electronic—and thus photophysical—properties depend on the direction of rolling, which can be specified by lattice vectors n and m  chiral species is metallic or semiconducting. The nanoscale-cylindrical shape of semi-conducting SWNTs confines electrons in one dimension along its circumference, leading to what is known as van Hove singularities in the electron density  SWNTs102. The diffusion length is limited by the presence of defects in the nanotube or the supporting substrate. Fluorescence occurs when the exciton relaxes back down to the band edge and emits a photon with energy equivalent to the exciton energy. SWNTs are commonly interrogated by exciting through a range of visible light in the range of the E22 transition, and their NIR E11 emission is then collected. Different semiconducting chirality species with different bandgaps/exciton energies can then be visualized using a 2D excitation-emission profile 107, sodium dodecylbenzene sulfonate (SDBS)110, and sodium cholate (SC)112, and/or enthalpy-driven interactions such as π−π bonding, hydrogen bonding , or ionic interactions between the SWNT surface and dispersants such as aromatic polymers, cationic polymers, and block polymers.Due to intrinsically strong vdW interactions, SWNTs tend to stick together as bundles and do not naturally disperse in an aqueous solution or biological media. Covalent and non-covalent surface modifications of SWNTs are used to promote solubility. Covalent modification is achieved by chemical reactions on the nanotube surface to introduce carboxyl, amine, sulfhydryl, or other functional groups Box 103. Whil28 has been developed to achieve selective recognition of specific molecules les Fig. . In CoPh123. Cognet et al. have observed single proton and diazonium salt binding and release from SDBS-functionalized SWNTs by detecting stepwise changes in fluorescence124. This approach was extended by Zhang et al.115 to detect nitric oxide with SWNTs deposited onto functionalized glass sides, and by Jin et al.125 to detect H2O2 with SWNTs embedded in type 1 collagen thin films. During measurements, each SWNT serves as an individual optical probe, and individual stepwise changes in sensor states correspond to single-molecule binding or release events. The observed bulk SWNT fluorescence is a combination of these single-molecule interactions, and the bulk concentration is obtained through hidden Markov modeling125. The collagen-based SWNT sensors have also been applied to detect real-time H2O2 generation with high spatial resolution from individual live A431 human epidermal carcinoma cells stimulated with epidermal growth factor117  Patterned nanophotonic structures typically utilize heterogeneous materials and interfaces . By conformally coating such structures with a thin SiO2 film via sputtering or ALD, one can make a homogeneous surface compatible with well-established silane chemistry or vesicle fusion to form a lipid bilayer membrane. Reprinted from ref. 171 with permission.172.While ALD-grown oxides have been used for surface modification of metal/dielectric nanophotonic substrates, nucleation of ALD of oxides on graphene is difficult due to graphene’s hydrophobic nature and lack of out-of-plane bonds. Several strategies have been utilized to overcome this limitation, including using physisorbed ozone, hydrogen plasma functionalization, organic self-assembled monolayers, and evaporated metal or oxide seed layers. Such strategies have proven successful, provided that a pristine graphene surface can be achieved174, nanovesicles, or (c) a pore-spanning lipid bilayer (Reprinted from ref. 175 with permission). In general, SLBs are formed directly on a solid substrate with a thin layer of water (~1 nm) between the membrane and the substrate. It is critical that the sensor material  does not adversely affect the conformation or functionality of membrane-bound molecules. Recent work has combined SLBs, lipid nanovesicles, and synaptic vesicles for SEIRA sensing47. Importantly, lipid bilayer membranes can also help prevent nonspecific adsorption of proteins onto the sensor surface. (d) The recently-developed solvent-assisted lipid bilayer (SALB) method can be used to form lipid bilayer membranes directly on bare gold surfaces without a SiO2 layer. SALB can be useful for SPR, SERS, and SEIRA, and is compatible with some vdW materials. Reprinted from ref. 176 with permission. For substrates or receptors that are not amenable to these methods, other options are available, such as the use of membrane-derived particles as biomimetic receptors. Such cell-derived materials may be directly dispersed as nanoparticles on the surface, or physically inserted into patterned substrates via a ‘squeegee’ method177.For applications in membrane biology and drug discovery, it is desirable to interface nanophotonic sensors with highly fluidic lipid bilayer membranes or nanovesicles that can incorporate a rich group of membrane-bound receptors . Membrane proteins are not easily manipulated in solution and do not fold properly outside the membrane, but researchers have used various schemes to address these challenges using a supported lipid bilayer (SLB)103. (f) The surface of graphene can be modified via different strategies, including non-covalent functionalization (π-stacking), intercalation of molecules between graphene and a substrate, and covalent chemical modification of graphene. Image credit: Kim Daasbjerg. (g) Illustration of surface modification and blocking strategies for graphene-coated Cu films for SPR biosensing. Reprinted with permission from ref. 39.(e) Covalent and noncovalent functionalization schemes for SWNTs. Reprinted with permission from ref. 2 surfaces. Graphene is normally hydrophobic in its pristine state, which hinders SLB formation. Interestingly, graphene is also known to exhibit “wetting transparency” to the underlying substrate178. For example, an SLB can be formed via vesicle rupture on graphene on top of a hydrophilic silica surface. In contrast, graphene on gold, which is hydrophobic, leads to the formation of an intact vesicle layer. Indeed, recent work showed that a lipid monolayer, bilayer, or layer of intact vesicles could be formed on graphene depending on the surface treatment179. Biological interfacing of vdW materials with soft lipid membrane interfaces can add unique options to augment the functionality of nanophotonic biosensors, and further research is highly desirable.(h) SLB formation on graphene is not as clearly understood as for gold or SiO130. Label-free optical SWNT sensors are preferable to traditional POC detection methods such as ELISA in that they do not require additional processing steps after sample collection and allow transient data collection131. One example is a fluorescent SWNT-based microarray for detecting real-time protein-protein interactions132. Here, chitosan-wrapped SWNTs are conjugated to nitrilotriacetic acid (NTA) groups that can chelate Ni2+. The NTA-Ni2+ complex then binds to a His-tag on the target proteins, and the binding event is detected by the reduction of SWNT fluorescence. This platform has been further engineered to monitor 1156 capture protein-protein analyte interactions in a signaling network important in apoptosis. Using a different molecular chelator, Dong et al.133 conjugated immunoglobulin-binding proteins to SWNT and detected IgG, IgM, IgG2a, and IgD. Capture protein-modified sensors can also be printed onto a microarray that examines cross-reactivity, competitive, and nonspecific binding of analyte mixtures134. Such optical nanosensors have great potential to advance real-time, multiplexed biomarker detection for disease diagnostics.SWNT-based sensors have also been developed to detect disease biomarkers at low concentrations, with potential application to POC diagnostics, enabling timely treatment at a reduced cost136. A central question that limits biological applications relates to the biocompatibility of SWNTs. Their toxicity has been evaluated in vitro, with a variety of factors including chirality, length137, synthesis method138, SWNT wrapping140 and cell type141, all affecting biocompatibility. SWNTs are a broad class of materials with varying dimensions, functionalization, and formulation, and since many aspects of a given preparation can affect biological responses142, it is important to evaluate toxicity on a case-by-case basis. In addition, response in cell culture might not always reflect in vivo tissue effects, where cell populations are far more heterogeneous, and materials might also be modified once introduced into the body. Thus, it is crucial to test SWNT sensors in vivo, under conditions reflecting the intended route of administration, site of action, and dose.The unique optoelectronic properties of SWNTs are also ideal for in vivo biosensing applications. SWNTs fluoresce within the NIR window (900–1500 nm), where scattering is reduced and tissue absorption is minimal, allowing SWNT fluorescence to penetrate through deeper layers of tissue relative to visible light7-wrapped SWNTs via tail vein injection to detect transient inflammation, using nitric oxide as a signaling marker in mouse liver. The authors demonstrated long-term nitric oxide monitoring by subcutaneous implantation of alginate hydrogel-encapsulated SWNT sensors. The sensor fluorescence signal remained stable for over 400 days, and histological analysis of the implantation sites showed negligible adverse response116. Harvey et al. loaded DNA-wrapped SWNT sensors into a semipermeable membrane and implanted these into the intraperitoneal (IP) space in mice. The sensors successfully detected oligonucleotide hybridization in vivo, and the mice exhibited no obvious behavior changes143. SWNT sensors have also been used to detect lipid concentrations in vivo in the mouse liver144. Galassi et al. injected DNA-wrapped SWNTs through the tail vein in mice, which localized to the liver144. These DNA SWNTs showed a wavelength shift in response to changing lipid concentrations, and once the mice were administered a high-calorie diet, the resulting fat accumulation within the liver could be detected and used to determine the onset of fatty liver disease. SWNTs implanted in the liver maintained the ability to shift wavelength in response to their analyte over a period of three months, showing the stability of such sensors.SWNTs have been widely applied in animal models. Iverson et al. delivered ss(AAAT)145. These sensors detected the ovarian cancer biomarker human epididymis protein 4 (HE4) from both exogenous administration and endogenous production. DNA-wrapped SWNTs encapsulated in poly(ethylene glycol) diacrylate hydrogels have also been used in various marine organisms for biologging purposes, with minimal changes in tissue architecture for catfish, shark, and eel as detected by high-resolution ultrasound146. These examples show that SWNT sensors of various designs have the potential to function safely in vivo.Williams et al. encapsulated antibody-conjugated/DNA-wrapped SWNTs into a dialysis bag and implanted them into the IP space of miceWe have explored nanophotonic biosensing technologies enabled by low-dimensional vdW materials. With continually improving large-scale synthesis methods for vdW materials, high-resolution lithography, and ultrasensitive detection schemes, it may soon be possible to harness these versatile materials for practical POC biosensing applications. Further in the future, this technology could grow to enable previously inaccessible applications such as label-free monitoring of protein conformational dynamics, flexible and wearable biosensors, and in vivo nanophotonic biosensors. Such real-time in vivo sensors could potentially provide quantitative measurements of biological networks, and in humans, could allow prolonged data collection for early detection of disease, or even be coupled to drug delivery devices to enable closed-loop disease control—analogous to the ‘artificial pancreas’ systems that have been developed for continuous glucose control in diabetes. We also expect vdW materials to benefit other functions beyond conventional sensing that will still contribute to better biosensors, such as harnessing vdW materials for on-chip liquid manipulation , high-gradient-field particle trapping, or building waveguide-integrated light sources and photodetectors.Research into graphene and 2D quantum materials for SEIRA sensing is still in its infancy. In the near future, we will likely witness innovations combining high-quality 2D materials with smart choices of substrates and device configurations. These efforts will undoubtedly improve the performance and expand the versatility of SEIRA-based sensors for a wide range of applications.Another exciting strategy for accessing physical and chemical information entails the physical confinement of individual analyte molecules in a configuration with lower degrees of freedom. One such detection modality is based on the confinement of molecules into structures fabricated in the matrix of the 2D material, such as nanoscale apertures or nanopores (Supplementary Note 1).147, and low-loss dielectric waveguides will present unique opportunities for future innovation. Two-dimensional TMDCs have demonstrated strong exciton resonances in optical spectra148, and recent work has shown that the presence of molecules can transform dark states into bright excitons, potentially enabling unambiguous detection of the adsorbed molecules. Excitons in 2D TMDCs can also be tuned by various approaches149. In addition, integration with birefringent and chiral metasurfaces e.g., chiral plasmons or twisted graphene layers151 or valley-dependent chiral coupling in 2D TMDCs152 for measuring chiro-optic response could advance enantioselective biochemical sensing applications153.The library of vdW materials and heterostructures is rapidly expanding to offer customizable choices for fabricating unique nanophotonic biosensors. For SEIRA and other biosensing applications, we envision that hybrid substrates integrating graphene, polar materials, vdW heterostructures, metal antennas, high-Q dielectric metasurfaces155. Ultimately, vdW materials may empower researchers to realize one of the overarching ambitions of nanophotonics—seamless integration of photonics and electronics in the field of biosensing.While this review focused on nanophotonic sensors, electronic and electrochemical sensors based on vdW materials have also been extensively investigatedSupplementary Information


We revealed lower total and daily functioning score in female group. Further analyses stratified by sex and activity of the disease presented many significant differences between the groups, revealing important issues for the discussion about gender specific differences in the HRQL of patients with sarcoidosis. In spite of clinical presentation may be similar, expectations and main concerns of sarcoidosis patient can vary between females and males. Therefore, it appears that in terms of education and symptomatic treatment accents should be put differently depending on the gender of the patient. Our results may also point to a need for more gender-oriented patient-physician communication which could enable better understanding, potentially improve adherence to therapy and decrease the risk of possible complications.Sarcoidosis is granulomatous disease, which complex etiology is yet to be fully discovered. In the majority of cases its course is self-limiting. However it can have different clinical manifestations and can be debilitating condition with great impact on health-related quality of life (HRQL). The aim of our study was to assess if there are any differences in HRQL dependent to gender. We examined a group of 33 males and 42 females (with no differences in mean age, disease activity, TLCO, FEV In over 90% of patients intrathoracic lymph nodes and/or lung parenchyma are involved2. This is important because it serves to improve understanding about the patient’s perception of how disease and treatment affect their overall satisfaction with life in various different areas of functioning3.Health-related quality of life (HRQL) has become a crucial element of evaluation in modern patient-oriented approach to decision making in medicine. This model is especially important when treating patients with sarcoidosis as the disease itself is rarely life-threatening, and the physiological impairment is usually not severe. Therefore, each decision with regards to treatment should be considered in the context of balance between medicinal benefits and quality of life. Further, HRQL assessments facilitate patient-physician communication5, but interestingly, also tend to present less advanced radiographic stages6. There are also differences in organ involvement—women more frequently suffer from skin, eye, liver and peripheral lymph node involvement8. Also, manifestations of Löfgren's syndrome differ between men and women, with erythema nodosum found more often in women, whereas a marked periarticular inflammation of the ankles or ankle arthritis without erythema nodosum is seen primarily in men7.Although gender affects epidemiology, pathophysiology, manifestation and treatment of a broad range of diseases, gender-specific oriented healthcare approach seems to still be neglected. Sarcoidosis is one of the diseases where gender plays an important role. Women more frequently suffer from sarcoidosis9. Therefore, it is not surprising that gender, among other various factors, significantly influences HRQL. However, despite increasing evidence that points to the importance in the understanding of this field, knowledge about gender differences specific to HRQL in sarcoidosis patients is still relatively scarce.Two genders manifest significant biological, behavioral, social and cultural differences. Sex differences are also visibly reflected in social conditions, lifestyles, health perception, and health care behaviorsThe purpose of our study was to identify associations between gender and HRQL scores using the Sarcoidosis Health Questionnaire (SHQ). The target of our study was not only limited to the three main domains described by this tool , but also focused on the results of individual questions which, when analyzed separately, may lead to important clinical conclusions.This study is a single institution, prospective analysis of patients admitted to the Department of Pneumology and Allergy of the Medical University of Lodz or the adjacent Outpatient Clinic. The study procedures were approved by the Ethical Committee for Human Studies of the Medical University of Lodz. All study participants gave informed written consent to participate in the study. The study was performed in accordance with the Declaration of Helsinki.All study participants were non-smoking, adult Caucasians with a confirmed (in the past as well as newly made) diagnosis of sarcoidosis. The diagnosis was based on histopathological examination or on typical clinical and radiological findings—Lofgren’s syndrome, chest CT suggestive of sarcoidosis supported by additional test results  after exclusion of other conditions. To avoid potential skewed results, we did not enroll patients dealing with any significant stressful life situation that was not related to their health status .We excluded patients with any other pulmonary or autoimmune disease as well as patients with confirmed extrapulmonary sarcoidosis of the heart, central nervous system, skin and/or eyes. Other form of extrapulmonary sarcoidosis  did not exclude the patients. We also excluded patients with acute coronary syndrome, severe heart failure (NYHA III and more), chronic kidney disease, any previously diagnosed mental illness and/or a history of malignancy in their past medical history.As a potentially significant cofounding factor, we also excluded patients currently receiving oral steroids or other medications for sarcoidosis other than non-steroid anti-inflammatory drugs and other painkillers.Patients were divided into study subgroups according to gender and disease activity, into active and inactive sarcoidosis group. Inactive sarcoidosis was diagnosed when complete radiological and clinical resolution was achieved or when radiological stabilization was noted in a patient without other signs or symptoms of pulmonary or extrapulmonary disease. Active sarcoidosis was diagnosed when one of the following criteria was met: present symptoms of pulmonary sarcoidosis , Loefgren syndrome and up to 3 month after, signs of extrathoracic sarcoidosis, radiological progression or worsening of the lung function tests, increased percentage of lymphocyte in broncho-alveolar lavage fluid, hypercalcemia or hypercalciuria.10. This is a short, self-administered questionnaire for persons with sarcoidosis of varying disease burden and organ involvement11. SHQ is a comprehensive measure analyzing three domains: daily functioning, physical functioning, and emotional functioning. Each domain is assessed by questions related to its characteristics, scored from 1 to 7. Then, scores were calculated according to the equation presented by the authors of the questionnaire11.To measure HRQL we used the validated Polish version of the SHQContinuous data were presented as mean with standard deviation (SD) or median with interquartile range (IQR) from LQ (25%) to UQ (75%), depending on the data normality. Variables were compared using the unpaired Student’s t test, Welch t test or the Wilcoxon rank sum test with continuity correction, depending on data normality and homogeneity of variance. The correlation analysis was performed using Spearman’s test.Categorical data were presented as absolute value and percentage. Such data were compared using Pearson’s Chi-square test (with Yates correction if appropriate) or Fisher’s exact test concordantly with test assumptions.https://www.R-project.org).Analysis was performed using R software  females and 33 (44%) males. Characteristics of study participants are presented in Table P = 0.14), sarcoidosis activity (P = 0.33), and presence of active Löfgren’s syndrome (P = 0.86). There were no between gender differences according to pulmonary function test results: TL,CO (P = 0.86), FEV1 (P = 0.48), FVC (P = 0.96), and FEV1/FVC (P = 0.95).Female group and male group did not differ according to age (P = 0.02). Analysis of individual domains revealed a significant difference only in physical functioning: 4.28 vs 4.87 (P = 0.02). However, in detailed analyses we found significant differences in questions from all domains as follows: “felt bodily pain” (P = 0.006), “bothered by sarcoidosis skin or hair problems” (P = 0.0005), “bothered by eye or eyesight problems” (P = 0.02), “had joint pains” (P = 0.02), “been bothered by headaches” (P = 0.0008), “worried about the amount of pain and discomfort” (P = 0.047) and “felt satisfied with the appearance of your body” (P = 0.049). All results of detailed analysis are presented in Table We found a significantly lower total SHQ score in the female group—4.64 vs 6.14 P = 0.0. AnalysiWhen the subgroups depending on disease activity, not gender, were analyzed, some associations with SHQ results were found. In active sarcoidosis, there were significantly lower scores for daily functioning, but not for physical functioning and total score Table .Table 3DFor individual questions, there were significant differences in the following questions: “Felt you were full of energy”, “Felt your breathing was completely comfortable during your normal daily activities”, “Worried about the amount of pain and discomfort”, “Felt that everything you did took a lot of effort”, “Felt that your physical problems interfered with your social activities when with family and friends”, “Felt that you accomplished all that you wanted”, “Felt bodily pain”, “Felt that your emotional problems affected your relationships with family, friends, or coworkers”, “Felt sarcoidosis controls your life”, “Had a good night’s sleep”, “Felt confidence in yourself and your abilities”, “Felt you were as healthy as others your age”, and for “Been discouraged by physical limitations in performing your normal daily activities or your job” Table .Then, we compared both sexes within active and non-active sarcoidosis group. In the female active sarcoidosis group we observed significantly lower scores for the following questions: “Been bothered by headaches”, “Bothered by sarcoidosis skin or hair problems”, “Felt discouraged by recent weight gain”, “Felt bodily pain”, “Felt satisfied with the appearance of your body”, but not for any of the main domains. Among female patients with non-active sarcoidosis, we noticed lower scores for physical functioning and for the following questions: “Been bothered by headaches”, “Felt bodily pain” and “Experienced wheezing” Table .Table 4DWe made also similar analysis for the genders separately, noticing that the active period of sarcoidosis influences SHQ in men and in women in different aspects. Namely, female patients with active disease had a lower score for daily functioning and a lower score in the following questions: “Bothered by sarcoidosis skin or hair problems”, “Worried about the amount of pain and discomfort”, “Felt that your physical problems interfered with your social activities when with family and friends”, “Felt that your emotional problems affected your relationships with family, friends, or coworkers”, “Felt satisfied with the appearance of your body”, “Felt you were as healthy as others your age” and “Been discouraged by physical limitations in performing your normal daily activities or your job” Table .Table 5SOn the other hand, male patients with active disease had lower scores for daily and physical functioning. When particular questions were analyzed, differences were found in following: “Felt your breathing was completely comfortable during your normal daily activities”, “Felt shortness of breath walking upstairs, the length of a city block, or up a small hill”, “Had a good night’s sleep”, “Experienced wheezing”, “Felt confidence in yourself and your abilities”, and “Felt you were as healthy as others your age” Table .12. Authors did not analyze individual elements of the questionnaire, but instead, analyzed pulmonary function tests and six-minute walking test results. After this analysis, they suggested that the following factors were associated with poor HRQL differences based on gender: reduction in TL,CO, reduction in 6MWT distance, and an increased sensation of dyspnea. Our groups did not differ significantly with regards to pulmonary function tests.The results of our study showed a significantly decreased HRQL in the female group of patients. In a more detailed analysis, the only domain which was statistically significantly decreased was physical functioning. This result is concordant with a previous study by Bourbonnais et al.worried about the amount of pain and discomfort and were more discouraged by physical limitations in performing their normal daily activities or job. On the other hand, active disease in male patients affected daily functioning as well as physical functioning domain. In particular questions analysis, we observed different pattern of answers. Notably, significant differences were observed in questions related mainly to somatic health  and self-confidence. When we analyze Table After stratification by sarcoidosis activity, we noticed that in the active sarcoidosis group, the sexes did not differ according to any main domains, but females had significantly lower scores concerning headaches, skin or hair problems, gaining weight, body appearance and bodily pain. However, in non-active sarcoidosis group the differences in the physical functioning appeared—women had significantly lower score in this domain. Similarly to the active sarcoidosis group, females had lower scores for questions concerning headaches and bodily pain when compared to males. Additionally, significant difference in wheezing experience between women and men groups with non-active sarcoidosis could be found. This results (except of bodily pain) present different constellation of answers than baseline stratification by activity within whole study group, revealing new areas for further research and improving communication with patients in everyday clinical practice. We also made similar analysis from another point of view—presenting sexes separately and comparing active and non-active sarcoidosis within these groups. We noticed dissimilar pattern of differences, which is supplementary to previous analysis. Namely, among female patients those with active disease had a lower score for daily functioning than those with non-active. In terms of the questions related to physical appearance, social functioning, and emotional state, women with active sarcoidosis were more After extensive review of the literature of the field, we did not identify a similar study which used our approach and analysis of individual elements of the questionnaire. This is a novel contribution to this field that complements existing knowledge by indicating areas for gender-oriented improvement in the understanding of patient’s perceptions, especially fears about the disease symptoms and prognosis. As a result, this would better facilitate patient-physician communication and, potentially, decrease the level of anxiety, further improving adherence to therapy.Our results can be divided into patients with pattern of answers associated more with pain and discomfort  and those bothered by physical appearance (skin/hair problems), eye or vision problems.16. This includes studies that evidently show a female predisposition to migraine and medication-overuse headache18, justifying our observations. However, despite a clear epidemiological and psychological association, the results indicate the need for an individualized approach to pain treatment and a need to identify the specific needs of female patients in this area. We should also be aware of the risk of medication-overuse in this group and thus, pay more attention towards, firstly, potential complications of NSAID overuse, and secondly, directed at the prevention of this phenomenon.There is a strong body of evidence which documents male and female gender discrepancies in perception of painInformation gathered involving eye and vision problems was difficult to analyze because none of the patients in this study experienced sarcoidosis-related visual symptoms. However, there is a wide range of information on these topics that is readily and publicly available. This information may raise anxiety among patients. As a result, it is important to maintain open channels of communication with the patient regarding issues such as this in order to calm patient’s worries by means of increased education and, in this particular case, regular ophthalmological assessment.7. Therefore, erythema nodosum, affecting esthetical self-esteem, may influence this result markedly. In our study, the number of patients presenting with Löfgren’s syndrome is too low, precluding reliable analysis. However, presented issue indicates that this topic also requires further research.Differences in scores in the question “bothered by sarcoidosis skin or hair problems” would be justified by presence of Löfgren’s syndrome. According to literature of the field, it is important to highlight that females present with different manifestations of Löfgren's syndrome, predominantly with erythema nodosum, while in men more common presentation is periarticular inflammation of the ankles or ankle arthritis without erythema nodosumA relatively low number of patients and a single-center character of study are the main limitations of our research. However, the strict exclusion criteria responsible for a lower number of participants also contributed to a more homogenous study population.Women with sarcoidosis have a lower HRQL score measured by SHQ. This group of patients presents significantly lower scores in questions that attempt to identify the degree of physical functioning impacted by disease.Specific areas connected with lower HRQL are associated with pain and discomfort, physical appearance and eye or vision problems. These results may point to a need for more gender-oriented patient-physician communication which could enable better understanding, potentially improve adherence to therapy and decrease the risk of possible complications.


A novel capacitive humidity sensor based on carbon black/polyimide composites is presented in this paper. The details of the fabrication, sensor characteristics, and effect of the carbon black additive are described. It was confirmed that the polyimide composite filled with a tiny amount of carbon black was suitable for a humidity sensing dielectric. The humidity sensors with three different dielectrics, which were pure polyimide, 0.01 wt% carbon black/polyimide, and 0.05 wt% carbon black/polyimide, were fabricated by a micro-electro-mechanical-system (MEMS) process. As the amount of the carbon black additive increased, the sensitivity of the humidity sensor increased. The humidity sensor with 0.05 wt% of carbon black had a much higher sensitivity of 15.21%  than that of the sensor with pure polyimide, which was 9.73% (0.1622%/% RH). The addition of carbon black also led to an enhancement in the hysteresis and response speed. The hysteresis of the humidity sensor decreased from 2.17 to 1.80% when increasing the amount of the carbon black additive. The response speed of the humidity sensor with 0.05 wt% of carbon black was measured to be ~10% faster than that of the sensor with pure polyimide. The long-term stability of the humidity sensors was demonstrated as well. Measurement of humidity, the amount of water vapor in air, is very important in many applications, including manufacturing, agriculture, climatology, and biomedical industry . There aFor accurate measurement of relative humidity, various humidity sensors with different sensing mechanisms have been suggested such as capacitive, resistive, electromagnetic, gravimetric, and optical measurements ,4. AmongThe dielectric constant of water vapor is around 80, and a humidity-sensitive dielectric material generally has a much lower dielectric constant. Therefore, absorption of water vapor by the dielectric results in an increase in the capacitance of humidity sensors . DiverseTo develop an improved capacitive humidity sensor, we suggest a carbon-polymer composite, which consists of polyimide and carbon black. Polyimide is suitable as a humidity sensing material because of its linear and large response to humidity and compatibility with the complementary metal-oxide-semiconductor (CMOS) process . In addiIn this paper, we report for the first time a novel capacitive humidity sensor based on a carbon black/polyimide composite. The humidity sensor is designed to have a parallel plate capacitor structure and be fabricated by the micro-electro-mechanical-system (MEMS) process. The characteristics of the developed humidity sensor such as sensitivity, hysteresis, dynamic response, and long-term stability are evaluated accurately by a computer-controlled measurement system. The comparison with the humidity sensor made of pure polyimide is also provided.In order to synthesize the carbon black/polyimide composite, a photodefineable polyimide solution  and carbon black nanopowders with a diameter of 100 nm  were employed. As mentioned above, in this work, the key parameter to achieve the novel sensing dielectric for the capacitive humidity sensor is the amount of the carbon black additive. Tiny amounts of carbon black were added to the polyimide solution to prevent an increase in the conductance of the composite. To verify the effect of the amount of carbon black on the sensing characteristics, three samples with different amounts of carbon black were prepared, which were 0 (pure polyimide), 0.01, and 0.05 wt%, respectively. Undesirable side effects of the carbon black additive on photolithography of the composite can also be avoided with these small amounts. After sealing, the carbon black additive in the composite solution was dispersed by using an ultrasonic bath for 60 h.The humidity sensor was designed to have a parallel plate structure for the measurement of the capacitance. The simplified cross-section of the sensor design is shown in 2 layer was grown was used as a substrate. The bottom electrode with a 300 nm-thick Au film was formed on the substrate by e-beam evaporation and photolithography. A 300 nm-thick SiO2 passivation layer was also deposited and patterned to expose the active region of the underlying bottom electrode. After that, the prepared carbon black/polyimide composite solution was spin-coated for the humidity sensing layer. The coated composite film was patterned by photolithography and was cured in a vacuum curing chamber. After the curing process, the 3 μm-thick carbon black/polyimide composite sensing layer was successfully obtained. At last, for the top electrode, a 300 nm-thick Au film was deposited by sputtering and patterned to have the hole shapes as described in The humidity sensor was fabricated by the MEMS process. For insulation, a 4-inch silicon wafer on which a 300 nm-thick SiOThe measurement system was fully automated and capable of multiple measurements up to 32 samples. The fabricated humidity sensors were wire-bonded to printed circuit boards (PCBs), and the PCBs were connected to a control and switch module . The signal from a selected sensor by the switch was transferred to a precision LCR meter . To control relative humidity, the PCBs were placed in a humidity generating chamber , and the variation of the capacitance of the humidity sensors was measured by using the LCR meter. When measuring the capacitance at each humidity level, to minimize the effect of possible fluctuations of the humidity chamber, ten data points were collected, and the average value was taken. In addition, because capacitance can arise from not only the sensors but also the PCBs, measurement cables, and air, one PCB on which the humidity sensor was not mounted was measured in the chamber to clarify the parasitic element. After that, the parasitic capacitance was subtracted from the measurement results of the actual humidity sensors. Every measurement was repeated at least ten times for a single device to check the reproducibility, and ten devices randomly picked from the same wafer were also verified to eliminate any possibility of errors from fabrication non-uniformity. The schematic of the measurement system is shown in 2 from the sensor output and the regression linear curve. The calculated coefficients of the sensors with 0, 0.01, and 0.05 wt% of carbon black are 0.979, 0.982, and 0.999, respectively. The sensor with 0.01 wt% of carbon black has a slightly higher sensitivity of 10.13%  than that of the sensor made of pure polyimide, which is 9.73% (0.1622%/% RH). The amount of 0.01 wt% of carbon black seems not enough to significantly change the dielectric property of the composite, which results in little difference in the sensitivity. On the other hand, the sensor with 0.05 wt% of carbon black shows a sensitivity of 15.21% (0.2535%/% RH), which is much higher than that of the sensor with pure polyimide. It is known that moisture in the polymer composite can be stored at the interfacial space between the additives and the polymer [The sensitivity of the humidity sensor with a good linearity can be expressed as follows: polymer . The inc.21% 0.25%/% RH, wThe hysteresis characteristic of humidity sensors when water is absorbed and desorbed is very important to measure humidity accurately. The capacitance of the fabricated sensor was measured during a cycle of water absorption (from low to high ambient relative humidity) and desorption (from high to low ambient relative humidity). The hysteresis error can be described as follows:To study the dynamic response of the humidity sensor, the humidity level in the chamber was ramped up and down between 20% RH and three different higher levels, which are 40, 60, and 80% RH, respectively. To evaluate the long-term stability of the humidity sensor, the capacitance was measured and recorded for 100 h at two different ambient conditions: low humidity level (20% RH) and high humidity level (80% RH). In summary, a novel capacitive humidity sensor based on carbon black/polyimide composites has been suggested. There have been efforts to develop resistive-type humidity sensors with carbon-polymer composites of which the conductance is enhanced. However, as far as we know, there have been few attempts to consider the composite as a dielectric for capacitive-type humidity sensors. In this paper, we have successfully demonstrated the possibility of using a carbon black/polyimide composite as a humidity sensing dielectric material to obtain high-performance capacitive humidity sensors. The suggested humidity sensors with polyimide composite filled with tiny amounts of carbon black showed improvements in the sensitivity, hysteresis, and response speed. In the case of the humidity sensor with 0.05 wt% carbon black, a higher sensitivity of 15.21% (0.2535%/% RH) was obtained compared to 9.73% (0.1622%/% RH) for the sensor with pure polyimide, which seems to be due to the presence of the interface between the carbon black additive and the polyimide matrix. In addition, because of the increased contact area with water molecules caused by the carbon black additive, a reduced hysteresis of 1.80% (compared to 2.17%) and a ~10% faster response speed were observed. The long-term stability of the humidity sensors with a small variation was verified as well. Further study exploring humidity sensors with various concentrations of carbon black and the phenomenon at high concentrations to determine the optimal proportion will be the subject of future work.


Non-coding ribonucleic acids (ncRNAs) are a diverse group of RNA molecules that are mostly not translated into proteins after transcription, including long non-coding RNAs (lncRNAs) with longer than 200 nucleotides non-coding transcripts and microRNAs (miRNAs) which are only 18–22 nucleotides. As families of evolutionarily conserved ncRNAs, lncRNAs activate and repress genes via a variety of mechanisms at both transcriptional and translational levels, whereas miRNAs regulate protein-coding gene expression mainly through mRNA silencing. ncRNAs are widely involved in biological functions, such as proliferation, differentiation, migration, angiogenesis, and apoptosis. Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis. The etiology of IPF is still unclear. Increasing evidence shows the close correlations between the development of IPF and aberrant expressions of ncRNAs than thought previously. In this study, we provide an overview of ncRNAs participated in pathobiology of IPF, seeking the early diagnosis biomarker and aiming for potential therapeutic applications for IPF. IPF is characterized by progressive lung scarring with constantly decreasing the function of the lungs. The prevalence of IPF shows that almost 5 million individuals suffer from this disease worldwide in the United States, and the 3 years and 5 years mortality rates of IPF are at approximately 50 and 80%, respectively . TherefoncRNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are transcribed from human genome such as message RNAs (mRNAs) but are not translated into proteins after transcription. These ncRNAs directly or indirectly participate in the regulation of multiple functions of intracellular pathobiological processes and affect gene expression by regulating the function of mRNA, DNA methylation, and histone modification and participate in the occurrence and development of lung diseases, thus providing new ideas for the diagnosis and drug treatment targets of diseases ,3,4.2The non-coding RNAs (ncRNAs), microRNAs (miRNAs), long non-coding RNAs (lncRNAs), idiopathic pulmonary fibrosis (IPF) were used as keywords searched in PubMed and web of science databases. The papers about reviews, meta-analysis, systematic reviews, books, and documents were excluded. Then, about 85,076 articles from PubMed and web of science databases in the past 5 years (2015–2019)  related 3The articles of ncRNAs and IPF are related in the following three areas: (1) the biogenesis and functions of miRNAs in IPF; (2) the biogenesis and functions of lncRNAs in IPF; and (3) the interaction networks among lncRNAs, miRNAs, and mRNA in IPF.3.13.1.1miRNAs are short single-stranded non-coding RNA molecules found in eukaryotic cells with a length of about 22nt, whose biological processes involve a series of complex steps. The precursor transcripts (pri-miRNAs) are a capped and polyadenylation transcript produced by RNA polymerase II . Then, umiRNAs are involved in many biological processes such as biological development, cell proliferation and differentiation, tissue damage repair, and organ fibrosis and exert a wide range of physiological regulation ,10,11. I3.1.2IPF is one of the most serious fibrotic pulmonary diseases, which commonly afflict the elderly. The main pathological manifestations are the alternation of fibrotic areas with mild or normal pulmonary parenchymal areas which simultaneously occur scar formation and honeycomb-like changes . In shorTo explore the potential of miRNAs as biomarkers of IPF, Li et al.  analyzedIn a recent study, Njock et al.  found thYang et al.  analyzed3.1.3IPF is because of the uncontrolled production of extracellular matrix by fibroblasts in lung injury, which leads to progressive exacerbations and irreversible damages . NumerouAt present, the mature IPF model is BML-induced pulmonary fibrosis model in mice. Zhang et al.  found thThe core pathogenesis of IPF is an abnormal epithelial–mesenchymal crosstalk, which hinders the normal repair process after alveolar damage ,27,28. L3.23.2.1lncRNAs are ncRNAs greater than 200 nucleotides in length. lncRNAs lack coding open reading frames and cannot encode proteins, but they can exert biological functions through interaction with other genetic materials . lncRNAsAlthough lncRNAs are different from other nucleotide sequences and do not have high expression abundance, they are expressed at specific stages of biological development with high tissue-cell specificity and may become biomarkers of various diseases .3.2.2The above has shown that lncRNAs are involved in a variety of biological processes, and substantial evidence suggests that mutations and disorders of lncRNAs may be closely related to the pathogenesis of IPF.Hao et al.  extractein situ hybridization, nuclear isolation, and RNA sequencing have confirmed that lncITPF is located in the nucleus and regulates its host gene ITGBL1 to promote fibrosis by affecting the acetylation of H3 and H4 histones in its promoter region. Then, they studied the upstream and downstream mechanisms of lncITPF in pulmonary fibrosis. The upstream mechanism of lncITPF is mediated by the TGF-β1/Smad2/3 signaling pathway, and the downstream mechanism regulates the acetylation of H3 and H4 histones of ITGBL1 gene by interacting with heterogeneous nuclear ribonucleoprotein L. To assess the potential of lncITPF as a therapeutic target, interfered sequence of lncITPF (sh-lncITPF) was applied to an animal model of pulmonary fibrosis, and the expression of lncITPF in clinical IPF patients was detected. The results showed that the fibrosis indexes of α-sma, collagen, and vimentin in the sh-lncITPF group were lower than those in the control group. The expression level of lncITPF in clinical IPF patients was significantly higher than that in healthy subjects, and the Pearson’s correlation analysis showed that lncITPF expression level was correlated with FVC% predicted. Therefore, lncITPF may become one of the new targets for clinical IPF treatment.Song et al.  first diIn addition, Gao et al.  first di3.3Currently, high-throughput sequencing technology was used to analyze the differentially expressed miRNAs in normal lung tissues and lung tissues of IPF patients, and then GO annotation and KEGG pathway enrichment analysis were used to screen the molecular targets most related to the diagnosis and prognosis of IPF, which laid the foundation for the follow-up clinical transformation therapy. We believe that identifying the diverging interaction network of lncRNAs and miRNAs orchestra and genes will provide important clues for understanding the mechanism of IPF and developing novel diagnostic and therapeutic strategies. At the same time, most of the latest progress of understanding of miRNA and lncRNA regulation in pulmonary fibrosis in the past 3 years are summarized and presented in It has been found that lncRNAs with target sequences similar to miRNAs can regulate the abundance of RNA by isolating miRNAs, or that lncRNAs can directly bind to miRNAs and regulate their functions. Although miRNAs and lncRNAs play an important role in the occurrence and progression of IPF, their regulatory networks in IPF remain unclear. Therefore, numerous studies ,42,43 hain vitro and in vivo experiments further demonstrated that overexpression of PFAL promoted the proliferation, migration, myofibroblastic transformation, extracellular matrix deposition, and fibrosis of lung fibroblasts by modulating miR-18a. On the contrary, the above fibrosis indexes were all decreased after the PFAL was knocked out. Further, they studied the intrinsic mechanism and showed that PFAL played the role of an endogenous RNA, competitively binds to miR-18a, and inhibits its expression and activity, thereby promoting lung fibroblast activation and fibrosis. In addition, they found that knock-out of miR-18a resulted in fibrosis of lung fibroblasts, whereas its overexpression reduced TGF-β1-induced pulmonary fibrosis. At the same time, the expression of miR-18a was decreased in patients with IPF by RT-PCR. Therefore, they believe that by knocking out PFAL and then regulating the expression of miR-18a, it may become a new treatment for pulmonary fibrosis.A recent study  showed tLiu et al.  found thhttp://starbase.sysu.edu.cn) and verified by dual-luciferase reporter assay. The results showed that miR-196a was a target of H19 in IPF. COL1A1 is a known target gene of miR-196a. To explore the relationship between H19, miR-196a, and COL1A1, they found that the expression of COL1A1 decreased with the decrease in H9, which could be reversed by microRNA-196a inhibitors. Therefore, they believe that H19 may competitively bind to microRNA-196a to regulate COL1A1 expression. Finally, in vitro and in vivo results have shown that downregulation of H19 attenuates lung fibroblast activation and pulmonary fibrosis, the phenomenon that can be reversed by miR-196a inhibitors. This confirmed once again that lncRNA H19 could promote the expression of COL1A1 through the competitive binding of microRNA-196a and accelerate the process of pulmonary fibrosis. Therefore, they believe that H19 plays an important role in the pathogenesis of IPF, and H19 is one of the directions of IPF gene-targeted therapy.In addition, Lu et al.  took lnc4in situ, and ELISA. Finally, the in vivo or in vitro experiments were conducted to verify the role of target miRNAs, target lncRNAs, and target genes in the pathogenesis of IPF by qRT-PCR, western blot, and transfection. The research model is reasonable, but there are also certain limitations. One miRNA may regulate the expression of multiple genes, and the same gene may be regulated by multiple miRNAs. This phenomenon also applies to lncRNAs. Therefore, this research model can clearly explain one of the modes of action but failed to link the multiple modes of IPF.In most studies, total RNA was extracted from lung tissue or blood samples of IPF patients and normal people, and transcriptome sequencing (including microRNAs and lncRNAs sequencing) was performed ,45. The Further need to demonstrate the correlation between gene expression and disease occurrence. In brief, the safety of gene therapy. For instance, Du et al.  found thIn addition, there is currently no uniform method for miRNA or lncRNA isolation, and the specimens used to extract total RNA mainly come from lung tissue or blood specimens of IPF patients. The extraction methods of these specimens belong to invasive examinations. Moreover, research on biological samples such as saliva and sputum in IPF patients is still less; therefore, the detection of miRNA expression in these samples to diagnose IPF needs further investigation. At present, there is no treatment for IPF etiology or reversal of IPF. The role of ncRNAs in the pathogenesis of IPF requires a lot of research to explore, which provides a new scheme for molecular targeted therapy of IPF.