Hsiao-Ting Hsueh

A CMOS Cantilever-Based Label-Free DNA SoC With Improved Sensitivity for Hepatitis B Virus Detection

This paper presents a highly-integrated DNA detection SoC, where several kinds of cantilever DNA sensors, a readout circuit, an MCU, voltage regulators, and a wireless transceiver, are integrated monolithically in a 0.35 μm CMOS Bio-MEMS process. The cantilever-based biosensors with embedded piezoresistors aim to transduce DNA hybridization into resistance variation without cumbersome labeling process. To improve detection sensitivity for low DNA concentration use, an oscillator-based self-calibrated readout circuit with high precision is proposed to convert small resistance variation ( of original resistance) of the sensor into adequate frequency variation and further into digital data. Moreover, its wireless capacity enables isolation of the sample solution from electrical wire lines and facilitates data transmission. To demonstrate the effectiveness of full system, it is applied to detect hepatitis B virus (HBV) DNA. The experimental results show that it has the capability to distinguish between one base-pair (1-bp) mismatch DNAs and match DNAs and achieves a limit of detection (LOD) of less than 1 pM.

A fully integrated hepatitis B virus DNA detection SoC based on monolithic polysilicon nanowire CMOS process

Polysilicon nanowire (poly-Si NW) based biosensor is integrated with the wireless acquisition circuits in a standard CMOS SoC for the first time. To improve detection quality, a chopper DDA-based analog front-end with features of low noise, high CMRR, and rail-to-rail input range is implemented. Additional temperature sensor is also included to compensate temperature drift of the biosensor. The results indicate that the detection limit is as low as 10fM. The capability to distinguish one base-pair mismatched DNAs is also demonstrated.

21.6 A smart CMOS assay SoC for rapid blood screening test of risk prediction

Rapid blood test is essential to disease control, risk assessment and point-of-care testing. Conventional enzyme-linked immunosorbent assay (ELISA) requires several hours or even days to get meaningful results. However, to some fierce contagious diseases, such as Ebola and SARS, the contagion can spread so fast that an instant and massive screening test is needed. A CMOS assay system-on-chip (SoC) offering a fast and cheap disease screening tool can be very helpful in the place where the medical resources are limited and the test is too costly to afford. Unlike the previously proposed CMOS biomolecular detection based on direct detection [1], a sandwiched assay detection protocol is adopted in this work, which possesses high sensitivity, high specificity and is free from pre-purified antigen process. As shown in Figure 1, a human blood sample containing the target biomolecules is applied on the proposed SoC. The test procedure includes blood filtration, biomolecular conjugation, electrolytic pumping, magnetic flushing and detection, automatically controlled by a micro-controller unit (MCU). The biomolecular signal is converted to the electrical signal by a CMOS-based Hall sensor array, as shown in the SEM image of Fig. 21.6.1, where the surface is coated with biomolecular probe. With the integration of the four LEDs and a battery, the detection steps can be indicated, providing an easy self-test point-of-care application.

A Smart CMOS Assay SoC for Rapid Blood Screening Test of Risk Prediction

A micro-controller unit (MCU) assisted immunoassay lab-on-a-chip is realized in 0.35 μm CMOS technology. The MCU automatically controls the detection procedure including blood filtration through a nonporous aluminum oxide membrane, bimolecular conjugation with antibodies attached to magnetic beads, electrolytic pumping, magnetic flushing and threshold detection based on Hall sensor array readout analysis. To verify the function of this chip, in-vitro Tumor necrosis factor- α (TNF- α) and N-terminal pro-brain natriuretic peptide (NT-proBNP) tests are performed by this 9 mm 2-sized single chip. The cost, efficiency and portability are considerably improved compared to the prior art.

A capacitive immunosensor using on-chip electrolytic pumping and magnetic washing techniques for point-of-care applications

This work presents a capacitive immunosensor using on-chip electrolytic pumping and magnetic washing techniques. The proposed device possesses the advantages such as simple operation, low power consumption, and portability. The proposed device was fabricated using typical micromachining process, and is suitable for mass-production. We also demonstrated the detection of N-Terminal pro-brain-Type natriuretic peptide (NT-proBNP) using the fabricated device integrated with a CMOS capacitance sensing chip. The proposed device potentially can be used as a portable system for point-of-care applications.

Sub-fM DNA sensitivity by self-aligned maskless thin-film transistor-based SoC bioelectronics

This is the first study to successfully achieve record DNA sensitivity (sub-fM) by self-aligned, maskless, dual-channel, and metal-gate-based thin-film transistor nano-wire FET. Both novel device architecture (dual-channel) and optimization of integration processes (microcrystalline silicon and self-aligned sidewall sub-50 nm critical dimension) of nano-wire FET enhance the sensitivity to biological entities substantially. Meanwhile, the proposed device is accomplished with an embedded VLSI CMOS circuit. It can thus offer high application potential to pH, protein, and DNA probing in SoC-based portable bioelectronics.

A parylene micropipette array for enabling simultaneous detection of different target analytes on a CMOS sensor array

This study reports a 4×1 parylene micropipette array for locally and selectively functionalizing the surface of a CMOS-based hall sensor array with different capture antibodies. The proposed device is the key to enable simultaneously detecting different target analytes in a sample solution on a SoC chip. The proposed parylene micropipette array was fabricated by using the embedded parylene channel fabrication process. Experiment results showed the micropipette can locally functionalize capture antibodies on the top of individual Hall sensors, and the functionalized magnetic beads can be effectively captured and detected by the hall sensors.

Low-cost and ultra-sensitive poly-Si nanowire biosensor for Hepatitis B Virus (HBV) DNA detection

Based on the improvements of the fabrication technologies, the dimension of the device has decreased to tens of nanometer. This scale approaches to most bio-molecules, such as DNAs and proteins. Therefore, the nano-scale device has become an important connection between semiconductor technologies and biomedical applications. However, few of previous studies consider the feasibility to integrate standard CMOS chip with biomolecular detections. In this work, we demonstrated a Hepatitis B Virus (HBV) DNA detection sensor with CMOS-compatible poly-silicon nanowire devices. The developed biosensor shows the detection limit with 100fM and the capability to distinguish 1 base-pair mismatched DNA. In addition, the design concept of this biosensor has been implemented in DNA biomolecular detection SoC by a commercialized 0.35μm TSMC process. This work demonstrated the potential of CMOS technologies in biomedical applications.