Terahertz refractive phenotype of living cells

Abstract

Cellular refractive index is a vital phenotypic parameter for understanding the cell functional activities. So far, there remains technical challenges to obtain refractive index of viable cells at the terahertz frequency in which contains rich information closely related to their physiological status. Here we introduce a label-free optical platform for interrogating cellular phenotypes to measure the refractive index of living cells in near-physiological environments by using terahertz spectroscopy with the combination of cellular encapsulation in a confined solution droplet. The key technical feature with cells encapsulated in aqueous droplets allows for keeping cellular viability while eliminating the strong adsorption of solvent water to terahertz signal. The obtained high signal-to-noise ratio enables to differentiate different cell types (e.g., E. coli, stem cell and cancer cell) and their states under stress conditions. The integrating of terahertz spectroscopy to droplet microfluidic further realizes automated and high-through sample preparation and detection, providing a practical toolkit for potential application in cellular health evaluation and phenotypic drug discovery.

On-Chip Photonic Detection Techniques for Non-Invasive In Situ Characterizations at the Microfluidic Scale

“…This approach improved the signal-to-noise ratio while preserving cellular viability and allowed for successfully determining the refractive indices of the cells. The high sensitivity and repeatability of the method permitted effective discrimination of cellular states and stress responses, demonstrating its versatility in biomedical applications [ 115 ]. THz spectroscopy coupled to microfluidics has also been applied to the characterization of xanthan gum colloids [ 116 ] and hydroxygraphene [ 117 ].…”

“… ( a ) Schematic representation of the microfluidic device integrated with automated droplet sampling and THz measurements. ( b ) Refractive index spectra of liver cancer cells after treatment by resveratrol drug for 0, 12, and 24 h. Figure adapted from [ 115 ], from the journal Frontiers in Bioengineering and Biotechnology , section Nanobiotechnology published by Frontiers 2023. …”

Detection of In Vivo-like Cells by a Biosensor Chip Based on Metamaterials in Terahertz Regime

“…Necrosed and ruptured cells are washed away with PBS in the sample testing process, leading to an increase in PBS content in the tested chip. Since the dielectric constant of water solutions and culture media is higher than that of living tumor cells [21,22], the ε a increases, resulting in a red shift in the resonance frequency. Additionally, the literature [22] confirms a decrease in cell viability and an increase in the dielectric constant, consistent with the test results from the biosensor.…”

“…Since the dielectric constant of water solutions and culture media is higher than that of living tumor cells [21,22], the ε a increases, resulting in a red shift in the resonance frequency. Additionally, the literature [22] confirms a decrease in cell viability and an increase in the dielectric constant, consistent with the test results from the biosensor. In summary, the designed THz biosensor chip has significant potential for cancer detection, as the frequency shift it detects agrees with the commercial method measurement.…”

Terahertz time-domain attenuated total reflection spectroscopy integrated with a microfluidic chip

“…Terahertz (THz) wave normally refers to the electromagnetic radiation with a frequency ranging from 0.1 THz to 10.0 THz, which is located between microwave and infrared regions ( Wang et al, 2020a ; Li et al, 2020 ; Yang et al, 2020 ; Meng et al, 2023 ). In the recent 2 decades, THz biological studies have attracted much attention among scientific communities, mainly thanks to the broad-band, label-free, and bio-sensitive features of THz wave ( Zaytsev et al, 2015 ; Zhou et al, 2016 ; Sun et al, 2018 ; Bai et al, 2020 ; Chen et al, 2020 ; Zhu et al, 2020 ; Shen J. et al, 2021 ; Shen S. et al, 2021 ; Zhang et al, 2022b ; Tang et al, 2022 ; Zhang et al, 2023 ). THz time-domain attenuated total reflection (THz TD-ATR) spectroscopy is an advanced THz technique, and superior to many conventional THz techniques due to its remarkable sensitivity by taking the advantage of evanescent-field detection ( Arikawa et al, 2008 ; Wang et al, 2019 ; Hu et al, 2021 ; Liao et al, 2022 ).…”