| With the discovery of DNA double helix structure,exploring the DNA sequence and its integrity of species has become a research hotspot all over the world.Traditional gene sequencing technology is generally based on biochemistry,using optical detection method to sequence DNA molecules.Although these sequencing methods have high accuracy,they still need a lot of complex chemical modifications and biological treatments,which increase the cost and time.The fourth generation DNA sequencing technology based on nanopore mainly uses physical methods and electrical signal detection technology.Voltage is applied at both ends of the nanopore,and the weak current signal generated by the change of the equivalent resistance of DNA passing through the nanopore is used for detection.Without chemical or biological treatment of DNA,such as chemical modification and marker insertion,and has the natural advantages of low cost and rapid detection.So it is considered to be the fourth generation DNA sequencing technology with broad application prospects.As for nanopore DNA sequencing technology,the main problem of its research is to design appropriate detection circuit and biosensor array for the signal generated by nanopore.The signals generated by nanopores are usually weak,noisy,fast and accompanied by high DC offset.Therefore,the requirements of nanopore detection circuit are very strict:high gain,low noise,small area and high throughput.At present,the research at home and abroad focuses on reducing the noise of detection circuit to improve the detection accuracy.The reported research usually uses complex chopper modulation and semi digital feedback technology to reduce the noise of detection circuit.However,the area and power consumption of a single detection circuit are large,so it is difficult to achieve high-throughput detection.In addition,these chips only realize the current detection function,which is only a part of the overall function of the actual DNA sequencing platform.For this reason,the electrical characteristics detection method of nanopore microfluidic system and the design of high-throughput and low-noise weak current sensor array are completedFor high-throughput biosensor design,a CTIA circuit design scheme is proposed,which shares half of the operational amplifier circuit.The simulation results show that the area and power consumption of the operational amplifier in the detection unit are reduced by 50%while ensuring high signal-to-noise ratio.In addition,based on digital correlation double sampling technology,a design scheme is proposed to distinguish the type of inserted base by using the difference between the non inserted base and the inserted base,which realizes the reduction of opamp mismatch and the elimination of DC offset caused by biochemical parameter deviation of microfluidic system.This paper also analyzes the electrical characteristics of nanopore microfluidic system,and proposes a multifunctional automatic integrated CMOS platform which integrates nanopore insertion detection,membrane capacitance detection and DNA sequencing.The whole process from sensor preparation to DNA sequencing is completed on one chip,which greatly reduces the complexity and time cost of the experiment.Based on TSMC 0.18?m CMOS process,a sequencing ASIC chip is implemented.The chip integrates a 16×5 sensor array and has the functions of film-forming detection,nanopore insertion detection and DNA sequencing.The post simulation results show that the chip can detect the capacitance of the film and the insertion of nanoholes in the range of 1p F?20p F;the equivalent input RMS noise current is 3.36p A,and the area of a single detection unit is as low as 7×10?m~2. |
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