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A CMOS Cantilever-Based Label-Free DNA SoC With Improved Sensitivity for Hepatitis B Virus Detection
Yu-Jie Huang, Che-Wei Huang, Tsung-Hsien Lin, Senior Member, IEEE, Chih-Ting Lin, Li-Guang Chen, Po-Yun Hsiao, Bi-Ru Wu, Hsiao-Ting Hsueh, Bing-Jye Kuo, Hann-Huei Tsai, Hsin-Hao Liao, Ying-Zong Juang, Chorng-Kuang Wang, Fellow, IEEE, and Shey-Shi Lu, Senior Member, IEEE

AbstractThis 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 m 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 selfcalibrated readout circuit with high precision is proposed to convert small resistance variation (0 6
0 02% 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. Index TermsCantilever, DNA SoC, hepatitis B virus, label-free, oscillator-based.

I. INTRODUCTION

EOXYRIBONUCLEIC acid (DNA) detection is an important analytical method in molecular biology, and it nds a wide range of applications from genetic disease diagnostics, medicine and drug discovery, to forensic investigation and food testing, etc. To date, optical detection method [1], [2] based on the use of uorescent labels attached to the target DNA is still the most common way adopted in labs. Many robust commercial products [3] are already available to customers for DNA/RNA

Manuscript received April 01, 2012; revised October 25, 2012; accepted January 27, 2013. This work was supported in part by the National Science Council (NSC) of R.O.C., Taiwan, under Contract NSC100-2221-E-002-247-MY3, and in part by the Ministry of Economic Affairs under Contract MOEA98-EC-17-A-07-S2-0123. This paper was recommended by Associate Editor K. Shepard. Y.-J. Huang, C.-W. Huang, T.-H. Lin, C.-T. Lin, L.-G. Chen, P.-Y. Hsiao, B.-R. Wu, B.-J. Kuo, C.-K. Wang, and S.-S. Lu are with the Graduate Institute of Electronics Engineering, National Taiwan University, Taipei 10617, Taiwan (e-mail: thlin@cc.ee.ntu.edu.tw; timlin@ntu.edu.tw; sslu@ntu.edu.tw). H.-T. Hsueh is with the Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan. H.-H. Tsai, H.-H. Liao, and Y.-Z. Juang are with the National Chip Implementation Center, National Applied Research Laboratories, Hsinchu 30078, Taiwan. Color versions of one or more of the gures in this paper are available online at http://ieeexplore.ieee.org. Digital Object Identier 10.1109/TBCAS.2013.2247761

analysis with high detection sensitivity. However, it suffers from many drawbacks, such as complex uorescent labeling process, time consuming, and high cost. Moreover, the necessary optical scanner system which comprises light sources, cameras, and lenses, etc. is normally bulky and hence inappropriate for rapid point-of-care testing (POCT) and outdoor applications. In recent years, with advancement of semiconductor technology, development of the electric DNA chips in complementary metal-oxide semiconductor (CMOS) technology has appeared. A fully electronic CMOS DNA sensor chip was presented [4] based on an electrochemical redox-cycling detection principle. There, the enzyme labels attached to the target molecules would react with suitable chemical substrates, and hence electrochemically redox-active compounds are formed to induce a measurable electron current. Instead of enzyme labeling, a similar electrochemical detection method by using intercalators was presented in 2006 [5]. The intercalators will specically connect with the double-stranded DNA molecules. Then electric current caused by the oxidization of intercalators can be observed. Furthermore, a CMOS uorescent-based biosensor [6] and a CMOS magnetic-based biosensor [7] have also appeared for DNA detection. Through the integration of the DNA microarray and electronic circuits in a single CMOS chip, these CMOS DNA chips possess several advantages, such as small size, low cost, reduced interference, and easy signal processing/analysis and hence open the possibility to allow access to new elds of application. However, additional time-consuming labeling steps or extra intercalators are still required for the target DNA molecules. To avoid cumbersome labeling process, a number of approaches are proposed [8], [9] for label-free bio-molecular detection. Most of them are also realized in CMOS technology based on capacitance measurement [10], electrical current [11][13], impedance spectroscopy [14], [15], and electrochemical detection using ion-sensitive eld-effect transistors (ISFETs) [16], [17]. The ISFET type DNA sensor is attractive for its easy implementation in standard CMOS process. However, a power-hungry heater, a large reference electrode, and stable environment are needed because ISFET is sensitive to temperature and potential hydrogen (pH) value. To fulll all the requirements addressed above, in this paper, we report a fully-integrated CMOS DNA detection system-on-a-chip (SoC) [18], where cantilever-based DNA sensors and the related detection circuitry are monolithically

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Fig. 1. Cross-section view of the micro-cantilever DNA sensor.

integrated. It can be used to perform label-free DNA detection with features of high sensitivity, small size, low cost, and great stability. Also, its wireless capacity enables isolation of the sample solution from electrical wire lines and facilitates data transmission. It can be remotely controlled to avoid contaminants and man-made interference from various operators. In the following sections, the structure, the extended fabrication process, and the sensing mechanism of the cantilever DNA sensor are introduced rst in Section II. Then the system architecture and the detailed design of the sub-circuits are illustrated in Section III. To demonstrate the effectiveness of full system, some experimental results of detection of two DNA sequences (20-mers DNA and hepatitis B virus DNA) are shown in Section IV. Finally, a conclusion will be given in Section V. II. CANTILEVER DNA SENSOR A. Structure and Fabrication Fig. 1 draws the cross-section view of the integrated polysilicon micro-cantilever DNA sensor. layer embedded in this sensor functions as a pizeoresistor. Some single-stranded DNA receptor molecules with predened sequence are immobilized on the top surface of the sensor to capture target DNA molecules. They are called probe DNAs here. To further improve the immobilization of these probe DNAs, the gold (Au) layer is chosen as the top surface material because it has been proved that the thiol-modied bio-molecules can be reliably bound to it [19]. Furthermore, the Au layer has excellent biocompatibility and stability so that it could be robust against surrounding changes when immersed into buffer solution and could withstand repetitive DNA detection and cleaning cycles. This device is fabricated in the CMOS Bio-Microelectromechanical Systems (Bio-MEMS) platform [20], which is based on two-poly four-metal (2P4M) CMOS technology followed by micromachining post-processing steps. Fig. 2 illustrates the detailed post-processing steps, which are developed by National Chip Implementation Center (CIC, Taiwan) and are described as follows: a) etching off the passivation layer over the layer (intersensor area; b) removing the silicon dioxide layer dielectric) surrounding the dened micro-cantilever by dry etching technology; c) depositing the Au layer on the top of the micro-cantilever by liftoff method; and d) releasing micro-cantilever structure by removing the underneath silicon substrate

Fig. 2. Post-processing steps.

Fig. 3. SEM images of the CMOS cantilever DNA sensors.

Fig. 4. Sensing mechanism of CMOS DNA cantilever sensor.

using dry etching technique. Here, the rst (M1) or second metal layer (M2) is adopted as an etching stop to decide the thickness or of the micro-cantilevers. The scanning electron microscope (SEM) images of the complete micro-cantilevers are shown in Fig. 3. In addition, several kinds of cantilever structures with the same intrinsic resistance are realized in this chip in order to nd out which structure has the best performance. An analog multiplexer with 39.5 ohm on-resistance connects these sensors to the readout circuit one at a time for individual sensor measurement. The effect of this on-resistance can be calibrated by our self-calibration readout circuit and will not affect the performance of this DNA sensor. B. Sensing Mechanism The sensing mechanism of the DNA cantilever sensor relies on the embedded polysilicon piezoresistor which acts as a physical transducer. As shown in Fig. 4, when the target DNA

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HUANG et al.: A CMOS CANTILEVER-BASED LABEL-FREE DNA SOC WITH IMPROVED SENSITIVITY FOR HEPATITIS B VIRUS DETECTION 3

Fig. 5. Block diagram of the proposed DNA detection SoC.

contains a sequence which matches that of the immobilized probe DNA on the surface of the sensor, hybridization process will occur and then induce the change of surface stress [21]. Such stress change causes the cantilever mechanical bending and therefore alters the resistance of the embedded piezoresistor. In this way, the specic DNA detection can be achieved by using electronic circuits to extract the resistance variation of the piezoresistor. III. SYSTEM ARCHITECTURE A. Circuit Blocks Fig. 5 depicts the system block diagram of the proposed wireless DNA detection SoC, in which cantilever DNA sensors, a self-calibrated readout circuit, a programmable microcontroller unit (MCU), voltage regulators, and an on-off keying (OOK) transmitter/receiver (TX/RX) are monolithically integrated. To signicantly reduce the average overall power consumption, normally, the chip operates in power-saving standby mode, which means only the wireless receiver and part of the MCU are intermittently turned on to catch wireless command signals from mobile devices, such as laptops. After receiving command signals, the OOK receiver will amplify and demodulate them into digital data. Then, these data will be sent to the MCU to dene systematic parameters and further activate the system into readout mode. In readout mode, the other parts of the system are awaked, whereas the receiver is turned off. Small resistance variation of the cantilever DNA sensor is transformed to adequate frequency variation by our proposed readout circuit rst. Then this frequency variation will be converted to digital code by the following frequency-to-digital (F-to-D) converter. After packaged in RS232 format by MCU, this digital data will be modulated to OOK wireless signals by the on-chip transmitter and then be transmitted to the mobile devices. B. Oscillator-Based Self-Calibrated Readout Circuit The purpose of the readout circuit is to recognize the resistance difference of the cantilever DNA sensor before and after DNA hybridization. There exist numerous approaches to detect
Fig. 6. Architecture and simplied circuits of the oscillator-based self-calibrated readout circuit.

the resistance variation [22][24]. For example, the bridge circuit architecture is traditionally adopted to translate the resistance variation into voltage variation [25]. However, the mismatch within the bridge topology and the offset problems pose severe design difculties. Another sensing topology by monitoring the current through the resistance was also presented to provide wide dynamic range detection [26]. Nevertheless, its precision is not sufcient for our sensor to identify the tiny resistance variation, which is smaller than 0.02% of the original resistance. To detect such small resistance variation, in this work, we propose an oscillator-based self-calibrated readout architecture, as depicted in Fig. 6. It is composed of a sensor-merged oscillator, a buffer, a divider, a mixer, a frequency-to-digital (F-to-D) converter, and a calibration controller. The ring-type oscillator is made of three RC-delay stages with different time constants. The piezoresistive DNA sensor modeled as a variable resistor is embedded in one delay stage, and hence the oscillation period will be linear with it. In particular, for a small resistance variation range, the shift of the oscillation frequency can also be seen as linear with the resistance variation of the piezoresistive DNA sensor. The output swing of the oscillator can be extended to rail-to-rail by an inverter buffer for the following digital circuit. A divider by 4 is connected at the output

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Fig. 8. An example to explain the functionality of the added mixer. Fig. 7. Simulated results of frequency pulling effect.

of the buffer to ensure that the output clock has a perfect 50% duty cycle and to prevent frequency-pulling effect caused at the input of mixer. Without it, by the external clock will shift if they are too the pulling effect from close, which degrades the sensing delity. As the simulated result shown in Fig. 7, the pulling range can be reduced effectively by adding this divider. Then, a simple D ip-op (DFF) acts as a mixer to down-convert the original oscillation frequency with to increase the relative frequency variation. A detailed explanation will be given in the next paragraph. Finally, an 8-bit corresponding to the measured oscilladigital output can be obtained through a F-to-D contion frequency verter (FDC), which is a digital counter used to linearly transfer the period change of oscillation to a digital count. The digital can be derived from the following equation: output

(1) is the initial down-converted frequency where is the frequency variation. (period) before detection, and It should be noted that this FDC digitizes the absolute difference of the oscillation frequency before and after hybridization. Therefore, for either positive or negative response signals, our sensor system is capable of processing them. An example is shown in Fig. 8 to explain the functionality of the added mixer. We assume the original divided oscillation is 10 MHz here for easy calculation. After frequency DNA hybridization, very small resistance variation (0.02%) of the piezoresistive DNA sensor will occur and therefore lead to an oscillation frequency shift of 2 kHz at the divider output . Compared with the original oscillation frequency of 10 MHz, this frequency shift is relatively much smaller, which complicates the following frequency discrimination. In view of it, a down-conversion mixer is added behind the oscillator. (9.9 MHz), the oscillation By down-conversion with frequency before DNA hybridization changes from original

10 MHz to 100 kHz, whereas the frequency shift caused by DNA hybridization keeps the same, which means that the relative frequency variation is equivalently amplied by 100 times. Therefore, the design constraint can be considerably relaxed. is designed to be around In our actual work, ), the divided fre24 MHz (sensor resistance is around quency is around 6 MHz, and the down-converted output is chosen at 200 kHz. The output frequency is frequency then digitized by the frequency-to-digital converter (FDC) with 8-bit resolution. The counting clock of the FDC is adjustable to be accommodated to various applications with different minimum frequency variation. Therefore, this readout circuit is frequency shift (1.2 kHz) caused capable of detecting of the designed DNA by estimated resistance variation sensor. The oscillator-based readout architecture eliminates the need of an analog-to-digital converter (ADC) as the FDC , is already in digital format. Also, to compensate output, for process-voltage-temperature (PVT) variations, a self-calibration mechanism is adopted, as depicted in Fig. 6. During would be calibration, the down-converted frequency adjusted by tuning the capacitor array codes, to alter the RC time constant of the delay stage. Along the process, the FDC output would converge to a pre-determined around target code, which corresponds to a calibrated 200 kHz before experiments. In this design, the effect of rapid temperature change during detection process should be taken into consideration because both the peizoresistive sensor and the oscillator-based readout are temperature-sensitive. According to the simulation result, the expected temperature sensitivity of this sensor-embedded , which means only temperreadout is ature change could yield the same output signal as one from 0.6 ohm variation and hence results in false detection. In view of it, it is necessary to add an extra precise temperature sensor in our system to calibrate this false shift for real-life use. C. Programmable Micro-Controller Unit (MCU) Fig. 9 shows the block diagram of the designed programmable micro-controller. The core of microcontroller is a central processing unit (CPU) and its instruction set is similar to that of the commercial peripheral interface controller (PIC)

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HUANG et al.: A CMOS CANTILEVER-BASED LABEL-FREE DNA SOC WITH IMPROVED SENSITIVITY FOR HEPATITIS B VIRUS DETECTION 5

Fig. 10. Schematic of the OOK receiver.

Fig. 9. Block diagram of the MCU.

CPU to avoid long developing time for the compiler of this CPU. This microcontroller is based on reduced instruction set computing (RISC) architecture and uses 4 clocks to form an instruction cycle. With 8-bit data buses and 14-bit program buses, it equips a 256-word data static random access memory (SRAM), a 2 k-word a program SRAM, and an 8-level stack. The peripheral includes an universal asynchronous receiver/transmitter (UART), a serial peripheral interface (SPI), a watch dog, and two timers. The basic function of UART is performing the data transformation between serial format and parallel one. However, in order to be applied to wireless communication, the UART must provide additional abilities. For example, to increase the accuracy of data recovery, each input bit is over-sampled eight times. The value of each sampled bit can be determined based on the majority of the over-sampled values (high or low) in the register. Besides, a cyclic redundancy checks (CRC) function is also designed for error detecting. There are four proprietary commands to operate the MCU in four system states: Idle, Convert, Transmit, and Continue. The Idle command asks the MCU to stay idle. In the Convert state, the MCU sends an active signal to start the operation of the FDC. The FDC will sample the analog signal only once and convert it into digital data, which are then stored in the data register inside UART. The Transmit command requests the MCU to transmit the data in data register only once by the OOK transmitter. The Continue command asks the MCU to measure and transmit the converted data to the portable device continuously. It should be mentioned that the RS-232 communication data format is used to communicate with portable devices conveniently. D. OOK Transmitter/Receiver Wireless communication capability is another essential element in portable/disposable microsystems. Generally speaking, the wireless circuitry tends to be more power-hungry than other analog blocks due to its high-frequency operation. For this reason, OOK modulation scheme is chosen to construct a receiver since it does not require power-hungry components such as mixers and voltage-controlled oscillators (VCOs). Also, it allows the transmitter to idle during the transmission of a zero, therefore conserving power. Instead of traditional direct-conversion [27] and super-heterodyne receivers which consume too much power and area, a

Fig. 11. Schematic of the OOK transmitter.

simple envelope detection based OOK receiver [28] is adopted for this application. This receiver is composed of a resistive feedback preamplier, cascaded ampliers, an envelope detector, and a comparator with an output buffer, as shown in Fig. 10. The input impedance of the preamplier is not matched but to high impedance instead. Therefore, an off-chip to coupling circuit is designed for connecting the low-impedance antenna and the high-input-impedance preamplier. The following cascaded ampliers consist of eight stages and provide 60-dB gain in total. Each stage adopts the current reuse technique for better power efciency. Then the signal will be demodulated by the envelope detector, which comprises a diode-connected NMOS transistor and a RC low-pass lter . The transistor size is speciin order to minimize cally large the channel resistance. Finally, a comparator is connected to strengthen the signal magnitude, followed by a buffer further used to convert the demodulated signal to a rail-to-rail format. The OOK transmitter comprises a ring-oscillator, a buffer (source follower), and a class-C power amplier (PA) as depicted in Fig. 11. The carrier signal is generated by the ring oscillator, and the on-off keying modulation is achieved by turning the ring oscillator on and off. The class-C power amplier drives a sinusoidal current through the off-chip inductor, which achieves a narrow band-pass frequency response in conjunction with the parasitic capacitance of the transistors and die pads. To prevent the data-rate degradation, a p-MOSFET switch is parallel-connected with the inductor, which accelerates the voltage decline at the output when the input signal changes from logic one to logic zero [29]. E. Low-Dropout Voltage Regulator In this system, several voltage regulators are included to provide each circuit block with a clean power source. The schematic of the regulator is shown in Fig. 12 and consists of a start-up circuit, a bandgap reference, and an error amplier.

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Fig. 12. Schematic of the low-dropout voltage regulator.

Controlled by the control signal (ON) from the MCU, each regulator would alter between active mode and quiet mode through the added power switches (M1-M5). Therefore, through them, the MCU has the ability to turn on or off each circuit block so as to achieve power management. The function of the bandgap reference is to generate a temperature insensitive voltage that is realized by typical current-mirroring bandgap reference topology. A start-up circuit is implemented to prevent the reluctance of the bandgap reference circuit to the supply voltage. It helps to drag down the gate voltage at the node A right after the supply voltage is applied, so that all transistors of bandgap reference can be biased correctly. The error amplier is based on simple single-ended op-amp architecture. Through negative feedback resistors (R1 and R2), the error amplier will lock the voltage at node B to the reference voltage generated by the bandgap reference. Consequently, an output voltage (VOUT) of the regulator is temperature independent and given by

Fig. 13. Chip micrograph.

TABLE I PERFORMANCE SUMMARY

(2) F. Measured System Performance This SoC is realized in a CMOS Bio-MEMS Process. Fig. 13 shows the chip micrograph of the proposed DNA detection chip, whose die area is . There are 18 micro-cantilever DNA sensors with different forms on the chip for investigations of device sensitivity. Although this chip endures necessary post processing to develop our DNA sensors, the integrated circuits still perform without degradation in the experiments. Table I summarizes the measured performance of this DNA detection SoC, and Table II compares this work with other CMOS DNA detection chips [6], [7], [10], [11], [16], [17]. This work exhibits the highest integration level, the smallest detectable DNA concentration of less than 1 pM, and unique wireless capacity among them. IV. EXPERIMENTAL RESULTS The experimental ow is drawn in Fig. 14. First, it takes about 2 hours to immobilize the probe DNAs on the top surface of the sensor before measurement. Then, the DNA sensor is immersed into the phosphate buffered saline (PBS) buffer to initialize the test suite. Next, the match or mismatch DNA sample is injected to hybridize the probe DNA for 15 minutes. After DNA hybridization, most nonspecic binding DNAs are washed away by the PBS buffer for 10 minutes to make sure that the stress change of cantilever is mainly caused by the double-stranded DNA, not by the non-specic binding DNA. Finally, the sensing chamber is dried for 20 minutes to obtain steady signals. The operation temperature in all experiments was at room temperature controlled by a temperature conditioner.

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TABLE II COMPARISON WITH THE PRIOR ARTS

Fig. 14. Designed experimental ow.

A. Preliminary Test To examine the accuracy and specicity of this chip, a preliminary test is performed rst. Here, 5 thiol-modied DNA sequence (5-HS-ATAGGTCGGTAGGTGAATGG-3) is chosen as the experimental probe DNA and immobilized on all-match DNA sample the DNA sensor rst. Then the (5-CCATTCACCTACCGACCTAT-3) and the all-mismatch DNA sample (5-GGTAAGTGGCGAGTTGGATA-3) are used as the target DNAs to be injected individually. The measured characteristics of frequency variation versus time are shown in Fig. 15, where black squares and red circles represent mismatch and match DNAs, respectively. Phosphate buffered saline buffer (PBS only) acts as the no-DNA control . In here to generate an initial-state oscillation frequency Wash State, the sensor experiences several times washing and produces relatively unstable signals due to environmental uctuations. As seen in Fig. 15, the frequency goes up for the match DNA from Initial State to Wash State, while it goes down for the mismatch DNA. This phenomenon might be caused by three possible reasons. First, the cantilever biosensors are tested in the open environment. Thus, the ion concentration
Fig. 15. Temporal responses of frequency variation for match and mismatch DNA conditions.

of the buffer may increase due to evaporation of the buffer solution. This evaporation and condensation phenomena will affect the stability of our cantilever sensors and the bio-molecules. Second, there are many particles, such as DNAs and ions, in the liquid environment. These particles would hit the cantilever sensors because of the electric eld and cause uncertain signals. Third, the piezoresistor is embedded at the bottom layer of the cantilever and hence is exposed to liquid environment. The resistance of the piezoresistor might be affected by the unstable ion concentration of the buffer. All these inuences are mostly attributed to the liquid buffer solution. This is also why we dry our sensors before steady-state measurement. Generally, this temporally unstable characteristic can be ignored if unbound particles are totally removed and the sensors are perfectly dried after washing procedure. The frequency shift between the Initial State baseline and the stable Steady State can be

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Fig. 17. Short-term Allan deviation according to the experimental data. Fig. 16. Temporal responses of frequency variation for match DNA with different concentrations.

interpreted as the change before and after DNA hybridization. As a consequence, the frequency change is about 112 kHz for match target DNA and is about 50 kHz for mismatch target DNA. Obviously, the frequency variation caused by the match DNA is larger than the mismatch DNA, which demonstrates unequivocally the sensing capability of the developed DNA SoC. It should be noted that the 50 kHz frequency change in mismatch sample is resulted from the non-specic binding of mismatch DNAs and can be seen as an interference noise. Normally, non-specic binding phenomenon happens infrequently in match DNA experiments. Therefore, under the same concentration, as long as the positive signal caused by the match DNA is larger than the non-specic binding noise of mismatch DNAs, then this noise can be ignored or eliminated by post signal process. This unwanted effect can be also alleviated by some previously proposed techniques [30]. Fig. 16 shows the experimental results when two match DNA ) samples with different DNA concentrations (100 pM and are added in this test to observe the difference. As a result, are induced by 40 kHz and 16 kHz frequency changes and 100 pM DNA, respectively. Thus, this DNA chip could recognize different concentrations of DNA from 100 pM . It should be emphasized that, to prevent the unwanted to effect due to saturation of DNA binding, the hybridization time shown here is designed to be about three times shorter than that in Fig. 15. According to previous researches [31], [32], the extent of the hybridization, and hence the sensitivity of the sensor, are strongly dependent on the hybridization time before saturation of binding. Therefore, the frequency variation (40 kHz) for match DNA here is also about three times smaller than that (112 kHz) in Fig. 15. Furthermore, to determine the resolution of this system, the analysis of the short term stability (noise oor) is further carried out according to the steady-state data from this practical experiment. As depicted in Fig. 17, the in practical experimental conshort-term Allen deviation at the averaging time of 160 secditions reaches to onds, which means the smallest frequency deviation that can be

Fig. 18. Frequency variation for different cantilever sensors in this chip.

detected in presence of noise is equal to 395 Hz [33]. Therefore, the useful measurement resolution limit of the proposed oscillator-based readout is about 395 Hz, which also is about 1.2 kHz declares that the limit of detection (0.02% frequency variation). In this work, several sensors with different structures are designed for sensitivity investigation, and the measured results are shown in Fig. 18. The geometry and the detailed information of all the designed cantilever sensors are also depicted in Fig. 19. Theoretically, a cantilever with smaller spring constant (larger L/W) will potentially possess higher sensitivity [34]. However, after our sensors experience structure releasing from the CMOS substrate, different initial bending of the cantilevers due to different residual stress can be observed. It will make a great impact on the performance of all the sensors, such as initial resistance ( frequency) and sensitivity. From our observation, the sensor with C10 structure is usually atter than other ones after structure releasing, which means it has lower residual stress. For this reason, although C10 does not has the smallest spring constant, it shows the best performance than other cantilevers, as can be seen in Fig. 19. Hence, the experimental data presented in other parts are also based on C10 cantilever structure. Besides, it should be noted that some measured frequency variation data shown in Fig. 18 go in opposite direction. It could be caused by difference residual stress and/or different target sequences (match and mismatch DNA) [35], [36]. The Fig. 20(a) shows the measured digital data through wireless transmission for match and mismatch DNA conditions. It

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Fig. 21. Measured divided frequency for different target DNA sequences before and after DNA hybridization.

Fig. 19. Detailed information of the designed cantilever sensors in this chip.

Fig. 22. Frequency variation ratio for match HBV DNAs with different concentrations (1 pM, 100 pM, and 10 nM). Fig. 20. (a) Measured digital data for match and mismatch DNA conditions. (b) Spectrum of the transmitter output. (c) Waveforms of the transmitted data and the recovered data displayed in the oscilloscope.

reveals the corresponding result to the frequency variation in Fig. 15. The output power of the wireless transmitter is about at 402 MHz MICS band, as shown in Fig. 20(b). Also, the waveform in Fig. 20(c) shows that the measured data could be transmitted wirelessly through OOK modulation and be recovered successfully by the receiver. B. HBV DNA Detection HBV infection is a common health problem and affects around 350 million people worldwide. Therefore, in order to demonstrate the practical value of this SoC, we further apply it to detect hepatitis B virus (HBV) DNA. In this experiment, the HBV probe (5-SH-CCGATCCATACTGCGGAAC-3) and several kinds of target DNA oligonucleotides were purchased from Genomics, Taiwan, to test the selectivity of our chip. The sequences of the experimental target DNA molecules are all-match (5-GTTCCGCAGTATGGATCGG-3), one base pair (1-bp) mismatch (5-GTTCCGTAGTATGGATCGG-3), 3-bp

mismatch (5-GTTCCGTGATATGGATCGG-3), and all-mismatch (5-ACCTTATCTACCTACCTAT-3), respectively. Fig. 21 depicts the measured divided frequency for different target DNA sequences before and after DNA hybridization. It can be seen clearly that the frequency difference of the all-match DNA is much larger than the others. Therefore, it has the capability to distinguish between one base-pair (1-bp) mismatch DNAs and match DNAs. Fig. 22 shows the frequency variation ratio for match HBV DNAs with different concentrations (1 pM, 100 pM, and 10 nM) for evaluating detection sensitivity. As mentioned above, the PBS buffer acts as our no-DNA control and also represents the initial-state oscillation frequency for each concentration. As can be seen, this chip can cover detection concentration range of specic HBV DNA from 1 pM to 10 nM, and the frequency variation ratio is almost linear with the log-scale DNA concentration. The error bar drawn here is calculated by standard error of the mean (SEM), along with 5 pieces of sensor samples for each concentration. It is noteworthy that the measured frequency variation ratio of 1 pM HBV DNA sample is about 0.9%, which is larger than our estimated frequency detection limit (0.02%). Therefore,

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the limit of detection (LOD) of this chip could reach less than 1 pM based on our measured results. It also suggests that the developed DNA detection SoC will be applicable for most clinical applications. C. Practical Issues The effect of the nonspecic binding is a critical issue for real-life bio-molecule detection applications. It can be seen as an interference noise to the detection system and should be suppressed in practical use. This effect can be alleviated by some previously proposed techniques. For example, some blocking agents or antifouling agent [30] can be pre-applied to the sensor chamber to prevent subsequent unspecic binding. Also, more effective washing step before readout can sometimes improve selectivity. These techniques will be added into next-generation systems to enhance the selectivity. Also, there is a trade-off between selectivity and the complexity of sample preparation. In fact, it is nearly impossible to guarantee no nonspecic binding in real-world applications. In view of it, some restrictions or notes should be stated in user guides before someone starts to use this sort of devices. Take our system for instance. Before it can be really used in real life, it should be tested under many situations and worst cases, such as many kinds of DNA sequences, unequal measurement time, different concentrations, various buffers, and large temperature variation, etc. Then a mapping table and some notes, which include highest tolerant concentrations of interferences with degree of accuracy, the limit of detection of analytes, recommended buffers, and operation period, will be provided for users. Therefore, when applying our system for different DNA discrimination, in order to get higher accuracy, it is better to know the rough concentration range of the target DNAs and the containments, just like the range from 1 pM to 10 nM in our experiment. V. CONCLUSION In this paper, a fully-integrated CMOS DNA detection SoC is successfully realized in a CMOS Bio-MEMS process. Peizoresistive cantilever sensors created by post processing enable label-free DNA detection. Thanks to the ability to amplify relative frequency variation, the proposed oscillator-based selfcalibration readout could convert very small resistance variation , 0.02% variation) caused by DNA hybridization into suf( cient frequency variation and hence effectively improves the sensitivity of DNA detection. The experimental results show that, for HBV DNA detection, the chip can successfully distinguish between one base-pair (1-bp) mismatch DNAs and match DNAs, and the limit of detection (LOD) of this chip could reach less than 1 pM. Consequently, with features of label-free detection, high sensitivity, small size, low cost, and wireless ability, this SoC is applicable for rapid point-of-care testing (POCT) and most clinical applications. ACKNOWLEDGMENT The authors would like to thank the National Chip Implementation Center (CIC), Taiwan, for chip fabrication.

REFERENCES
[1] DNA Microarrays: A Practical Approach, M. E. Schena, Ed., 1st ed. Oxford, U.K: Oxford Univ. Press, 2000. [2] G. C. Kennedy et al., Large-scale genotyping of complex DNA, Nature Biotechnol., vol. 21, no. 10, pp. 12331237, Sep. 2003. [3] R. A. Irizarry, B. M. Bolstad, F. Collin, L. M. Cope, B. Hobbs, and T. P. Speed, Summaries of affymetrix genechip probe level data, Nucleic Acids Res., vol. 31, no. 4, 2003. [4] M. Schienle, C. Paulus, A. Frey, F. Hoffmann, B. Holzap, P. Schindler-Bauer, and R. Thewes, A fully electronic DNA sensor with 128 positions and in-pixel A/D conversion, IEEE J. Solid-State Circuits, vol. 39, no. 12, pp. 24382444, Dec. 2004. [5] N. Gemma, S. Ouchi, H. Funaki, J. Okada, and S. Hongo, CMOS integrated DNA chip for quantitative DNA analysis, in Proc. IEEE Int. Solid-State Circuits Conf., Dig. Tech. Papers, 2006, pp. 560561. [6] B. Jang, P. Cao, A. Chevalier, A. Ellington, and A. Hassibi, A CMOS uorescence-based biosensor microarray, in Proc. IEEE Int. SolidState Circuits Conf., Dig. Tech. Papers, 2009, pp. 436437. [7] H. Wang, Y. Chen, A. Hassibi, A. Scherer, and A. Hajimiri, A frequency-shift CMOS magnetic biosensor array with single-bead sensitivity and no external magnet, in Proc. IEEE Int. Solid-State Circuits Conf., Dig. Tech. Papers, 2009, pp. 438439. [8] J. Fritz et al., Translating biomolecular recognition into nanomechanics, Science, vol. 288, pp. 316318, Apr. 2000. [9] T. Sakata and Y. Miyahara, Direct detection of single-base extension reaction using genetic eld effect transistor, in Proc. 3rd Annu. Int. IEEE EMBS Special Topic Conf. Microtechnologies in Medicine and Biology, 2005, pp. 219222. [10] C. Stagni, C. Guiducci, L. Benini, B. Ricco, S. Carrara, B. Samor, C. Paulus, M. Schienle, M. Augustyniak, and R. Thewes, CMOS DNA sensor array with integrated A/D conversion based on label-free capacitance measurement, IEEE J. Solid-State Circuits, vol. 41, no. 12, pp. 29562964, Dec. 2006. [11] F. Heer, M. Keller, G. Yu, J. Janata, M. Josowicz, and A. Hierlemann, CMOS electro-chemical DNA-detection array with on-chip ADC, in Proc. IEEE Int. Solid-State Circuits Conf., Dig. Tech. Papers, 2008, pp. 168169. [12] M. Stanacevic, K. Murari, A. Rege, G. Cauwenberghs, and N. Thakor, VLSI potentiostat array with oversampling gain modulation for widerange neurotransmitter sensing, IEEE Trans. Biomed. Circuits Syst., vol. 1, no. 1, pp. 6372, Feb. 2007. [13] C. Yang, Y. Huang, B. L. Hassler, R. M. Worden, and A. J. Mason, Amperometric electrochemical microsystem for a miniaturized protein biosensor array, IEEE Trans. Biomed. Circuits Syst., vol. 3, no. 3, pp. 160168, Jun. 2009. [14] A. Manickam, A. Chevalier, M. McDermott, A. D. Ellington, and A. Hassibi, A CMOS electrochemical impedance spectroscopy (EIS) biosensor array, IEEE Trans. Biomed. Circuits Syst., vol. 4, no. 6, pp. 379390, Dec. 2010. [15] H. Mazhab-Jafari, L. Soleymani, and R. Genov, 16-channel CMOS impedance spectroscopy DNA analyzer with dual-slope multiplying ADCs, IEEE Trans. Biomed. Circuits Syst., vol. 6, no. 5, pp. 468478, Oct. 2012. [16] D. M. Garner, H. Bai, P. Georgiou, T. G. Constandinou, S. Reed, L. M. Shepherd, W. Wong, K. T. Lim, and C. Toumazou, A multichannel DNA SOC for rapid point-of-care gene detection, in Proc. IEEE Int. Solid-State Circuits Conf., Dig. Tech. Papers, 2010, pp. 492493. [17] S.-J. Kim and E. Yoon, Label-free CMOS biosensor with on-chip noise reduction scheme for real-time quantitative monitoring of biomolecules, IEEE Trans. Biomed. Circuits Syst., vol. 6, no. 3, pp. 189196, Jun. 2012. [18] Y.-J. Huang, C.-W. Huang, T.-H. Lin, C.-T. Lin, L.-G. Chen, P.-Y. Hsiao, B.-R. Wu, H.-T. Hsueh, B.-J. Kuo, H.-H. Tsai, H.-H. Liao, Y.-Z. Juang, C.-K. Wang, and S.-S. Lu, A fully-integrated cantilever-based DNA detection SoC in a CMOS bio-MEMS process, in Proc. IEEE Symp. VLSI Circuits, 2011, pp. 5051. [19] M. Hegner, P. Wagner, and G. Semenza, Immobilizing DNA on gold via thiol modication for atomic force microscopy imaging in buffer solutions FEBS, FEBS Lett., vol. 336, pp. 452456, 1993. [20] H.-H. Tsai, C.-F. Lin, Y.-Z. Juang, I.-L. Wang, Y.-C. Lin, R.-L. Wang, and H.-Y. Lin, Multiple type biosensors fabricated using the CMOS BioMEMS platform, Sens. Actuator B, vol. 144, pp. 407412, 2010. [21] G. Wu, H. Ji, K. Hansen, T. Thundat, R. Datar, R. Cote, M. F. Hagan, A. K. Chakraborty, and A. Majumdar, Origin of nanomechanical cantilever motion generated from biomolecular interactions, Proc. Nat. Acad. Sci., vol. 98, pp. 15601564, 2001.

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HUANG et al.: A CMOS CANTILEVER-BASED LABEL-FREE DNA SOC WITH IMPROVED SENSITIVITY FOR HEPATITIS B VIRUS DETECTION 11

[22] N. Lajnef, S. Chakrabartty, N. Elvin, and A. Elvin, Piezo-powered oating gate injector for self-powered fatigue monitoring in biomechanical implants, in Proc. IEEE Int. Symp. Circuits and Systems, 2007, pp. 8992. [23] M. Grassi, P. Malcovati, and A. Baschirotto, A 160 dB equivalent dynamic range auto-scaling interface for resistive gas-sensors arrays, IEEE J. Solid-State Circuits, vol. 42, no. 3, pp. 518528, Mar. 2007. [24] M. Grassi, P. Malcovati, and A. Baschirotto, A 0.1% accuracy 100 ohm-20 mohm dynamic range integrated gas-sensor interface circuit with 13 + 4 bit digital output, in Proc. Eur. Solid-State Electron Circuits Conf., 2005, pp. 351354. [25] J.-B. Begueret, M. R. Benbrahim, Z. Li, F. Rodes, and J.-P. Dom, Converters dedicated to long-term monitoring of strain gauge transducers, IEEE J. Solid-State Circuits, vol. 32, no. 3, pp. 349356, Mar. 1997. [26] M. Grassi, P. Malcovati, and A. Baschirotto, A 141-dB dynamic range CMOS gas-sensor interface circuit without calibration with 16-bit digital output word, IEEE J. Solid-State Circuits, vol. 42, no. 7, pp. 15431554, Jul. 2007. [27] A. Behzad et al., A fully integrated MIMO multiband direct conversion CMOS transceiver for WLAN applications (802.11n), IEEE J. Solid-State Circuits, vol. 42, pp. 27952808, 2007. [28] Y.-T. Lin, T. Wang, S.-S. Lu, and G.-W. Huang, A 0.5 V 3.1 mW fully monolithic OOK receiver for wireless local area sensor network, in Proc. Asian Solid-State Circuits Conf., 2005, pp. 373376. [29] H. Yu and K. Naja, Low-power interface circuits for bio- implantable microsystems, in Proc. IEEE Int. Solid-State Circuits Conf., Dig. Tech. Papers, 2003, pp. 194197. [30] L. A. Ruiz-Taylor, T. L. Martin, F. G. Zaugg, K. Witte, P. Indermuhle, S. Nock, and P. Wagner, Monolayers of derivatized poly(L-lysine)grafted poly(ethylene glycol) on metal oxides as a class of biomolecular interfaces, Proc. Nat. Acad. Sci., vol. 98, no. 3, pp. 852857, Jan. 2001. [31] J. Wang and A.-N. Kawde, Pencil-based renewable biosensor for label-free electrochemical detection of DNA hybridization, Analytica Chimica Acta, vol. 431, pp. 219224, 2001. [32] J. Wang, D. Xu, A. Erdem, R. Polsky, and M. A. Salazar, Genomagneticelectrochemical assays of DNA hybridization, Talanta, vol. 56, pp. 931938, 2003. [33] L. Rodriguez-Pardo, J. Faria, C. Gabrielli, H. Perrot, and R. Brendel, Resolution in quartz crystal oscillator circuits for high sensitivity microbalance sensors in damping media, Sens. Actuators B, vol. 103, pp. 318324, 2004. [34] S. D. Senturia, Microsystem Design. Boston, MA, USA: Kluwer, 2001. [35] K.-M. Hansen et al., Cantilever-based optical deection assay for discrimination of DNA single-nucleotide mismatches, Anal. Chem., vol. 73, pp. 15671571, 2001. [36] S. Zheng, J. H. Choi, S. M. Lee, K. S. Hwang, S. K. Kim, and T. S. Kim, Analysis of DNA hybridization regarding the conformation of molecular layer with piezoelectric microcantilevers, Lab Chip, vol. 11, pp. 6369, 2011. Yu-Jie Huang was born in Kaohsiung, Taiwan, in 1984. He received the B.S. degree in electrical engineering from National Cheng Kung University, Tainan, Taiwan, in 2006. Currently, he is working toward the Ph.D. degree in electronic engineering at National Taiwan University, Taipei, Taiwan. His research interests include CMOS mixed-signal integrated circuit design and system-on-a-chip design for wireless sensing and biomedical applications.

Tsung-Hsien Lin (M03SM09) received the B.S. degree in electronics engineering from National Chiao-Tung University, Taiwan, and the Ph.D. degree in electrical engineering from University of California, Los Angeles, Los Angeles, CA, USA, in 2001. In March 2000, he joined Broadcom Corporation, Irvine, CA, USA, where he was a Senior Staff Scientist, during which time he involved in analog/RF/ mixed-signal circuit design and participated in wireless transceiver developments. In 2004, he joined the Graduate Institute of Electronics Engineering and the Department of Electrical Engineering, National Taiwan University, Taipei, Taiwan, where he is currently a Professor. His research interests are in the design of wireless transceivers, clock and frequency generation systems, delta-sigma modulators, and transducer interface circuits. Dr. Lin was the recipient of the Best Presentation Award for his paper presented at the 2007 IEEE VLSI-DAT Symposium. He was awarded the Teaching Excellence Award from National Taiwan University in 2007, 2008, and 2009. He served on the IEEE Asian Solid-State Circuit Conference (A-SSCC) Technical Program Committee (TPC) from 2005 to 2011 and was the TPC Vice-Chair for 2011 A-SSCC. He was a Guest Editor for the IEEE JOURNAL OF SOLID-STATE CIRCUITS in 2012. He serves on the ISSCC International Technical Program Committee since 2010, and on the IEEE VLSI-DAT TPC since 2011. He is currently an Associate Editor for IEEE JOURNAL OF SOLID-STATE CIRCUITS.

Chih-Ting Lin was born in Taiwan in 1974. He received the B.S. degree in civil engineering and M.S. degree in applied mechanics from National Taiwan University, Taipei, Taiwan, in 1996 and 1998, respectively, and the M.S. and Ph.D. degrees in electrical engineering and computer science from the University of Michigan, Ann Arbor, MI, USA, in 2003 and 2006, respectively. Since September 2006, he has been with the Graduate Institute of Electronics Engineering and the Department of Electrical Engineering at National Taiwan University. His current research interests include bio-MEMS, CMOS bio-chips, nano fabrication, and biomolecular detection technology.

Li-Guang Chen was born in Taipei, Taiwan, in 1987. He received the B.S. degree in electrical engineering and M.S. degree in electrical engineering from National Taiwan University, Taipei, Taiwan, in 2009 and 2011, respectively. His masters thesis focused on low-power and energy-efcient wireless RF transmitters. Currently, he works at the Sitronix Corporation, Taipei, Taiwan, as a Circuit Design Engineer involved with LCD drivers.

Che-Wei Huang was born in Taoyuan, Taiwan, in 1982. He received the B.S. degree from Chang Gung University, Taoyuan, Taiwan, and the M.S. and Ph.D. degrees from National Taiwan University, Taipei, Taiwan, all in electronics engineering, in 2005, 2008, and 2012, respectively. His research interests are CMOS based chemical and biosensor platform technologies.

Po-Yun Hsiao was born in Chia-Yi, Taiwan. He received the B.S. degree in electrical engineering from National Tsing-Hua University, Hsinchu City, Taiwan, and the M.S. degree in electrical engineering from National Taiwan University, Taipei, Taiwan, in 2009 and 2011, respectively. In 2011, he joined the RF department at MediaTek Inc., Taipei, Taiwan. His research interests are in the area of low-power analog circuit design for biomedical applications, and wireless front-end circuit and lter design for cellular applications.

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12 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS

Bi-Ru Wu was born in Yilan, Taiwan. She received the B.S. degree in mechanical engineering from National Central University, Jhongli City, Taiwan, and the M.S. degree in electrical engineering from National Taiwan University, Taipei, Taiwan, in 2008 and 2010, respectively. In 2010, she joined the Raydium Semiconductor Corporation, Taiwan. Her research interest is in the area of digital circuit design.

Hsiao-Ting Hsueh received the B.S. degree in life science from National Taiwan University, Taipei, Taiwan, in 2009. Currently, he is working toward the Ph.D. degree at the Graduate Institute of Biomedical Electronics and Bioinformatics at National Taiwan University. His current research interests are silicon nanowire FET chem/biosensors and organic FET chem/biosensors.

Ying-Zong Juang received the M.S. and Ph.D degrees in electrical engineering from National ChengKung University, Tainan City, Taiwan, in 1992 and 1998, respectively. He joined the Institute of Chip Implementation Center (CIC), Science-Based Industrial Park, Hsinchu, Taiwan, in October 1998. At CIC, he majored in RF circuit design and device modeling works. From 1999 to 2000, he joined a project to create a new process ow to implement BCD devices on the same chip. Currently, he is the Researcher and Department Manager of CISD/CIC. He organized several projects including RF top-down design for front-end system, RF SiP design platform, and 0.35/0.18 CMOS BioMEMS implementation environment. His topics of interest include RF/MEMS module design, CMOS BioMEMS, and mixed-signal design for RF front-ends.

Bing-Jye Kuo was born in Taiwan in 1978. He received the B.S. degree in electronics engineering and the M.S. degree in electronics from National ChiaoTung University (NCTU), Hsinchu, Taiwan, in 2000 and 2004, respectively. Since 2002, he has been with the Nanoelectronics and Gigascale Systems Laboratory at NCTU. In 2004, he joined MediaTek Inc., Hsinchu, Taiwan, as a Design Engineer responsible for the on-chip RF ESD protection circuit design and transmitter circuit design. His research interests include GSM transmitter circuit design and on-chip RF ESD protection circuit design.

Hann-Huei Tsai received the B.S. and M.S. degrees in electrical engineering from National Cheng-Kung University, Tainan City, Taiwan, in 1992 and 1994, respectively. He had worked at Taiwan Semiconductor Manufacturing Company, Hsinchu, Taiwan, as a Process Integration Engineer and Section Manager from 1996 to 2006. He joined the National Chip Implementation Center, Hsinchu, Taiwan, in 2006. His topics of interest topics include CMOS MEMS, CMOS BioMEMS, and high voltage technology.

Chorng-Kuang Wang (M90SM00F08) was born in Taiwan in 1947. He received the B.S. degree in electronic engineering from National Chiao-Tung University, Hsinchu, Taiwan, and the M.S. degree in geophysics from National Central University, Jhongli City, Taiwan, in 1970 and 1973, respectively, and the M.S. and Ph.D. degrees in electrical engineering and computer science from the University of California, Berkeley, Berkeley, CA, USA, in 1979 and 1986, respectively. He has held industrial positions with Itron, New Taipei City, Taiwan (19731977), and National Semiconductor, Rockwell, and IBM, all in California (19791991), where he was involved in the development of CMOS memory, data modems and disk-drive integrated circuits. He acted as a Consultant to the Computer and Communication Research Lab of the Industrial Technology Research Institute (19912000) and an Advisor to the Ministry of Education Advisory Ofce (19972001) in Taiwan. From 1991 to 1998, he was with the Department of Electrical Engineering, National Central University, Jhongli City, Taiwan, where he was a Professor. Since then, he has been a Professor in the Department of Electrical Engineering at National Taiwan University, Taipei, Taiwan. His research interests are in the areas of wireless transceiver system and circuit design, high-speed data link circuits, mm-wave CMOS development, exible electronics, and telemedicine. Dr. Wang has been involved in chairing and launching programs for technical and executive committees of AP-ASIC, A-SSCC and ISSCC. He currently serves as an ex-ofcio member of the SSCS AdCom, a member of the IEEE Donald O. Pederson Award in Solid-State Circuits Committee, and a member of the IEEE Jun-ichi Nishizawa Medal Committee. He was named an IEEE Fellow in 2008 for contributions to communications circuit design and for leadership in promoting the profession.

Hsin-Hao Liao received the B.S. and M.S. degrees in chemical engineering from National Tsing-Hua University, Hsinchu City, Taiwan, in 1996 and 1998, respectively. He worked at the Taiwan Semiconductor Manufacturing Company, Hsinchu, Taiwan, as a Process and Integration Engineer from 2000 to 2009. He joined the National Chip Implementation Center, Hsinchu, Taiwan, in 2009 for CMOS MEMS process and technology development. His topics of interest include CMOS MEMS sensor applications and CMOS microsystem integration.

Shey-Shi Lu (S89M91SM92) was born in Taipei, Taiwan, in 1962. He received the B.S. degree from National Taiwan University (NTU), Taipei, Taiwan, the M.S. degree from Cornell University, Ithaca, NY, USA, and the Ph.D. degree from the University of Minnesota, Minneapolis-St. Paul, MN, USA, all in electrical engineering, in 1985, 1988, and 1991, respectively. His M.S. thesis concerned the planar doped barrier hot electron transistor. His doctoral dissertation concerned the uniaxial stress effect on AlGaAs-GaAs quantum well/barrier structures. In August 1991, he joined the Department of Electrical Engineering at NTU, where he is currently a Professor. From August 2007 to July 2010, he was also the Director of the Graduate Institute of Electronics Engineering at NTU. His research interests are in the areas of RF integrated circuits (RFICs)/monolithic microwave integrated circuits (MMICs) and micromachined RF components.