Towards a Single Bio-molecule Detector Based on CMOS Nanofluidic Platform

Abstract

Cytokines secretion is a core component of the function of many cell therapy products: It affects the tissue repair capacity of induced Pluripotent Stem Cells (iPSCs) and Mesenchymal Stem cells (MSCs) and the tumorigenicity of Chimeric Antigen Receptor (CAR) T-cell therapies. Ideally, we would be able to continuously monitor the secretome of these cell therapies as they are transformed and expanded in manufacturing.However, state-of-theart techniques for monitoring typically low concentrations of cytokines require either Mass Spectroscopy (MS) or immunoassays like Enzyme-linked Immunosorbent Assay (ELISA). We propose the use of CMOS technology to build a proteomic platform with a single biomolecule resolution. A prototype chip has been designed and fabricated using standard foundary process incorporating a new implementation of a Solid State Nanopore (SSN) of size 55nm×162nm×100nm (w×l×h) with nanofluidic access channels that bridge the buffer solution between the assay space in the packaging structure – a poly carbonate/Polydimethylsiloxane (PDMS) package- and the nanopore on the chip. A silicon Single Photon Avalanche Detectors (SPADs) was also implemented and placed near the nanochannels to utilize fluorescence labeling imaging techniques. In addition, a read-out amplifier that achieves a midband gain of 36.2 dB at a 3 dB bandwidth of 0.1-3.6 MHz is also implemented on the same silicon die, paving the way to superior performance compared to ionic current read-out systems used earlier for electrical biomolecule detection, thanks to low parasitics as a result of integration. The aforementioned modalities integrated on a single chip open the space for the use of CMOS platforms in the electrical and optical interrogation of biomolecules, opening a new horizon for near real-time biomarker assays. The following thesis builds on earlier work that was performed in [1][2] with the objective of expanding on different techniques to interface and characterize the performance of these modalities, especially after post-processing the chips with the aid of tools at MIT.nano. The thesis explores the further deployment of integrated SPAD in a Fluorescence Lifetime Imaging (FLIM) system to image fluorescence-labeled molecules, showcasing the capabilities of the CMOS nanofluidic platform to detect biomarkers such as cytokines.