Nov 17, 20193 min read

A novel MEMS based microfluidic CTC detection system for a LoC device

Updated: Jun 1, 2020

This is a novel microfluidic system design for a lab on a chip (LoC) device for cancer risk prediction. Microfluidic circuit consist of three major sub systems: micro-channel, micro-mixer and a droplet generator. The LoC device design is carried out in three stages and this is the initial stage which is the design and simulation of the microfluidic system. Second and third stages are the magnetic based separation and microelectronic system design.

Introduction

Cancer is the second largest cause of death in the world in 2018. cancer cells divide relentlessly and turns into solid tumors by flooding the blood with abnormal cells. Generally cancer diagnosis is done through extraction of tissue from the affected area (Solid biopsy).

Figure 1 : Solid biopsy techniques used for cancer diagnosis

Source: Breast biopsy Wiki, trans-rectal biopsy of the prostate- Mayo clinic

Tissue extraction through solid biopsy is invasive, time consuming and expensive. Liquid biopsy is the alternative option which is the analysis of bio-markers available in a non-solid biological tissue. There are several bio-markers that can be used in liquid biopsy procedures. The following three bio-markers are mainly used for cancer diagnosis applications and Circulating tumor Cells (CTCs) are used in the proposed system.

Figure 2 : Cancer biomarkers

Source: Marrugo-Ramírez J et al. International Journal of Molecular Science 19 (2018)

Circulating tumor cells are rare cells present in the blood of cancer patients. They are shed from both primary and metastatic tumors and are believed to play a key role in cancer progression. CTCs can serve as indicators of metastatic disease and possibly recurrence after surgery in some tumor types. The CTC count has been reported to correlate with overall tumor burden, and hence CTCs have been proposed as a tool for monitoring disease progression and response to therapy. This research is focused on developing a microfluidic device to count the number of CTCs available in a blood sample to predict early cancer risk.

Proposed system

The overall system is designed as a lab on a chip device to be used for cancer diagnosis and risk prediction. This article discuss about the microfluidic circuit design of the LoC device. Three different reservoirs are used to store anti Ep-CAM magnetic beads , Oil and blood. These fluids are controlled through electroosmotic fluid control methods. The antibody conjugated magnetic beads are first incubated with the blood sample that might contain CTCs. The incubation is performed by the use of a micromixer specially designed to obtain the required mixing ration between blood and magnetic beads. Then the blood is directed towards a droplet generator. Oil will act as the continuous phase and the blood droplets are being generated.The fluid parameters and microfludic circuit design parameters are optimized to generate the desired size droplets.

Figure 3 : Overall system

Simulations for system design

Design parameters of the system is optimized through Ansys Fluent and COMSOL Multiphysics simulations

Droplet Generation

A droplet is generated such that if CTCs are available in blood one droplet contains not more than one CTC. Since the average size of a CTC cell is around 20 microns (diameter) the droplet size is optimized to a diameter which is around 30 microns. The blood and oil velocities were changed in order to obtain the required diameter for the blood droplet. The droplet formation is shown in the following video.

Micro mixer

The anti EpCAM magnetic particles should be properly mixed with blood to obtain good results in the separation process. The recommended mixing ratio is around 20:1. The simulation results were optimized by changing the micro-channel design parameters and fluid velocities to obtain the required mixing ratio for the fluids. A scaled up micro mixer design simulation is shown in the video below. The real parameters and design features are further explained in the publication.

Fluid flow control

Fluid velocities were controlled based on electroosmotic flow control techniques. Depending on the potential difference and the material used fluid velocities were controlled to match the requirements. Figure 4 illustrates the results of the electroosmotic simulation done in COMSOL Multiphysics.

Figure 5 : Electroosmotic Simulations

Results

Based on the required velocities to generate the desired size droplet the dimensional parameters of the microfluidic circuit was optimized. The finalized dimensional parameters of critical sections of the fluid circuit are as illustrated in Figure 6.