Electronic Microflow Cytometry for Surface Expression Analysis of Cancer Cells
Proposal Objectives:
Cellular heterogeneity is the hallmark of cancer with individual cancer cells differing in their tumor initiating potential and therapeutic resistance. Tumor cell heterogeneity is often obscured by population level measurements in systems biology and medicine; yet it has significant implications in disease progression. This proposal is about bio-analytical technologies that are capable of analyzing individual cancer cells and offer exciting opportunities for early-detection and monitoring of cancer while it is still manageable, and for gaining biological insight to develop effective therapies.
While capable of analyzing single cells in detail, current technologies are exclusively limited to large well-equipped laboratories due to their high cost, operational complexity and bulky instrumentation. This proposal will address these shortcomings by developing a fundamentally different single cell analysis platform that is fast, low-cost, portable and hence more amenable to point-of-care use than conventional technologies. To achieve this, we will develop a lab-on-a-chip platform that integrates microfluidic cell sorting with electronic sensing by utilizing engineering approaches from multiple technical disciplines including microfluidics, electronics and telecommunications. To further enhance the broader impact of this program, we will be involved with outreach activities to (1) attract K-12 and high school students to STEM education by engaging with local and elementary schools, (2) engage undergraduate students in research activities, (3) attract underrepresented students in engineering by utilizing Georgia Tech's diverse student body, (4) promote teaching and training by contributing to teacher education programs, (5) disseminate the results of the proposed research program to the society through media releases and lab website.
Flow cytometry is an invaluable technique for comprehensive biophysical and biochemical analysis of single cells. In flow cytometry, single cells in a fluid stream are interrogated one by one and subsequently sorted based on the measured properties. The objective of this proposal is to integrate inherently parallel microfluidic cell sorting with a parallel electronic sensor array to create a fundamentally different flow cytometer. The research tasks to be undertaken as part of this project are (1) to develop a scalable electronic sensor that utilizes resistive pulse sensing to simultaneously detect particles in multiple microfluidic channels from a single electrical output, (2) to design a microfluidic cell sorter based on magnetophoresis and integrate it with the developed electronic sensor array to quantify sorted cells, (3) to analyze surface expression of cancer cells by magnetic pre-labeling and benchmark against established laboratory techniques. In this proposal, we combine two traditionally distinct technical disciplines, microfluidics and telecommunications to design a scalable electronic readout mechanism for interfacing microfluidic chips. Our technology relies on multiplexing an array of micromachined Coulter counters each designed to produce a distinct digital code when a particle is detected. These digital codes are developed using the same principles of Code Division Multiple Access (CDMA) telecommunication networks and can be uniquely recovered through simple mathematical calculations. This approach will be used to increase number of sensors without increasing the hardware complexity. Instead, complexity in the hardware will be shifted towards computational algorithms to decode the signal. We will then integrate this sensor with magnetophoretic sorting of tumor cells to quantify the expression of a protein with clinical utility for managing and guiding cancer therapy.
