Advanced Microscopy

We develop advanced optical techniques that detect linear scattered light from small particles for studying important physical and chemical processes in living systems. The high sensitivity and the fast acquisition rate of our optical systems enable direct observation of the rapid motions of individual small particles in three dimensions.
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Linear scattering and absorption are the most fundamental light-matter interactions. Due to their simplicity and reliability, they have been used as the primary contrast mechanism for optical microscopy. The high spatial and temporal resolution of optical microscopy has made it an indispensable tool in life science research. Scientists have discovered that many disease-related phenomena originate from the interplays between individual molecules. However, conventional scattering-based or absorption-based optical microscopy is not sensitive enough to observe nanoscopic objects or single molecules. This is because the scattering and absorption signal of a nano-sized object is typically very weak compared to the background. As a result, detecting and imaging small particles or single molecules has been heavily reliant on fluorescence labeling. In modern laboratories, single-molecule fluorescence measurements have become routine, thanks to advancements in scientific light detectors and cameras. Unfortunately, the precision, speed, and observation time of fluorescence measurements are fundamentally limited by the photobleaching and saturation of the signal. Therefore, it is difficult to monitor dynamics of nano-objects and their interactions with sufficient spatiotemporal resolutions.

We believe the next-generation optical microscope technique should exploit the most basic light-matter interaction, that is, to take advantage of linear scattering and absorption (extinction) of light for image formation. In many circumstances, scattering-based approaches avoid the aforementioned limitations of the fluorescence method. A linear scattering signal is stable and indefinite, facilitating long-term observation. The strength of a linear scattering signal can be increased by raising illumination intensity. In addition, given a sufficient sensitivity, scattering-based imaging requires no label, allowing us to study living systems in their most native forms. To enhance the sensitivity of scattering-based imaging, we design the optical system and detect the signal by widefield interferometry (e.g., iSCAT microscopy and COBRI microscopy). Our current methods have the sensitivity to directly observe the dynamics of individual particles of 10 nm. In addition to the high sensitivity, the interferometric measurements also enable high precision at an ultrahigh image acquisition rate (100,000 frames per second). The ultrahigh speed and ultrahigh precision of scattering-based optical microscopy offers the opportunity to investigate dynamics in living systems with unprecedented clarity.

We believe that the forthcoming optical microscope technology should exploit the fundamental interaction between light and matter, specifically linear scattering and absorption, to create images. Scattering-based methods can avoid the limitations of fluorescence techniques in many situations. Linear scattering signals are stable and indefinite, allowing for high-speed and long-term observation. Additionally, scattering-based imaging can be label-free, allowing for the study of living systems in their natural forms. To enhance the sensitivity of scattering-based imaging, we design the optical system and detect the signal by widefield interferometry (e.g., iSCAT microscopy and COBRI microscopy). Our current methods have the capability to directly observe the dynamics of individual particles as small as 10 nm, with an ultrahigh image acquisition rate of 100,000 frames per second. The ultrahigh speed and precision of scattering-based optical microscopy offer an unparalleled opportunity to study dynamics in living systems with exceptional clarity.
 
More information:
iSCAT microscopy at 500,000 Hz
COBRI microscopy for single virus tracking at 100,000 Hz
High-speed imaging and tracking of 10 nm gold nanoparticles
Spiral-phase iSCAT: iPSF engineering + iSCAT

 
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