Aleksandar Vacic

Label-free biomarker detection from whole blood.

Label-free nanosensors can detect disease markers to provide point-of-care diagnosis that is low-cost, rapid, specific and sensitive. However, detecting these biomarkers in physiological fluid samples is difficult because of ionic screening. Here, we overcome this limitation by using distinct components within the sensor to perform purification and detection.1 A microfluidic purification chip captures multiple biomarkers simultaneously from blood samples and releases them, after washing, into purified buffer for sensing by a silicon nanoribbon detector. This two-stage approach isolates the detector from the complex environment of whole blood, and reduces its minimum required sensitivity by effectively pre-concentrating the biomarkers. We show specific and quantitative detection of two model cancer antigens from a 10 uL sample of whole blood in less than 20 minutes.

Semiconducting Nanowire Field-Effect Transistor Biomolecular Sensors

Recent studies have demonstrated the ability of semiconducting nanowire (NW) field-effect transistors (FETs) to serve as highly sensitive label-free sensors for biochemicals, including small molecules, proteins, and nucleic acids. The nanoscale confinement of the channel current in concert with the large-surface area-to-volume ratio enables charged molecules bound to the surface to effectively gate the device. Functionalization of the NW surface with specific receptors therefore enables direct electronic detection of particular molecules of interest. The original work in the field relied on NWs grown by the chemical vapor deposition method, which require hybrid bottom-up fabrication processes for device realization. The lack of reproducibility with these techniques and the associated inability to leverage the central advantage of complementary MOSFETs, namely, very large scale integration, have recently led a number of groups to create NW sensors using only traditional top-down fabrication techniques. In this paper, we focus primarily on these most recent studies and discuss necessary future studies as dictated by experimental and theoretical considerations.

Determination of Molecular Configuration by Debye Length Modulation

Silicon nanowire field effect transistors (FETs) have emerged as ultrasensitive, label-free biodetectors that operate by sensing bound surface charge. However, the ionic strength of the environment (i.e., the Debye length of the solution) dictates the effective magnitude of the surface charge. Here, we show that control of the Debye length determines the spatial extent of sensed bound surface charge on the sensor. We apply this technique to different methods of antibody immobilization, demonstrating different effective distances of induced charge from the sensor surface.

A Nanoelectronic Enzyme-Linked Immunosorbent Assay for Detection of Proteins in Physiological Solutions

Semiconducting nanowires are promising ultrasensitive, label-free sensors for small molecules, DNA, proteins, and cellular function. Nanowire field-effect transistors (FETs) function by sensing the charge of a bound molecule. However, solutions of physiological ionic strength compromise the detection of specific binding events due to ionic (Debye) screening. A general solution to this limitation with the development of a hybrid nanoelectronic enzyme-linked immunosorbent assay (ne-ELISA) that combines the power of enzymatic conversion of a bound substrate with electronic detection is demonstrated. This novel configuration produces a local enzyme-mediated pH change proportional to the bound ligand concentration. It is shown that nanowire FETs configured as pH sensors can be used for the quantitative detection of interleukin-2 in physiologically buffered solution at concentrations as low as 1.6 pg mL(-1). By successfully bypassing the Debye screening inherent in physiological fluids, the ne-ELISA promises wide applicability for ligand detection in a range of relevant solutions.

Multiplexed SOI BioFETs

Nanoscale Field Effect Transistors have emerged as a promising technology for ultrasensitive, unlabeled diagnostic applications. However, their use as quantitative sensors has been problematic because of the need for individual sensor calibration. In this work we demonstrate an internal calibration scheme for multiplexed nanoribbon field effect sensors by utilizing the initial current rates rather than end point detection. A linear response is observed consistent with initial binding kinetics. Moreover, we are able to show that top-down fabrication techniques yield reproducible device results with minimal fluctuations, enabling internal calibration.

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

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.

Label-free biomarker detection from whole blood

Label-free nanosensors can detect disease markers to provide point-of-care diagnosis that is low-cost, rapid, specific and sensitive. However, detecting these biomarkers in physiological fluid samples is difficult because of ionic screening. Here, we overcome this limitation by using distinct components within the sensor to perform purification and detection.1 A microfluidic purification chip captures multiple biomarkers simultaneously from blood samples and releases them, after washing, into purified buffer for sensing by a silicon nanoribbon detector. This two-stage approach isolates the detector from the complex environment of whole blood, and reduces its minimum required sensitivity by effectively pre-concentrating the biomarkers. We show specific and quantitative detection of two model cancer antigens from a 10 uL sample of whole blood in less than 20 minutes.

Quantitative nanoscale field effect sensors

Semiconductor nanowire field effect transistors have emerged as a promising technology for development of label-free biomolecular sensors for rapid diagnostics. However, their practical application has been hindered due to the significant device-to-device variations in electrical properties and the need for individual sensor calibration. Recent advances in device fabrication and demonstrations of multiplexed sensing and quantification might make this technology more competitive with respect to the current cutting-edge techniques such as surface plasmon resonance.

Calibration methods for silicon nanowire BioFETs

Nanowire Field Effect Transistors have emerged as a promising technology for point-of-care application. However, their application as quantitative sensors has not been well explored. In this work we propose a calibration scheme for multiplexed nanoribbon field effect sensors by utilizing the initial current rate rather than the end point detection. A linear response of nanosensors is observed in medically relevant range of analyte concentration. Moreover, we are able to show that top-down fabrication technique yields reproducible result and devices with uniform electrical characteristics. In addition, we demonstrate that device calibration can be done by using either baseline current or device transconductance normalization.

Limits of detection for silicon nanowire BioFETs

Over the past decade, silicon nanowire/nanoribbon field-effect transistors (NWFETs) have demonstrated phenomenal sensitivity to the detection of biomolecular species, with limits of detection (LOD) down to femtomolar concentrations [1].However, a fundamental understanding of these limits has been lacking until now. Several well known factors limit the LOD; among them, ionic concentration, efficiency of the biomolecule-specific surface functionalization, binding constants, and the delivery of the analyte to the sensor surface. However, the signal-to-noise ratio (SNR) of these bioFET sensors, and the device parameters that determine the LOD, are not well understood. For example, it has been commonly claimed [2] that NWFET sensitivity is maximized in the subthreshold operating regime of the device. We show here, contrary to this claim, that the SNR is maximized at maximum transconductance due to the effects of 1/f noise. These devices currently have a LOD of 4 electronic charges in ambient conditions..