Reagentless, Structure-Switching, Electrochemical Aptamer-Based Sensors.

The development of structure-switching, electrochemical, aptamer-based sensors over the past ∼10 years has led to a variety of reagentless sensors capable of analytical detection in a range of sample matrices. The crux of this methodology is the coupling of target-induced conformation changes of a redox-labeled aptamer with electrochemical detection of the resulting altered charge transfer rate between the redox molecule and electrode surface. Using aptamer recognition expands the highly sensitive detection ability of electrochemistry to a range of previously inaccessible analytes. In this review, we focus on the methods of sensor fabrication and how sensor signaling is affected by fabrication parameters. We then discuss recent studies addressing the fundamentals of sensor signaling as well as quantitative characterization of the analytical performance of electrochemical aptamer-based sensors. Although the limits of detection of reported electrochemical aptamer-based sensors do not often reach that of gold-standard methods such as enzyme-linked immunosorbent assays, the operational convenience of the sensor platform enables exciting analytical applications that we address. Using illustrative examples, we highlight recent advances in the field that impact important areas of analytical chemistry. Finally, we discuss the challenges and prospects for this class of sensors.

[1]  A. Heeger,et al.  An electronic, aptamer-based small-molecule sensor for the rapid, label-free detection of cocaine in adulterated samples and biological fluids. , 2006, Journal of the American Chemical Society.

[2]  Yuguo Tang,et al.  An aptasensor for detection of potassium ions based on RecJ(f) exonuclease mediated signal amplification. , 2014, The Analyst.

[3]  Arica A Lubin,et al.  Sequence-specific, electronic detection of oligonucleotides in blood, soil, and foodstuffs with the reagentless, reusable E-DNA sensor. , 2006, Analytical chemistry.

[4]  A. Steel,et al.  Electrochemical quantitation of DNA immobilized on gold. , 1998, Analytical chemistry.

[5]  Chunhai Fan,et al.  A target-responsive electrochemical aptamer switch (TREAS) for reagentless detection of nanomolar ATP. , 2007, Journal of the American Chemical Society.

[6]  H. Bayley,et al.  Stochastic sensors inspired by biology , 2001, Nature.

[7]  S. Satija,et al.  Using Self-Assembly To Control the Structure of DNA Monolayers on Gold: A Neutron Reflectivity Study , 1998 .

[8]  Arica A Lubin,et al.  Optimization of electrochemical aptamer-based sensors via optimization of probe packing density and surface chemistry. , 2008, Langmuir : the ACS journal of surfaces and colloids.

[9]  M. Zuker,et al.  Using reliability information to annotate RNA secondary structures. , 1998, RNA.

[10]  Ying Liu,et al.  Simultaneous detection of cell-secreted TNF-α and IFN-γ using micropatterned aptamer-modified electrodes. , 2012, Biomaterials.

[11]  Ryan J. White,et al.  Random walk on a leash: a simple single-molecule diffusion model for surface-tethered redox molecules with flexible linkers. , 2013, Journal of the American Chemical Society.

[12]  Y. Liu,et al.  An aptasensor for electrochemical detection of tumor necrosis factor in human blood. , 2013, The Analyst.

[13]  Eric Bakker,et al.  Solid contact potentiometric sensors for trace level measurements. , 2006, Analytical chemistry.

[14]  Jacqueline K Barton,et al.  DNA electrochemistry with tethered methylene blue. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[15]  Ryan J. White,et al.  The Current and Future Role of Aptamers in Electroanalysis , 2014 .

[16]  Ryan J. White,et al.  Enhancing the analytical performance of electrochemical RNA aptamer-based sensors for sensitive detection of aminoglycoside antibiotics. , 2014, Analytical chemistry.

[17]  Ryan J. White,et al.  Monitoring Cooperative Binding Using Electrochemical DNA-Based Sensors , 2014, Langmuir : the ACS journal of surfaces and colloids.

[18]  Charles R. Martin,et al.  Resistive-Pulse SensingFrom Microbes to Molecules , 2000 .

[19]  A. Heeger,et al.  Effect of molecular crowding on the response of an electrochemical DNA sensor. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[20]  Chunhai Fan,et al.  Aptamer-based biosensors , 2008 .

[21]  R. Wightman,et al.  Electrochemical Analysis of Neurotransmitters. , 2015, Annual review of analytical chemistry.

[22]  Kevin W Plaxco,et al.  Aptamer-based electrochemical detection of picomolar platelet-derived growth factor directly in blood serum. , 2007, Analytical chemistry.

[23]  E. Ferapontova,et al.  An RNA aptamer-based electrochemical biosensor for detection of theophylline in serum. , 2008, Journal of the American Chemical Society.

[24]  A. Heeger,et al.  Label-free electronic detection of thrombin in blood serum by using an aptamer-based sensor. , 2005, Angewandte Chemie.

[25]  E. Ferapontova,et al.  Effect of the DNA end of tethering to electrodes on electron transfer in methylene blue-labeled DNA duplexes. , 2012, Langmuir : the ACS journal of surfaces and colloids.

[26]  T. Hianik,et al.  Influence of ionic strength, pH and aptamer configuration for binding affinity to thrombin. , 2007, Bioelectrochemistry.

[27]  Samantha T. Mensah,et al.  Nanomolar detection limits of Cd²⁺, Ag⁺, and K⁺ using paper-strip ion-selective electrodes. , 2014, Analytical chemistry.

[28]  L. Sombers,et al.  Enzyme-modified carbon-fiber microelectrode for the quantification of dynamic fluctuations of nonelectroactive analytes using fast-scan cyclic voltammetry. , 2013, Analytical chemistry.

[29]  Kurt V. Gothelf,et al.  Optimization of the Electrochemical RNA‐Aptamer Based Biosensor for Theophylline by Using a Methylene Blue Redox Label , 2009 .

[30]  Kevin W Plaxco,et al.  Re-engineering aptamers to support reagentless, self-reporting electrochemical sensors. , 2010, The Analyst.

[31]  Kevin W Plaxco,et al.  Surface chemistry effects on the performance of an electrochemical DNA sensor. , 2009, Bioelectrochemistry.

[32]  Arica A Lubin,et al.  Continuous, real-time monitoring of cocaine in undiluted blood serum via a microfluidic, electrochemical aptamer-based sensor. , 2009, Journal of the American Chemical Society.

[33]  D. Lafontaine,et al.  A loop loop interaction and a K-turn motif located in the lysine aptamer domain are important for the riboswitch gene regulation control. , 2007, RNA.

[34]  Kevin W Plaxco,et al.  Linear, redox modified DNA probes as electrochemical DNA sensors. , 2007, Chemical communications.

[35]  A. Anne,et al.  3'-Ferrocene-labeled oligonucleotide chains end-tethered to gold electrode surfaces: novel model systems for exploring flexibility of short DNA using cyclic voltammetry. , 2003, Journal of the American Chemical Society.

[36]  Itamar Willner,et al.  Electronic aptamer-based sensors. , 2007, Angewandte Chemie.

[37]  Guo-Li Shen,et al.  Reusable electrochemical sensing platform for highly sensitive detection of small molecules based on structure-switching signaling aptamers. , 2007, Analytical chemistry.

[38]  Tao Ye,et al.  Nanoscale spatial distribution of thiolated DNA on model nucleic acid sensor surfaces. , 2013, ACS nano.

[39]  Ryan J. White,et al.  Achieving Reproducible Performance of Electrochemical, Folding Aptamer-Based Sensors on Microelectrodes: Challenges and Prospects , 2014, Analytical chemistry.

[40]  Bo Zhang,et al.  Nanoelectrodes: recent advances and new directions. , 2012, Annual review of analytical chemistry.

[41]  Jonathan Richards,et al.  Electrochemical aptamer scaffold biosensors for detection of botulism and ricin toxins. , 2015, Chemical communications.

[42]  Jiani Xie,et al.  A universal strategy for aptamer-based nanopore sensing through host-guest interactions inside α-hemolysin. , 2015, Angewandte Chemie.

[43]  M. Stojanović,et al.  Aptamer-based folding fluorescent sensor for cocaine. , 2001, Journal of the American Chemical Society.

[44]  Kevin W Plaxco,et al.  Real-Time, Aptamer-Based Tracking of Circulating Therapeutic Agents in Living Animals , 2013, Science Translational Medicine.

[45]  Koji Sode,et al.  Novel electrochemical sensor system for protein using the aptamers in sandwich manner. , 2005, Biosensors & bioelectronics.

[46]  Kevin W Plaxco,et al.  On the Signaling of Electrochemical Aptamer-Based Sensors: Collision- and Folding-Based Mechanisms. , 2009, Electroanalysis.

[47]  Joe C. Liang,et al.  Kinetic and Equilibrium Binding Characterization of Aptamers to Small Molecules using a Label-Free, Sensitive, and Scalable Platform , 2014, Analytical chemistry.

[48]  Dmitrii E. Makarov,et al.  A mechanistic study of electron transfer from the distal termini of electrode-bound, single-stranded DNAs. , 2010, Journal of the American Chemical Society.

[49]  Kevin W Plaxco,et al.  Preparation of electrode-immobilized, redox-modified oligonucleotides for electrochemical DNA and aptamer-based sensing , 2007, Nature Protocols.

[50]  Ryan J. White,et al.  Rationally Designing Aptamer Sequences with Reduced Affinity for Controlled Sensor Performance , 2015, Sensors.

[51]  A. Stein,et al.  Rational design of all-solid-state ion-selective electrodes and reference electrodes , 2016 .

[52]  Michael Zuker,et al.  Mfold web server for nucleic acid folding and hybridization prediction , 2003, Nucleic Acids Res..

[53]  H. Seo,et al.  Electrochemical and Vibrational Spectroscopic Characterization of Self-Assembled Monolayers of 1,1‘-Disubstituted Ferrocene Derivatives on Gold , 2000 .

[54]  Andrew D Ellington,et al.  In vitro selection of molecular beacons. , 2003, Nucleic acids research.

[55]  R. Rando,et al.  Specific binding of aminoglycoside antibiotics to RNA. , 1995, Chemistry & biology.

[56]  A. Heeger,et al.  Comparison of the signaling and stability of electrochemical DNA sensors fabricated from 6- or 11-carbon self-assembled monolayers. , 2006, Langmuir : the ACS journal of surfaces and colloids.

[57]  Ciara K O'Sullivan,et al.  Aptamer conformational switch as sensitive electrochemical biosensor for potassium ion recognition. , 2006, Chemical communications.

[58]  Kevin W Plaxco,et al.  Exploiting binding-induced changes in probe flexibility for the optimization of electrochemical biosensors. , 2010, Analytical chemistry.

[59]  Kayla Hill,et al.  Comprehensive analytical comparison of strategies used for small molecule aptamer evaluation. , 2015, Analytical chemistry.

[60]  F. Ricci,et al.  Determinants of the detection limit and specificity of surface-based biosensors. , 2013, Analytical chemistry.

[61]  Kevin W Plaxco,et al.  Reagentless measurement of aminoglycoside antibiotics in blood serum via an electrochemical, ribonucleic acid aptamer-based biosensor. , 2010, Analytical chemistry.

[62]  Shusheng Zhang,et al.  Electrochemical biosensor for detection of adenosine based on structure-switching aptamer and amplification with reporter probe DNA modified Au nanoparticles. , 2008, Analytical chemistry.

[63]  A. Pardi,et al.  NMR chemical exchange as a probe for ligand-binding kinetics in a theophylline-binding RNA aptamer. , 2009, Journal of the American Chemical Society.

[64]  Kevin W Plaxco,et al.  Comparing the properties of electrochemical-based DNA sensors employing different redox tags. , 2009, Analytical chemistry.

[65]  Ying Liu,et al.  Aptamer-based electrochemical biosensor for interferon gamma detection. , 2010, Analytical chemistry.

[66]  A. Steel,et al.  Immobilization of nucleic acids at solid surfaces: effect of oligonucleotide length on layer assembly. , 2000, Biophysical journal.

[67]  Xiao-li Xu,et al.  Development of an electrochemical aptamer-based sensor with a sensitive Fe3O4 nanopaticle-redox tag for reagentless protein detection , 2011 .

[68]  Ryan J. White,et al.  Heterogeneous Electrochemical Aptamer-Based Sensor Surfaces for Controlled Sensor Response. , 2015, Langmuir : the ACS journal of surfaces and colloids.

[69]  Ying Liu,et al.  Detecting multiple cell-secreted cytokines from the same aptamer-functionalized electrode. , 2015, Biosensors & bioelectronics.

[70]  Itamar Willner,et al.  Label-free and reagentless aptamer-based sensors for small molecules. , 2006, Journal of the American Chemical Society.

[71]  N. Curtis,et al.  Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children , 2006, Thorax.

[72]  Kurt V Gothelf,et al.  Effect of serum on an RNA aptamer-based electrochemical sensor for theophylline. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[73]  S. Shishido,et al.  Rational design of a structure-switching DNA aptamer for potassium ions , 2014, FEBS open bio.

[74]  Emilie Viennois,et al.  Microelectrode miRNA sensors enabled by enzymeless electrochemical signal amplification. , 2015, Analytical chemistry.

[75]  U. Landegren,et al.  Protein detection using proximity-dependent DNA ligation assays , 2002, Nature Biotechnology.

[76]  Ryan J. White,et al.  Monitoring Charge Flux to Quantify Unusual Ligand-Induced Ion Channel Activity for Use in Biological Nanopore-Based Sensors , 2014, Analytical chemistry.

[77]  R. Prins,et al.  Decomposition of the ferricenium cation by nucleophilic reagents , 1972 .

[78]  H. Bayley,et al.  Protein Detection by Nanopores Equipped with Aptamers , 2012, Journal of the American Chemical Society.

[79]  Y. Gogotsi,et al.  Platinized carbon nanoelectrodes as potentiometric and amperometric SECM probes , 2013, Journal of Solid State Electrochemistry.

[80]  C. Demaille,et al.  Dynamics of electron transport by elastic bending of short DNA duplexes. Experimental study and quantitative modeling of the cyclic voltammetric behavior of 3'-ferrocenyl DNA end-grafted on gold. , 2006, Journal of the American Chemical Society.

[81]  Eun Jeong Cho,et al.  Applications of aptamers as sensors. , 2009, Annual review of analytical chemistry.

[82]  Kevin W Plaxco,et al.  Engineering new aptamer geometries for electrochemical aptamer-based sensors , 2009, Defense + Commercial Sensing.

[83]  A. Ulman,et al.  Formation and Structure of Self-Assembled Monolayers. , 1996, Chemical reviews.

[84]  A. Vallée-Bélisle,et al.  Using distal-site mutations and allosteric inhibition to tune, extend, and narrow the useful dynamic range of aptamer-based sensors. , 2012, Journal of the American Chemical Society.

[85]  Youdong Mao,et al.  Studies of temperature-dependent electronic transduction on DNA hairpin loop sensor. , 2003, Nucleic acids research.

[86]  Zimple Matharu,et al.  Detecting Transforming Growth Factor-β Release from Liver Cells Using an Aptasensor Integrated with Microfluidics , 2014, Analytical chemistry.

[87]  Kevin W Plaxco,et al.  High specificity, electrochemical sandwich assays based on single aptamer sequences and suitable for the direct detection of small-molecule targets in blood and other complex matrices. , 2009, Journal of the American Chemical Society.

[88]  Dinshaw J. Patel,et al.  Solution structure of the tobramycin–RNA aptamer complex , 1998, Nature Structural Biology.

[89]  Jinghong Li,et al.  Label-free nanopore proximity bioassay for platelet-derived growth factor detection. , 2015, Analytical chemistry.