Publications by authors named "Mark A Reed"

60 Publications

Discovery of a series of 2-((1-phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

ChemMedChem 2021 Mar 23. Epub 2021 Mar 23.

University Health Network, Krembil Research Institute, CANADA.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, compound 12f exhibited a strong IDO1 inhibitory activity (IC50 = 0.16 µM, EC50= 0.3 µM). SAR and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the most promising compounds, 9d and 12f, were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.
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http://dx.doi.org/10.1002/cmdc.202100107DOI Listing
March 2021

Furazans in Medicinal Chemistry.

J Med Chem 2021 02 11;64(4):1786-1815. Epub 2021 Feb 11.

Treventis Corporation, Toronto, Ontario M5T 0S8, Canada.

Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms. While the 1,2,4- and 1,3,4-oxadiazoles have seen widespread application in medicinal chemistry, 1,2,5-oxadiazoles (furazans) are less common. This Review provides a summary of the application of furazan-containing molecules in medicinal chemistry and drug development programs from analysis of both patent and academic literature. Emphasis is placed on programs that reached clinical or preclinical stages of development. The examples provided herein describe the pharmacology and biological activity of furazan derivatives with comparative data provided where possible for other heterocyclic groups and pharmacophores commonly used in medicinal chemistry.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01901DOI Listing
February 2021

A Gd@C single-molecule electret.

Nat Nanotechnol 2020 Dec 12;15(12):1019-1024. Epub 2020 Oct 12.

National Laboratory of Solid State Microstructures, Collaborative Innovation Center of Advanced Microstructures, and School of Physics, Nanjing University, Nanjing, China.

Electrets are dielectric materials that have a quasi-permanent dipole polarization. A single-molecule electret is a long-sought-after nanoscale component because it can lead to miniaturized non-volatile memory storage devices. The signature of a single-molecule electret is the switching between two electric dipole states by an external electric field. The existence of these electrets has remained controversial because of the poor electric dipole stability in single molecules. Here we report the observation of a gate-controlled switching between two electronic states in Gd@C. The encapsulated Gd atom forms a charged centre that sets up two single-electron transport channels. A gate voltage of ±11 V (corresponding to a coercive field of ~50 mV Å) switches the system between the two transport channels with a ferroelectricity-like hysteresis loop. Using density functional theory, we assign the two states to two different permanent electrical dipole orientations generated from the Gd atom being trapped at two different sites inside the C cage. The two dipole states are separated by a transition energy barrier of 11 meV. The conductance switching is then attributed to the electric-field-driven reorientation of the individual dipole, as the coercive field provides the necessary energy to overcome the transition barrier.
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http://dx.doi.org/10.1038/s41565-020-00778-zDOI Listing
December 2020

Overcoming the sensitivity vs. throughput tradeoff in Coulter counters: A novel side counter design.

Biosens Bioelectron 2020 Nov 22;168:112507. Epub 2020 Aug 22.

Department of Electrical Engineering, Yale University, New Haven, CT, United States; Department of Applied Physics, Yale University, New Haven, CT, United States. Electronic address:

Microfabricated Coulter counters are attractive for point of care (POC) applications since they are label free and compact. However, these approaches inherently suffer from a trade off between sample throughput and sensitivity. The counter measures a change in impedance due to displaced fluid volume by passing cells, and thus the counter's signal increases with the fraction of the sensing volume displaced. Reducing the size of the sensing region requires reductions in volumetric throughput in the absence of increased hydraulic pressure and sensor bandwidth. The risk of mechanical clog formation, rendering the counter inoperable, increases markedly with reductions in the size of the constriction aperture. We present here a microfluidic coplanar Coulter counter device design that overcomes the problem of constriction clogging while capable of operating in microfluidic channels filled entirely with highly conductive sample. The device utilizes microfabricated planar electrodes projecting into one side of the microfluidic channel and is easily integrated with upstream electronic, hydrodynamic, or other focusing units to produce efficient counting which could allow for dramatically increased volumetric and sample throughput. The design lends itself to simple, cost effective POC applications.
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http://dx.doi.org/10.1016/j.bios.2020.112507DOI Listing
November 2020

Continuous Label-Free Electronic Discrimination of T Cells by Activation State.

ACS Nano 2020 07 25;14(7):8646-8657. Epub 2020 Jun 25.

Department of Electrical Engineering, School of Engineering and Applied Sciences, Yale University, New Haven, Connecticut 06511, United States.

The sensitivity and speed with which the immune system reacts to host disruption is unrivaled by any detection method for pathogenic biomarkers or infectious signatures. Engagement of cellular immunity in response to infections or cancer is contingent upon activation and subsequent cytotoxic activity by T cells. Thus, monitoring T cell activation can reliably serve as a metric for disease diagnosis as well as therapeutic prognosis. Rapid and direct quantification of T cell activation states, however, has been hindered by challenges associated with antigen target identification, labeling requirements, and assay duration. Here we present an electronic, label-free method for simultaneous separation and evaluation of T cell activation states. Our device utilizes a microfluidic design integrated with nanolayered electrode structures for dielectrophoresis (DEP)-driven discrimination of activated naïve T cells at single-cell resolution and demonstrates rapid (<2 min) separation of T cells at high single-pass efficiency as quantified by an on-chip Coulter counter module. Our device represents a microfluidic tool for electronic assessment of immune activation states and, hence, a portable diagnostic for quantitative evaluation of immunity and disease state. Further, its ability to achieve label-free enrichment of activated immune cells promises clinical utility in cell-based immunotherapies.
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http://dx.doi.org/10.1021/acsnano.0c03018DOI Listing
July 2020

The Brain Exposure Efficiency (BEE) Score.

ACS Chem Neurosci 2020 01 27;11(2):205-224. Epub 2019 Dec 27.

Krembil Research Institute , University Health Network , 60 Leonard Avenue , Toronto , Ontario M5T 2S8 , Canada.

The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration are important to neurological drug design. A novel prediction algorithm, termed the Brain Exposure Efficiency Score (BEE), is presented. BEE addresses the need to incorporate the role of trans-BBB influx and efflux active transporters by considering key brain penetrance parameters, namely, steady state unbound brain to plasma ratio of drug () and dose normalized unbound concentration of drug in brain (). BEE was devised using quantitative structure-activity relationships (QSARs) and molecular modeling studies on known transporter proteins and their ligands. The developed algorithms are provided as a user-friendly open source calculator to assist in optimizing a brain penetrance strategy during the early phases of small molecule molecular therapeutic design.
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http://dx.doi.org/10.1021/acschemneuro.9b00650DOI Listing
January 2020

Enhancing Lithium Insertion with Electrostatic Nanoconfinement in a Lithography Patterned Precision Cell.

ACS Nano 2019 Jul 5;13(7):8481-8489. Epub 2019 Jul 5.

Department of Electrical Engineering , Yale University , New Haven , Connecticut 06511 , United States.

The rapidly growing demand for portable electronics, electric vehicles, and grid storage drives the pursuit of high-performance electrical energy storage (EES). A key strategy for improving EES performance is exploiting nanostructured electrodes that present nanoconfined environments of adjacent electrolytes, with the goal to decrease ion diffusion paths and increase active surface areas. However, fundamental gaps persist in understanding the interface-governed electrochemistry in such nanoconfined geometries, in part because of the imprecise and variable dimension control. Here, we report quantification of lithium insertion under nanoconfinement of the electrolyte in a precise lithography-patterned nanofluidic cell. We show a mechanism that enhances ion insertion under nanoconfinement, namely, selective ion accumulation when the confinement length is comparable to the electrical double layer thickness. The nanofabrication approach with uniform and accurate dimensional control provides a versatile model system to explore fundamental mechanisms of nanoscale electrochemistry, which could have an impact on practical energy storage systems.
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http://dx.doi.org/10.1021/acsnano.9b04390DOI Listing
July 2019

Trapping of sub-100 nm nanoparticles using gigahertz acoustofluidic tweezers for biosensing applications.

Nanoscale 2019 Aug;11(31):14625-14634

State Key Laboratory of Precision Measuring Technology & Instruments, College of Precision Instrument and Optoelectronics Engineering, Tianjin University, Tianjin 300072, China.

In this study, we present a nanoscale acoustofluidic trap (AFT) that manipulates nanoparticles in a microfluidic system actuated by a gigahertz acoustic resonator. The AFT generates independent standing closed vortices with high-speed rotation. Via careful design and optimization of geometric confinements, the AFT was able to effectively capture and enrich sub-100 nm nanoparticles with a low power consumption (0.25-5 μW μm-2) and rapid trapping (within 30 s), showing significantly enhanced particle-operating ability as compared to its acoustic and optical counterparts; using specifically functionalized nanoparticles (SFNPs) to selectively capture target molecules from the sample, the AFT led to the molecular concentration enhancement of ∼200 times. We investigated the feasibility of the SFNP-assisted AFT preconcentration method for biosensing applications and successfully demonstrated the capability of this method for the detection of serum prostate-specific antigen (PSA). The AFT was prepared via a fully CMOS-compatible process and thus could be conveniently integrated on a single chip, with potential for "lab-on-a-chip" or point-of-care (POC) nanoparticle-based biosensing applications.
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http://dx.doi.org/10.1039/c9nr03529jDOI Listing
August 2019

Charge Transfer from Carbon Nanotubes to Silicon in Flexible Carbon Nanotube/Silicon Solar Cells.

Small 2017 12 10;13(48). Epub 2017 Nov 10.

Department of Chemical and Environmental Engineering, Yale University, New Haven, CT, 06511, USA.

Mechanical fragility and insufficient light absorption are two major challenges for thin flexible crystalline Si-based solar cells. Flexible hybrid single-walled carbon nanotube (SWNT)/Si solar cells are demonstrated by applying scalable room-temperature processes for the fabrication of solar-cell components (e.g., preparation of SWNT thin films and SWNT/Si p-n junctions). The flexible SWNT/Si solar cells present an intrinsic efficiency ≈7.5% without any additional light-trapping structures. By using these solar cells as model systems, the charge transport mechanisms at the SWNT/Si interface are investigated using femtosecond transient absorption. Although primary photon absorption occurs in Si, transient absorption measurements show that SWNTs also generate and inject excited charge carriers to Si. Such effects can be tuned by controlling the thickness of the SWNTs. Findings from this study could open a new pathway for designing and improving the efficiency of photocarrier generation and absorption for high-performance ultrathin hybrid SWNT/Si solar cells.
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http://dx.doi.org/10.1002/smll.201702387DOI Listing
December 2017

Nanoelectronic Platform for Ultrasensitive Detection of Protein Biomarkers in Serum using DNA Amplification.

Anal Chem 2017 11 17;89(21):11325-11331. Epub 2017 Oct 17.

Department of Electrical Engineering, Yale University , New Haven, Connecticut 06511, United States.

Silicon nanowire field effect transistors (NWFETs) are low noise, low power, ultrasensitive biosensors that are highly amenable to integration. However, using NWFETs to achieve direct protein detection in physiological buffers such as blood serum remains difficult due to Debye screening, nonspecific binding, and stringent functionalization requirements. In this work, we performed an indirect sandwich immunoassay in serum combined with exponential DNA amplification and pH measurement by ultrasensitive NWFET sensors. Measurements of model cytokine interleukin-2 concentrations from <20 fM to >200 pM were demonstrated, surpassing the conventional NWFET urease-based readout. Our approach paves way for future development of universal, highly sensitive, miniaturized, and integrated nanoelectronic devices that can be applied to a wide variety of analytes.
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http://dx.doi.org/10.1021/acs.analchem.7b02036DOI Listing
November 2017

Smartphone-Enabled Colorimetric Trinitrotoluene Detection Using Amine-Trapped Polydimethylsiloxane Membranes.

ACS Appl Mater Interfaces 2017 Apr 11;9(16):14445-14452. Epub 2017 Apr 11.

State Key Laboratory of Precision Measuring Technology & Instruments, Tianjin University , Tianjin 300072, China.

A smartphone-enabled platform for easy and portably colorimetric analysis of 2,4,6-trinitrotoluene (TNT) using amine-trapped PDMS is designed and implemented. The amine-trapped polydimethylsiloxane (PDMS) is simply prepared by immersing the cured PDMS in aminosilane solutions forming an amine-containing polymer. After contacting with TNT-containing solutions, the colorless PDMS showed a rapid colorimetric change which can be easily identified by the naked eye. The amine-trapped PDMS was carefully optimized to achieve visible detection of TNT at concentrations as low as 1 μM. Using an integrated camera in the smartphone, pictures of colored PDMS membranes can be analyzed by a home-developed mobile application. Thus, the TNT amount can be precisely quantified. Direct TNT detection in real samples (e.g., drinking, tap, and lake waters) is demonstrated as well. The smartphone-enabled colorimetric method using amine-trapped PDMS membranes realizes a convenient and efficient approach toward a portable system for field TNT detections.
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http://dx.doi.org/10.1021/acsami.7b03314DOI Listing
April 2017

Extended Gate Field-Effect Transistor Biosensors for Point-Of-Care Testing of Uric Acid.

Methods Mol Biol 2017 ;1572:189-203

Department of Electrical Engineering, Yale University, New Haven, CT, 06520, USA.

An enzyme-free redox potential sensor using off-chip extended-gate field effect transistor (EGFET) with a ferrocenyl-alkanethiol modified gold electrode has been used to quantify uric acid concentration in human serum and urine. Hexacyanoferrate (II) and (III) ions are used as redox reagent. The potentiometric sensor measures the interface potential on the ferrocene immobilized gold electrode, which is modulated by the redox reaction between uric acid and hexacyanoferrate ions. The device shows a near Nernstian response to uric acid and is highly specific to uric acid in human serum and urine. The interference that comes from glucose, bilirubin, ascorbic acid, and hemoglobin is negligible in the normal concentration range of these interferents. The sensor also exhibits excellent long term reliability and is regenerative. This extended gate field effect transistor based sensor is promising for point-of-care detection of uric acid due to the small size, low cost, and low sample volume consumption.
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http://dx.doi.org/10.1007/978-1-4939-6911-1_13DOI Listing
February 2018

Metal-coated microfluidic channels: An approach to eliminate streaming potential effects in nano biosensors.

Biosens Bioelectron 2017 Jan 24;87:447-452. Epub 2016 Aug 24.

Department of Electrical Engineering, Yale University, New Haven, CT 06511, United States; Department of Applied Physics, Yale University, New Haven, CT 06511, United States. Electronic address:

We report a method to suppress streaming potential using an Ag-coated microfluidic channel on a p-type silicon nanowire (SiNW) array measured by a multiplexed electrical readout. The metal layer sets a constant electrical potential along the microfluidic channel for a given reference electrode voltage regardless of the flow velocity. Without the Ag layer, the magnitude and sign of the surface potential change on the SiNW depends on the flow velocity, width of the microfluidic channel and the device's location inside the microfluidic channel with respect to the reference electrode. Noise analysis of the SiNW array with and without the Ag coating in the fluidic channel shows that noise frequency peaks, resulting from the operation of a piezoelectric micropump, are eliminated using the Ag layer with two reference electrodes located at inlet and outlet. This strategy presents a simple platform to eliminate the streaming potential and can become a powerful tool for nanoscale potentiometric biosensors.
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http://dx.doi.org/10.1016/j.bios.2016.08.065DOI Listing
January 2017

Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid.

Bioorg Med Chem Lett 2016 Jan 10;26(1):100-4. Epub 2015 Nov 10.

Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax, NS B3H 4R2, Canada. Electronic address:

N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure-activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone.
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http://dx.doi.org/10.1016/j.bmcl.2015.11.022DOI Listing
January 2016

Direct Observation of Charge Inversion in Divalent Nanofluidic Devices.

Nano Lett 2015 Aug 30;15(8):5046-51. Epub 2015 Jun 30.

§Department of Electrical Engineering, Pennsylvania State University, State College, Pennsylvania 16801, United States.

Solid-state nanofluidic devices have proven to be ideal systems for studying the physics of ionic transport at the nanometer length scale. When the geometrical confining size of fluids approaches the ionic Debye screening length, new transport phenomena occur, such as surface mediated transport and permselectivity. Prior work has explored these effects extensively in monovalent systems (e.g., predominantly KCl and NaCl). In this report, we present a new characterization method for the study of divalent ionic transport and have unambiguously observed divalent charge inversion at solid/fluid interfaces. This observation has important implications in applications ranging from biology to energy conversion.
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http://dx.doi.org/10.1021/acs.nanolett.5b01115DOI Listing
August 2015

Direct, rapid, and label-free detection of enzyme-substrate interactions in physiological buffers using CMOS-compatible nanoribbon sensors.

Nano Lett 2014 Sep 28;14(9):5315-22. Epub 2014 Aug 28.

Department of Electrical Engineering, Yale University , New Haven, Connecticut 06511, United States.

We demonstrate the versatility of Al2O3-passivated Si nanowire devices ("nanoribbons") in the analysis of enzyme-substrate interactions via the monitoring of pH change. Our approach is shown to be effective through the detection of urea in phosphate buffered saline (PBS), and penicillinase in PBS and urine, at limits of detection of <200 μM and 0.02 units/mL, respectively. The ability to extract accurate enzyme kinetics and the Michaelis-Menten constant (Km) from the acetylcholine-acetylcholinesterase reaction is also demonstrated.
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http://dx.doi.org/10.1021/nl502366eDOI Listing
September 2014

Voltage gated ion and molecule transport in engineered nanochannels: theory, fabrication and applications.

Nanotechnology 2014 Mar 25;25(12):122001. Epub 2014 Feb 25.

Department of Electrical Engineering, Yale University, New Haven, CT 06520, USA.

Nanochannels remain at the focus of growing scientific and technological interest. The nanometer scale of the structure allows the discovery of a new range of phenomena that has not been possible in traditional microchannels, among which a direct field effect control over the charges in nanochannels is very attractive for various applications, since it offers a unique opportunity to integrate wet ionics with dry electronics seamlessly. This review will focus on the voltage gated ionic and molecular transport in engineered gated nanochannels. We will present an overview of the transport theory. Fabrication techniques regarding the gated nanostructures will also be discussed. In addition, various applications using the voltage gated nanochannels are outlined, which involves biological and chemical analysis, and energy conversion.
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http://dx.doi.org/10.1088/0957-4484/25/12/122001DOI Listing
March 2014

Complementary metal oxide semiconductor-compatible silicon nanowire biofield-effect transistors as affinity biosensors.

Nanomedicine (Lond) 2013 Nov;8(11):1839-51

State Key Laboratory of Precision Measuring Technology & Instruments, Tianjin University, Tianjin 300072, China.

Affinity biosensors use biorecognition elements and transducers to convert a biochemical event into a recordable signal. They provides the molecule binding information, which includes the dynamics of biomolecular association and dissociation, and the equilibrium association constant. Complementary metal oxide semiconductor-compatible silicon (Si) nanowires configured as a field-effect transistor (NW FET) have shown significant advantages for real-time, label-free and highly sensitive detection of a wide range of biomolecules. Most research has focused on reducing the detection limit of Si-NW FETs but has provided less information about the real binding parameters of the biomolecular interactions. Recently, Si-NW FETs have been demonstrated as affinity biosensors to quantify biomolecular binding affinities and kinetics. They open new applications for NW FETs in the nanomedicine field and will bring such sensor technology a step closer to commercial point-of-care applications. This article summarizes the recent advances in bioaffinity measurement using Si-NW FETs, with an emphasis on the different approaches used to address the issues of sensor calibration, regeneration, binding kinetic measurements, limit of detection, sensor surface modification, biomolecule charge screening, reference electrode integration and nonspecific molecular binding.
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http://dx.doi.org/10.2217/nnm.13.156DOI Listing
November 2013

Highly specific and sensitive non-enzymatic determination of uric acid in serum and urine by extended gate field effect transistor sensors.

Biosens Bioelectron 2014 Jan 7;51:225-31. Epub 2013 Aug 7.

Department of Electrical Engineering, Yale University, New Haven, CT 06520, USA. Electronic address:

A potentiometric non-enzymatic sensor using off-chip extended-gate field effect transistor (EGFET) with a ferrocenyl-alkanethiol modified gold electrode is demonstrated for determining the uric acid concentration in human serum and urine. Hexacyanoferrate (II) and (III) ions are used as redox reagent. This potentiometric sensor measures the interface potential on the ferrocene immobilized gold electrode, which is modulated by the redox reaction between uric acid and hexacyanoferrate ions. The device shows a near Nernstian response to uric acid and is highly specific. The interference that comes from glucose, bilirubin, ascorbic acid and hemoglobin is negligible in normal concentration range of these interferents. The sensor also exhibits excellent long term reliability. This extended gate field effect transistor based sensors can be used as a point of care UA testing tool, due to the small size, low cost, and low sample volume consumption.
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http://dx.doi.org/10.1016/j.bios.2013.07.061DOI Listing
January 2014

Performance limitations for nanowire/nanoribbon biosensors.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2013 Nov-Dec;5(6):629-45. Epub 2013 Jul 29.

Department of Applied Physics, Yale University, New Haven, CT, USA.

Field-effect transistor-based biosensors (bioFETs) have shown great promise in the field of fast, ultra-sensitive, label-free detection of biomolecules. Reliability and accuracy, when trying to measure small concentrations, is of paramount importance for the translation of these research devices into the clinical setting. Our knowledge and experience with these sensors has reached a stage where we are able to identify three main aspects of bioFET sensing that currently limit their applications. By considering the intrinsic device noise as a limitation to the smallest measurable signal, we show how various parameters, processing steps and surface modifications, affect the limit of detection. We also introduce the signal-to-noise ratio of bioFETs as a universal performance metric, which allows us to gain better insight into the design of more sensitive devices. Another aspect that places a limit on the performance of bioFETs is screening by the electrolyte environment, which reduces the signal that could be potentially measured. Alternative functionalization and detection schemes that could enable the use of these charge-based sensors in physiological conditions are highlighted. Finally, the binding kinetics of the receptor-analyte system are considered, both in the context of extracting information about molecular interactions using the bioFET sensor platform and as a fundamental limitation to the number of molecules that bind to the sensor surface at steady-state conditions and to the signal that is generated. Some strategies to overcome these limitations are also proposed. Taken together, these performance-limiting issues, if solved, would bring bioFET sensors closer to clinical applications.
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http://dx.doi.org/10.1002/wnan.1235DOI Listing
May 2014

Predictive simulations and optimization of nanowire field-effect PSA sensors including screening.

Nanotechnology 2013 Jun 3;24(22):225503. Epub 2013 May 3.

AIT Austrian Institute of Technology, Donau-City-Strasse 1, A-1220 Vienna, Austria.

We apply our self-consistent PDE model for the electrical response of field-effect sensors to the 3D simulation of nanowire PSA (prostate-specific antigen) sensors. The charge concentration in the biofunctionalized boundary layer at the semiconductor-electrolyte interface is calculated using the propka algorithm, and the screening of the biomolecules by the free ions in the liquid is modeled by a sensitivity factor. This comprehensive approach yields excellent agreement with experimental current-voltage characteristics without any fitting parameters. Having verified the numerical model in this manner, we study the sensitivity of nanowire PSA sensors by changing device parameters, making it possible to optimize the devices and revealing the attributes of the optimal field-effect sensor.
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http://dx.doi.org/10.1088/0957-4484/24/22/225503DOI Listing
June 2013

Regenerative electronic biosensors using supramolecular approaches.

ACS Nano 2013 May 8;7(5):4014-21. Epub 2013 Apr 8.

Department of Electrical Engineering, Yale University, New Haven, Connecticut 06520, United States.

A supramolecular interface for Si nanowire FETs has been developed with the aim of creating regenerative electronic biosensors. The key to the approach is Si-NWs functionalized with β-cyclodextrin (β-CD), to which receptor moieties can be attached with an orthogonal supramolecular linker. Here we demonstrate full recycling using the strongest biomolecular system known, streptavidin (SAv)-biotin. The bound SAv and the linkers can be selectively removed from the surface through competitive desorption with concentrated β-CD, regenerating the sensor for repeated use. An added advantage of β-CD is the possibility of stereoselective sensors, and we demonstrate here the ability to quantify the enantiomeric composition of chiral targets.
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http://dx.doi.org/10.1021/nn306034fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665757PMC
May 2013

Quantitative probing of surface charges at dielectric-electrolyte interfaces.

Lab Chip 2013 Apr;13(7):1431-6

Department of Electrical Engineering, Yale University, New Haven, Connecticut 06520, USA.

The intrinsic charging status at the dielectric-electrolyte interface (DEI) plays a critical role for electrofluidic gating in microfluidics and nanofluidics, which offers opportunities for integration of wet ionics with dry electronics. A convenient approach to quantitatively probe the surface charges at the DEI for material pre-selection purpose has been lacking so far. We report here a low-cost, off-chip extended gate field effect transistor configuration for direct electrostatic probing the charging status at the DEI. Capacitive coupling between the surface charges and the floating extended gate is utilized for signal transducing. The relationship between the surface charge density and the experimentally accessible quantities is given by device modeling. The multiplexing ability makes measuring a local instead of a globally averaged surface charge possible.
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http://dx.doi.org/10.1039/c3lc41351aDOI Listing
April 2013

Striving for a zero-error patient surgical journey through adoption of aviation-style challenge and response flow checklists: a quality improvement project.

Paediatr Anaesth 2013 Jul 4;23(7):571-8. Epub 2013 Feb 4.

Department of Anesthesiology and Pain Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.

Aims: We describe our aim to create a zero-error system in our pediatric ambulatory surgery center by employing effective teamwork and aviation-style challenge and response 'flow checklists' at key stages of the patient surgical journey. These are used in addition to the existing World Health Organization Surgical Safety Checklists (Ann Surg, 255, 2012 and 44).

Background: Bellevue Surgery Center is a freestanding ambulatory surgery center affiliated with Seattle Children's Hospital, WA, USA. Approximately three thousand ambulatory surgeries are performed each year across a variety of surgical disciplines.

Methods: Key points in the patient surgical journey were identified as high risk (different time points from the WHO safer surgery checklists). These were moments when the team, patient, and equipment have to been reconfigured to maximize patient safety. These points were departure from induction room, arrival in the operating room, departure from operating room, and arrival in the postanesthesia care unit. Traditionally, the anesthesiologist has memorized a list of 'do-not-forget items' for each of these stages. We recognized the potential for error to occur if the process was solely the responsibility of one individual and their memory. So we created 'flow checklists' executed by the team at every one of these high-risk points. We adopted a challenge and response system for these flow checklists as this is a tried and tested system widely used in aviation for critical tasks such as configuring an aircraft pretakeoff and prelanding.

Results: A staff survey with a 72% response rate (n = 29) showed that the team valued the checklists and thought they contributed to patient safety. To date, we have had zero incidence of omitting any of the 24 items listed on the four flow checklists.

Conclusions: We have created a reproducible model of care involving multiple checklists at high-risk points in the patient surgical journey. The model is reliable and has a high degree of staff engagement. It promotes patient safety by ensuring the patient, team and equipment are correctly configured at every key transition stage in the surgical journey. We have been able to achieve this with no measurable increase in turnover times or reduction in operating room efficiency.
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http://dx.doi.org/10.1111/pan.12121DOI Listing
July 2013

Record high efficiency single-walled carbon nanotube/silicon p-n junction solar cells.

Nano Lett 2013 Jan 17;13(1):95-9. Epub 2012 Dec 17.

Department of Electrical Engineering, Yale University, New Haven, Connecticut 06520, USA.

Carrier transport characteristics in high-efficiency single-walled carbon nanotubes (SWNTs)/silicon (Si) hybrid solar cells are presented. The solar cells were fabricated by depositing intrinsic p-type SWNT thin-films on n-type Si wafers without involving any high-temperature process for p-n junction formation. The optimized cells showed a device ideality factor close to unity and a record-high power-conversion-efficiency of >11%. By investigating the dark forward current density characteristics with varying temperature, we have identified that the temperature-dependent current rectification originates from the thermally activated band-to-band transition of carriers in Si, and the role of the SWNT thin films is to establish a built-in potential for carrier separation/collection. We have also established that the dominant carrier transport mechanism is diffusion, with minimal interface recombination. This is further supported by the observation of a long minority carrier lifetime of ~34 μs, determined by the transient recovery method. This study suggests that these hybrid solar cells operate in the same manner as single crystalline p-n homojunction Si solar cells.
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http://dx.doi.org/10.1021/nl3035652DOI Listing
January 2013

Electric field modulation of the membrane potential in solid-state ion channels.

Nano Lett 2012 Dec 20;12(12):6441-7. Epub 2012 Nov 20.

Department of Electrical Engineering, Yale University, New Haven, Connecticut 06520, United States.

Biological ion channels are molecular devices that allow a rapid flow of ions across the cell membrane. Normal physiological functions, such as generating action potentials for cell-to-cell communication, are highly dependent on ion channels that can open and close in response to external stimuli for regulating ion permeation. Mimicking these biological functions using synthetic structures is a rapidly progressing yet challenging area. Here we report the electric field modulation of the membrane potential phenomena in mechanically and chemically robust solid-state ion channels, an abiotic analogue to the voltage-gated ion channels in living systems. To understand the complex physicochemical processes in the electric field regulated membrane potential behavior, both quasi-static and transient characteristics of converting transmembrane ion gradients into electric potential are investigated. It is found that the transmembrane potential can be adequately tuned by an external electrical stimulation, thanks to the unique properties of the voltage-regulated selective ion transport through a nanoscale channel.
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http://dx.doi.org/10.1021/nl303820aDOI Listing
December 2012

Quantification of the affinities and kinetics of protein interactions using silicon nanowire biosensors.

Nat Nanotechnol 2012 May 27;7(6):401-7. Epub 2012 May 27.

Department of Electrical Engineering, Yale University, New Haven, Connecticut 06520, USA.

Monitoring the binding affinities and kinetics of protein interactions is important in clinical diagnostics and drug development because such information is used to identify new therapeutic candidates. Surface plasmon resonance is at present the standard method used for such analysis, but this is limited by low sensitivity and low-throughput analysis. Here, we show that silicon nanowire field-effect transistors can be used as biosensors to measure protein-ligand binding affinities and kinetics with sensitivities down to femtomolar concentrations. Based on this sensing mechanism, we develop an analytical model to calibrate the sensor response and quantify the molecular binding affinities of two representative protein-ligand binding pairs. The rate constant of the association and dissociation of the protein-ligand pair is determined by monitoring the reaction kinetics, demonstrating that silicon nanowire field-effect transistors can be readily used as high-throughput biosensors to quantify protein interactions.
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http://dx.doi.org/10.1038/nnano.2012.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180882PMC
May 2012

Tunable aqueous virtual micropore.

Small 2012 Mar 23;8(6):907-12. Epub 2012 Jan 23.

Physics Division, Oak Ridge National Laboratory, PO Box 2008, Bldg. 6010, Oak Ridge, TN 37831, USA.

A charged microparticle can be trapped in an aqueous environment by forming a narrow virtual pore--a cylindrical space region in which the particle motion in the radial direction is limited by forces emerging from dynamical interactions of the particle charge and dipole moment with an external radiofrequency quadrupole electric field. If the particle satisfies the trap stability criteria, its mean motion is reduced exponentially with time due to the viscosity of the aqueous environment; thereafter the long-time motion of particle is subject only to random, Brownian fluctuations, whose magnitude, influenced by the electrophoretic and dielectrophoretic effects and added to the particle size, determines the radius of the virtual pore, which is demonstrated by comparison of computer simulations and experiment. The measured size of the virtual nanopore could be utilized to estimate the charge of a trapped micro-object.
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http://dx.doi.org/10.1002/smll.201101739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3309109PMC
March 2012

Mapping of near field light and fabrication of complex nanopatterns by diffraction lithography.

Nanotechnology 2012 Feb 4;23(4):045301. Epub 2012 Jan 4.

Department of Electrical Engineering and Applied Physics, Yale University, New Haven, CT 06520, USA.

We report a single-step lithographic approach for precisely mapping near field light diffraction in photoresist and fabricating complex subwavelength structures. This method relies on the diffraction of UV light from opaque patterns on a photomask, and utilizes the central diffraction maximum (known as the 'Poisson spot' for an opaque disk) and its higher orders. By correlating pattern geometries with the resulting diffraction, we demonstrate that the near field light intensity can be quantified to high precision and is in good agreement with theory. The method is further extended to capture higher order diffraction, which is utilized to fabricate unconventional subwavelength nanostructures with three-dimensional topographies. The simplicity of this process and its capability for light mapping suggest it to be an important tool for near field optical lithography.
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http://dx.doi.org/10.1088/0957-4484/23/4/045301DOI Listing
February 2012

Minority carrier lifetime and surface effects in VLS-grown axial p-n junction silicon nanowires.

Adv Mater 2011 Oct;23(37):4306-11

Department of Electrical Engineering and Applied Physics, Yale University, New Haven, CT 06511, USA.

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http://dx.doi.org/10.1002/adma.201101429DOI Listing
October 2011