Gradient High-Q Dielectric Metasurfaces for Broadband Sensing and Control of Vibrational Light-Matter Coupling.

Surface-enhanced infrared absorption spectroscopy (SEIRA) has emerged as a powerful technique for ultrasensitive chemical-specific analysis. SEIRA can be realized by employing metasurfaces that can enhance light-matter interactions in the spectral bands of molecular vibrations. Increasing sample complexity emphasizes the need for metasurfaces that can operate simultaneously at different spectral bands, both accessing rich spectral information over a broad band, and resolving subtle differences in the absorption fingerprints through narrow-band resonances. Here, a novel concept of resonance-gradient metasurfaces is introduced, where the required spectral selectivity is achieved via local high-quality-factor (high-Q) resonances, while the continuous coverage of a broad band is enabled by the gradual adjustment of the unit-cell dimensions along the planar structure. The highly tailorable design of the gradient metasurfaces provides flexibility for shaping the spectral sampling density to match the relevant bands of target analytes while keeping a compact device footprint. The versatility of the gradient metasurfaces is demonstrated through several sensing scenarios, including polymer mixture deconvolution, detecting a multistep bioassay, and identification of the onset of vibrational strong coupling regime. The proposed gradient-resonance platform significantly contributes to the rapidly evolving landscape of nonlocal metasurfaces, enabling applications in molecular detection and analysis of fundamental light-matter interaction phenomena.

Spectral Tuning of High-Harmonic Generation with Resonance-Gradient Metasurfaces.

High-index dielectric subwavelength structures and metasurfaces are capable of enhancing light-matter interaction by orders of magnitude via geometry-dependent optical resonances. This enhancement, however, comes with a fundamental limitation of a narrow spectral range of operation in the vicinity of one or few resonant frequencies. Here, this limitation is tackled by introducing an innovative and practical approach to achieve spectrally tunable enhancement of light-matter interaction with resonant metasurfaces. Resonance-gradient metasurfaces are designed and fabricated with varying geometrical parameters that translate into resonant frequencies dependence on one of the coordinates of the metasurface. The metasurfaces are composed of bone-like nanoresonators, which are made of germanium and support high-quality optical resonances in the mid-IR spectral range. The concept is applied to observe the resonant enhancement of the third and fifth harmonics generated from the gradient metasurfaces being used in conjunction with a tunable excitation laser to provide a wide spectral coverage of resonantly-enhanced tunable generation of multiple optical harmonics.

Plasmon-enhanced circular dichroism spectroscopy of chiral drug solutions.

We investigate the potential of surface plasmon polaritons at noble metal interfaces for surface-enhanced chiroptical sensing of dilute chiral drug solutions with nl volume. The high quality factor of surface plasmon resonances in both Otto and Kretschmann configurations enables the enhancement of circular dichroism differenatial absorption thanks to the large near-field intensity of such plasmonic excitations. Furthermore, the subwavelength confinement of surface plasmon polaritons is key to attain chiroptical sensitivity to small amounts of drug volumes placed around ≃100 nm by the metal surface. Our calculations focus on reparixin, a pharmaceutical molecule currently used in clinical studies for patients with community-acquired pneumonia, including COVID-19 and acute respiratory distress syndrome. Considering realistic dilute solutions of reparixin dissolved in water with concentration ≤5 mg/ml and nl volume, we find a circular-dichroism differential absorption enhancement factor of the order ≃20 and chirality-induced polarization distortion upon surface plasmon polariton excitation. Our results are relevant for the development of innovative chiroptical sensors capable of measuring the enantiomeric imbalance of chiral drug solutions with nl volume.

Artificial intelligence-coupled plasmonic infrared sensor for detection of structural protein biomarkers in neurodegenerative diseases.

Diagnosis of neurodegenerative disorders (NDDs) including Parkinson's disease and Alzheimer's disease is challenging owing to the lack of tools to detect preclinical biomarkers. The misfolding of proteins into oligomeric and fibrillar aggregates plays an important role in the development and progression of NDDs, thus underscoring the need for structural biomarker-based diagnostics. We developed an immunoassay-coupled nanoplasmonic infrared metasurface sensor that detects proteins linked to NDDs, such as alpha-synuclein, with specificity and differentiates the distinct structural species using their unique absorption signatures. We augmented the sensor with an artificial neural network enabling unprecedented quantitative prediction of oligomeric and fibrillar protein aggregates in their mixture. The microfluidic integrated sensor can retrieve time-resolved absorbance fingerprints in the presence of a complex biomatrix and is capable of multiplexing for the simultaneous monitoring of multiple pathology-associated biomarkers. Thus, our sensor is a promising candidate for the clinical diagnosis of NDDs, disease monitoring, and evaluation of novel therapies.

Antenna-coupled infrared nanospectroscopy of intramolecular vibrational interaction.

Many photonic and electronic molecular properties, as well as chemical and biochemical reactivities are controlled by fast intramolecular vibrational energy redistribution (IVR). This fundamental ultrafast process limits coherence time in applications from photochemistry to single quantum level control. While time-resolved multidimensional IR-spectroscopy can resolve the underlying vibrational interaction dynamics, as a nonlinear optical technique it has been challenging to extend its sensitivity to probe small molecular ensembles, achieve nanoscale spatial resolution, and control intramolecular dynamics. Here, we demonstrate a concept how mode-selective coupling of vibrational resonances to IR nanoantennas can reveal intramolecular vibrational energy transfer. In time-resolved infrared vibrational nanospectroscopy, we measure the Purcell-enhanced decrease of vibrational lifetimes of molecular vibrations while tuning the IR nanoantenna across coupled vibrations. At the example of a Re-carbonyl complex monolayer, we derive an IVR rate of (25±8) cm-1 corresponding to (450±150) fs, as is typical for the fast initial equilibration between symmetric and antisymmetric carbonyl vibrations. We model the enhancement of the cross-vibrational relaxation based on intrinsic intramolecular coupling and extrinsic antenna-enhanced vibrational energy relaxation. The model further suggests an anti-Purcell effect based on antenna and laser-field-driven vibrational mode interference which can counteract IVR-induced relaxation. Nanooptical spectroscopy of antenna-coupled vibrational dynamics thus provides for an approach to probe intramolecular vibrational dynamics with a perspective for vibrational coherent control of small molecular ensembles.

High-throughput spatiotemporal monitoring of single-cell secretions via plasmonic microwell arrays.

Methods for the analysis of cell secretions at the single-cell level only provide semiquantitative endpoint readouts. Here we describe a microwell array for the real-time spatiotemporal monitoring of extracellular secretions from hundreds of single cells in parallel. The microwell array incorporates a gold substrate with arrays of nanometric holes functionalized with receptors for a specific analyte, and is illuminated with light spectrally overlapping with the device's spectrum of extraordinary optical transmission. Spectral shifts in surface plasmon resonance resulting from analyte-receptor bindings around a secreting cell are recorded by a camera as variations in the intensity of the transmitted light while machine-learning-assisted cell tracking eliminates the influence of cell movements. We used the microwell array to characterize the antibody-secretion profiles of hybridoma cells and of a rare subset of antibody-secreting cells sorted from human donor peripheral blood mononuclear cells. High-throughput measurements of spatiotemporal secretory profiles at the single-cell level will aid the study of the physiological mechanisms governing protein secretion.

Metasurface-Enhanced Infrared Spectroscopy: An Abundance of Materials and Functionalities.

Infrared spectroscopy provides unique information on the composition and dynamics of biochemical systems by resolving the characteristic absorption fingerprints of their constituent molecules. Based on this inherent chemical specificity and the capability for label-free, noninvasive, and real-time detection, infrared spectroscopy approaches have unlocked a plethora of breakthrough applications for fields ranging from environmental monitoring and defense to chemical analysis and medical diagnostics. Nanophotonics has played a crucial role for pushing the sensitivity limits of traditional far-field spectroscopy by using resonant nanostructures to focus the incident light into nanoscale hot-spots of the electromagnetic field, greatly enhancing light-matter interaction. Metasurfaces composed of regular arrangements of such resonators further increase the design space for tailoring this nanoscale light control both spectrally and spatially, which has established them as an invaluable toolkit for surface-enhanced spectroscopy. Starting from the fundamental concepts of metasurface-enhanced infrared spectroscopy, a broad palette of resonator geometries, materials, and arrangements for realizing highly sensitive metadevices is showcased, with a special focus on emerging systems such as phononic and 2D van der Waals materials, and integration with waveguides for lab-on-a-chip devices. Furthermore, advanced sensor functionalities of metasurface-based infrared spectroscopy, including multiresonance, tunability, dielectrophoresis, live cell sensing, and machine-learning-aided analysis are highlighted.

Dielectric Tetramer Nanoresonators Supporting Strong Superchiral Fields for Vibrational Circular Dichroism Spectroscopy.

Chirality (C) is a fundamental property of objects, in terms of symmetry. It is extremely important to sense and distinguish chiral molecules in the fields of biochemistry, science, and medicine. Vibrational circular dichroism (VCD) spectroscopy, obtained from the differential absorption of left- and right- circularly polarized light (CPL) in the infrared range, is a promising technique for enantiomeric detection and separation. However, VCD signals are typically very weak for most small molecules. Dielectric metasurfaces are an emerging platform to enhance the sensitivity of VCD spectroscopy of chiral molecules via superchiral field manipulation. Here, we demonstrate a dielectric metasurface consisting of achiral germanium (Ge) tetramer nanoresonators that provide a proper and accessible high C enhancement (CE). We realize a maximum C enhancement (CE_max) with respect to the incident CPL (CE_max = Cmax/CRCP) of more than 750. The volume-averaged C enhancement (CE_ave = Cave/CRCP) is 148 in the 50 nm thick region above the sample surface and 215 in the central region of the structure. Especially, the corresponding CE_ave values are more than 89 and 183 even when a 50 nm thick chiral lossy molecular layer is coated on the metasurface. The metasurface benefits from geometrically achiral nanostructure design to eliminate intrinsic background chiral-optical signal from the substrate, which is useful in chiral sensing, enantioselectivity, and VCD spectroscopy applications in the mid-infrared range.

Advances and applications of nanophotonic biosensors.

Nanophotonic devices, which control light in subwavelength volumes and enhance light-matter interactions, have opened up exciting prospects for biosensing. Numerous nanophotonic biosensors have emerged to address the limitations of the current bioanalytical methods in terms of sensitivity, throughput, ease-of-use and miniaturization. In this Review, we provide an overview of the recent developments of label-free nanophotonic biosensors using evanescent-field-based sensing with plasmon resonances in metals and Mie resonances in dielectrics. We highlight the prospects of achieving an improved sensor performance and added functionalities by leveraging nanostructures and on-chip and optoelectronic integration, as well as microfluidics, biochemistry and data science toolkits. We also discuss open challenges in nanophotonic biosensing, such as reducing the overall cost and handling of complex biological samples, and provide an outlook for future opportunities to improve these technologies and thereby increase their impact in terms of improving health and safety.

Real-time monitoring of single-cell secretion with a high-throughput nanoplasmonic microarray.

Proteins secreted by cells play significant roles in mediating many physiological, developmental, and pathological processes due to their functions in intra/intercellular communication and signaling. Conventional end-point methods are insufficient for understanding the temporal response in cell secretion process, which is often highly dynamic. Furthermore, cellular heterogeneity makes it essential to analyze secretory proteins from single cells. To uncover individual cellular activities and the underlying kinetics, new technologies are needed for real-time analysis of the secretomes of many cells at single-cell resolution. This study reports a high-throughput biosensing microarray platform, which is capable of label-free and real-time secretome monitoring from a large number of living single cells using a biochip integrating ultrasensitive nanoplasmonic substrate and microwell compartments having volumes of ∼0.4 nL. Precise synchronization of image acquisition and microscope stage movement of the developed optical platform enables spectroscopic analysis with high temporal and spectral resolution. In addition, our system allows simultaneous optical imaging of cells to track morphology changes for a comprehensive understanding of cellular behavior. We demonstrated the platform performance by detecting interleukin-2 secretion from hundreds of single lymphoma cells in real-time over many hours. Significantly, the analysis of the secretion kinetics allows us to study cellular response to the stimulations in a statistical way. The new platform is a promising tool for the characterization of single-cell functionalities given its versatility, throughput and label-free configuration.

Wafer-Scale Functional Metasurfaces for Mid-Infrared Photonics and Biosensing.

Metasurfaces have emerged as a breakthrough platform for manipulating light at the nanoscale and enabling on-demand optical functionalities for next-generation biosensing, imaging, and light-generating photonic devices. However, translating this technology to practical applications requires low-cost and high-throughput fabrication methods. Due to the limited choice of materials with suitable optical properties, it is particularly challenging to produce metasurfaces for the technologically relevant mid-infrared spectral range. These constraints are overcome by realizing functional metasurfaces on almost completely transparent free-standing metal-oxide membranes. A versatile nanofabrication process is developed and implemented for highly efficient dielectric and plasmonic mid-infrared metasurfaces with wafer-scale and complementary metal-oxide-semiconductor (CMOS)-compatible manufacturing techniques. The advantages of this method are revealed by demonstrating highly uniform and functional metasurfaces, including high-Q structures enabling fine spectral selectivity, large-area metalenses with diffraction-limited focusing capabilities, and birefringent metasurfaces providing polarization control at record-high conversion efficiencies.  Aluminum plasmonic devices and their integration into microfluidics for real-time and label-free mid-infrared biosensing of proteins and lipid vesicles are further demonstrated. The versatility of this approach and its compatibility with mass-production processes bring infrared metasurfaces markedly closer to commercial applications, such as thermal imaging, spectroscopy, and biosensing.

Nanophotonic biosensors harnessing van der Waals materials.

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.

Imaging-based spectrometer-less optofluidic biosensors based on dielectric metasurfaces for detecting extracellular vesicles.

Biosensors are indispensable tools for public, global, and personalized healthcare as they provide tests that can be used from early disease detection and treatment monitoring to preventing pandemics. We introduce single-wavelength imaging biosensors capable of reconstructing spectral shift information induced by biomarkers dynamically using an advanced data processing technique based on an optimal linear estimator. Our method achieves superior sensitivity without wavelength scanning or spectroscopy instruments. We engineered diatomic dielectric metasurfaces supporting bound states in the continuum that allows high-quality resonances with accessible near-fields by in-plane symmetry breaking. The large-area metasurface chips are configured as microarrays and integrated with microfluidics on an imaging platform for real-time detection of breast cancer extracellular vesicles encompassing exosomes. The optofluidic system has high sensing performance with nearly 70 1/RIU figure-of-merit enabling detection of on average 0.41 nanoparticle/µm2 and real-time measurements of extracellular vesicles binding from down to 204 femtomolar solutions. Our biosensors provide the robustness of spectrometric approaches while substituting complex instrumentation with a single-wavelength light source and a complementary-metal-oxide-semiconductor camera, paving the way toward miniaturized devices for point-of-care diagnostics.

Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer.

CD4 T cells have been implicated in cancer immunity for their helper functions. Moreover, their direct cytotoxic potential has been shown in some patients with cancer. Here, by mining single-cell RNA-seq datasets, we identified CD4 T cell clusters displaying cytotoxic phenotypes in different human cancers, resembling CD8 T cell profiles. Using the peptide-MHCII-multimer technology, we confirmed ex vivo the presence of cytolytic tumor-specific CD4 T cells. We performed an integrated phenotypic and functional characterization of these cells, down to the single-cell level, through a high-throughput nanobiochip consisting of massive arrays of picowells and machine learning. We demonstrated a direct, contact-, and granzyme-dependent cytotoxic activity against tumors, with delayed kinetics compared to classical cytotoxic lymphocytes. Last, we found that this cytotoxic activity was in part dependent on SLAMF7. Agonistic engagement of SLAMF7 enhanced cytotoxicity of tumor-specific CD4 T cells, suggesting that targeting these cells might prove synergistic with other cancer immunotherapies.

Infrared Metasurface Augmented by Deep Learning for Monitoring Dynamics between All Major Classes of Biomolecules.

Insights into the fascinating molecular world of biological processes are crucial for understanding diseases, developing diagnostics, and effective therapeutics. These processes are complex as they involve interactions between four major classes of biomolecules, i.e., proteins, nucleic acids, carbohydrates, and lipids, which makes it important to be able to discriminate between all these different biomolecular species. In this work, a deep learning-augmented, chemically-specific nanoplasmonic technique that enables such a feat in a label-free manner to not disrupt native processes is presented. The method uses a highly sensitive multiresonant plasmonic metasurface in a microfluidic device, which enhances infrared absorption across a broadband mid-IR spectrum and in water, despite its strongly overlapping absorption bands. The real-time format of the optofluidic method enables the collection of a vast amount of spectrotemporal data, which allows the construction of a deep neural network to discriminate accurately between all major classes of biomolecules. The capabilities of the new method are demonstrated by monitoring of a multistep bioassay containing sucrose- and nucleotides-loaded liposomes interacting with a small, lipid membrane-perforating peptide. It is envisioned that the presented technology will impact the fields of biology, bioanalytics, and pharmacology from fundamental research and disease diagnostics to drug development.

Hybrid Metal-Dielectric Metasurfaces for Refractive Index Sensing.

Hybrid metal-dielectric nanostructures have recently gained prominence because they combine strong field enhancement of plasmonic metals and the several low-loss radiation channels of dielectric resonators, which are qualities pertaining to the best of both worlds. In this work, an array of such hybrid nanoantennas is successfully fabricated over a large area and utilized for bulk refractive index sensing with a sensitivity of 208 nm/RIU. Each nanoantenna combines a Si cylinder with an Al disk, separated by a SiO2 spacer. Its optical response is analyzed in detail using the multipoles supported by its subparts and their mutual coupling. The nanoantenna is further modified experimentally with an undercut in the SiO2 region to increase the interaction of the electric field with the background medium, which augments the sensitivity to 245 nm/RIU. A detailed multipole analysis of the hybrid nanoantenna supports our experimental findings.

Arbitrarily high time bandwidth performance in a nonreciprocal optical resonator with broken time invariance.

Most present-day resonant systems, throughout physics and engineering, are characterized by a strict time-reversal symmetry between the rates of energy coupled in and out of the system, which leads to a trade-off between how long a wave can be stored in the system and the system's bandwidth. Any attempt to reduce the losses of the resonant system, and hence store a (mechanical, acoustic, electronic, optical, or of any other nature) wave for more time, will inevitably also reduce the bandwidth of the system. Until recently, this time-bandwidth limit has been considered fundamental, arising from basic Fourier reciprocity. In this work, using a simple macroscopic, fiber-optic resonator where the nonreciprocity is induced by breaking its time-invariance, we report, in full agreement with accompanying numerical simulations, a time-bandwidth product (TBP) exceeding the 'fundamental' limit of ordinary resonant systems by a factor of 30. We show that, although in practice experimental constraints limit our scheme, the TBP can be arbitrarily large, simply dictated by the finesse of the cavity. Our results open the path for designing resonant systems, ubiquitous in physics and engineering, that can simultaneously be broadband and possessing long storage times, thereby offering a potential for new functionalities in wave-matter interactions.

Rapid and Digital Detection of Inflammatory Biomarkers Enabled by a Novel Portable Nanoplasmonic Imager.

New point-of-care diagnostic devices are urgently needed for rapid and accurate diagnosis, particularly in the management of life-threatening infections and sepsis, where immediate treatment is key. Sepsis is a critical condition caused by systemic response to infection, with chances of survival drastically decreasing every hour. A novel portable biosensor based on nanoparticle-enhanced digital plasmonic imaging is reported for rapid and sensitive detection of two sepsis-related inflammatory biomarkers, procalcitonin (PCT) and C-reactive protein (CRP) directly from blood serum. The device achieves outstanding limit of detection of 21.3 pg mL-1 for PCT and 36 pg mL-1 for CRP, and dynamic range of at least three orders of magnitude. The portable device is deployed at Vall d'Hebron University Hospital in Spain and tested with a wide range of patient samples with sepsis, noninfectious systemic inflammatory response syndrome (SIRS), and healthy subjects. The results are validated against ultimate clinical diagnosis and currently used immunoassays, and show that the device provides accurate and robust performance equivalent to gold-standard laboratory tests. Importantly, the plasmonic imager can enable identification of PCT levels typical of sepsis and SIRS patients in less than 15 min. The compact and low-cost device is a promising solution for assisting rapid and accurate on-site sepsis diagnosis.

Early sepsis diagnosis via protein and miRNA biomarkers using a novel point-of-care photonic biosensor.

Sepsis is a condition characterized by a severe stage of blood-infection often leading to tissue damage, organ failure and finally death. Fast diagnosis and identification of the sepsis stage (sepsis, severe sepsis or septic shock) is critical for the patient's evolution and could help in defining the most adequate treatment in order to reduce its mortality. The combined detection of several biomarkers in a timely, specific and simultaneous way could ensure a more accurate diagnosis. We have designed a new optical point-of-care (POC) device based on a phase-sensitive interferometric biosensor with a label-free microarray configuration for potential high-throughput evaluation of specific sepsis biomarkers. The sensor chip, which relies on the use of metallic nanostructures, provides versatility in terms of biofunctionalization, allowing the efficient immobilization of different kind of receptors such as antibodies or oligonucleotides. We have focused on two structurally different types of biomarkers: proteins, including C-reactive protein (CRP) and Interleukin 6 (IL6), and miRNAs, using miRNA-16 as an example. Limits of Detection (LoD) of 18 µg mL-1, 88 µg mL-1 and 1 µM (6 µg mL-1) have been respectively obtained for CRP, IL6 and miRNA-16 in individual assays, with high accuracy and reproducibility. The multiplexing capabilities have also been assessed with the simultaneous analysis of both protein biomarkers.

Angle-multiplexed all-dielectric metasurfaces for broadband molecular fingerprint retrieval.

Infrared spectroscopy resolves the structure of molecules by detecting their characteristic vibrational fingerprints. Subwavelength light confinement and nanophotonic enhancement have extended the scope of this technique for monolayer studies. However, current approaches still require complex spectroscopic equipment or tunable light sources. Here, we introduce a novel metasurface-based method for detecting molecular absorption fingerprints over a broad spectrum, which combines the device-level simplicity of state-of-the-art angle-scanning refractometric sensors with the chemical specificity of infrared spectroscopy. Specifically, we develop germanium-based high-Q metasurfaces capable of delivering a multitude of spectrally selective and surface-sensitive resonances between 1100 and 1800 cm-1. We use this approach to detect distinct absorption signatures of different interacting analytes including proteins, aptamers, and polylysine. In combination with broadband incoherent illumination and detection, our method correlates the total reflectance signal at each incidence angle with the strength of the molecular absorption, enabling spectrometer-less operation in a compact angle-scanning configuration ideally suited for field-deployable applications.