Detecting Protein Alteration within an Exosome by Means of a Coated Dielectric Microsphere Resonator

Exosomes have great potential to be used as a liquid biopsy tool for cancer diagnosis, and hence can facilitate early stage cancer diagnosis [1] . Cancerous exosomes have slightly altered protein content in comparison to healthy ones, and hence through detection of such protein alteration, cancerous exosomes can be distinguished. In order to detect such protein alteration in a label free manner, the protein fraction of the exosome is translated into an external property of the exosome namely refractive index, and afterwards by the means of a coated microresonator the refractive index variation is sensed. To determine the refractive index, using the Maxwell-Garnett mixing formula [2] , the exosome is modelled as a compound material containing water and a protein fraction, where the protein fraction is slightly varied in cancerous exosomes. Microsphere resonators capable of sustaining whispering gallery modes have shown promising ultra-high sensitivity in detecting single bio elements such as a single virus or even a single molecule nucleic acid [3] - [5] , however their sensitivity has to be further improved to detect only 1% alteration in the protein content. In order to further improve the sensitivity, a thin dielectric shell with a refractive index higher than the microsphere’s refractive index is added, which through reducing the radiation loss improves the quality factor and hence the sensitivity of the resonator. Additionally the shell, due to its higher refractive index, localizes the electric field toward the surface and hence amplifies the electric field strength at the sensing location. It is shown that adding a 150nm thick Si 3 N 4 shell to a 30 µ m silica microsphere in an aquatic medium improves the resonator’s quality factor from 1.0×10 5 to 8.1×10 7 and additionally the electric field strength at the sensing location is 2 . 5 times enhanced (cf. Fig 1. a-c ). A 50nm exosome is placed in the vicinity of the resonator and as the figure of merit, the resonance wavelength shift is determined for exosomes with 30%, 31%, and 35% protein fraction. The results are summarized in the table within Fig 1. d , where it is shown that for the 30% case in the absence of the shell only 0.081pm wavelength shift is achieved, while presence of the shell improved this shift about 106 times to 8.64pm. The achievable shift difference between 30% and 35% protein content exosomes without any shell is 15fm while in the presence of the shell enhances the shift to 60fm and consequently the microsphere with the 150nm Si 3 N 4 shell can even resolve 1% protein alteration through showing about 10fm wavelength shift. We have shown that the improved microresonator due to its unprecedented sensitivity is capable of characterizing exosomes based on their protein content.