We use an optical positioning and linking (OPAL) platform based on optical tweezers to fabricate a grating coupler on a microtoroid-shaped optical resonator for highly efficient coupling of light into the resonator, which acts as a chemical sensor. Light is coupled into and out of the microtoroid through a grating fabricated from 0.5 µm polystyrene particles on the rim of the microtoroid, which acts as a fiber-free coupler. Unlike a tapered fiber coupler, this particle grating is highly robust and not susceptible to mechanical and vibrational noise, paving the way for field-portable sensing devices.
Nitric oxide (NO) sensing is important for many applications including air quality and climate change monitoring. Current sensors have limited sensitivity, selectivity, and are affected by environmental interference such as humidity, which affects their accuracy. We use an ultra-sensitive optical sensing platform known as FLOWER (frequency locked optical whispering evanescent resonator) and combine it with a custom synthesized polymer coating to detect NO at a concentration of 6 ppt, which to the best of our knowledge is the lowest experimentally reported detection of NO to date. In addition, we demonstrate that our sensor is selective and humidity resistant.
More sensitive toxic gas sensors can provide earlier warning by detecting lower concentrations at greater distances from the source than conventional technologies. Recently, microtoroid whispering gallery mode optical resonators with selective polymer coatings have demonstrated part-per-trillion sensitivity to several gases, making them one of the most sensitive gas detection technologies. However, these sensors are currently coupled to laser sources via fragile and vibration-sensitive tapered optical fibers, hindering their translation from the laboratory into the field. Here we design and assemble periodic nanostructures onto the rim of microtoroids to improve free-space coupling efficiency, obviating the need for the tapered optical fiber.
Whispering gallery mode microtoroid optical resonators are one of the most sensitive and rapid sensors in existence. However, the need for a tapered optical fiber to couple light into these sensors hinders translation out of laboratory as the fiber is fragile and suffers from mechanical vibration. Here, we developed a free space coupling system together with a compatible fluidic platform which allows monitoring of molecular interactions in real time. We obtained Q-factors as high as 1.6×10^8 with this approach. The large effective coupling area, ~10 μm in diameter for a numerical aperture of 0.14, provides high coupling stability during biosensing experiments.
Microtoroid resonators are one of the most sensitive chemical sensing technologies. However, coupling light into microtoroids typically requires equipment such as vibration-isolation tables and piezoelectric nanopositioning stages. Translating microtoroids to platforms with small size, weight, power, and cost for chemical vapor sensing remains a challenge. We demonstrate an approach to position photonic nanostructures on the surface of microtoroids to facilitate free-space coupling via inexpensive optics. We have designed the nanophotonic coupler using finite element simulations with novel boundary conditions to accommodate a large simulation domain. The nanophotonic coupler is assembled using a custom manufacturing platform based on automated optical tweezers.
Ultra-sensitive and selective gas sensing plays a role in defense and environmental mentoring. Current highly sensitive techniques such as graphene lack selectivity and highly selective techniques such as microresonator soliton dual comb spectroscopy techniques lack the sensitivity of the techniques such as graphene. We have previously developed an ultra-sensitive biosensor known as FLOWER that enables the detection of single macromolecules. FLOWER is based on optical microresonator technology. Here, we adapt FLOWER for highly sensitive and selective chemical sensing by combining it with custom synthesized sorbent polymer coatings. We demonstrate part-per-trillion selective detection of DIMP as well as formaldehyde and ammonia.
Label-free detection techniques are widely used in biological and environmental sensing. In particular, whispering gallery mode microtoroid resonators have been used to detect single nanoparticles and molecules by relying on the ultrahigh quality factor of these resonators together with frequency locking for ultra-precise resonance tracking. However, material property characterization on a particle-by-particle basis remains a challenge in these label-free schemes. Here we characterize single particle material properties using microtoroid optical resonators combined with spectroscopic techniques.
Vaccines for the COVID-19 pandemic are limited and so effective drugs are needed. The binding affinity of several SARS-CoV-2 variants to human ACE2 receptors was measured using a frequency-locked optical whispering evanescent resonator (FLOWER) system. The advantage of FLOWER is that it is label-free and so drug candidates do not need to be labeled and it is ultra-sensitive so drugs over a wide range of binding affinities can be tested. The dissociation equilibrium constants of spike-RBD wild type as well as two variants, were analyzed and compared. Several drug candidates which inhibit the spike-RBD binding to ACE2, predicted by in-silico simulation, were screened using a competitive binding assay and the corresponding inhibitor constants were measured.
Sensitive, label-free, and selective sensors are of importance for a wide variety of applications, in particular medical diagnostics, and environmental monitoring. Microtoroid optical resonators, when combined with frequency locking, balanced detection, and data processing techniques, are capable of single molecule detection. We have developed such a system called FLOWER (frequency locked optical whispering evanescent resonator). We discuss our latest work on using FLOWER for a variety of applications including medical diagnostics for ovarian cancer and Alzheimer’s disease, chemical threat sensing, and drug screening. In addition, we discuss our next generation sensing platforms.
Whispering gallery mode microtoroid optical resonators are one of the most sensitive and rapid optical sensors in existence. These sensors can detect extremely low analyte concentrations down to attomolar levels on the order of seconds. How these sensors have such a rapid response time even at these low concentrations is a question in the field. Here, we show that total analyte arrival and binding time can occur in seconds using flow visualization and finite-element simulations.
Thermal effects need to be accurately measured and/or controlled to generate continuous kinetic binding curves with whispering gallery mode (WGM) microcavity sensors. We use a high spatial resolution optical frequency domain reflectometry system at 780 nm to capture the Rayleigh backscattering signal within a microtoroid optical resonator for temperature calibration. It is shown that this system has a temperature detection accuracy of 30 mK. This technique characterizes thermal effects in the microcavity and the surrounding environment, thus enabling lower limits of detection to be achieved.
Detecting single molecules without labels or capture probes is of great interest for both medical applications and scientific research. Frequency-locked microtoroid optical resonators are capable of label-free single molecule detection, however, this approach requires a priori knowledge of the molecule to be detected as well as surface functionalization of the cavity. Optical frequency microcombs can be a precise source of spectral information on molecules, however, microcombs have not been generated in an aqueous biological sensing environments due to altered dispersion, coupling instability, and reduced quality factor of the resonator. Here we suggest a way toward single-molecule spectroscopy by demonstrating frequency comb generation in water and air at visible wavelengths using a microtoroid optical resonator. Local anomalous dispersion is achieved because of the interaction between different transverse mode families in an overall normal dispersion region. With this approach, the advantageous structure and material of the microtoroid resonator for biosensing is preserved. We believe that in the future this will enable single molecule detection and identification simultaneously in both air and liquid at any wavelength with no labels or capture probes.
Currently there are no biomarkers for ovarian cancer. We discover an ovarian cancer biomarker using mass spectrometry and use microtoroid resonators for label-free ultra-sensitive detection of this marker in ovarian cancer tumor-implanted mice. After characterizing the sensor response with standard solutions, we then perform a quantitative analysis to investigate the concentration of the biomarker in several mouse vaginal lavage samples. The results show that the biomarker levels increase with time, revealing the progression of tumors implanted in mice.
Whispering gallery mode (WGM) optical microresonators with high quality (Q) factors have been widely used to sense biomolecules due to their small mode volume and narrow linewidth resonance. Previously, we reported a frequency locked optical whispering evanescent resonator (FLOWER) system for real time single macromolecule detection. Here, we explore the detection limit of FLOWER via numerical simulation based on coupled mode theory. These results predict that frequency locked microcavities with ultra-high-Q can detect resonance shifts as small as 0.05 attometers at 1 millisecond time interval and are limited by shot noise and laser intensity noise.
We use a system known as FLOWER (frequency locked optical whispering evanescent resonator) to rapidly detect trace amounts of the chemical warfare agent surrogates DIMP and DMMP. We use sorbent polymer layers covalently bound to the surface of the microtoroid cavity to selectively adsorb target gases. As the target gas diffuses into the polymer layer, a measurable change in the resonance frequency of the toroid occurs. We demonstrate 80 ppt (part per trillion) sensing of DIMP; two orders of magnitude better than what can be achieved using mass spectroscopy.
High Q whispering gallery mode optical resonators are capable of rapid and ultra-sensitive biological detection at attomolar concentrations in under 30 seconds. One main question in the field is how these sensors detect such low concentrations of molecules so quickly. Calculations based on diffusion alone suggest that transport to these sensors should take hours to days. Here, we show using bromothymol blue dye flow visualization methods that transport to a microtoroid optical resonator can take place in seconds. We reconcile these results with finite element simulations.
We use a microtoroid sensing platform known as FLOWER (frequency locked optical whispering evanescent resonator) to detect small molecule drug targets at attomolar concentrations. FLOWER combines whispering gallery mode optical resonator technology with frequency locking feedback control, balanced detection, and data-processing techniques. We have previously demonstrated label-free detection down to single macromolecules. To use FLOWER as a drug screening platform, we couple the high selectivity and detection capabilities of G-protein coupled receptors (GPCRs) for small ligands with FLOWER. We demonstrate detection of the peptide dynorphin A at attomolar concentrations using a microtoroid resonator coated with a lipid bilayer containing GPCRs.
Accurate measurement of Amyloid-β biomarkers in blood serum has been highly sought after for early detection of Alzheimer’s Disease (AD). However, non-specific binding and low levels of Amyloid-β in blood pose a problem for traditional immunoassays. Here, we propose a lipid-functionalized biosensor for real-time, label-free detection of Amyloid-β by interaction with whispering gallery modes (WGM) of a microtoroid optical resonator. Non-specific binding is reduced by uniform surface coverage of the lipid, and protein-lipid interactions enhance the shift in resonance frequency. The lipid surface functionalization scheme enables increased accuracy and sensitivity of Amyloid-β and potential for blood-based screening of AD.
Whispering-gallery mode (WGM) microtoroid optical resonators have been used for highly sensitive biological and chemical sensing. With the help of auto-balanced detection and data processing techniques, frequency locked optical whispering evanescent resonator (FLOWER) has successfully reduced external noise and achieved detection of single macromolecules. FLOWER, however, can only analyze the size of particles and not their shape. To determine the shape of non-spherical particles interacting with different polarized WGM modes, we built a dual-FLOWER system to perform multi-mode locking. We demonstrate the ability of this system to detect particle shape by detecting gold nanorods and spheres.
Most biosensors rely on immobilized antibodies or aptamers. In contrast, receptor proteins exist naturally in lipid bilayers and are highly specific to small molecules. We use a frequency-locked optical whispering evanescent resonator (FLOWER) system for real-time quantification of rhodopsin incorporation into an artificial lipid membrane and observe photo-induced molecular transformations upon light activation. Our study of proteolipid membrane coated microtoroids for probing the local activity of G-protein coupled receptors was further expanded to kappa-opioid receptors and their endogenous ligand Dynorphin-A. G-protein coupled receptor signaling probed by a microtoroid-proteolipid system will facilitate drug discovery and therapeutic interventions.
The light confinement properties of high quality (Q) factor microtoroid whispering-gallery mode (WGM) optical resonators prevent efficient coupling between far-field radiation and the WGM. Instead, light is most commonly evanescently coupled to the WGM using optical fibers that have been tapered to micron-scale thickness. These tapers, however, break easily and are sensitive to environmental vibrations and fluid flow fluctuations. This limits their effectiveness in mass-produced and/or field-portable biochemical sensing applications. Here we present a gold nanorod grating as an experimentally-feasible alternative for robust coupling of free-space light to a microtoroid resonator, and we simulate its performance with a novel finite-element 3D beam envelope method. 3D simulations of the full system are not tractable due to its large size. Previously, simulations of nanostructures on microtoroids have been performed on a thin wedge of the 3D system with perfect electrical conductor (mirror) boundary conditions. While these simulations provided some insight, they do not accurately model typical travelling-wave WGM experiments because they can only simulate standing waves. The standing wave nodes and antinodes significantly alter interactions between the WGM and the nanostructure. In our new method, we use a small wedge domain with custom boundary conditions that accurately simulate the travelling wave and nanophotonic interactions. Using this approach, we have designed and simulated a grating for far-field WGM coupling. With the grating, it is possible to maintain a high Q-factor of 3×10^6. We anticipate that our proposed modeling approach can solve a variety of other nanoparticle-microtoroid coupled systems in the future.
Utilization of frequency locking for tracking optical resonances of microresonators is an emergent technique, which has relevance in label-free biosensing, owing to its extremely high sensitivity in detecting adsorption on a microcavity’s surface. In this study, we demonstrate the capabilities of a technique known as FLOWER (Frequency Locked Optical Whispering Evanescent Resonator) in a real-life problem: the detection of human chorionic gonadotropin (hCG) in urine samples. hCG, besides being a hormone secreted during pregnancy, is a performance enhancing agent prone to be abused by athletes, and is routinely investigated in doping laboratories. The gold standard in hCG detection is mass spectrometry. As the lowest limit of detection by mass spectrometry is close to the cut-off value for a positive result, various other measurement techniques such as optical interferometry, photoluminescence, or electrochemical sensors have been used to try to enhance measurement sensitivity. These methods, however, do not show a significant improvement in the limit of detection over mass spectrometry and they mostly have a narrow detection range. In addition, measurement selectivity is another issue. Here, we use microtoroidal optical resonators functionalized with antibodies against hCG, and track their resonances using frequency locking upon analyte infusion. Urine samples from pregnant women were measured using our setup. Our results demonstrate that FLOWER can detect the presence of hCG in a large concentration range from 1 fM to 10 nM.
Subwavelength systems such as optical nanoantennas are widely used for optical sensing due to their ultrahigh field localization. Compared to isolated nanoantennas, hybrid sensor systems composed of optical nanocavities and microcavities enjoy higher quality factor (Q) plasmonic-cavity modes, as well as larger resonance shifts for any given sensing target. We have shown that rational engineering of the coupling between nanoantennas can maximize the system’s sensitivity. This can be achieved through near-field optimization of the system to maximize the field enhancement and suppression of the far-field radiation to maintain the highest possible Q. Finite element eigenvalue analysis shows that a trimer plasmonic nanoantenna coupled to a whispering gallery mode (WGM) of a microtoroid cavity supports higher Q and field enhancement than single nanorods that are randomly scattered on the surface of microcavity. We have studied the robustness of this system against any possible perturbation in geometry of trimers such as length, angle or gap between the nanoantennas. On the basis of this study, a general design approach is introduced, which helps engineers to enhance the efficacy of plasmonic-photonics based biosensors.
Local field enhancement of plasmonic nanoantennas below the diffraction limit plays an important role in a variety of applications, including surface-enhanced Raman scattering, spontaneous emission enhancement, nanolasing, enhanced nonlinear effects and biosensing. Yet due to the radiation and ohmic loss of these nanocavities, their quality factor (Q) is much smaller than a typical optical microcavity Q factor, such as that of a microsphere or microtoroid. Coupling a nanoantenna to an optical microcavity increases the Q of the hybrid plasmonic-photonic system, however, this dramatically degrades the Q of the original microcavity. Here, we propose a judicious hybridization of a plasmonic dark mode of a gold nanoring and whispering gallery mode (WGM) of a microtoroid. It is shown through finite element simulation that the hybridized WGM and dark mode of the proposed plasmonic gold nanoring solves the aforementioned issues in two ways. First, the small radiation loss of the dark mode minimizes Q degradation and allows the system to maintain its ultra-high Q. Second, the nanoring enhances the field on the microcavity’s surface which in turn increases the interaction between, for example, a biomolecular target and the WGM. We have shown that the proposed system generates larger resonance shifts compared to a microcavity loaded with same volume of conventional linear gold nanoantennas . This results in significant enhancement in the system’s sensitivity. We have repeated the same simulations for different materials and volumes.
Optical whispering gallery mode (WGM) biochemical sensors operate by tracking changes in resonant frequency as materials enter the evanescent near-field of the resonator. To achieve the smallest limit of detection, it is desirable for WGM sensors to exhibit as large a frequency shift as possible for a material of a given size and refractive index, as well as the ability to track as small a frequency shift as possible. Previously, plasmonic nanoantennas have been coupled to WGM resonators to increase the magnitude of resonance shifts via plasmonic enhancement of the electric field, however this approach also results in increased scattering from the WGM, which degrades its quality factor, making it less sensitive to extremely small frequency shifts. This degradation is caused by the ohmic and scattering dissipation caused by metallic nanoantennas. Using simulations, we show here that the precise positioning of nanoantennas coupled to a microtoroid WGM resonator can be used to overcome this drawback and achieve ultrahigh-Q plasmonic cavity modes simultaneously with electric field enhancement. It is shown that a nanoantenna composed of two similarly coupled nanorods supports higher Q modes than a single nanorod antenna. Our results have immediate application in the context of optical sensing.
Recently exosomes have attracted interest due to their potential as cancer biomarkers. We report the real time, label‐free sensing of single exosomes in serum using microtoroid optical resonators. We use this approach to assay the progression of tumors implanted in mice by specifically detecting low concentrations of tumor‐derived exosomes. Our approach measures the adsorption of individual exosomes onto a functionalized silica microtoroid by tracking changes in the optical resonant frequency of the microtoroid. When exosomes land on the microtoroid, they perturb its refractive index in the evanescent field and thus shift its resonance frequency. Through digital frequency locking, we are able to rapidly track these shifts with accuracies of better than 10 attometers (one part in 10^11). Samples taken from tumor‐implanted mice from later weeks generated larger frequency shifts than those from earlier weeks. Control samples taken from a mouse with no tumor generated no such increase in signal between subsequent weeks. Analysis of shifts from tumor-implanted mouse samples show a distribution of unitary steps, with the maximum step having a height of ~1.2 fm, corresponding to an exosome size of 44 ± 4.8 nm. This size range corresponds to that found by performing nanoparticle tracking analysis on the same samples. Our results demonstrate development towards a minimally‐invasive tumor "biopsy" that eliminates the need to find and access a tumor.
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