Fabrication of solid-state nanopores via tip-controlled local breakdown

纳米孔装置由薄膜中的纳米级孔组成。 在电场的影响下，单个分子通过孔隙。 化学信息，如DNA序列，可以通过监测通过孔的电流来确定，当孔被过境分子局部阻塞时，电流动态波动。 纳米孔测序装置目前基于嵌入在脆弱的脂质双层膜中的蛋白质孔。人们对用基于标准半导体材料如氮化硅的固态孔代替这些生物孔非常感兴趣。 固态孔将更坚固，批量生产更便宜，并且可能具有更高的分辨率，降低测序错误率。 然而，尽管对固态孔装置有很大兴趣，但用于制造固态孔的方法是有限的。 主要的挑战是缺乏用于制造固态孔的工业可扩展的工艺，该工艺允许将孔与固态测序方案所需的其他纳米级元件整合。 最近，我们已经开发出一种新的方法，用于制造亚5纳米孔。 在我们的方法中，我们称之为尖端控制局部击穿（TCLB），由原子力显微镜（AFM）控制的导电尖端与氮化物膜接触。 施加电压脉冲导致在几百毫秒内形成纳米级孔，该纳米级孔可以通过随后的AFM扫描检测到。 这种方法是强大的，因为它是（1）便宜，（2）潜在地易于规模化的工业和（3）可以使亚5nm的孔，可以通过原子力显微镜纳米精度定位。 在这项提案中，我们将超越我们最初的原理证明，并证明TCLB有潜力成为一种具有工业竞争力的孔制造方法，可以推动新兴的固态纳米孔测序方案。

A nanopore device consists of a nanoscale pore in a thin membrane. Under the influence of an electric field, single molecules transit through the pore. Chemical information, like DNA sequence, can be determined from monitoring electric current through the pore, which dynamically fluctuates as the pore is locally blocked by the transiting molecule. Nanopore sequencing devices are currently based on protein pores embedded in fragile lipid bilayer membranes. There is great interested in replacing these biological pores with solid-state pores based on standard semiconductor materials such as silicon nitride. Solid-state pores would be more robust, cheaper to mass-produce and might potentially have a higher resolution, decreasing sequencing error-rates. Yet, despite the great interest in solid-state pore devices, approaches for fabricating solid-state pores are limited. The main challenge is the lack of industrially scalable processes for fabricating solid-state pores that permit integration of the pores with other nanoscale elements required for solid-sate sequencing schemes. Recently, we have developed a new approach for fabrication of sub 5 nm pores. In our approach, which we call Tip-Controlled Local Breakdown (TCLB), a conductive tip controlled by an atomic force microscope (AFM) is brought into contact with a nitride membrane. Application of a voltage pulse leads within several hundred milliseconds to formation of a nanoscale pore that can be detected by a subsequent AFM scan. This approach is powerful because it is (1) inexpensive, (2) potentially easy to scale to industry and (3) can make sub 5nm pores that can be positioned with nm precision via AFM. In this proposal we will go beyond our initial proof-of-principle and demonstrate that TCLB has potential to be an industrially competitive pore fabrication approach that could drive emerging solid-state nanopore sequencing schemes.