  The author discusses the laser interference method to measure the size of
small bio-particles: extracellular vesicles (EVs), exosomes and viruses of
nanometer scale in flow cytometry. By introducing a new laser configuration in
place of conventional optical system of the flow cytometry, the interference
fringe (periodic intensity modulation) is created inside the flow which
provides a calibrated scale for the size measurement. The fringe pitch is
precisely determined by the crossing angle of laser beams and the wavelength.
The transverse size of the beam spot can be much larger than wavelength, for
example, 30 micro-meters, where the flow cell design in conventional system can
be used with moderated dimensional tolerance. The interaction length of sample
with laser becomes longer: ~30 micro-meter and thus the scattering light and
fluorescent light in case of labeled particle becomes much higher. Importantly,
those signals are modulated in MHz frequency range associated with the periodic
intensity modulation of the interference fringe. By measuring modulation depth,
we can determine the particle size. We may utilize a bandpass filter or the
digital signal processing of FFT, and thus we can drastically improve S/N
ratio. This is because of the narrow spectrum of signal and thus effectively
eliminates noise from various debris contained in the sample, and also low
frequency shot noise in the photo detector signal. Thanks to the
above-mentioned merits, it will be possible to measure the size of EVs and
exosomes in particle-by-particle basis in reliable dimensional scale at
nano-meter resolution. It will be also possible to realize the fast virus
detection system for screening passengers in the airport at the current
pandemic of COVID-19 and in future.
