A Low-Noise and Wide-Bandwidth Transimpedacne Amplifier Design for Bionanopore Applications Jeong-Dae Yun and Jungsuk Kim1
Jong-Bum Park2
Department of Biomedical Engineering, Gachon University Incheon, South Korea 1
[email protected] (Corresponding)
Convergent SoC Research Center Korea Electronics Technology Institute (KETI) Seongnam-si, South Korea 2
[email protected] (Co-corresponding)
Abstract— This paper presents a low-noise and wide-bandwidth transimpedance amplifier for bionanopore applications. Using a capacitive-feedback transimpedance amplifier for a headstage, the input-referred noise is drastically reduced, which enables one to accurately monitor DNA translocation. To achieve a wide bandwidth, an intermediator-and-differentiator structure and a split-resistor technique are proposed in this work. Keywords- Bionanoporet; α-hemolysin; DNA; low noise; wide bandwidth; Trnasimpedance amplifier; Integrator; differentiator.
I.
INTRODUCTION
Over the past decades, studies for human gene sequencing have been performed to predict an incurable illness, accurately diagnose diseases. Various gene sequencing methods based on chemical or optical analysis have devised since 1970s [1]. But, they require complex procedures such as DNA amplification and optical labeling, so resulting in high cost and slow process to sequence. Recently, lots of scientists have developed nextgeneration sequencing methods, and among them, a nanopore method offers a great promise as the next-gen. sequencing due to its low-cost and high-speed analysis [2]. When a singlestranded DNA (ssDNA) traverses a nanometer pore by electrophoresis, small ionic currents corresponding to DNA bases are generated from the pore. By detecting the variations in the pico-ampere range, we can sequence DNA. Empirically, the current varies from 30 to 150 pA as ssDNA passes through an α-hemolysin nanopore (α-HL) [3]. To amplify the minute current and convert it to a readable voltage range for digitization, hence, we need a low-noise transimpedance amplifier (TIA). In general, the TIA must have a root-mean-square (RMS) input noise of 3pA or lower to meet the requirement of a 20 dB signal-to-noise ratio (SNR). For nanopore sequencing, it also has been known that ssDNA should be captured into the nanopore at the speed of 1ms/nucleotide [2]. Thus, TIAs need a bandwidth of 10 KHz or higher. A TIA can be implemented using the resistive or capacitive feedback. A capacitive-feedback TIA (cf-TIA) generally shows a superior noise performance to resistive-feedback TIA [4] because the feedback capacitor does not have a thermal noise. However, this scheme requires a high-impedance DC path to supply a DC bias to the input node. Usually, cf-TIA works as an integrator that requires a differentiator. A dominant Pole in the integrator, which limits a bandwidth, is cancelled out by a
Zero in the differentiator, thus enabling a wide bandwidth [4]. But, parasitic capacitances arose from the high-impedance path affect the Pole and Zero locations, and thus it is not possible to completely compensate the Pole and Zero. Motivated by this, a low-noise and wide-bandwidth TIA employing an integratorintermediator-differentiator topology is proposed, designed and verified for nanopore applications. II.
PROPOSED TRANSIMPEDANCE AMPLIFIER ANALYSIS
A. Proposed TIA Architecgture Fig. 1 displays the proposed TIA for nanopore applications, which consists of three stages: 1) Integrator, 2) intermediator, and 3) differentiator. The headstage has a capacitive feedback that is in parallel with a high-impedance resistor to provide a DC bias. As stated before, the high resistor causes a big parasitic capacitance, which restricts a 3-dB bandwidth. To lessen the parasitics, in this work, we apply a split-resistor technique [5] to the high resistor. An intermediator topology is newly added for the second stage. This cancels out the Pole and Zero deviated from the original location by the parasitics. Because the intermediator decouples the integrator from the differentiator, we can independently compensate the deviated Pole and Zero. Finally, the differentiator offers programmable gains by using a variable resistor for RE. Under the assumption that the core amplifiers (Amp1, Amp2, Amp3) have high gains, a transimpedance gain of the proposed TIA approximates to
RA R (1 + sRB C 2 ) RE (1 + sRD C4 ) × C × 1 + sR AC1 RB (1 + sR C C3 ) R
D
Integrator
Intermedia tor
(1)
Differenti ator
Here, the Poles and Zeros can be eliminated by adjusting the capacitances. Accordingly, the TIA proposed in this work can achieve a wide bandwidth and its DC gain is determined by (RA×RC×RE)/(RB×RD). III.
RESULT
To verify the proposed TIA scheme, a Texas Instruments TLC-072 BiMOS amplifier is adopted for the core amplifiers. Also, for the high-impedance resistors, we used Surface Mount Technology (SMT) resistor and capacitor models produced by Stackpole and Murata Electronics. In this design, 50GΩ, 10GΩ, 25MΩ, 1MΩ, 80MΩ, 1pF, 5pF, 100fF and 1pF are employed
This work was supported by Gachon University research fund of GCU2015-0035 and by NRF-2015R1C1A1A02037697.
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Fig. 1. Proposed TIA architecture, where an integrator-intermediator-differentiator topology is used to achieve a low noise and a wide bandwidth.
for RA, RB, RC, RD, RE, C1, C2, C3 and C4, respectively. The 50GΩ and 10GΩ are divided into series resistors with a 2GΩ, as shown in Fig 1, to reduce the parasitic capacitances [5]. Fig. 2 shows the gain spectrum that varies 179.8, 187.5, 193.7 and 199.8 dBΩ by setting RE to 8, 20, 40 and 80 MΩ. It also shows that the proposed TIA has a wide 3-dB bandwidth of 100 KHz with the high gains. Fig. 3 displays an input-referred noise spectrum, where an input noise of 2.57pARMS is estimated in a bandwidth of 100 KHz. This noise level meets the requirement of 3pARMS for nanopore applications. Fig. 4 shows the transient waveform of DNA translocation events, where an α-HL sensor is emulated with a 1GΩ for an open channel and a 5GΩ for translocation [3]. As a result, this waveform has an openchannel current of ~145pA and a translocation of ~30pA in the case when the gain is set to 199.8 dBΩ. IV.
Fig. 2. Gain spectrums within a bandwidth of 100 KHz
CONCLUSION
A low-noise and wide-bandwidth transimpedance amplifier is proposed and verified using the electrical model of an α-HL. It has an input noise of 2.57pARMS and a 3-dB bandwidth of 100 KHz that enable to detect ssDNA translocation events. Thus, the proposed transimpedance amplifier topology can be applied for nanopore and other electrochemical applications. REFERENCES [1] [2] [3]
[4]
[5]
L. Franca, E. Carrilho, and T. Kist, “A reveiw of DNA sequencing techniques,” Q. Rev. Biophys., vol. 35, no. 2, pp. 169-22, 2002. R.D. Maitra, J. Kim and W.B. Dunbar, “Recent advances in nanopore sequencing”, Electrophoresis, vol. 33, no. 23pp. 3418-3428, 2012. J. Kim, R. Maitra, K. Pedrotti, and W. Dunbar, “Detecting single-abasic residues within a DNA atrand immobilized in abiological nanopore using an integrated CMOS sensor”, Sens Actuators B Chem, vol 177, pp. 1075-1082, 2013. D. Kim, B. Goldstein, W. Tang, F. Sigworth, E. Culurciello, “Noise analysis and performance comparison of low current measurement systems for biomedical applications”, IEEE Trans. Biomed. Circ. syst., vol.7, no.1, 2013. C. Ciofi, F. Curpi, G. Pace, and G. Scandurra, “How to enlarge the bandwidth without increasing the noise in op-amp-based transimpedance amplifier”, IEEE Trans. Instrum. Measurements, vol.55, no.3, pp. 814818, 2006.
Fig. 3. Input-referred noise spectrum from 0.1 to 100 KHz
Fig. 4. Transient waveform emulating DNA translocation events.
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