A field-effect transistor-based biosensor, also known as a biosensor field-effect transistor (Bio-FET or BioFET), field-effect biosensor (FEB), or biosensor MOSFET, is a

field-effect transistor The field-effect transistor (FET) is a type of transistor that uses an electric field to control the flow of current in a semiconductor. FETs (JFETs or MOSFETs) are devices with three terminals: ''source'', ''gate'', and ''drain''. FETs contro ...

(based on the

MOSFET The metal–oxide–semiconductor field-effect transistor (MOSFET, MOS-FET, or MOS FET) is a type of field-effect transistor (FET), most commonly fabricated by the controlled oxidation of silicon. It has an insulated gate, the voltage of which d ...

structure) that is gated by changes in the surface potential induced by the binding of

molecules A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioche ...

. When charged molecules, such as

biomolecules A biomolecule or biological molecule is a loosely used term for molecules present in organisms that are essential to one or more typically biological processes, such as cell division, morphogenesis, or development. Biomolecules include large ...

, bind to the FET gate, which is usually a

dielectric In electromagnetism, a dielectric (or dielectric medium) is an electrical insulator that can be polarised by an applied electric field. When a dielectric material is placed in an electric field, electric charges do not flow through the mate ...

material, they can change the charge distribution of the underlying

semiconductor A semiconductor is a material which has an electrical resistivity and conductivity, electrical conductivity value falling between that of a electrical conductor, conductor, such as copper, and an insulator (electricity), insulator, such as glas ...

material resulting in a change in conductance of the FET channel. A Bio-FET consists of two main compartments: one is the biological recognition element and the other is the field-effect transistor. The BioFET structure is largely based on the

ion-sensitive field-effect transistor An ion-sensitive field-effect transistor (ISFET) is a field-effect transistor used for measuring ion concentrations in solution; when the ion concentration (such as H+, see pH scale) changes, the current through the transistor will change accord ...

(ISFET), a type of

metal-oxide-semiconductor field-effect transistor The metal–oxide–semiconductor field-effect transistor (MOSFET, MOS-FET, or MOS FET) is a type of field-effect transistor (FET), most commonly fabricated by the controlled oxidation of silicon. It has an insulated gate, the voltage of which d ...

(MOSFET) where the

metal gate A metal gate, in the context of a lateral metal–oxide–semiconductor (MOS) stack, is the gate electrode separated by an oxide from the transistor's channel – the gate material is made from a metal. In most MOS transistors since about the mid ...

is replaced by an

ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

-sensitive

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

electrolyte An electrolyte is a medium containing ions that is electrically conducting through the movement of those ions, but not conducting electrons. This includes most soluble salts, acids, and bases dissolved in a polar solvent, such as water. Upon dis ...

solution and

reference electrode A reference electrode is an electrode which has a stable and well-known electrode potential. The high stability of the electrode potential is usually reached by employing a redox system with constant (buffered or saturated) concentrations of each ...

Mechanism of operation

Bio-FETs couple a

transistor upright=1.4, gate (G), body (B), source (S) and drain (D) terminals. The gate is separated from the body by an insulating layer (pink). A transistor is a semiconductor device used to Electronic amplifier, amplify or electronic switch, switch e ...

device with a bio-sensitive layer that can specifically detect bio-molecules such as nucleic acids and proteins. A Bio-FET system consists of a semiconducting

that acts as a

transducer A transducer is a device that converts energy from one form to another. Usually a transducer converts a signal in one form of energy to a signal in another. Transducers are often employed at the boundaries of automation, measurement, and contr ...

separated by an insulator layer (e.g. SiO₂) from the biological recognition element (e.g. receptors or probe molecules) which are selective to the target molecule called analyte.Alena Bulyha, Clemens Heitzinger and Norbert J Mauser: Bio-Sensors: Modelling and Simulation of Biologically Sensitive Field-Effect-Transistors, ERCIM News, 04,2011. Once the analyte binds to the recognition element, the charge distribution at the surface changes with a corresponding change in the electrostatic surface potential of the semiconductor. This change in the surface potential of the semiconductor acts like a gate voltage would in a traditional

, i.e. changing the amount of current that can flow between the source and drain electrodes. This change in current (or conductance) can be measured, thus the binding of the analyte can be detected. The precise relationship between the current and analyte concentration depends upon the region of transistor operation.

Fabrication of Bio-FET

The fabrication of Bio-FET system consists of several steps as follows: # Finding a substrate suitable for serving as a FET site, and forming a FET on the substrate, # Exposing an active site of the FET from the substrate, # Providing a sensing film layer on active site of FET, # Providing a receptor on the sensing film layer in order to be used for ion detection, # Removing a semiconductor layer, and thinning a dielectric layer, # Etching the remaining portion of the dielectric layer to expose an active site of the FET, # Removing the photoresist, and depositing a sensing film layer followed by formation of a photoresist pattern on the sensing film, # Etching the unprotected portion of the sensing film layer, and removing the photoresistYuji Miyahara, Toshiya Sakata, Akira Matsumoto: Microbio genetic analysis based on Field Effect Transistors, Principles of Bacterial Detection: Biosensors, Recognition Receptors and Microsystems.

Advantages

The principle of operation of Bio-FET devices based on detecting changes in electrostatic potential due to binding of analyte. This the same mechanism of operation as

glass electrode A glass electrode is a type of ion-selective electrode made of a doped glass membrane that is sensitive to a specific ion. The most common application of ion-selective glass electrodes is for the measurement of pH. The pH electrode is an example ...

sensors which also detect changes in surface potential but were developed as early as the 1920s. Due to the small magnitude of the changes in surface potential upon binding of biomolecules or changing pH, glass electrodes require a high impedance amplifier which increases the size and cost of the device. In contrast, the advantage of Bio-FET devices is that they operate as an intrinsic amplifier, converting small changes in surface potential to large changes in current (through the transistor component) without the need for additional circuitry. This means BioFETs have the capability to be much smaller and more affordable than glass electrode-based

biosensor A biosensor is an analytical device, used for the detection of a chemical substance, that combines a biological component with a physicochemical detector. The ''sensitive biological element'', e.g. tissue, microorganisms, organelles, cell recep ...

s. If the transistor is operated in the

subthreshold region Subthreshold conduction or subthreshold leakage or subthreshold drain current is the current between the source and drain of a MOSFET when the transistor is in subthreshold region, or weak-inversion region, that is, for gate-to-source voltages be ...

, then an exponential increase in current is expected for a unit change in surface potential. Bio-FETs can be used for detection in fields such as

medical diagnostics Medical diagnosis (abbreviated Dx, Dx, or Ds) is the process of determining which disease or condition explains a person's symptoms and signs. It is most often referred to as diagnosis with the medical context being implicit. The information re ...

, biological research,

environmental protection Environmental protection is the practice of protecting the natural environment by individuals, organizations and governments. Its objectives are to conserve natural resources and the existing natural environment and, where possible, to repair dam ...

and food analysis. Conventional measurements like optical, spectrometric, electrochemical, and SPR measurements can also be used to analyze biological molecules. Nevertheless, these conventional methods are relatively time-consuming and expensive, involving multi-stage processes and also not compatible to real-time monitoring,K.Y.Park, M.S.Kim, K.M.Park, and S.Y.Choi: Fabrication of BioFET sensor for simultaneous detection of protein and DNA, Electrochem.org. in contrast to Bio-FETs. Bio-FETs are low weight, low cost of mass production, small size and compatible with commercial planar processes for large-scale circuitry. They can be easily integrated into digital microfluidic devices for

Lab-on-a-chip A lab-on-a-chip (LOC) is a device that integrates one or several laboratory functions on a single integrated circuit (commonly called a "chip") of only millimeters to a few square centimeters to achieve automation and high-throughput screening. ...

. For example, a microfluidic device can control sample droplet transport whilst enabling detection of bio-molecules,

signal processing Signal processing is an electrical engineering subfield that focuses on analyzing, modifying and synthesizing ''signals'', such as audio signal processing, sound, image processing, images, and scientific measurements. Signal processing techniq ...

, and the data transmission, using an all-in-one chip. Bio-FET also does not require any labeling step, and simply utilise a specific molecular (e.g. antibody, ssDNA) on the sensor surface to provide selectivity. Some Bio-FETs display fascinating electronic and optical properties. An example FET would is a glucose-sensitive based on the modification of the gate surface of ISFET with SiO₂ nanoparticles and the enzyme glucose oxidase (GOD); this device showed obviously enhanced sensitivity and extended lifetime compared with that without SiO₂ nanoparticles. Classification of BioFET

Optimization

The choice of reference electrode (liquid gate) or back-gate voltage determines the carrier concentration within the field effect transistor, and therefore its region of operation, therefore the response of the device can be optimised by tuning the gate voltage. If the transistor is operated in the

then an exponential increase in current is expected for a unit change in surface potential. The response is often reported as the change in current on analyte binding divided by the initial current (

\Delta I/I_

), and this value is always maximal in the subthreshold region of operation due to this exponential amplification. For most devices, optimum signal-to-noise, defined as change in current divided by the baseline noise, (

\Delta I/\delta i_\text

) is also obtained when operating in the subthreshold region, however as the noise sources vary between devices, this is device dependent. One optimization of Bio-FET may be to put a hydrophobic passivation surface on the source and the drain to reduce non-specific biomolecular binding to regions which are not the sensing-surface. Many other optimisation strategies have been reviewed in the literature.

History

The

(metal-oxide-semiconductor field-effect transistor, or MOS transistor) was invented by

Mohamed M. Atalla Mohamed M. Atalla ( ar, محمد عطاالله; August 4, 1924 – December 30, 2009) was an Egyptian-American engineer, physicist, cryptographer, inventor and entrepreneur. He was a semiconductor pioneer who made important contributions to ...

and

Dawon Kahng Dawon Kahng ( ko, 강대원; May 4, 1931 – May 13, 1992) was a Korean-American electrical engineer and inventor, known for his work in solid-state electronics. He is best known for inventing the MOSFET (metal–oxide–semiconductor field-effe ...

in 1959, and demonstrated in 1960. Two years later,

Leland C. Clark Leland C. Clark Jr. (December 4, 1918 – September 25, 2005) was an American biochemist born in Rochester, New York. He is most well known as the inventor of the Clark electrode, a device used for measuring oxygen in blood, water and other liquid ...

and Champ Lyons invented the first

in 1962. Biosensor MOSFETs (BioFETs) were later developed, and they have since been widely used to measure

physical Physical may refer to: *Physical examination In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally co ...

chemical A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent elements by physical separation methods, i.e., wi ...

biological Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary in ...

and

environmental A biophysical environment is a biotic and abiotic surrounding of an organism or population, and consequently includes the factors that have an influence in their survival, development, and evolution. A biophysical environment can vary in scale f ...

parameters. The first BioFET was the

(ISFET), invented by

Piet Bergveld Piet Bergveld (; born 26 January 1940) is a Dutch electrical engineer. He was professor of biosensors at the University of Twente between 1983 and 2003. He is the inventor of the ion-sensitive field-effect transistor (ISFET) sensor. Bergveld's w ...

for

electrochemical Electrochemistry is the branch of physical chemistry concerned with the relationship between electrical potential difference, as a measurable and quantitative phenomenon, and identifiable chemical change, with the potential difference as an outco ...

and

applications in 1970. Other early BioFETs include the

adsorption Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the ''adsorbate'' on the surface of the ''adsorbent''. This process differs from absorption, in which a f ...

FET (ADFET)

patented A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...

by P.F. Cox in 1974, and a

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...

-sensitive MOSFET demonstrated by I. Lundstrom, M.S. Shivaraman, C.S. Svenson and L. Lundkvist in 1975. The ISFET is a special type of MOSFET with a gate at a certain distance, and where the

is replaced by an

-sensitive

solution and

. The ISFET is widely used in

biomedical Biomedicine (also referred to as Western medicine, mainstream medicine or conventional medicine)

applications, such as the detection of DNA hybridization,

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

detection from

blood Blood is a body fluid in the circulatory system of humans and other vertebrates that delivers necessary substances such as nutrients and oxygen to the cells, and transports metabolic waste products away from those same cells. Blood in the c ...

antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

detection,

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

measurement, pH sensing, and genetic technology. By the mid-1980s, other BioFETs had been developed, including the

gas sensor A gas detector is a device that detects the presence of gases in an area, often as part of a safety system. A gas detector can sound an alarm to operators in the area where the leak is occurring, giving them the opportunity to leave. This type of ...

FET (GASFET),

pressure sensor A pressure sensor is a device for pressure measurement of gases or liquids. Pressure is an expression of the force required to stop a fluid from expanding, and is usually stated in terms of force per unit area. A pressure sensor usually act ...

FET (PRESSFET),

chemical field-effect transistor A ChemFET is a chemically-sensitive field-effect transistor, that is a field-effect transistor used as a sensor for measuring chemical concentrations in solution. When the target analyte concentration changes, the current through the transistor will ...

(ChemFET), reference ISFET (REFET), enzyme-modified FET (ENFET) and immunologically modified FET (IMFET). By the early 2000s, BioFETs such as the

DNA field-effect transistor A DNA field-effect transistor (DNAFET) is a field-effect transistor which uses the field-effect due to the partial charges of DNA molecules to function as a biosensor. The structure of DNAFETs is similar to that of MOSFETs, with the exception of th ...

(DNAFET), gene-modified FET (GenFET), and cell-potential BioFET (CPFET) had been developed. Current research in this area has produced new formations of the BioFET such as the Organic Electrolyte Gated FET (OEGFET).

References