ABSTRACT
Whispering gallery mode (WGM) microtoroid resonators are one of the most sensitive biochemical sensors in existence, capable of detecting single molecules. The main barrier for translating these devices out of the laboratory is that light is evanescently coupled into these devices though a tapered optical fiber. This hinders translation of these devices as the taper is fragile, suffers from mechanical vibration, and requires precise positioning. Here, we eliminate the need for an optical fiber by coupling light into and out from a toroid via free-space coupling and monitoring the scattered resonant light. A single long working distance objective lens combined with a digital micromirror device (DMD) was used for light injection, scattered light collection, and imaging. We obtain Q-factors as high as 1.6 × 10 8 with this approach. Electromagnetically induced transparency (EIT)-like and Fano resonances were observed in a single cavity due to indirect coupling in free space. This enables improved sensing sensitivity. The large effective coupling area (~10 µm in diameter for numerical aperture = 0.14) removes the need for precise positioning. Sensing performance was verified by combining the system with the frequency locked whispering evanescent resonator (FLOWER) approach to perform temperature sensing experiments. A thermal nonlinear optical effect was examined by tracking the resonance through FLOWER while adjusting the input power. We believe that this work will be a foundation for expanding the implementation of WGM microtoroid resonators to real-world applications.
ABSTRACT
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus mutates, finding effective drugs becomes more challenging. In this study, we use ultrasensitive frequency locked microtoroid optical resonators in combination with in silico screening to search for COVID-19 drugs that can stop the virus from attaching to the human angiotensin-converting enzyme 2 (hACE2) receptor in the lungs. We found 29 promising candidates that could block the binding site and selected four of them that were likely to bind very strongly. We tested three of these candidates using frequency locked optical whispering evanescent resonator (FLOWER), a label-free sensing method based on microtoroid resonators. FLOWER has previously been used for sensing single macromolecules. Here we show, for the first time, that FLOWER can provide accurate binding affinities and sense the inhibition effect of small molecule drug candidates without labels, which can be prohibitive in drug discovery. One of the candidates, methotrexate, showed binding to the spike protein 1.8 million times greater than that to the receptor binding domain (RBD) binding to hACE2, making it difficult for the virus to enter cells. We tested methotrexate against different variants of the SARS-CoV-2 virus and found that it is effective against all four of the tested variants. People taking methotrexate for other conditions have also shown protection against the original SARS-CoV-2 virus. Normally, it is assumed that methotrexate inhibits the replication and release of the virus. However, our findings suggest that it may also block the virus from entering cells. These studies additionally demonstrate the possibility of extracting candidate ligands from large databases, followed by direct receptor-ligand binding experiments on the best candidates using microtoroid resonators, thus creating a workflow that enables the rapid discovery of new drug candidates for a variety of applications.
ABSTRACT
Sensitive and rapid biosensors are of critical importance for a variety of applications including infectious disease detection and monitoring as well as medical diagnostics and drug discovery. Whispering gallery mode microtoroid optical resonators are among the most sensitive biochemical sensors in existence. When combined with frequency-locking and data-processing techniques, these sensors have been shown to be capable of single-molecule detection in under 30 s. The sensitivity of these sensors is affected by how a concentration of analyte molecules is transported to the surface of the sensors and the average time it takes the molecules to bind at that concentration. Currently, one question in the field is that at these low concentrations, how these microsensors achieve such rapid response times. Here, we reconcile theory and experiment and demonstrate through flow visualization experiments and finite-element simulations that the total analyte arrival and binding time can be on the order of seconds. This fast response time provides an advantage over nanoscale sensors such as nanowires or nanorods. We anticipate that these results can help us to control, with confidence, when and how many molecules bind to these sensors, thus enabling the building of faster and more sensitive sensors.
Subject(s)
Biosensing Techniques , NanotubesABSTRACT
We present the design and feasibility testing of a multimodal co-registered endoscope based on a dual-path optical system integrated with a scanning piezo. This endoscope incorporates three different imaging modalities. A large field of view reflectance imaging system enables visualization of objects several millimeters in front of the endoscope, while optical coherence microscopy and multiphoton microscopy are employed in contact with tissue to further analyze suspicious areas. The optical system allows multiple different imaging modalities by employing a dual optical path. One path features a low numerical aperture and wide field of view to allow reflectance imaging of distant objects. The other path features a high numerical aperture and short working distance to allow microscopy techniques such as optical coherence microscopy and multiphoton microscopy. Images of test targets were obtained with each imaging modality to verify and characterize the imaging capabilities of the endoscope. The reflectance modality was demonstrated with a 561 nm laser to allow high contrast with blood vessels. It achieved a lateral resolution of 24.8 µm at 5 mm and a working distance from 5 mm to 30 mm. Optical coherence microscopy (OCM) was performed with a 1300 nm super-luminescent diode since this wavelength experiences low relative scattering to allow for deeper tissue imaging. Measured OCM lateral and axial resolution was 4.0 µm and 14.2 µm, respectively. Multiphoton microscopy (MPM) was performed with a custom 1400 nm femtosecond fiber laser, a wavelength suitable for exciting multiple exogenous and some endogenous fluorophores, as well as providing information on tissue composition through harmonic generation processes. A 4.0 µm MPM lateral resolution was measured.
