个性化DNA测序：CMOS多模传感器平台

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"Lab-on-CMOS技术是一种将多种生物传感功能集成到单片CMOS（互补金属氧化物半导体）芯片上的平台，旨在实现个性化DNA测序。这种平台结合了高灵敏度的离子敏感场效应晶体管（ISFET）、双模式图像与化学传感器以及太赫兹（THz）超材料传感器，以实现无标记、低成本和高通量的测序方法。" 本文主要介绍了三种基于CMOS的无标记传感器技术： 1. 高灵敏度离子敏感场效应晶体管（ISFET）传感器：ISFET是一种能够感知溶液中离子浓度变化的设备。通过pH-to-time-to-voltage转换（pH-TVC），该传感器能够将pH值变化转化为时间信号，再进一步转化为电压输出，从而实现对DNA序列中碱基的精确检测。这种转换机制提高了检测的精度和速度，是个性化DNA测序的重要组成部分。 2. 双模式传感器：这种传感器融合了图像和化学检测两种模式，能够提供更高的准确度。图像模式可能用于捕获DNA分子的物理特性，而化学模式则可检测分子间的相互作用或特定化学反应，两者结合能够更全面地分析DNA序列。 3. 太赫兹超材料传感器：利用THz频段的电磁共振特性，这种传感器能够探测到DNA分子的独特指纹，从而识别不同的碱基序列。电气共振检测方法使得这种传感器在微小尺度上具有高灵敏度，适用于大规模个人化测序应用。开发的CMOS多模传感器平台集成了这些技术，为未来的个性化DNA测序提供了可扩展的解决方案。这一平台的创新之处在于它能够在单一芯片上整合多种生物传感功能，降低了设备成本，提高了数据处理速度，有助于推动精准医学的发展。关键词包括个性化DNA测序、无标记传感器、ISFET、超材料传感器和多模态技术。 Lab-on-CMOS技术通过集成多种生物传感技术，为实现精准医学中的个性化DNA测序提供了强大工具。这些技术的创新性不仅体现在其无标记、高效率和低成本上，还体现在它们的多功能性和灵活性，能够满足未来生物医学研究和临床应用的需求。

Lab-on-CMOS: A Multi-modal CMOS Sensor

Platform towards Personalized DNA Sequencing

Yu Jiang

, Xu Liu

, Xiwei Huang

, Yang Shang

, Mei Yan

, Hao Yu

School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore 639798

Ministry of Education Key Lab of RF Circuits and Systems, Hangzhou Dianzi University, China 310018

*Email: haoyu@ntu.edu.sg

Abstract—Precision medicine requires scalable bio-

instrument for a personalized DNA sequencing, which can be

label-free, cost-efficient, and high-throughput. This paper

mainly presents three kinds of CMOS-based label-free sensors,

including: i) a high-sensitivity ion-sensitive field-effect

transistor (ISFET) sensor with pH-to-time-to-voltage

conversion (pH-TVC); ii) a dual-mode sensor with image and

chemical modes for high accuracy; and iii) a THz metamaterial

sensor with electrical resonance detection. The developed

CMOS multi-modal sensor platform can show a scaled solution

for future personalized DNA sequencing.

Keywords— personalized DNA sequencing; label-free

sensors; ISFET; metamaterial sensor; multi-modal

NTRODUCTION

DNA detection, categorized as sequencing and

genotyping, plays a significant role for modern human

health. Sequencing, detection of the order of nucleotides in

DNA strands, enables studies of metagenomics, genetic

disorders, diseases, and genomic medicine. Genotyping,

targeted sequencing or mutation of specific DNA, is

deployed for single nucleotide polymorphism (SNP)

detections, most of which are associated with diseases and

deficiencies [1]. Sanger sequencing was successfully

employed in DNA detection since 1970s, which is expensive

and time-consuming for large-scale sequencing [2]. Next

generation sequencing technologies are later developed for

high-throughput sequencing with low cost, including

pyrosequencing (454), sequencing by oligo ligation detection

(SOLiD), and Illumina sequencing [3]. However, these

methods require fluorescent labels and bulky optical

instruments and hence are not feasible for personalized

diagnosis.

Large-array CMOS-compatible sensor foresees a strong

potential in the future personalized DNA sequencing. Same

as computer and communication devices, it follows the

Moore’s law that is scalable for millions of DNA strands to

be detected simultaneously on a single chip. State-of-the-art

methods include ion-sensitive field-effect transistor (ISFET)

based [4]-[6] and CMOS-compatible nanopore based [7].

This paper introduces the latest development of CMOS-

based multi-modal sensor platform for personalized DNA

sequencing, which includes: i) a high-sensitivity ISFET

sensor by pH-to-time-to-voltage conversion (pH-TVC); ii) a

dual-mode ion-image sensor with high accuracy; and iii) a

proposed THz metamaterial sensor.

II. CMOS

H-TVC

ISFET

ENSOR

For a CMOS ISFET device, an Ag/AgCl electrode in

solution works as a remote gate, and a floating gate (FG)

structure is formed between the passivation layer and gate

oxide, as shown in Fig. 1(a). In order to reduce fabrication

cost, passivation layer in standard CMOS process is utilized

as ion sensitive layer. However, this layer will introduce a

small capacitance C

pass

to the device model in Fig. 1(b),

which will capacitively decrease the coupling strength from

solution to ISFET [5]. Besides, in conventional testing

method shown in Fig. 1(c), ISFET works in saturation region

as a source-drain follower, and pH change in solution is

linearly corresponded to pixel output. As a result, pH

sensitivity is greatly affected by the passivation capacitance,

especially in larger sensor array with smaller sensing area.

To improve signal to noise ratio for better sequencing

performance, high-sensitivity ISFET sensor with pH-TVC

readout scheme is proposed, in which ISFET worked in

weak inversion region is adopted to exponentially improve

pH sensitivity.

A. pH-TVC Readout Scheme

To deal with the sensitivity attenuation effect, a pH-to-

time-to-voltage conversion scheme is proposed in Fig. 2.

Each pixel contains three transistors: MN

is the ISFET

device, MN

is the row-selected device, and MN

is the reset

device. At first stage, node N

is pre-charged to power

This work was supported by NRF-POC fund, NTU iFood fund fro

Singapore and the National Natural Science Foundation (Grant No.

61501156) from China.

ref

pass

tcfg

fgd

fgs

Passivation Layer

P-substrate

n+n+

ref

DSB

chem

=f(pH)

Solution

Semiconductor

tcp

Ag/AgCl

ref

pass

VDD

SOURCE

Electrolyte

(a) (b) (c)

Fig. 1. (a) Cross section of an ISFET implemented in 1P6M CMOS

rocess. (b) A capacitance-dependent CMOS ISFET model. (c) A

conventional testing method, ISFET works in saturation region, derive

from [8]

2266

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个性化DNA测序：CMOS多模传感器平台

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