24.6 A CMOS micro-flow cytometer for magnetic label detection and classification

Abstract

Flow cytometry is widely used in medicine for hematology, immunology, chemotherapy and pathology, as well as in food and water safety. While present instruments are predominantly used in laboratory environments, there is a growing and unmet need for devices that can be used in point-of-care (PoC) settings. The main impediments to PoC solutions are the fluorescent labels, which require sophisticated sample pre-processing and calibration to reduce background, and optics that are difficult to miniaturize. Label-free approaches such as reported in [1] eliminate this problem but have limited applications due to a lack of specificity. Substituting magnetic labels avoids this limitation and eliminates the need for preprocessing, but present solutions use μHall sensors [2] or giant-magneto-resistors (GMRs) [3], which are not available in standard CMOS technology. CMOS LC-tank spectrometry [4] is amenable to integration but does not achieve the bandwidth and sensitivity required for flow cytometry. In this paper, we present a magnetic flow cytometer integrated in standard CMOS technology assembled in a single-use microfluidic cartridge that meets all the above-mentioned requirements.Many applications require differentiation between multiple biomarkers. Optical instruments employ fluorescent labels that fluoresce at different wavelengths to accomplish this. Magnetic labels with superparamagnetic nanoparticles (SPNPs) embedded in a polymer matrix exhibit frequency-dependent complex susceptibility. At low frequency, the susceptibility depends both on size and material composition, but at frequencies beyond 1GHz the material properties dominate [5]. For example, at 2GHz the phase of the susceptibility of iron oxide and cobalt differ by about 60 degrees. Therefore, variations of the complex susceptibility of SPNPs with different material compositions can be used to distinguish between label classes independent of label count or signal strength.Figure 24.6.1 shows the magnetic sensor consisting of a primary excitation coil with embedded secondary pickup coils. The primary excitation coil generates about 0.35mT of magnetic flux density. The secondary coil consists of two pick-up coils each with area 30×30μm 2 . Magnetic labels passing over either of them modulate the flux coupling between the primary and secondary coils, generating a pulse at the output as shown in the figure. A twisted pair interconnect carries the signal from the pick-up coils to the receiver. A center tap of the secondary coil provides the bias voltage to the input transistors of receiver circuit. Coupled quadrature oscillators (QOSC) excite the primary of the sensor and a dummy to generate both in-phase and quadrature signals for demodulation [6].Figure 24.6.2 shows the architecture of the chip along with off-chip postprocessing circuitry. Each arm of the QOSC is biased at 4mA to ensure adequate signal swing for the mixer. The negative transconductance (< -25mS) of the cross-coupled transistors is sufficient to sustain oscillation even in presence of the los...

A Magnetic Flow Cytometer With Integrated Microfluidics

“…The measured bipolar response of the chip to Dynabeads is shown in Figure 9. The measured response to labeled cells is presented in [2]. The throughput of the system is 50 beads/s or 20 labeled cells/s, which is comparable to the point-of-care flow cytometer described in [1].…”

“…For clarity, the GHz modulation is omitted from the graph. Demodulation occurs on-chip with a synchronous quadrature receiver [2].…”

“…In this paper, we present a flow cytometer that uses magnetic labels and a custom CMOS integrated circuit for self-contained detection. Details of the electronic circuit design are presented in [2]. This paper describes the theory of operation and microfluidic integration.…”

Analysis and Design of Coupled Inductive Bridges for Magnetic Sensing Applications

“…Frequency shift oscillators [6] are compact and have the highest sensitivity, but suffer from oscillator long-term drift [7], [8]. Integrated transformers, on the other hand [9], [10], are more suitable for cell sorting applications but use additional tuning inductors to achieve their required single-bead sensitivity. In addition, the physical implementations of these systems rely on an intuitive approach, often with only qualitative prediction of performance metrics.…”

A portable battery powered microfluidic impedance cytometer with smartphone readout: towards personal health monitoring

“…Also, digitizing the analog output of the sensor, which is a small peak carried on a baseline signal which drifts randomly with time, requires a very high resolution and high-end analog-to-digital converter. In the literature, various analog LIA chip architectures have been presented including designs using a single supply, a decrease in supply voltage and power consumption, a reduction in chip area, and exploitation of new architectures to improve performance (Marschner et al 2009;Gnudi et al 1999;Azzolini et al 2008;D'Amico et al 2010;Lee et al 2012;Manickam et al 2012;Kassanos et al 2013;Kassanos et al 2014;Murali et al 2014;Huang and Palermo 2013;Mayahernández et al 2014;Gu and Mcfarlane 2015). Various integrated LIA chips have been developed with a power consumption as low as 207.7 μW (Gu and Mcfarlane 2015) and areas as small as 0.013 mm 2 (Maya-hernández et al 2014).…”