Large‐Scale Nanophotonic Structures for Long‐Term Monitoring of Cell Proliferation

Abstract

labeled assays tend to be constrained by:(1) the cellular expression of a given cell type, and (2) the availability of tags for specific cell expression. In most of the labeled assays, "signal quenching" is often associated with false experimental positives, [11] which decreases assay reliability. Furthermore, labeled assays are laborious, costly, unsuitable for real-time cell analysis, and sometimes require the usage of toxic reagents, such as radioactive labels. [12] Label-free biosensors utilize biophysical properties of a given analyte, such as its mass (e.g., in quartz crystal microbalance), refractive index (e.g., in plasmonic nanobiosensors), or molecular charge (e.g., in potentiometric and amperometric sensors) to monitor the response of the analyte in real-time. [13] Recently, nanomaterialbased label-free photonic biosensors have revealed unprecedented information on DNA and protein molecular interactions. [14] However, few attempts have been made to apply label-free photonic biosensors to cellular assays, as it is challenging to develop nanostructured substrates with large surface areas that promote both sensing and long-term cell survival. Meanwhile, photonic techniques have been coupled with microscopy tools to enhance live cell imaging and distinguish different types of cell behavior such as cell activation, adhesion, proliferation, migration, and apoptosis. [15] In comparison to these "imaging"-based techniques, "sensor"-based techniques generate average responses proportional to the concentrations of a given analyte. Such an average response captures real-time kinetics of cell behavior. In this work, we develop novel nanomushroom (NM) structures (NM-based sensors) for labelfree, long-term cell proliferation detection with high sensitivity, on a large interrogation area, specifically suitable for clinically relevant cell experiments (e.g., drug testing) that require large interrogation areas involving standard 96-well assay plates. Moreover, the unique features of our NM-based sensors can be complementary to existing imaging-based tools to probe cell kinetics in real-time with high accuracy.The developed NM structures are 45-60 nm in height and ≈20 nm in width, evenly distributed with ≈10 nm spacing on a standard glass slide (25 mm × 75 mm). Each NM consists of a silicon dioxide (SiO 2 ) stem of 30-40 nm in height, covered by a gold (Au) cap of 15-20 nm in thickness (Figure 1a). These structures were fabricated by a simple, high-throughput, three-step process based on well-established principles of gold Innovative sensing materials have enabled the discovery of cell biology principles at the nanoscale. In order to evaluate cell behavior and responses, it is necessary to accurately monitor cell proliferation. However, it remains challenging to develop nanomaterials possessing pertinent properties for sensing, while ensuring long-term cell survival and unaltered cellular responses. This work develops highly sensitive, large-scale, and biocompatible nanoplasmonic biosensors for long-term monitoring of ...

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