Nano Today
Volume 8, Issue 1, February 2013, Pages 56-74
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Review
Solid-state and biological nanopore for real-time sensing of single chemical and sequencing of DNA

https://doi.org/10.1016/j.nantod.2012.12.008Get rights and content

Summary

Sensitivity and specificity are two most important factors to take into account for molecule sensing, chemical detection and disease diagnosis. A perfect sensitivity is to reach the level where a single molecule can be detected. An ideal specificity is to reach the level where the substance can be detected in the presence of many contaminants. The rapidly progressing nanopore technology is approaching this threshold. A wide assortment of biomotors and cellular pores in living organisms perform diverse biological functions. The elegant design of these transportation machineries has inspired the development of single molecule detection based on modulations of the individual current blockage events. The dynamic growth of nanotechnology and nanobiotechnology has stimulated rapid advances in the study of nanopore based instrumentation over the last decade, and inspired great interest in sensing of single molecules including ions, nucleotides, enantiomers, drugs, and polymers such as PEG, RNA, DNA, and polypeptides. This sensing technology has been extended to medical diagnostics and third generation high throughput DNA sequencing. This review covers current nanopore detection platforms including both biological pores and solid state counterparts. Several biological nanopores have been studied over the years, but this review will focus on the three best characterized systems including α-hemolysin and MspA, both containing a smaller channel for the detection of single stranded DNA, as well as bacteriophage phi29 DNA packaging motor connector that contains a larger channel for the passing of double stranded DNA. The advantage and disadvantage of each system are compared; their current and potential applications in nanomedicine, biotechnology, and nanotechnology are discussed.

Highlights

► Nanopore based single molecule analysis is currently an area of great interest in many disciplines. ► We review the concept of nanopores as well as types and attributes of various biological and synthetic nanopores. ► We discuss the current and potential applications of nanopores in nanomedicine, biotechnology, and nanotechnology.

Introduction

Translocation of ions, DNA, RNA, polypeptides and other macromolecules across the membrane within or between cells is a fundamental and ubiquitous process. The transportation process involves a wide assortment of passive pores, active ion channels, and viral motors with elegant and highly-ordered structures. The novel and sophisticated design of the transport machineries have inspired the development of nanopores for single molecule detection.

Nanopore based analysis is currently an area of great interest in many disciplines with the potential for incredibly versatile applications. These include sensing small molecules such as ions, nucleotides, enantiomers, and drugs, as well as larger polymers such as PEG, RNA, DNA, and polypeptides. Single pore sensing is a label-free single molecule recognition approach requiring very low sample volumes without sample preparations or amplifications. The detection can be carried out with high sensitivity in the presence of large number of contaminants. This review encompasses the concept of nanopores; types of nanopores along with their advantages and disadvantages; and their current and potential applications in nanomedicine and nanotechnology. The field of nanopore has skyrocketed over the last decade, as evidenced by 900+ publications from Pubmed. Thus a significant amount of nanopore literatures is not covered due to the limitations of space. For more in-depth analysis of past advances, interested readers are encouraged to read several excellent reviews published over the years [1], [2], [3], [4], [5].

Section snippets

Principles of nanopore detection

The stochastic nanopore technique is based on the working principle of the classical Coulter Counter or the ‘resistive-pulse’ routine [6], which demonstrated sizing of micron sized particles with a micron sized aperture. In the nanopore technique, charged polymers are electrophoretically driven though a nanometer sized aperture (typically a few nm to tens of nm) embedded in a thin membrane. The nanopore is located in an electrochemical chamber separated into cis- and trans-compartments, each

Types and attributes of various nanopores

Nanopores are classified into three classes: (1) Biological pores embedded in a lipid bilayer; (2) Synthetic nanopores fabricated in solid substrates, such as Si3N4, Al2O3, TiO2, and graphene; and (3) Hybrid of biological and synthetic nanopores.

Comparison of biological and synthetic nanopores

While the basic principles of nanopores are the same, there are significant differences to note between biological and synthetic pores, as outlined below:

  • (1)

    Reproducibility: Biological channel proteins harvested in bacteria are extremely reproducible at the atomic level. The pore size cannot be reproduced as precisely by fabrication techniques in synthetic pores, although the precision with which nanopores in graphene can be formed is approaching atomic precision [68]. The size and shape of the

Current and prospective applications

Nanopore has the superiority to reach single molecule sensing due to its intrinsic properties, such as label-free, amplification-free, and potentials for high-throughput screening. As a result, they have become increasingly attractive for a wide range of applications, as discussed below.

Perspectives

Several first, second and third generation DNA sequencing approaches exist in the market, but they often require substantial biochemical labeling, extensive sample preparations, low throughput, requires massive data processing, costly, and not practical for long read-lengths. Nanopore technology has the potential to overcome many of the aforementioned challenges and significant strides have been made towards that goal, even though challenges remain. The most promising data is from MspA and

Acknowledgements

We thank Hui Zhang, Zhengyi Zhao, Tao Zeng, Jing Yan, Juan Liu, for assistance in preparation of this review. Research in P.G. lab was supported by NIH grants R01 EB003730, R01 EB012135, U01 CA151648, R01 GM059944, and NIH Nanomedicine Development Center: Phi29 DNA Packaging Motor for Nanomedicine, through the NIH Roadmap for Medical Research (PN2 EY 018230) directed by P.G. Research in J.L. lab was supported by National Basic Research Program of China (no. 2011CB935704). Research in H-C W's

Farzin Haque – Ph.D. is a Research Assistant Professor in the University of Kentucky College of Pharmacy, Department of Pharmaceutical Sciences. He received his B.A. degree in Biochemistry and Mathematics (2004) from Lawrence University and a Ph.D. degree in Chemistry (2008) from Purdue University. He held a postdoctoral appointment (2009–2011) at the University of Cincinnati, with Professor Peixuan Guo. Dr. Haque's scholarly interest broadly focuses on Nanoscience and Nanotechnology in Biology

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    Farzin Haque – Ph.D. is a Research Assistant Professor in the University of Kentucky College of Pharmacy, Department of Pharmaceutical Sciences. He received his B.A. degree in Biochemistry and Mathematics (2004) from Lawrence University and a Ph.D. degree in Chemistry (2008) from Purdue University. He held a postdoctoral appointment (2009–2011) at the University of Cincinnati, with Professor Peixuan Guo. Dr. Haque's scholarly interest broadly focuses on Nanoscience and Nanotechnology in Biology and Medicine. These include, nanopore-based technology for single molecule detection and sensing of chemicals and biopolymers; and RNA Nanotechnology – construction of RNA nanoparticles for therapeutic and diagnostic applications.

    Jinghong Li – Ph.D. is Cheung Kong Professor in the Department of Chemistry at Tsinghua University, China. He received his Ph.D. from Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences (CAS) in 1996. He held a postdoc or research scientist position at University of Illinois at Urbana-Champaign, University of California at Santa Barbara, Clemson University, and Evonyx Inc., USA (1997–2001). He has received several awards including National Science Fund for Distinguished Young Scholars, National Excellent Doctoral Dissertation of China, Distinguished Young Scholars for Chinese Academy of Sciences, the Young Electrochemistry Prize of Chinese Chemical Society, and the Li Foundation Prize, USA. His research interests include electroanalytical chemistry, bioelectrochemistry and sensors, physical electrochemistry and interfacial electrochemistry, electrochemical materials science and nanoscopic electrochemistry, fundamental aspects of energy conversion and storage, advanced battery materials, and photoelectrochemistry. He has published over 230 papers in international, peer-reviewed journals with >10 invited review articles. http://www.researcherid.com/rid/D-4283-2012.

    Hai-Chen Wu – Ph.D. obtained his Ph.D. in organic chemistry from University of Cambridge (Cambridge, UK) in 2005. He then moved to Oxford and carried out his postdoctoral research under the supervision of Prof. Hagan Bayley in Department of Chemistry, University of Oxford until the end of 2008. Since early 2009, he has been a principal investigator at the Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences (Beijing, China). Dr Wu's main research interest focuses on modification of nanomaterials and applying them in biosensing studies.

    Xing-Jie Liang – Ph.D. obtained his Ph.D. at National Key Laboratory of Biomacromolecules, Institute of Biophysics at CAS. He finished his postdoc at Center for Cancer Research, NCI, NIH, and worked as a Research Fellow at Surgical Neurology Branch, NINDS. Dr. Liang worked on Molecular imaging at School of Medicine, Howard University before joining as deputy director of CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China. Dr. Liang is current editorial board member of Acta Biophysica Sinica, and Current Nanoscience. Developing drug delivery strategies for prevention/treatment of AIDS and cancers are ongoing research projects in Dr. Liang's lab based on understanding of basic physio-chemical and biological processes of nanomedicine.

    Peixuan Guo – Ph.D. is William Farish Endowed Chair in Nanobiotechnology, and director of the Nanobiotechnology center at the university of Kentucky, and director of NIH/NCI Cancer Nanotechnology Platform Partnership Program: “RNA Nanotechnology for Cancer Therapy”. He obtained his Ph.D from University of Minnesota, and postdoctoral training at NIH, joined Purdue University in 1990, was tenured in 1993, became a full Professor in 1997, and was honored as a Purdue Faculty Scholar in 1998. He constructed phi29 DNA-packaging motor, discovered phi29 motor pRNA, pioneered RNA nanotechnology, incorporated phi29 motor channel into lipid membranes for single-molecule sensing with potential for high-throughput dsDNA sequencing. He is a member of two US prominent national nanotech initiatives sponsored by NIH, NSF, NIST, and National Council of Nanotechnology, director of one NIH Nanomedicine Development Center from 2006 to 2011. His work was featured hundreds of times over radio, TV such as ABC, NBC, newsletters NIH, NSF, MSNBC, NCI, and ScienceNow. http://nanobio.uky.edu/Guo/peixuanguo.html.

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