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This article has been accepted for inclusion in a future issue of this journal. Content is final as presented, with the exception of pagination.

IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS 1

A CMOS Cantilever-Based Label-FreeDNA SoC With Improved Sensitivity

for Hepatitis B Virus DetectionYu-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 detec-tion SoC, where several kinds of cantilever DNA sensors, a readoutcircuit, an MCU, voltage regulators, and a wireless transceiver,are integrated monolithically in a CMOS Bio-MEMSprocess. The cantilever-based biosensors with embedded piezore-sistors aim to transduce DNA hybridization into resistance varia-tion without cumbersome labeling process. To improve detectionsensitivity for low DNA concentration use, an oscillator-based self-calibrated readout circuit with high precision is proposed to con-vert small resistance variation ( of original resis-tance) of the sensor into adequate frequency variation and furtherinto digital data. Moreover, its wireless capacity enables isolationof the sample solution from electrical wire lines and facilitates datatransmission. To demonstrate the effectiveness of full system, it isapplied to detect hepatitis B virus (HBV) DNA. The experimentalresults show that it has the capability to distinguish between onebase-pair (1-bp) mismatch DNAs and match DNAs and achieves alimit of detection (LOD) of less than 1 pM.

Index TermsCantilever, DNASoC, hepatitis B virus, label-free,oscillator-based.

I. INTRODUCTION

DEOXYRIBONUCLEIC acid (DNA) detection is an im-

portant analytical method in molecular biology, and it

finds a wide range of applications from genetic disease diagnos-

tics, medicine and drug discovery, to forensic investigation and

food testing, etc. To date, optical detection method [1], [2] based

on the use of fluorescent 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; ac-

cepted January 27, 2013. This work was supported in part by theNational Science Council (NSC) of R.O.C., Taiwan, under ContractNSC100-2221-E-002-247-MY3, and in part by the Ministry of EconomicAffairs under Contract MOEA98-EC-17-A-07-S2-0123. This paper wasrecommended 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 Instituteof Electronics Engineering, National Taiwan University, Taipei 10617, Taiwan(e-mail: [email protected]; [email protected]; [email protected]).

H.-T. Hsueh is with the Graduate Institute of Biomedical Electronics andBioinformatics, National Taiwan University, Taipei 10617, Taiwan.

H.-H. Tsai, H.-H. Liao, and Y.-Z. Juang are with the National Chip Imple-mentation Center, National Applied Research Laboratories, Hsinchu 30078,Taiwan.

Color versions of one or more of the figures in this paper are available onlineat http://ieeexplore.ieee.org.

Digital Object Identifier 10.1109/TBCAS.2013.2247761

analysis with high detection sensitivity. However, it suffers from

many drawbacks, such as complex fluorescent labeling process,

time consuming, and high cost. Moreover, the necessary op-

tical 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 tech-nology, development of the electric DNA chips in complemen-

tary metal-oxide semiconductor (CMOS) technology has ap-

peared. A fully electronic CMOS DNA sensor chip was pre-

sented [4] based on an electrochemical redox-cycling detec-

tion 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 la-

beling, a similar electrochemical detection method by using in-

tercalators was presented in 2006 [5]. The intercalators will

specifically connect with the double-stranded DNA molecules.

Then electric current caused by the oxidization of intercala-

tors can be observed. Furthermore, a CMOS fluorescent-basedbiosensor[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 ac-

cess to new fields of application. However, additional time-con-

suming labeling steps or extra intercalators are still required for

the target DNA molecules.

To avoid cumbersome labeling process, a number of ap-

proaches are proposed [8], [9] for label-free bio-molecular

detection. Most of them are also realized in CMOS technologybased on capacitance measurement [10], electrical current

[11][13], impedance spectroscopy [14], [15], and electro-

chemical detection using ion-sensitive field-effect transistors

(ISFETs)[16],[17]. The ISFET type DNA sensor is attractive

for its easy implementation in standard CMOS process. How-

ever, 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 fulfill 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

1932-4545/$31.00 2013 IEEE
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2 IEEE TRANSACTIONS ON BIOMEDICAL CIRCUITS AND SYSTEMS

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 contami-

nants and man-made interference from various operators.

In the following sections, the structure, the extended fabrica-tion process, and the sensing mechanism of the cantilever DNA

sensor are introduced first inSection II. Then the system archi-

tecture and the detailed design of the sub-circuits are illustrated

inSection 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 Sec-

tion IV. Finally, a conclusion will be given in Section V.

II. CANTILEVERDNA SENSOR

A. Structure and Fabrication

Fig. 1 draws the cross-section view of the integrated

micro-cantilever DNA sensor. polysilicon

layer embedded in this sensor functions as a pizeoresistor.

Some single-stranded DNA receptor molecules with prede-

fined 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-modified

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 immersedinto buffer solution and could withstand repetitive DNA detec-

tion and cleaning cycles.

This device is fabricated in the CMOS Bio-Microelectrome-

chanical Systems (Bio-MEMS) platform [20], which is based on

two-poly four-metal (2P4M) CMOS technology fol-

lowed by micromachining post-processing steps. Fig. 2 illus-

trates 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

sensor area; b) removing the silicon dioxide layer (inter-

layer dielectric) surrounding the defined 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-can-tilever 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 first (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-can-

tilevers are shown inFig. 3. In addition, several kinds of can-

tilever structures with the same intrinsic resistance are realized

in this chip in order to find out which structure has the best per-

formance. 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 re-

lies on the embedded polysilicon piezoresistor which acts as aphysical transducer. As shown inFig. 4, when the target DNA
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HUANGet 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 piezore-

sistor. In this way, the specific DNA detection can be achieved

by using electronic circuits to extract the resistance variation of

the piezoresistor.

III. SYSTEMARCHITECTURE

A. Circuit Blocks

Fig. 5 depicts the system block diagram of the proposed wire-

less 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

significantly 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

define 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 fre-

quency variation by our proposed readout circuit first. Then this

frequency variation will be converted to digital code by the fol-

lowing 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 resis-

tance difference of the cantilever DNA sensor before and afterDNA hybridization. There exist numerous approaches to detect

Fig. 6. Architecture and simplified circuits of the oscillator-based self-cali-

brated readout circuit.

the resistance variation[22][24]. For example, the bridge cir-

cuit architecture is traditionally adopted to translate the resis-

tance variation into voltage variation[25]. However, the mis-

match within the bridge topology and the offset problems pose

severe design difficulties. Another sensing topology by moni-

toring the current through the resistance was also presented to

provide wide dynamic range detection [26]. Nevertheless, its

precision is not sufficient for our sensor to identify the tiny re-

sistance 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 inFig. 6. It is composed of a sensor-merged oscil-

lator, 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 vari-

ation 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 fol-lowing digital circuit. A divider by 4 is connected at the output
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Fig. 7. Simulated results of frequency pulling effect.

ofthebuffer toensure thattheoutputclock has a perfect50% duty cycle and to prevent frequency-pulling effect caused

by the external clock at the input of mixer. Without it,

the pulling effect from will shift if they are too

close, which degrades the sensing fidelity. As the simulated re-

sult shown in Fig. 7, the pulling range can be reduced effectively

by adding this divider. Then, a simple D flip-flop (DFF) acts as

a mixer to down-convert the original oscillation frequency with

to increase the relative frequency variation. A detailed ex-

planation will be given in the next paragraph. Finally, an 8-bit

digital output corresponding to the measured oscilla-

tion frequency can be obtained through a F-to-D con-

verter (FDC), which is a digital counter used to linearly transfer

the period change of oscillation to a digital count. The digital

output can be derived from the following equation:

(1)

where is the initial down-converted frequency

(period) before detection, and is the frequency variation.

It should be noted that this FDC digitizes the absolute differ-

ence 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 inFig. 8to explain the functionality

of the added mixer. We assume the original divided oscillation

frequency is 10 MHz here for easy calculation. After

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.

By down-conversion with (9.9 MHz), the oscillationfrequency before DNA hybridization changes from original

Fig. 8. An example to explain the functionality of the added mixer.

10 MHz to 100 kHz, whereas the frequency shift caused by

DNA hybridization keeps the same, which means that the rela-

tive frequency variation is equivalently amplified by 100 times.Therefore, the design constraint can be considerably relaxed.

In our actual work, is designed to be around

24 MHz (sensor resistance is around ), the divided fre-

quency is around 6 MHz, and the down-converted output

frequency is chosen at 200 kHz. The output frequency is

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

capable of detecting frequency shift (1.2 kHz) caused

by estimated resistance variation of the designed DNA

sensor. The oscillator-based readout architecture eliminatesthe need of an analog-to-digital converter (ADC) as the FDC

output, , is already in digital format. Also, to compensate

for process-voltage-temperature (PVT) variations, a self-cal-

ibration mechanism is adopted, as depicted inFig. 6. During

calibration, the down-converted frequency would be

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

target code, which corresponds to a calibrated around

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 readoutare temperature-sensitive. According to the simulation result,

the expected temperature sensitivity of this sensor-embedded

readout is , which means only temper-

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 pro-

grammable micro-controller. The core of microcontroller is a

central processing unit (CPU) and its instruction set is similarto that of the commercial peripheral interface controller (PIC)
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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 pro-

gram buses, it equips a 256-word data static random accessmemory (SRAM), a 2 k-word a program SRAM, and an 8-level

stack. The peripheral includes an universal asynchronous re-

ceiver/transmitter (UART), a serial peripheral interface (SPI), a

watch dog, and two timers.

The basic function of UART is performing the data trans-

formation 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 accu-

racy 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 alsodesigned for error detecting. There are four proprietary com-

mands 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 communi-

cation data format is used to communicate with portable devices

conveniently.

D. OOK Transmitter/Receiver

Wireless communication capability is another essential ele-

ment 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-het-erodyne receivers which consume too much power and area, a

Fig. 10. Schematic of the OOK receiver.

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 preamplifier, cascaded amplifiers, an envelope de-

tector, and a comparator with an output buffer, as shown in

Fig. 10. The input impedance of the preamplifier is not matched

to but to high impedance instead. Therefore, an off-chip

coupling circuit is designed for connecting the low-impedance

antenna and the high-input-impedance preamplifier. The fol-

lowing cascaded amplifiers consist of eight stages and provide

60-dB gain in total. Each stage adopts the current reuse tech-nique for better power efficiency. Then the signal will be

demodulated by the envelope detector, which comprises a

diode-connected NMOS transistor and a RC low-pass filter

. The transistor size is specifi-

cally large in order to minimize

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 amplifier (PA) as de-

picted 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 am-

plifier drives a sinusoidal current through the off-chip inductor,

which achieves a narrow band-pass frequency response in con-

junction 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 inFig. 12and consists ofa start-up circuit, a bandgap reference, and an error amplifier.
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Fig. 12. Schematic of the low-dropout voltage regulator.

Controlled by the control signal (ON) from the MCU, each reg-

ulator 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 referencetopology. A start-up circuit is implemented to prevent the re-

luctance 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 amplifier is based

on simple single-ended op-amp architecture. Through negative

feedback resistors (R1 and R2), the error amplifier 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

(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-can-

tilever DNA sensors with different forms on the chip for investi-

gations of device sensitivity. Although this chip endures neces-

sary post processing to develop our DNA sensors, the integrated

circuits still perform without degradation in the experiments.

Table Isummarizes the measured performance of this DNA de-

tection SoC, andTable IIcompares this work with other CMOSDNA 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 ca-

pacity among them.

IV. EXPERIMENTALRESULTS

The experimental flow 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 hy-bridization, most nonspecific binding DNAs are washed away

Fig. 13. Chip micrograph.

TABLE IPERFORMANCESUMMARY

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-specific binding DNA. Finally, the sensing

chamber is dried for 20 minutes to obtain steady signals. The op-

eration temperature in all experiments was at room temperaturecontrolled by a temperature conditioner.
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TABLE IICOMPARISONWITH THEPRIOR ARTS

Fig. 14. Designed experimental flow.

A. Preliminary Test

To examine the accuracy and specificity of this chip, a

preliminary test is performed first. Here, 5 thiol-modified

DNA sequence (5-HS-ATAGGTCGGTAGGTGAATGG-3) is

chosen as the experimental probe DNA and immobilized on

the DNA sensor first. Then the all-match DNA sample

(5-CCATTCACCTACCGACCTAT-3) and the all-mismatchDNA 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

here to generate an initial-state oscillation frequency . In

Wash State, the sensor experiences several times washing

and produces relatively unstable signals due to environmental

fluctuations. 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 biosensorsare tested in the open environment. Thus, the ion concentration

Fig. 15. Temporal responses of frequency variation for match and mismatchDNA conditions.

of the buffer may increase due to evaporation of the buffer solu-

tion. This evaporation and condensation phenomena will affectthe 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 field 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 influences 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 betweenthe Initial State baseline and the stable Steady State can be
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Fig. 16. Temporal responses of frequency variation for match DNA withdifferent 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-specific binding of

mismatch DNAs and can be seen as an interference noise. Nor-

mally, non-specific binding phenomenon happens infrequently

in match DNA experiments. Therefore, under the same con-centration, as long as the positive signal caused by the match

DNA is larger than the non-specific 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. 16shows 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,

40 kHz and 16 kHz frequency changes are induced by

and 100 pM DNA, respectively. Thus, this DNA chip

could recognize different concentrations of DNA from 100 pM

to . It should be emphasized that, to prevent the unwantedeffect due to saturation of DNA binding, the hybridization time

shown here is designed to be about three times shorter than that

inFig. 15. According to previous researches[31],[32], the ex-

tent of the hybridization, and hence the sensitivity of the sensor,

are strongly dependent on the hybridization time before satura-

tion 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 res-

olution of this system, the analysis of the short term stability

(noise floor) is further carried out according to the steady-state

data from this practical experiment. As depicted in Fig. 17, the

short-term Allen deviation in practical experimental con-

ditions reaches to at the averaging time of 160 sec-onds, which means the smallest frequency deviation that can be

Fig. 17. Short-term Allan deviation according to the experimental data.

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 theproposed oscillator-based readout is about 395 Hz, which also

declares that the limit of detection is about 1.2 kHz

(0.02% frequency variation).

In this work, several sensors with different structures are de-

signed for sensitivity investigation, and the measured results are

shown inFig. 18. The geometry and the detailed information of

all the designed cantilever sensors are also depicted inFig. 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 dif-

ferent residual stress can be observed. It will make a great im-pact on the performance of all the sensors, such as initial resis-

tance ( frequency) and sensitivity. From our observation, the

sensor with C10 structure is usually flatter than other ones after

structure releasing, which means it has lower residual stress. For

this reason, although C10 does not has the smallest spring con-

stant, it shows the best performance than other cantilevers, as

can beseen 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 inFig. 18go in opposite direction. It could be caused

by difference residual stress and/or different target sequences

(match and mismatch DNA)[35],[36].

TheFig. 20(a)shows the measured digital data through wire-less transmission for match and mismatch DNA conditions. It
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Fig. 19. Detailed information of the designed cantilever sensors in this chip.

Fig. 20. (a) Measured digital data for match and mismatch DNA conditions.(b) Spectrum of the transmitter output. (c) Waveforms of the transmitted dataand 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 inFig. 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

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

Fig. 22. Frequency variation ratio for match HBV DNAs with differentconcentrations (1 pM, 100 pM, and 10 nM).

mismatch (5-GTTCCGTGATATGGATCGG-3), and all-mis-

match (5-ACCTTATCTACCTACCTAT-3), respectively.

Fig. 21depicts 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 specific 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 thanour 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 nonspecific binding is a critical issue forreal-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 unspecific binding.

Also, more effective washing step before readout can some-

times 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 nonspecific binding in real-world applications. In view ofit, 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, recom-

mended 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 thecontainments, 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 en-

able label-free DNA detection. Thanks to the ability to amplify

relative frequency variation, the proposed oscillator-based self-

calibration readout could convert very small resistance variation

( , 0.02% variation) caused by DNA hybridization into suf-ficient frequency variation and hence effectively improves the

sensitivity of DNA detection. The experimental results show

that, for HBV DNA detection, the chip can successfully distin-

guish 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 detec-

tion, 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 Implemen-tation Center (CIC), Taiwan, for chip fabrication.

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Yu-Jie Huang was born in Kaohsiung, Taiwan,in 1984. He received the B.S. degree in electricalengineering from National Cheng Kung University,Tainan, Taiwan, in 2006.

Currently, he is working toward the Ph.D. degreein electronic engineering at National Taiwan Univer-sity, Taipei, Taiwan. His research interests include

CMOS mixed-signal integrated circuit design andsystem-on-a-chip design for wireless sensing andbiomedical applications.

Che-Wei Huang was born in Taoyuan, Taiwan, in1982. He received the B.S. degree from Chang GungUniversity, 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 chemicaland biosensor platform technologies.

Tsung-Hsien Lin (M03SM09) received the B.S.degree in electronics engineering from NationalChiao-Tung University, Taiwan, and the Ph.D.degree in electrical engineering from University ofCalifornia, Los Angeles, Los Angeles, CA, USA, in2001.

In March 2000, he joined Broadcom Corporation,Irvine, CA, USA, where he was a Senior Staff Sci-

entist, during which time he involved in analog/RF/mixed-signal circuit design and participated in wire-less transceiver developments. In 2004, he joined the

Graduate Institute of Electronics Engineering and the Department of ElectricalEngineering, National Taiwan University, Taipei, Taiwan, where he is currentlya Professor. His research interests are in the design of wireless transceivers,clock and frequency generation systems, delta-sigma modulators, and trans-ducer interface circuits.

Dr. Lin was the recipient of the Best Presentation Award for his paper pre-sented at the 2007 IEEE VLSI-DAT Symposium. He was awarded the TeachingExcellenceAward fromNationalTaiwan University in 2007, 2008, and 2009. Heserved on the IEEE Asian Solid-State Circuit Conference (A-SSCC) TechnicalProgram Committee (TPC) from 2005 to 2011 and was the TPC Vice-Chair for2011 A-SSCC. He was a Guest Editor for the IEEE JOURNAL OFSOLID-STATECIRCUITS in 2012. He serves on the ISSCC International Technical ProgramCommittee since 2010, and on the IEEE VLSI-DAT TPC since 2011. He is cur-rently an Associate Editor for IEEE JOURNAL OFSOLID-STATECIRCUITS.

Chih-Ting Linwas born in Taiwan in 1974. He re-ceived the B.S. degree in civil engineering and M.S.degree in applied mechanics from National TaiwanUniversity,Taipei, Taiwan, in 1996 and 1998, respec-tively, and the M.S. and Ph.D. degrees in electricalengineering and computer science from the Univer-sity of Michigan, Ann Arbor, MI, USA, in 2003 and2006, respectively.

Since September 2006, he has been with theGraduate Institute of Electronics Engineering andthe Department of Electrical Engineering at National

Taiwan University. His current research interests include bio-MEMS, CMOSbio-chips, nano fabrication, and biomolecular detection technology.

Li-Guang Chen wasbornin Taipei,Taiwan, in 1987.He received the B.S. degree in electrical engineeringand M.S. degree in electrical engineering from Na-tional TaiwanUniversity, Taipei, Taiwan, in 2009and2011, respectively.

His masters thesis focused on low-power andenergy-efficient wireless RF transmitters. Currently,he works at the Sitronix Corporation, Taipei, Taiwan,as a Circuit Design Engineer involved with LCDdrivers.

Po-Yun Hsiao was born in Chia-Yi, Taiwan. Hereceived the B.S. degree in electrical engineeringfrom National Tsing-Hua University, Hsinchu City,Taiwan, and the M.S. degree in electrical engineeringfrom National Taiwan University, Taipei, Taiwan, in2009 and 2011, respectively.

In 2011, he joined the RF department at MediaTekInc., Taipei, Taiwan. His research interests are in thearea of low-power analog circuit design for biomed-ical applications, and wireless front-end circuit andfilter design for cellular applications.

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Bi-Ru Wuwas born in Yilan, Taiwan. She receivedthe B.S. degree in mechanical engineering from Na-tional Central University, Jhongli City, Taiwan, andthe M.S. degree in electrical engineering from Na-tional TaiwanUniversity, Taipei, Taiwan, in 2008 and2010, respectively.

In 2010, she joined the Raydium SemiconductorCorporation, Taiwan. Her research interest is in the

area of digital circuit design.

Hsiao-Ting Hsueh received the B.S. degree in lifescience from National Taiwan University, Taipei,Taiwan, in 2009.

Currently, he is working toward the Ph.D. degreeat the Graduate Institute of Biomedical Electronicsand Bioinformatics at National Taiwan University.His current research interests are silicon nanowireFET chem/biosensors and organic FET chem/biosen-sors.

Bing-Jye Kuo was born in Taiwan in 1978. He re-ceived the B.S. degree in electronics engineering andthe M.S. degree in electronics from National Chiao-Tung University (NCTU), Hsinchu, Taiwan, in 2000and 2004, respectively.

Since 2002, he has been with the Nanoelectronicsand Gigascale Systems Laboratory at NCTU. In2004, he joined MediaTek Inc., Hsinchu, Taiwan,as a Design Engineer responsible for the on-chipRF ESD protection circuit design and transmittercircuit design. His research interests include GSM

transmitter circuit design and on-chip RF ESD protection circuit design.

Hann-Huei Tsaireceived the B.S. and M.S. degreesin electrical engineering from National Cheng-KungUniversity, Tainan City, Taiwan, in 1992 and 1994,respectively.

He had worked at Taiwan Semiconductor Manu-facturing Company, Hsinchu, Taiwan, as a ProcessIntegration Engineer and Section Manager from1996 to 2006. He joined the National Chip Imple-mentation Center, Hsinchu, Taiwan, in 2006. Histopics of interest topics include CMOS MEMS,CMOS BioMEMS, and high voltage technology.

Hsin-Hao Liao receivedthe B.S. andM.S.degrees in

chemical engineering from National Tsing-Hua Uni-versity, Hsinchu City, Taiwan, in 1996 and 1998, re-spectively.

He worked at the Taiwan SemiconductorManufac-turing Company, Hsinchu, Taiwan, as a Process andIntegration Engineer from 2000 to 2009. He joinedthe National Chip Implementation Center, Hsinchu,Taiwan, in 2009 for CMOS MEMS process and tech-nology development. His topics of interest includeCMOS MEMS sensor applications and CMOS mi-

crosystem integration.

Ying-Zong Juang received the M.S. and Ph.D de-grees in electrical engineering from National Cheng-Kung University, Tainan City, Taiwan, in 1992 and1998, respectively.

He joined the Institute of Chip Implementa-tion Center (CIC), Science-Based Industrial Park,Hsinchu, Taiwan, in October 1998. At CIC, hemajored in RF circuit design and device modeling

works. From 1999 to 2000, he joined a projectto create a new process flow to implement BCDdevices on the same chip. Currently, he is the

Researcher and Department Manager of CISD/CIC. He organized severalprojects including RF top-down design for front-end system, RF SiP designplatform, and 0.35/0.18 CMOS BioMEMS implementation environment. Histopics of interest include RF/MEMS module design, CMOS BioMEMS, andmixed-signal design for RF front-ends.

Chorng-Kuang Wang (M90SM00F08) wasborn in Taiwan in 1947. He received the B.S. degreein electronic engineering from National Chiao-TungUniversity, Hsinchu, Taiwan, and the M.S. degreein geophysics from National Central University,Jhongli City, Taiwan, in 1970 and 1973, respectively,and the M.S. and Ph.D. degrees in electrical engi-neering and computer science from the Universityof California, Berkeley, Berkeley, CA, USA, in 1979and 1986, respectively.

He has held industrial positions with Itron, NewTaipei City, Taiwan (19731977), and National Semiconductor, Rockwell, andIBM, all in California (19791991), where he was involved in the developmentof CMOS memory, data modems and disk-drive integrated circuits. He acted asa Consultant to the Computer and Communication Research Lab of the Indus-trial Technology Research Institute (19912000) and an Advisor to the Ministryof Education Advisory Office (19972001) in Taiwan. From 1991 to 1998, hewas with the Department of Electrical Engineering, National Central Univer-sity, Jhongli City, Taiwan, where he was a Professor. Since then, he has been aProfessor in the Department of Electrical Engineering at National Taiwan Uni-versity, Taipei, Taiwan. His research interests are in the areas of wireless trans-ceiver system and circuit design, high-speed data link circuits, mm-waveCMOS

development, flexible electronics, and telemedicine.Dr. Wang has been involved in chairing and launching programs for tech-

nical and executive committees of AP-ASIC, A-SSCC and ISSCC. He currentlyserves as an ex-officio member of the SSCS AdCom, a member of the IEEEDonald O. Pederson Award in Solid-State Circuits Committee, and a member ofthe IEEE Jun-ichi Nishizawa Medal Committee. He was named an IEEE Fellowin 2008 for contributions to communications circuit design and for leadershipin promoting the profession.

Shey-Shi Lu (S89M91SM92) was born inTaipei, Taiwan, in 1962. He received the B.S. degreefrom 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 bar-rier hot electron transistor. His doctoral dissertationconcernedthe uniaxial stress effect on AlGaAs-GaAs

quantum well/barrier structures. In August 1991, he joined the Department ofElectrical Engineering at NTU, where he is currently a Professor. From Au-gust 2007 to July 2010, he was also the Director of the Graduate Institute ofElectronics Engineering at NTU. His research interests are in the areas of RFintegrated circuits (RFICs)/monolithic microwave integrated circuits (MMICs)and micromachined RF components.

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