Patent Application
20230022648
Label-free bio-assays are sensing platforms that directly measure biomolecular and cellular interactions, provide extensive perspectives on the affinity and specificity as well as the thermodynamics and kinetics of various biological systems.
Few examples of a biologically-modified field-effect transistor (BioFET) are illustrated in (a) Cheung, K. M.; Abendroth, J. M.; Nakatsuka, N.; Zhu, B.; Yang, Y.; Andrews, A. M.; Weiss, P. S. Detecting DNA and RNA and Differentiating Single-Nucleotide Variations via Field-Effect Transistors. Nano Lett. 2020, 20 (8), 5982-5990, (b) Nakatsuka, N.; Yang, K. A.; Abendroth, J. M.; Cheung, K. M.; Xu, X.; Yang, H.; Zhao, C.; Zhu, B.; Rim, Y. S.; Yang, Y.; et al. Aptamer-Field-Effect Transistors Overcome Debye Length Limitations for Small-Molecule Sensing. Science (80-.). 2018, 362 (6412), 319-324, (c) Kaisti, M. Detection Principles of Biological and Chemical FET Sensors. Biosens. Bioelectron. 2017, 98 (April), 437-448, and (d) Patolsky, F.; Zheng, G.; Lieber, C. M. Nanowire-Based Biosensors. Anal. Chem. 2006, 78 (13), 4260-4269.
The main recognizable obstacle in the application of BioFETs is the electronic screening length which is critical in highly-concentrated ionic solutions.
The screening length is reflected by the Debye length (λD), which at room temperature is defined as
where 1B=0.7 nm is the Bjerrum length, NAV is the Avogadro's number, zi and nB,i are the valence and solution concentration of ion type i, correspondently, where the summation accounts for the various types of ions.
In a characteristic physiological solution, λD=1-2 nm, which is significantly smaller than typical surface-bound antibody (˜10 nm), for example, which seriously affects the possibility to sense target biomoleucles. Therefore, in case of serum, for example, the sample ion concentration needs to be significantly decreased, that might influence the biological events, or shorter bioreceptors have to be employed.
The protonation of the amphoteric sites by the solution yields a surface charge density (σ0) which depends on the solution acidity. The interactions at the electrolyte-Oxide interface (EOI) are determined by the site-binding model. To force local charge neutrality, an equivalent counter-charged solvent ions are adsorbed on the EOI, resulting in the appearance of the double layer.
De facto, the problem of screening length is most severe at the double layer. The concentrations of ions at a distance x from the EOI are defined by the Boltzmann distributions:
where n+,B and n−,B are the positive and negative bulk ion concentrations, ψ(x) is the electric potential, and q, k and T take their conventional meaning. Correspondingly, the 1D Poisson-Boltzmann equation is
where ε is the relative electrolyte permittivity.
For EOI surface potential ψ0<kT/q, the double layer adheres to the Debye-Huckel model and the co- and counter-ions concentrations are linear with the electric potential and, therefore, a surplus of counter-ions forces an equivalent lack of co-ions. On the other hand, according to the Gouy-Chapman model, ψ0>kT/q, the population of counter-ions is substaintially greater. The Gouy-Chapman approximation is more relevant in the context of bioFETs, as it conforms to ψ0 values of applicable dielectrics for a considerable pH range and ionic strengths; hence, the double layer total ion concentration (n0) is considerably greater than nB under the Gouy-Chapman approximation. Also, the integration of the one-dimensional Poisson-Boltzmann equation for relevant symmetric and asymmetric electrolyte produces the Grahame equation which sets the affinity between n0 and σ0 as Σin0i=ΣinBi+2πσ02/εkT, where i counts the ion species; the Grahame expression suggests that n0 is always higher than nB and the surplus concentration depends solely on σ0.
The Poisson-Boltzmann equation accounts for the electrostatic behavior while other phenomena, i.e. e.g. steric effects and dielectric decrement, affect the double layer kinetics as well. However, all these phenomena also show n0>>nB. Therefore, the electrostatic potential distribution and the double layer total ion concentration are independent of nB close to the interface and the surplus ions near the interface entail an appreciable reduced λD. Therefore, the maximum screening takes place at the EOI and diminishes with the Debye distance.
Furthermore—The CMOS BioFET research has focused primarily on the modification of a standard silicon metal-oxide-semiconductor FET (MOSFET) into a BioFET by removal of the top metal gate and biofunctionalization of the gate dielectric (or very small modifications in that spirit as, for example, the extended gate BioFET), which yielded only very few recognizable achievements.
This should not come as a great surprise, as the functionality of a MOSFET is fundamentally different than the required functionality of a BioFET. The uniform band-bending at the MOSFET silicon/gate-dielectric interface, due to the biasing of the top metal gate, triggers a homogeneous modulation of the conductive channel.
On the other hand, the silicon/gate-dielectric band bending in a BioFET is fundamentally non-uniform, as it depends on local biological interactions that are distributed on top of the active sensing area (i.e., gate dielectric). Hence, the biological-solid interface of the BioFET is far more complex and non-uniform compared with the all-solid-state interface of the MOSFET; e.g., the inevitable non-uniform distribution of receptor molecules on the top of the active sensing area implies a non-uniform distribution of binding events, which results in a spatially distributed silicon/gate-dielectric band bending. Therefore, in order to directly probe the electrostatic signature of biological events, the BioFET design needs to address the challenge of the non-uniform biological-solid interface.
There is a growing need to provide a device and a method for biological sensing that overcomes said disadvantages of the prior art devices.
Specific and label-free sensing of biological events is important in various technological applications ranging from medical devices to home security, as well as for the understanding of fundamental questions related to the electronic nature of biological interactions. The biologically modified field-effect transistor (BioFET) is a promising device for specific and label-free biosensing due to its sub-micron footprint, inherent signal amplification and the ability to perform multiplexing in an ultra-small sample volume.
Debye screening length poses a significant obstacle towards the realization of a BioFET. Debye length prevents recognition of biological events that take place at a distance from the active sensing area that is greater than the Debye length. In fact, the obstacle of screening distance is more acute at the solid-solution interface (double layer) as, inherently, the solution ion population at the interface is significantly higher than the bulk solution. Therefore, the screening length at the interface is substantially smaller than its bulk value. One way to address the small screening length at the interface is to bias the solution relative to the sample and realize bulk screening length at the interface. However, biasing of the solution directly affects the conductive channel, as well.
The current application addresses the Debye length challenge with the novel Meta-Nano-Channel (MNC) BioFET. The MNC BioFET, which is fabricated in a complementary-metal-oxide-silicon (CMOS) process, allows to decouple the electrostatics of the double layer from the electrodynamics of the conductive channel.
The application explores the mechanism of sensing with the MNC BioFET and demonstrates how the double layer can be biased in order to optimize the screening length, but at the same time maintain a conductive channel that is extremely sensitive to potential variations triggered by biological interactions.
Specific and label-free detection of biological interactions is paramount to a plethora of technological applications ranging from home-care diagnostics to new approaches for smart agriculture, as well as the ability to inquire into fundamental phenomena related to biological events. The biologically-modified field-effect transistor (BioFET) fabricated in a complementary metal-oxide-semiconductor (CMOS) process is a favourable system for the realization of specific and label-free bio-detection due to the stability of sensor characteristics, operation flexibility including the potential for multiplexing, low power and low cost. The Meta-Nano-Channel BioFET (MNC BioFET) is a novel multi-gate biosensor realized with silicon-on-insulator (SOI) technology and fabricated in a CMOS process. The MNC BioFET allows to form conductive channels of various shapes and sizes. This is used to optimize the coupling between the electrostatic events induced by the biological interactions and the electrostatics of the underlying silicon-based transistor. As an example , in the current application, we demonstrate specific and label-free sensing of prostate specific antigen (PSA) with the MNC BioFET, and show the dependency of the sensor signal on the channel configuration.
In the current application, a novel Meta-Nano-Channel (MNC) BioFET is suggested to address the ‘non-uniformity’ challenge of BioFET. The MNC BioFET is a multiple-gate device that includes six independent gates. Each gate ‘maps’ the active sensing area differently. As all the gates are electrostatically coupled. An infinite amount of current-voltage (I-V) curves can be generated, each providing different information on the active sensing area, where the biological interactions take place.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.
The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:
It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.
In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the embodiments of the disclosure.
However, it will be understood by those skilled in the art that the present embodiments of the disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present embodiments of the disclosure.
The subject matter regarded as the embodiments of the disclosure is particularly pointed out and distinctly claimed in the concluding portion of the specification. The embodiments of the disclosure, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings.
It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.
Because the illustrated embodiments of the disclosure may for the most part, be implemented using electronic components and circuits known to those skilled in the art, details will not be explained in any greater extent than that considered necessary as illustrated above, for the understanding and appreciation of the underlying concepts of the present embodiments of the disclosure and in order not to obfuscate or distract from the teachings of the present embodiments of the disclosure.
Any reference in the specification to a method should be applied mutatis mutandis to a system capable of executing the method and should be applied mutatis mutandis to a computer readable medium that is non-transitory and stores instructions for executing the method.
Any reference in the specification to a system should be applied mutatis mutandis to a method that may be executed by the system and should be applied mutatis mutandis to a computer readable medium that is non-transitory and stores instructions executable by the system.
Any reference in the specification to a computer readable medium that is non-transitory should be applied mutatis mutandis to a method that may be applied when executing instructions stored in the computer readable medium and should be applied mutatis mutandis to a system configured to execute the instructions stored in the computer readable medium.
And/or referred to additionally or alternatively. “A and/or B” means only A or only B or A and B.
There is provided a biosensor 100 such as a Meta-Nano-Channel (MNC) biosensor to address the ‘Debye challenge’ of the BioFET technology.
According to one example—the MNC biosensor may include six independent gates which may be electrostatically coupled to each other. The multiple gates allow to electrostatically decouple the solution double layer from the conductive channel and in this manner allow the possibility to manipulate the screening length at the solid-solution interface without affecting the transduction performance of the BioFET.
Label-free bio-assays are sensing platforms that directly measure biomolecular and cellular interactions, provide extensive perspectives on the affinity and specificity as well as the thermodynamics and kinetics of various biological systems. The biologically-modified field-effect transistor (BioFET) is an attractive device for specific and label-free sensing, that directly probes the electrostatics and electrodynamics of biological interactions and processes. BioFETs realized in a Complementary Metal Oxide Semiconductor (CMOS) processes have low power, low cost, ultra-low noise levels and high gain. These properties directly lead to enhanced sensing performance in terms of high sensitivity (signal vs. concentration), extremely low limit-of-detection (LOD) and high dynamic range. Furthermore, the built-in miniaturization directly implies small sample size and the potential for multiplexing.
One of the main obstacles in the application of BioFETs is the screening length which is especially significant in highly-concentrated ionic solutions. The screening length is characterized by the Debye length (λD) which at room temperature is defined as
where 1B=0.7 nm is the Bjerrum length, NAv is the Avogadro' s number, zi and nB,i are the valence and solution concentration of ion type i, correspondingly, and the summation accounts for the various types of ions. In a characteristic physiological solution, λD=1-2 nm which is significantly smaller than typical surface-bound antibody size (˜10 nm), for example, which seriously affects the possibility to sense target biomoleucles. For example, in case of serum, the ion concentration needs to be significantly decreased which might influence the biological events, or shorter bioreceptors have to be employed.
Electrostatic control of the Debye screening length at the BioFET electrolyte-oxide interface (EOI) was recently suggested in various studies. The protonation of the amphoteric sites by the solution yields a surface charge density (σ0) which depends on the solution acidity. The interactions at the oxide-solution interface are described by the site-binding model. To force local charge neutrality, an equivalent counter-charged solvent ions are adsorbed on the EOI, resulting in the appearance of the double layer. De facto, the problem of screening length is most severe at the double layer. The concentrations of ions at a distance x from the EOI are defined by the Boltzmann distributions:
where n+,B and n−,B are the positive and negative bulk ion concentrations, ψ(x) is the electric potential, and q, k and T have their conventional meaning. Correspondingly, the 1D Poisson-Boltzmann equation is
where ε is the relative electrolyte permittivity. For EOI surface potential ψ0<kT/q, the double layer adheres to the Debye-Huckel model and the co- and counter-ions concentrations are linear with the electric potential and therefore a surplus of counter-ions forces an equivalent lack of co-ions. On the other hand, according to the Gouy-Chapman model, ψ0>kT/q, the population of counter-ions is substantially greater. The Gouy-Chapman approximation is more relevant in the context of BioFETs, as it conforms to ψ0 values for applicable dielectrics in a considerable pH range and ionic strengths. Hence, the double layer total ion concentration (n0) is considerably greater than nB under the Gouy-Chapman approximation. Also, the integration of the one-dimensional Poisson-Boltzmann equation for relevant symmetric and asymmetric electrolyte produces the Grahame equation which sets the affinity between n0 and σ0 as Σin0i=ΣinBi+2πσ02/εkT, where i counts the ion species. The Grahame expression suggests that n0 is always higher than nB and the surplus concentration depends solely on σ0.
The Poisson-Boltzmann equation accounts for the electrostatic behaviour while other phenomena, i.e., e.g., steric effects and dielectric decrement, affect the double layer kinetics as well. However, all these phenomena also show n0>>nB. Therefore, the electrostatic potential distribution and the double layer total ion concentration are independent of nB close to the interface and the surplus ions near the interface entail an appreciable reduced λD. Therefore, the maximum screening takes place at the EOI and diminishes with the distance from EOI.
In the below, a Meta-Nano-Channel (MNC) BioFET is suggested to address the ‘Debye challenge’ of the BioFET technology. The MNC BioFET comprises of six independent gates which control the screening length at the double layer, and the position/shape/size of the conductive channel in the BioFET. The presence of multiple gates allows to electrostatically decouple the solution double layer from the conductive channel and the possibility to manipulate the screening length at the solid-solution interface without affecting the transduction performance of the BioFET.
Examples of device fabrication and geometry. The MNC BioFET were fabricated using the mass production Tower Semiconductor RF CMOS SOI platform. The devices are formed in the thin device layer of the SOI (silicon on isolator). The 145 nm silicon device layer is located on a 0.4 μm buried oxide (BOX) layer of a 200 mm wafers. The device layer has an average of ˜3×1017 cm-3 phosphorous doping with a certain gradient from the top to bottom interfaces. Four electrodes are formed in the device layer. Source and drain N+ regions are strongly doped with Arsenic (7×1019 cm−3).
Two lateral P+ gates (JFET-like) are implanted with Boron 2×102° cm-3. The P+ gates are formed in a self-aligned way using 200 nm Polysilicon over a 5.5 nm gate oxide. The same polysilicon (P− doped) layer is used to form two transverse gates adjacent to the source and drain regions.
The channel length is 10 μm and the space between the P+ diffusion regions ranges from 0.5 to 1 μm for different device splits. A trench having a width of 0.6 μm is etched in the end of the process flow using an additional CMOS mask, as shown in
Electrical measurements. The current-voltage curves are measured using a probe station and a Keysight B1500 Semiconductor Parametric Analyzer. A 1 μl PBS of 10 mM pH7 droplet is applied on the chip active area (see
Surface modifications and surface characterization. Silicon samples with a native oxide layer are cleaned by sonication in ethyl acetate, acetone and 2-propanol for two minutes each. The samples are then rinsed in deionized (DI) water and then put in piranha solution (7:3 H2SO4:H2O2) at 70° C. for 25 minutes. Samples are then rinsed with copious amounts of DI water and dried under a clean nitrogen stream. 3-aminopropyl trimethoxysilane (APTMS) solution was prepared as 1% v:v in methanol. The dried samples are placed in vials containing APTMS solution for 3 hours and then sonicated three times for three minutes in methanol. The samples are then transferred to DI water for 24 hours to induce hydrolysis and then dried and placed in an oven for 1 hour at 120° C. for curing. Hydrolysis is assumed to release the amine moieties from interactions with surface silanol groups of the APTMS molecule, thus releasing the amine moiety to extend away from the interface. Curing is suggested to stabilize the covalent bonds between the silane molecules and the oxide of the surface. The next step towards formation of a silicon-based biosensor for the specific detection of PSA as a biomarker is to modify these surfaces with glutaraldehyde crosslinker, which serves to anchor the anti-PSA antibodies. The surfaces are immersed in 0.5% aqueous solution of glutaraldehyde for one hour, to achieve an aldehyde-terminated surface. In the steps that followed, the surfaces are immersed in 10 μg/ml solution of anti-PSA, produced in rabbit, in 0.1 M PBS, pH 7.4 overnight. This strategy is based on the common knowledge that antibodies are typically immobilized to aldehyde-terminated surfaces based on the reaction between amine moieties of the antibody and the aldehyde group16. Surface characterization was performed with electrochemical impedance spectroscopy (Palmsens 4, Palmsens Inc.), atomic force microscopy (Multiview 4000, Nanonics Imaging Inc.) and spectroscopic ellipsometry (J.A. Woollam Alpha-SE Ellipsometer).
Numerical calculations. Sentaurus Device tool by Synopsys is employed for the three-dimensional device calculations. The Poisson and continuity equations are solved at every point. The device calculations account for doping-dependent mobility. The 1:1 electrolyte is emulated as an intrinsic semiconductor with a permittivity of 80 and an energy bandgap of Eg=1.5 eV to ensure the fulfilment of (Eg/2−qΨ)>>kT to validate the Boltzmann approximation in electrolytes. The semiconductor hole (p) and electron (n) concentrations are adapted to emulate the positive and negative ion densities: p=n=NAvc0×10−3 cm−3, where c0 is the solution ionic strength. The effective density of states in the conduction (NC) and the valence (NV) bands are considered: NC=NV=neE
where Ns is the fixed number of surface sites per unit area, aH
Ion concentration, electric field, pH level and Debye length at the vicinity of EOI are different from the values in the bulk solution away from the interface. A numerical example is presented in
In the following a method is suggested to overcome this challenge and decouple the double layer from the conductive channel.
The degenerated n-type source and drain regions define the length of these channels. Six gates surround the active area of MNC BioFET: top reference electrode gate (VGR), a backgate (VGB), two lateral gates (VGL2, VGL2) and two transverse gates (VGT). The width of the ADL is defined by the p-type regions which form p-n junctions on both of its sides. These p-n junctions form the lateral gates of the MNC BioFET.
The additional two transverse gates are present on top of the gate dielectric parallel to the source and drain, as shown in
The transverse gates may be insulated from the solution and form metal-oxide-silicon (MOS) capacitors with respect to the ADL. The transverse gates may decouple the double layer from the conductive channel.
The transverse gates can eliminate the formation of a top channel as the negative bias will deplete or invert the ADL directly below the transverse gates.
The transverse gates permit the independent control of the electrostatic conditions at the double layer by the reference electrode without affecting the conductive channel.
For any biasing of the reference electrode the formation of a top conductive channel is prohibited once the transverse gates are negatively biased which means that the active SOI regions just below the transverse gates are either depleted or inverted, i.e. populated with hole minority carriers, and in this way prevent the formation of a top conductive channel even for positive biasing of the reference electrode
Similarly, negative biasing of the top reference electrode results in the formation of bottom and middle channels, as shown in
Next, it is demonstrated how to govern the Debye screening length using the MNC BioFET in order to manipulate the electrostatic potential, and the subsequent formation of the channel configuration inside the ADL.
In the case in which positive VGR is required to null the surface electric fields to maximize the surface Debye length (for example, for negatively charged amphoteric sites, such as in the case of Si3N4 or SiO2 interfacing with a pH7 electrolytes), the challenge is more acute, as positive VGR implies accumulated front interface and hence the formation a top channel. This means that any biasing of the double layer, to affect the surface Debye length, will also affect the conductive channel which depends both on top and middle channels. This imposes a constraint on the conductive channel, as such biasing might imply conditions that are not favourable for sensing. The biasing of the double layer for the optimization of Debye length should not affect the conductive channel. We employ VGT in order to decouple the biasing of the double layer from the conductive channel.
The above demonstrates how the MNC BioFET ensures that neither accumulated or depleted Si/SiO2 interface generates a top channel. Nevertheless, it is important for the middle conductive channel to have sensitivity towards front surface potential variations, that are induced by biological interactions at the MNC BioFET active sensing area. This sensitivity is explored next and presented in
Debye screening length limitation is a fundamental challenge in biological sensing in solution based on BioFETs. In practice, the effective screening length at the EOI is inherently smaller than in the bulk solution as the ion population is significantly higher at the EOI. This renders the screening length challenge even more severe as the biological interactions takes place inside or at the close proximity to the EOI. One straightforward approach to overcome the EOI screening length is to bias the reference electrode with respect to substrate in order to achieve bulk Debye length at the EOI. However, biasing the reference electrode affects also the band bending at the BioFET silicon/gate-dielectric interface and hence the conductive channel.
The application demonstrated a MNC BioFET that provides decoupling of the double layer electrostatics from the electrodynamics of the conductive channel, and therefore allows an independent control of the DL. Both numerical calculations and experimental results of the MNC BioFETs fabricated in an industrial CMOS SOI technology confirmed the operation principles. We believe that the MNC BioFETs, that have all the advantages of conventional BioFETs and also additional ability to control the Debye layer and the conductive channel separately, are promising devices for specific and label-free sensing of biological analytes.
The MNC BioFET may be biofunctionalized for the purpose of specific and label-free detection of prostate specific antigen (PSA). To this end, anti-PSA antibodies are chemically tethered to the active sensing area. The different surface chemical treatments are described in the Methodology section and, in general, follow procedures reported previously. Briefly, the different steps of the modification are shown in
The additional positive surface charges also allow the formation of a top channel for the higher VGL values (SI§ 2). Similar to the measurements performed for the unmodified MNC device, the introduction of PSA on the APTMS-modified MNC device does not affect the current (VDS=0.1 V, VGB=−20 V). Lastly, specific and label-free sensing of PSA is pursued and the experimental measurements are repeated for an MNC BioFET modified with anti-PSA molecules. The results are presented in
The data set suggests few interesting points. Firstly, VTGR increases upon introduction of 100 ng/ml of PSA and decreases upon the introduction of 1 μg/ml which could reflect different state of the anti-PSA/PSA complex. For example, the lower PSA concentration could result in the formation of sparse complexes that thermodynamically could be more tilted towards the active sensing area, whereas the higher PSA concentration could form more compact complexes that force a more upright configuration. It is very common in the literature to find descriptions of the receptor-analyte system in an upright vertical configuration normal to the surface of the active sensing area. Clearly, in such case any interaction between the target protein and the surface are excluded. Still, recent studies show that the adsorption of proteins on dielectric surfaces conclude primarily a horizontal configuration with the Fc and two Fab parts interfacing the substrate. Note, that horizontal configuration is apparent albeit the electrostatic repulsion between the dielectric surface and the target protein. The horizontal configuration is more probable in a sparse system in which effects of steric hindrance are less pronounced. Unlike the vertical configuration, the horizontal configuration can result in various molecule-dielectric interactions (or molecule interactions with various APTMS moieties, for example) that are completely absent in the case of the vertical configuration in which no direct interaction between the target protein and the surface are considered.
The horizontal configuration allows for various direct interactions of the target proteins, such as: 1) interactions with the dielectric amphoteric sites; 2) side-chain charge of amino acids exhibit differential adhesion to different materials; 12) strong binding is attributed to basic residues (His, Lys, Arg), and electrostatic interactions are considered as the dominant force binding peptides to the negatively charged surfaces) adsorption of surface-bound proteins to surfaces is favorable in terms of entropy and enthalpy. One mechanism describes how the free energy of adsorption is governed by high positive entropy which is due to the loss of organized water that hydrates the protein and the surface prior to adsorption. This indicates that one proton is exchanged upon adsorption. Clearly, all the above interactions which are expected for the low PSA concentration could yield variation in surface potential, and shift in threshold voltage, that is of the opposite polarity relative to shift recorded for the higher PSA concentration.
Another interesting observation is how the VTGR shift decreases with increasing VGL where for VGL=−1.5 V the VTGR shift is ˜130 mV and for VGL=0 V VTGR shift is ˜80 mV (This trend is also evident for the data presented in
The width of the conductive channel increases with VGL increase (insets
Finally, the distribution of the data points for the anti-PSA-modified MNC BioFET, as reflected in
Surface biofunctionalization by covalent binding provides the best stability towards temperature, flow rate, pH and ionic strength variations. Therefore, chemical adsorption reflects a more orderly and stable interactions which should manifest a higher repeatability and hence the small error bars of
A correlation between the channel properties and the sensing signal is demonstrated and specifically it is shown how a nanowire-shaped channel which is shifted away from the Si/SiO2 interface provides a superior sensing.
In
All three figures illustrate various parts of the biosensor 100—(a) substrate 141, (b) oxide layer 142, (d) regions 143 and 144 located below the lateral gates, (e) gate oxide 157, and (f) oxide 171 in which the fluid is filled.
In
In
In
The additional electrodes may affect the electrical field of the fluid. Also, need to have the case in which the electrode are in touch with the solution and then we can have ion current flowing between them as well as the reference electrode.
It should be noted that any gate may be replaced by one or more gates (for example one or more independently controlled gates)—for better controlling the biosensor. In
The array may be a grid, any ordered array, a non-ordered arrangement of biosensors, and the like.
The array may be controlled by one or more control units 113 and may be biased by one or more readout units 112.
Method 400 may start by step 410 of providing a biosensor. The biosensor may include a semiconductor active region; a sensing region configured to contact a fluid; and multiple electrodes that may include decoupling electrodes and additional electrodes.
Step 410 may be followed by step 420 of receiving fluid by a fluid compartment of the biosensor.
Steps 410 and 420 may be followed by step 430 of operating the biosensor in the first mode. It should be noted, that steps 410 and 420 may be followed by step 440.
Step 430 may include biasing the decoupling electrodes to prevent the formation of a top conductive channel within the semiconductor active region and independently controlling by the additional electrodes, (i) one or more properties of one or more other conductive channels formed within the semiconductor active region, and (ii) a Debye length at the interface between the sensing region and the fluid.
The one or more properties may include at least one out of location, shape, volume, area of cross section, any property that may affect the sensing function of the one or more conductive channels, and the like.
There may be any number of conductive channels.
The decoupling electrodes may include one or more decoupling gates. The additional electrodes may include one or more additional gates. The decoupling electrodes may be decoupling gates and the additional electrodes may be additional gates.
Step 430 may include controlling, by the additional gates, the Debye length by depleting a double layer of charged particles at the interface. The decoupling gates may be isolated from the fluid. The decoupling gates may be electrically coupled to the fluid. The additional gates may include a top gate configured to contact the fluid, a bottom gate, and two lateral gates; and wherein the decoupling gates may be two transverse gates.
Method 400 may also include step 440 of operating the biosensor in a second mode.
Step 440 may include biasing the decoupling electrodes to facilitate a formation of a top conductive channel within the semiconductor active region; and wherein the control of the one or more properties of one or more other conductive channels formed within the semiconductor active region depends on a control of the Debye length at the interface between the sensing region and the fluid.
Each one of steps 430 and 440 includes sensing the fluid. This may include sensing at least one interaction between the fluid and the sensing area. The sensing may include sensing only a part of the fluid, sensing any property of the fluid, and the like.
Each one of steps 430 and 440 may include performing one or measurements—in one or more conditions.
The method may also include determining when to operate in each mode.
The method may include operating the biosensor in any other mode.
Steps 430 and 440 refer to the manner in which the sensing is done. It should be noted, that the method may also include step 450 of performing one or more additional operations. Although illustrates as a separate step—at least one additional operation may be executed when in the first mode, when in the second mode, or when in any other mode).
Examples of the one or more additional operations may include sensing a source-drain current, sensing any other signal from the biosensor that is indicative of the fluid, controlling the temperature of the fluid, biasing the fluid, introducing, by two or more gates of the multiple gates, an ion current within the fluid (for example, during an excitation period that may differ than any sensing period, or may overlap with a sensing period), and the like.
The semiconductor active region may be formed above a buried oxide layer of an SOI (silicon on isolator) structure.
The semiconductor active region, the sensing region and the multiple gates may be CMOS fabricated.
Method 500 may start by step 510 of providing a biosensor. The biosensor may include a semiconductor active region; a sensing region configured to contact a fluid; and multiple electrodes that may include decoupling electrodes and additional electrodes.
Step 510 may be followed by step 520 of receiving fluid by a fluid compartment of the biosensor.
Steps 510 and 520 may be followed by step 530 of operating the biosensor in the first mode. Step 530 may include biasing the decoupling electrodes to electrostatically decouple the interface between the sensing region and the fluid from one or more conductive channels formed within the semiconductor active region.
Method 500 may also include step 530 of operating the biosensor in a second mode, where the interface is electrostatically coupled to the one or more conductive channel.
Step 530 and/or 540 may include sensing the fluid.
Steps 530 and 540 refer to the manner in which the sensing is done. It should be noted that the method may also include step 550 of performing one or more additional operations. Although illustrates as a separate step—at least one additional operation may be executed when in the first mode, when in the second mode, or when in any other mode).
Examples of the one or more additional operations may include sensing a source-drain current, sensing any other signal from the biosensor that is indicative of the fluid, controlling the temperature of the fluid, biasing the fluid, introducing, by two or more gates of the multiple gates, an ion current within the fluid, and the like.
Method 600 may start by step 610 of providing a biosensor. The biosensor may include a semiconductor active region; a sensing region configured to contact a fluid; and multiple electrodes that may include decoupling electrodes and additional electrodes.
Step 610 may be followed by step 620 of receiving fluid by a fluid compartment of the biosensor.
Steps 610 and 620 may be followed by step 630 of sensing the fluid.
Step 630 may include controlling, by the multiple electrodes, one or more properties of one or more conductive channels formed within the semiconductor active region; wherein different values of the one or more properties of the one or more conductive channels may be associated with different sensing functions of the biosensor.
The providing of the different sensed results that may be associated with the different values of the one or more properties of the one or more conductive channels.
For example—sensed information about the fluid may be provided when setting the one or more properties of the one or more channels in various combinations—for example according to at least some of the examples illustrated in
Any reference to any of the terms “comprise”, “comprises”, “comprising” “including”, “may include” and “includes” may be applied to any of the terms “consists”, “consisting”, “consisting essentially of”. For example—any of the rectifying circuits illustrated in any figure may include more components that those illustrated in the figure, only the components illustrated in the figure or substantially only the components illustrated in the figure.
In the foregoing specification, the invention has been described with reference to specific examples of embodiments of the invention. It will, however, be evident that various modifications and changes may be made therein without departing from the broader spirit and scope of the invention as set forth in the appended claims.
Moreover, the terms “front, ” “back, ” “top, ” “bottom, ” “over, ” “under ” and the like in the description and in the claims, if any, are used for descriptive purposes and not necessarily for describing permanent relative positions. It is understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments of the invention described herein are, for example, capable of operation in other orientations than those illustrated or otherwise described herein.
Those skilled in the art will recognize that the boundaries between logic blocks are merely illustrative and that alternative embodiments may merge logic blocks or circuit elements or impose an alternate decomposition of functionality upon various logic blocks or circuit elements. Thus, it is to be understood that the architectures depicted herein are merely exemplary, and that in fact many other architectures can be implemented which achieve the same functionality.
Any arrangement of components to achieve the same functionality is effectively “associated” such that the desired functionality is achieved. Hence, any two components herein combined to achieve a particular functionality can be seen as “associated with” each other such that the desired functionality is achieved, irrespective of architectures or intermedial components. Likewise, any two components so associated can also be viewed as being “operably connected,” or “operably coupled,” to each other to achieve the desired functionality.
Furthermore, those skilled in the art will recognize that boundaries between the above described operations merely illustrative. The multiple operations may be combined into a single operation, a single operation may be distributed in additional operations and operations may be executed at least partially overlapping in time. Moreover, alternative embodiments may include multiple instances of a particular operation, and the order of operations may be altered in various other embodiments.
Also for example, in one embodiment, the illustrated examples may be implemented as circuitry located on a single integrated circuit or within a same device. Alternatively, the examples may be implemented as any number of separate integrated circuits or separate devices interconnected with each other in a suitable manner.
However, other modifications, variations and alternatives are also possible. The specifications and drawings are, accordingly, to be regarded in an illustrative rather than in a restrictive sense.
In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. The word ‘comprising’ does not exclude the presence of other elements or steps then those listed in a claim. Furthermore, the terms “a” or “an,” as used herein, are defined as one or more than one. Also, the use of introductory phrases such as “at least one ” and “one or more ” in the claims should not be construed to imply that the introduction of another claim element by the indefinite articles “a ” or “an ” limits any particular claim containing such introduced claim element to inventions containing only one such element, even when the same claim includes the introductory phrases “one or more ” or “at least one ” and indefinite articles such as “a ” or “an. ” The same holds true for the use of definite articles. Unless stated otherwise, terms such as “first” and “second” are used to arbitrarily distinguish between the elements such terms describe. Thus, these terms are not necessarily intended to indicate temporal or other prioritization of such elements.
While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.
