Study on noise and sensitivity improvement of solid-state nanopores for DNA sensing applications

Abstract

DNA sequencing technology has attracted more attention for applications to personal diseases or personalized medicine. Nanopore based system is attractive for 3rd generation DNA sequencing technology due to its label-free, amplification-free, real-time single molecule sensing, long read-length (> 1kbp) and possibility to portable system. While biological nanopores demonstrate the visible performance of DNA sequencing, solid-state nanopores still have limitations to overcome. In introductory part (chapter 1 and chapter 2), general overview of nanopore system for DNA sequencing application is described. First, the history and basic principle of nanopore sensing are presented in chapter 1. Also, the technologies for next generation DNA sequencing is introduced briefly and the current situation of nanopore-based sequencer in the DNA sequencing market is described. In chapter 2, the current limitations of solid-state nanopores are reviewed in terms of DNA sequencing applications. Also, literature survey on previous research to improve the sensing properties of solid-state nanopore are described. In chapter 3, highly sensitive and low noise nanopore platform in boron nitride membrane on a pyrex substrate is demonstrated. This work is performed in two approaches to reduce both the dielectric noise and flicker noise of device, which is one of the bottlenecks to making highly sensitive 2-D membrane nanopore devices. Flicker noise is minimized by employing multiple layers of BN with sub 100 nm opening size to enhance the mechanical stability of membrane. From our results, we proposed that the flicker noise has a correlation with the stiffness of membrane material, which is one property of mechanical stability. In chapter 4, a fabrication scheme of a solid state nanopore with ZnO membrane directly deposited on top of quartz substrate by atomic layer deposition (ALD) and the characteristics of DNA translocation through this membrane are presented. Prior to that, transfer-free fabrication process of solid-state nanopore platform based on quartz substrate with the membrane of 2 μm opening aperture by using a polycrystalline Si (poly-Si) as a protection layer is introduced for reliable and reproducible process. ZnO membrane is chosen due to its high isoelectric point (~9.5) as well as its chemical and mechanical stability. Not only this device shows an extremely low noise level as it is fabricated on highly insulating and low dielectric quartz substrate but also it shows that the translocation speed of DNA through ZnO nanopore is more than one order of magnitude slower as compared to that of SiNx nanopore device. We propose that the electrostatic interaction between positively charged ZnO pore wall, resulted from high isoelectric point of ZnO, and negatively charged phosphate backbone provides additional frictional force to slow down the DNA translocation. In this dissertation, three major issues of solid-state nanopores for DNA sequencing application are discussed. These issues include (i) enhancing signal to noise ratio (SNR) (ii) improving spatial resolution (iii) retarding DNA translocation velocity. From the work of chapter 3, the sensitive platform and the understanding of 1/f noise in 2-D nanopores were suggested. From the work of chapter 4, we proposed a ZnO nanopore platform that can slow down the DNA rate efficiently with low noise. Further work will explore the interaction of ZnO pore wall with specific nucleotides for DNA-based applications such as ideal DNA sequencing or single nucleotide polymorphism (SNP) detection.