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WO2006000064A2 - Dispositif de regulation du flux de porteurs de charge a travers un nanopore dans une membrane et procede de fabrication de ce dispositif - Google Patents

Dispositif de regulation du flux de porteurs de charge a travers un nanopore dans une membrane et procede de fabrication de ce dispositif Download PDF

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Publication number
WO2006000064A2
WO2006000064A2 PCT/BE2005/000102 BE2005000102W WO2006000064A2 WO 2006000064 A2 WO2006000064 A2 WO 2006000064A2 BE 2005000102 W BE2005000102 W BE 2005000102W WO 2006000064 A2 WO2006000064 A2 WO 2006000064A2
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WIPO (PCT)
Prior art keywords
nanopore
membrane
electrode
nanofluidic device
flow
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PCT/BE2005/000102
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English (en)
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WO2006000064A3 (fr
Inventor
Gustaaf Borghs
Carmen Bartic
Kristiaan De Greve
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Interuniversitair Microelektronica Centrum Vzw
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Priority claimed from GB0414390A external-priority patent/GB0414390D0/en
Application filed by Interuniversitair Microelektronica Centrum Vzw filed Critical Interuniversitair Microelektronica Centrum Vzw
Publication of WO2006000064A2 publication Critical patent/WO2006000064A2/fr
Publication of WO2006000064A3 publication Critical patent/WO2006000064A3/fr

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    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K10/00—Organic devices specially adapted for rectifying, amplifying, oscillating or switching; Organic capacitors or resistors having potential barriers
    • H10K10/40—Organic transistors
    • H10K10/46—Field-effect transistors, e.g. organic thin-film transistors [OTFT]

Definitions

  • the present invention relates to nanofluidic devices for controlling the flow of charged carriers in a fluid through at least one nanopore in a membrane, by means of controlling the charge distribution in the at least one nanopore, to a method for the manufacturing of such devices and to a method for controlling the charge distribution in at least one nanopore in a membrane by modifying the electrical potential distribution inside the nanopore.
  • ion channels are pores through a cell membrane through which ions can be transported in and/or out of the cell under the influence of an electrochemical gradient, i.e. an electrical field and/or concentration gradient.
  • an electrochemical gradient i.e. an electrical field and/or concentration gradient.
  • This is the so-called 'passive' transport mode, which is opposite to the active transport mode which occurs against an electrochemical gradient, and which requires dedicated, energy consuming vesicles [Alberts B., Johnson A., Lewis J., Raff M., Roberts K., Walter P., "Molecular biology of the Cell", 4 th ed., Garland Science, New York, 2002].
  • ion channels are proteins that fold in such a way that they form natural conducting nanopores dispersed in the membrane of the cells, thereby controlling the ionic fluxes in and out of the cell.
  • Many ion channels can selectively allow or block the flow of particular ion species through the membrane.
  • the pores are highly sensitive for particular ions and they can open and close in response to various factors such as e.g. ligand binding, changes in the electrical field or membrane tension. This process is also called gating. In this gating process the electrochemical potential profile of the channel effectively changes, which subsequently alters its transport properties.
  • the actual transport mechanisms and the kinetics of the gating event can differ from one pore to another (e.g.
  • nanoporous materials have been used and/or modified in ion flow conducting experiments [Steinle E. D. et. al., 'Ion channel mimetic micropore and nanotube membrane sensors', Anal. Chem., 74, 2002, pp. 2416-2422],[Jirage K.B. et al. "Nanotubule-based filtration membranes", Science, 278, 1997, pp. 655 - 658]. In these structures, it is a chemical stimulus (i.e. interaction with the analyte species), which switches on the ion transport through the pore.
  • an alumina membrane containing gold nanotubes has been rendered hydrophobic [Steinle E. D. et. al., 'Ion channel mimetic micropore and nanotube membrane sensors', Anal. Chem., 74, 2002, pp. 2416-2422]. Therefore, initially the ion channel is in off state. Once the analyte has been added in the solution, water and ions could penetrate through the membrane and a given ion current was measured.
  • the possibility of externally controlling the ion flow through nanochannels, preferably electrically, offers intriguing prospects in a wide scope of fields, including (but not restricted to) battery applications, biosensors, filtration membranes, etc.
  • the present invention provides a nanofluidic device for controlling the flow of charge carriers in at least one nanopore by modifying the electrical potential distribution inside the nanopore.
  • the device comprises: - a membrane having a thickness and having a first side and a second side, - a first electrode being positioned at the first side of the membrane and a second electrode being positioned at the second side of the membrane, the second side being opposite to the first side.
  • the thickness of the membrane typically is the smallest dimension of the membrane.
  • the membrane may be laying in a plane, and then the thickness is the dimension measured perpendicularly to the plane.
  • the membrane comprises at least one nanopore extending through the membrane over the thickness of the membrane, over its thickness, so as to form a channel connecting the first and second side of the membrane.
  • a third electrode is integrated in said at least one nanopore.
  • the nanopore may be located perpendicular to the plane of the membrane.
  • the nanopore may have a longitudinal axis of which the direction is inclined with respect to a line perpendicular to the plane of the membrane.
  • the nanofluidic device allows controlling the flow of charge carriers through at least one nanopore in which the behaviour of the at least one nanopore, and thus the flow of the charge carriers, can be externally, electrically controlled.
  • the device according to the invention is suitable for being integrated into larger device-structures such as, for example, lab-on-chip.
  • the at least one nanopore may be located at pre-determined positions. This leads to accurately positioned nanopores in the membrane.
  • the at least one nanopore may have a smallest pore diameter located within one Debye screening length from said third electrode, wherein the smallest diameter is equal to or smaller than twice the Debye length of the nanopore.
  • the nanopore may be defined by an IC-compatible fabrication method.
  • the nanopore may for example be defined by a lithographic process forming a lithographically defined nanopore pattern and may subsequently be etched based on said lithographically defined nanopore pattern.
  • the lithographic process may be any of optical lithography, X-ray lithography, electron-beam lithography, focused ion beam lithography or nano-imprint lithography.
  • the at least one nanopore may have a smallest pore diameter smaller than or equal to 100 nm.
  • the at least one nanopore may have a smallest pore diameter of between 1 and 100 nm, preferably between 10 and 15 nm and more preferably between 0.5 and 5 nm.
  • the membrane may have a thickness of smaller than or equal to 100 ⁇ m.
  • the membrane may have a thickness between 10 ⁇ m and 100 ⁇ m, preferably between 100 nm and 10 ⁇ m.
  • the inner surface wall of the nanopore may be chemically modified with voltage-sensitive dipolar molecules.
  • There may be a first space between the first electrode and the first side of the membrane and a second space between the second electrode and the second side of the membrane, wherein the first space is adapted for receiving a first solution and the second space is adapted for receiving a second solution.
  • the first solution may be different from the second solution or the first solution may be equal to the second solution.
  • the first and/or second solutions may extend through said nanopore.
  • the first solution comprises water or a solvent, an analyte and a first electrolyte.
  • the second solution comprises water or a solvent and a second electrolyte.
  • the concentration of the first electrolyte in the first solution can be equal or substantially equal to the concentration of the second electrolyte in the second solution. In another embodiment, the concentration of the first electrolyte in the first solution is different from the concentration of the second electrolyte in the second solution, different being understood as higher or lower. In a preferred embodiment, the first electrolyte and the second electrolyte are the same while the first solution comprises a charged analyte. The said device can then be used to transfer analyte from said first solution to said second solution. In another embodiment, a first analyte is present in the first solution, and a second analyte is present in the second solution.
  • This second analyte can be the same as the first analyte, or different.
  • the concentration of these two said analytes can be equal or different.
  • the said device can then be used to transport the first analyte from the first solution into the second solution.
  • the said device can also be used to transfer the second analyte from the second solution into the first solution, and for transferring both analytes from their initial solution to the solution opposite of the pore.
  • the device according to embodiments of the present invention is used as a transistor or in a transistor means.
  • the device is an ionic transistor.
  • the device according to embodiments of the present invention is a filter or is used in a filter means, filtering charged species based on their charge.
  • the device according to embodiments of the present invention is a sensor for sensing an analyte in solution or is used in a sensor.
  • the device according to embodiments of the present invention is used as part of a galvanic cell, the establishment of the equilibrium potential over the membrane of which is modified and controlled by means of the third electrode. In all of these applications, a feature resides in the full electrostatic control over the potential and charge distribution in the channel by means of said third contact.
  • the present invention provides a method for forming a nanofluidic device for controlling the flow of charge carriers in a fluid through at least one nanopore by modifying the electrical potential distribution inside the nanopore.
  • the method according to the second aspect of the present invention comprises: - providing a membrane having a thickness and having a first side and a second side, - defining at least one nanopore in said membrane, - etching said at least one nanopore through the membrane over the thickness of the membrane, such that the at least one nanopore connects the first side and the second side of the membrane by forming a channel, - providing a first electrode at said first side of the membrane and a second electrode at said second side of the membrane, and - providing at least one third electrode, said at least one third electrode being integrated in the at least one nanopore.
  • the method may comprise providing a plurality of nanopores in the membrane, wherein a third electrode is integrated into at least one nanopore.
  • a third electrode may be integrated in each of the plurality of nanopores, each third electrode being adapted for being addressed independently from the other third electrodes.
  • Providing at least one third electrode may comprise extending the third electrode over an entire inner surface of the at least one nanopore.
  • providing at least one third electrode may comprises not extending the third electrode over an entire inner surface of the at least one nanopore, but only extending it over part of the inner surface thereof.
  • Defining at least one nanopore in the membrane may be performed by using an IC-compatible fabrication method. Defining at least one nanopore in the membrane may be performed lithographically.
  • Defining at least one nanopore in the membrane may be performed by means of any of optical lithography, X-ray lithography, electron-beam lithography, focused ion beam lithography or nano-imprint lithography. Etching said at least one nanopore may be performed by wet anisotropic etching or by dry anisotropic etching. Defining at least one nanopore may be performed such that the at least one nanopore has a smallest pore diameter equal to or smaller than the Debye length of the nanopore. Defining at least one nanopore may be performed such that the at least one nanopore has a smallest pore diameter equal to or smaller than 100 nm.
  • Defining at least one nanopore may be performed such that the at least one nanopore has a pore diameter of between 1 and 100 nm, preferably between 10 and 15 nm and more preferably between 0.5 and 5 nm.
  • the present invention provides a method for controlling the flow of charge carriers in at least one nanopore in a membrane.
  • the method comprises: - providing a nanofluidic device comprising a membrane having a thickness and having a first side and a second side, a first electrode positioned at the first side of the membrane and a second electrode positioned at a second side of the membrane, the membrane comprising at least one nanopore, preferably at a pre-determined position, extending through the membrane over the thickness of the membrane so as to form a channel connecting the first and second side of the membrane and a third electrode integrated in the at least one nanopore, - providing a first solution between said first side and said first electrode and a second solution between said second side and said second electrode, - applying a first and a second electrical voltage to respectively the first electrode and second electrode, and - applying a third electrical voltage to the third electrode, the third electrical voltage being independent from the first and second electrical voltage.
  • an electric field is present in the pore with a component of the electric field extending transversally through the pore, transversally meaning perpendicular to the inner surface of said pore as described in the first aspect of this invention.
  • This transversal electric field influences the creation of a double layer potential at the walls of the nanopore.
  • the dimensions of the pore are preferably chosen such that full control can be exerted over the potential in at least one zone of the channel, such that no connection from the first to the second solution can be found that does not intersect with this zone.
  • the present invention provides a method for determining a voltage to be applied to an electrode for controlling the flow of charge carriers in at least one nanopore in a membrane, the electrode being positioned in a nanopore extending through a membrane and forming a channel connecting a first side of the membrane with a second side of the membrane.
  • the method comprises: - in a first step loading pre-determined relationships between the flow of charge carriers through the nanopore and at least a voltage to be applied at the electrode, e.g. a list of such relationships, - in a second step determining the required flow of charge carriers, - selecting from a combination of the first step and the second step the voltage to be applied to the electrode.
  • the present invention also provides a computer program product which when executed on a processing device executes the method according to an embodiment of the present invention for determining a voltage to be applied to an electrode for controlling the flow of charge carriers in at least one nanopore in a membrane.
  • the present invention also provides a machine readable data storage device storing the computer program product of the present invention.
  • the present invention also provides the use of a nanofluidic device according to the present invention as a biosensor or as an ionic transistor. Particular and preferred aspects of' the invention are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not merely as explicitly set out in the claims.
  • Fig. 1 illustrates a model for the electrode/solution double layer region.
  • Fig. 2 schematically illustrates the build-up of an electrical double-layer at a liquid-solid interface (A), the modification of the double layer by means of an applied gate voltage Vg over a channel wall (B-C) and an equivalent capacitor model (D).
  • Fig. 3 is an example of a nanofluidic device according to a first aspect of the present invention.
  • Fig. 4 is a schematic illustration of a cross-section (parallel to the membrane surface) of a nanopore.
  • Fig. 5 is a schematic illustration of the working principle a nanofluidic device according to an embodiment of the invention.
  • the same reference signs refer to the same or analogous elements.
  • the present invention therefore provides a nanofluidic device for controlling the flow of charge carriers, such as e.g.
  • a nanofluidic device for modifying the electrical potential distribution inside a nanopore is provided. For example, this can be in order to induce changes in the nanopore permeability for differently charged chemical species.
  • the device according to the present invention may, for example, be an artificial ion transistor based on nano- fabrication technologies, i.e.
  • the ion flow through the nanopore is controlled by the potential distribution inside that nanopore.
  • the potential distribution is defined by the double layer potentials generated at the walls of the nanopore. It is known that at the interface between a solid surface and a solution comprising one or more electrolytes, a so-called double-layer is formed [Hunter, R.J., "Zeta potential in colloid science", Academic Press, London, 1981].
  • the diffuse layer of this double layer extends over a Debye screening length, which is dependent on the nature and the concentration of the one or more electrolytes in a fluid.
  • the double layer capacitance consists of a series network of a Helmholtz-layer capacitance and a diffuse layer capacitance.
  • the Helmholtz-layer is indicated by reference number 1 and the diffuse layer is indicated by reference number 2.
  • the latter describes the zone of essentially mobile ions in which a net charge (and electrical potential) extends into the fluid, effectively screening the charge in the Stern layer and at the interface itself.
  • the Helmholtz layer 1 having an inner Helmholtz plane (IHP) and an outer Helmholtz plane (OHP), is used to model the effect of the finite size of the hydrated ions 3 by which these ions are prevented from approaching the surface 4 of a solid 5 any closer than their ionic radius.
  • IHP inner Helmholtz plane
  • OHP outer Helmholtz plane
  • the double layer potential formed at a given surface while immersed in a given ionic solution depends on the pH of the solution and the ionic strength thereof, as well as on the charge on the pore inner surface.
  • the nanofluidic device according to the first aspect of the present invention can operate in a fluid, e.g. an aqueous environment, where different charged species, e.g. ions, are present.
  • the charged species, e.g. ions act as carrier species.
  • the nanofluidic device according to the first aspect of the present invention comprises a membrane, the membrane comprising at least one pore extending through the membrane.
  • the pores have nanoscale dimensions (see further), therefore, in the further description the pores will be referred to as nanopores.
  • a nanofluidic device 10 according to the first aspect of the present invention and as illustrated in Fig. 3, comprises a first electrode 11 , a second electrode 12 and a membrane (not shown in the figure). The membrane lies in a plane and has a first surface and a second surface.
  • the membrane comprises at least one nanopore 13 situated at pre-determined positions and extending through the membrane such as to form a channel connecting the first and second surface of the membrane.
  • the first electrode 11 is positioned at the side of the first surface of the membrane and the second electrode 12 is positioned at the side of the second surface of the membrane.
  • a first solution 14 may be present e.g. between the first surface of the membrane and the first electrode 11 and a second solution 15 may be present between the second surface of the membrane and the second electrode 12.
  • the first solution 14 may be the same or may different from the second solution 15.
  • the first solution 14 may comprise a first analyte and a first fluid.
  • the second solution 15 may comprise a second fluid and may or may not comprise a second analyte.
  • the first and second analyte may preferably be at least one ion or at least one charged molecule.
  • the first and the second fluid may be the same or may be different from each other.
  • the first and second analyte may be the same or may be different from each other.
  • the first analyte may be present in the first solution 14 in a first concentration.
  • the second analyte may be present in the second solution 15 in a second concentration.
  • the first and second concentration may be the same or may be different from each other.
  • the first and second electrodes 11 , 12 may be conductive, e.g.
  • the first and second electrode 11 , 12 may not be attached to the membrane.
  • standard conductive electrodes e.g. metallic electrodes, such as Pt- or Ag/AgCI electrodes, and electrode cells may be used for biasing the respective solutions 14, 15.
  • a standard voltage source may be used for biasing the electrodes 11 , 12 at the appropriate electric potentials.
  • a low-impedance source may be used but in other embodiments also a high-impedance source may be used.
  • the nanofluidic device 10 comprises a third electrode 16 which is integrated with the at least one nanopore 13.
  • the third electrode 16 will be used to control the charge density at the walls of the at least one nanopore 13 for given pH and ionic strength values and therefore, obtain the desired potential distribution inside the at least one nanopore 13.
  • the third electrode may, for example, comprise a metal (e.g. Cu, Au, Pt, Ag) or a degenerate semiconductor or may be an alloy of several metals, the electric conductivity of which is such, that the electrode surfaces may be regarded as electrical equipotential surfaces.
  • the third electrode 16 may, according to embodiments of the invention, extend over the entire inner surface of the nanopore 13.
  • a nanofluidic device 10 is provided, the dimensions of which can be accurately predetermined and reproduced, and which can be accurately and reliably positioned on a predefined position on a substrate.
  • the membrane may preferably comprise a layer of IC-compatible material and may be physically attached to an IC-compatible substrate (not shown in the figure) which may be locally removed in order to expose the first and second surface of the membrane to respectively the first and second solution 14, 15 (see further).
  • the substrate may be a semiconductor substrate, such as e.g. Si, GaAs, Ge, or an insulating material, such as e.g. pyrex, silica, mica, SiC, diamond, sapphire, or any other suitable substrate.
  • the membrane may be a "thin membrane" by which it is meant that the membrane thickness may be smaller than 10 ⁇ m.
  • the membrane thickness may be between 100 nm and 10 ⁇ m. In other embodiments, however, the membrane thickness may be larger, e.g. between 10 ⁇ m and 100 ⁇ m.
  • the membrane may comprise a thin metal sheet wherein the metal may, for example, be Au, Pt, Al, Ta, ITO, carbon or any other suitable metal, or may comprise a conducting or semiconducting polymer, such as e.g. poly(3,4-ethylenedioxythiophene) or PEDOT, a semiconductor material such as e.g. Si, or an insulating material such as e.g. SiO 2 , Si 3 N 4 , SiC, Ta 2 O 5 , AI 2 O 3 , polycarbonate, polyethylene, parylene C or any other suitable insulating material.
  • a conducting or semiconducting polymer such as e.g. poly(3,4-ethylenedioxythiophene) or PEDOT
  • a semiconductor material such as e.g. Si
  • an insulating material such as e.g. SiO 2 , Si 3 N 4 , SiC, Ta 2 O 5 , AI 2 O 3 , polycarbonate, polyethylene, parylene C or any other suitable
  • the membrane may comprise combinations of the above-described materials, wherein with combinations is meant stacks of layers of materials or materials classes as described above, such as e.g. SiO 2 on top of a Si layer.
  • the diameter or width of the at least one nanopore 13 present in the membrane may depend on the particular application. In embodiments according to the invention, the diameter of the nanopore 13 may be equal over the entire thickness of the membrane, i.e. the nanopore 13 may have uniform diameter over its entire length. In other embodiments according to the invention, the diameter of the nanopore 13 may be variable throughout the thickness of the membrane, and thus the nanopore 13 may have a non ⁇ uniform diameter over its length. In both cases, the minimum diameter of the nanopore 13 should be accurately determined.
  • the dimensions of the nanopore 13 are chosen such that for at least one particular zone of the nanopore 13, the potential throughout this zone can be modified.
  • 'zone' is meant a three-dimensional volume, enclosed within the nanopore 13, that locally fills the entire nanopore 13, i.e. no path through the nanopore 13 can be found, from the first surface to the second surface of the membrane or vice versa, that does not intersect this volume.
  • the surface charge on the fluid-solid interface can be changed, and subsequently the potential and charge distribution in the channel of the nanopore 13 is changed.
  • the third electrode 16 may preferably be covered with a dielectric layer 17, because, when the third electrode 16 would not be covered with a dielectric layer 17, charge transfer might occur over the interface of the electrode 16 and the solution(s) 14, 15 inside the nanopore 13, giving rise to an electrical current being drawn from the third electrode 16, and a more difficult biasing scheme in which the potential drop over the dielectric capacitor would be absent.
  • the dielectric layer 17 may comprise a single layer or may comprise a stack of layers.
  • the dielectric layer 17 may, but should not necessarily be, morphologically and/or structurally equal to the internal surface of the entire nanopore 13.
  • the dielectric layer 17 may, for example, be SiO2, SiOx (non-stoechiometric silica), silicon nitride, or any other suitable dielectric material.
  • the dielectric layer 17 also extends over the entire nanopore 13 and in that case the inner surface of the nanopore 13 or the 'pore inner surface' is formed by the dielectric layer 17 (or any layer on top of that, see further). If the third electrode 16 does not cover the entire nanopore 13, the pore inner surface may mainly form the interface of the nanopore 13 with the membrane (with possibly an extra layer covering it in order to change the surface charge thereof).
  • the dielectric layer 17 and the pore inner surface (or the respective covering layers of these two interfaces) may but do not have to be equal. In this case, equal may refer to the chemical composition, but also to morphology of the surface (amorphous vs.
  • AI 2 O 3 may be used as dielectric layer.
  • a charge is developed on the solid material, in the case of the invention the inner pore surface, when immersed in a solution 14, 15 comprising a fluid and an analyte. This depends on the pH according to -log(conc(H 3 0 + )).
  • the H 3 O + and OH concentrations compensate each other, giving rise to a net zero charge.
  • the H 3 O + concentration dominates, giving a net positive charge on the surface. This depends on many aspects such as e.g. the morphology of the surface in the case of an immersed solid (porosity, amorphous vs. crystalline etc.). In Marek Kosmulski, "The pH- dependent surface charging and the points of zero charge", Journal of colloid and Interface science, 253 (2002), p.77-78, an illustration of pH dependence of the surface charge can be found.
  • the dielectric layer 17 covering the third electrode 16 may itself be covered with a pore inner surface layer 19 (not shown in the Fig. 3 but illustrated in Fig. 4) which separates the dielectric layer 17 from the solution, e.g.
  • the pore inner surface layer 19 may be, for example, silica, silicon nitride, alumina, mica, or any other suitable material.
  • the material of the pore inner surface layer 19 should be chosen such as to give an appropriate surface charge under the conditions chosen for the experiment to be conducted with a device according to the present invention.
  • the layer forming the inner surface of the nanopore 13, also called the interfacial layer, which is either the third electrode 16, the dielectric layer 17 or the pore inner surface layer 19, may be chosen such that the charge which develops at the interface is minimal under the chosen conditions of pH and ionic strength, which allows for optimum modification of the surface charge in the nanopore 13 by means of the third electrode 16 integrated in the nanopore 13.
  • the longitudinal direction or length of the pore may be perpendicular or substantially perpendicular to the first and second surface of the membrane 18.
  • the length of the nanopore 13 may be characterised by the distance between the first and second surface of the membrane 18, in other words, may be determined by the thickness of the membrane 18.
  • the longitudinal direction of the nanopore 13 may not be substantially perpendicular to the first and second surface.
  • the nanopore may be etched in a plasma non-perpendicular to the membrane 18, but still forming a channel connecting the first surface with the second surface.
  • the length of the nanopore 13 may be different from the thickness of the membrane 18, more particularly the length of the nanopore 13 may be larger than the thickness of the membrane 18.
  • FIG. 4 A schematic illustration of a possible layer stack inside a nanopore 13 is shown in Fig. 4. It has to be understood that this is only an example and that this is not limiting the invention.
  • a nanopore 13 extending through a membrane 18 comprises a third electrode 16 which is positioned at an inner surface of the nanopore 13.
  • the third electrode 16 is, in the example given, covered with a dielectric layer 17.
  • a pore inner surface layer 19 is provided on top of the dielectric layer 17 .
  • the dimensions of the at least one nanopore 13 are chosen such that full control can be exerted over the potential in at least one zone of the channel, such that no connection through the nanopore 13 from the first to the second solution 14, 15 can be found that does not intersect with this zone (see above).
  • the interface between a solid surface, which according to the invention is the pore inner surface and/or dielectric layer 17 covering the third electrode 16 and/or the pore inner surface layer 19, and a solution 14, 15 comprising at least one electrolyte, a double layer is formed.
  • the diffuse layer 2 of the double layer extends over a Debye screening length, which is dependent on the nature and concentration of the at least one analyte in the solution 14, 15 in the pore channel.
  • This Debye screening length is a measure for the ultimate extension of electric fields in the solution 14, 15. Therefore, in order to have full electrical control in at least one cross-section of the nanopore 13 near the third electrode 16, the diameter of the nanopore 13 near the third electrode 16 should be chosen such that it does not exceed twice the Debye length of the nanopore 13 in the particular application.
  • the diameter or width of the at least one nanopore 13 in the vicinity of the third electrode 16, also defined as the smallest diameter of the nanopore 13 in case of a non-uniform width may be between 1 nm and 100 nm. More preferred, the width or smallest dimension of the nanopore 13 may be between 10 nm and 15 nm. Still more preferred, the width or smallest dimension of the nanopore 13 may be between 0.5 nm and 5 nm.
  • the inner surface of the nanopore 13 may be modified. For example, the inner surface of the nanopore 13 may be morphologically altered or may be changed by providing an accurately determined layer into the pore.
  • This layer may, for example, comprise alumina, silica, silicon nitride, mica, or any other suitable material provided that is gives rise to an appropriate surface charge under the given circumstances.
  • the inner surface of the nanopore 13 may be coated with voltage sensitive dye molecules. Voltage sensitive dyes may be dipolar molecules that change their polarisation under influence of an electrical field. This change in polarisation allows for additional, essentially electrical control of the electrical potential profile in the nanopore 13, and may or may not result in a change of the transport of an analyte through the nanopore 13.
  • the nanofluidic device 10 as described in the first aspect of the present invention may be used as a transistor or in a transistor means.
  • the nanofluidic device 10 may be an ionic transistor.
  • the device 10 according to the first aspect of the present invention may be a filter or may be used in a filter means for filtering charged species based on their charge.
  • one of the features resides in the full electrical control over the potential and charge distribution in the channel of the nanopore 13 by means of the third electrode 16.
  • the benefit of a nanofluidic device 10 according to the first aspect of the present invention compared to conventional protein ion channels is its IC- compatible fabrication method, which allows mass fabrication.
  • the nanofluidic device 10 according to the first aspect of the invention allows circumventing the problems of limited stability and lifetime related to the use of biological materials.
  • This device 10 furthermore provides an additional degree of freedom in applying a potential over the third electrode 16, independent of the potential applied the first and second electrodes 11 , 12 on either side of the nanopore 13.
  • the robustness and controllability of the manufacturing method which also allows for straightforward integration into electronic circuitry, offers a clear advantage over the inherent randomness of the nanotube-approach.
  • the nanofluidic device 10 according to the first aspect of the invention can be used to transport all types of charged species across the nanopore 13, such as e.g. anions, cations, charged biomolecules, ....
  • the possibility of modifying the internal pore surface allows for the intrinsic surface charge (a function of the composition and morphology of the surface, the local pH and ionic strength) to be changed independently of the gate-voltage- induced charge on the pore wall, gate voltage referring to the voltage applied to the third electrode 16 integrated in the membrane 18 near the nanopore 13.
  • gate voltage referring to the voltage applied to the third electrode 16 integrated in the membrane 18 near the nanopore 13.
  • a double layer potential drop occurs at the nanopore walls 20 and the dielectric layer 17 covering the third electrode 16, due to spontaneous charge separation.
  • the value of this potential drop depends on the particular experimental conditions, such as analyte concentration and pH, ion size, density of surface sites on the pore inner surface or nanopore walls 20.
  • a first-order Debye-Huckel model see e.g.
  • the Debye length is schematically indicated by the dashed lines in Fig. 5.
  • Fig. 5A illustrates a nanopore 13, comprising a third electrode 16 which does not completely cover the nanopore 13, and without a bias being applied at this third electrode 16, in the example given the gate electrode (e.g.
  • the gate is not connected to a charge reservoir).
  • charge separation is illustrated, as this occurs independently of the bias applied to the third or gate electrode 16 and which results in a net negative surface charge in the nanopore 13, a net positive charge in the diffuse layer 2, which extends over the entire width of the nanopore 13, at least in the vicinity of the third or gate electrode 16.
  • the extension of the Debye- Iength, and hence the diffuse layer 2 of the double-layer capacitor, is indicated by means of a dashed line 21.
  • both the surface charge on the electrode-covered part of the nanopore 13, which may or may not be equal to the entire inner surface or nanopore wall 20 of the nanopore 13, and the diffuse layer charge are changed.
  • a net positive potential is applied to the third or gate electrode 16, such that additional negative charges are attracted to the gate electrode's dielectric layer 17, partly screening the positive charge on the gate electrode 16 itself, as well as negative charges in the nanopore 13, further screening the positive charge on this gate electrode 16.
  • the permeability of the nanopore 13 and thus of the membrane 18 is changed from preferably cationic to preferably anionic.
  • FIG. 5C the applied negative potential yields a net positive surface charge (even overcoming the built-in negative surface charge), as well as a net positive charge in the diffuse layer 2.
  • FIG. 5B illustrates the opposite case than the one illustrated in Fig. 5B.
  • a negative charge exists on the gate electrode 16, a positive charge screening this, both at the pore surface and inside the nanopore 16, cationic permeability is increased (with regard to A) and anionic permeability decreased (again compared with A).
  • the voltage to be applied to the electrodes 11 , 12, 16 may be determined by means of 'voltage vs. current' experiments, changing both the electric field over the longitudinal and perpendicular directions of the nanopore 13.
  • Spontaneous separation of charge between the fluid phase and the solid interface can be caused by several mechanisms (difference in the affinity 0 of the two phases for different ions being the mechanism occurring at most solid-liquid interfaces) resulting in the creation of the double layer.
  • Equilibrium is established when the electrochemical potential is the same for each ion that can move freely between phases. This equilibrium can be shifted by applying an electric field perpendicular to the pore inner surface: this will result in a charge build-up at this inner surface, and a subsequent change of the charge distribution inside the diffuse layer.
  • an embodiment of the invention comprises an approach based on the chemical modification of the nanopore walls 20 with voltage-sensitive dipolar molecules (i.e. hyperpolarizable chromophores and proteins).
  • voltage-sensitive dipolar molecules i.e. hyperpolarizable chromophores and proteins.
  • a protein molecule in solution can be represented by a set of polarizable dipoles embedded into a dielectric medium of solvent molecules. Under influence of an electrical field applied onto the conductive, e.g.
  • a method for the manufacturing of a nanofluidic device 10 according to the first aspect of the invention is provided.
  • a substrate is provided.
  • the substrate may, for example, be a semiconductor substrate, such as e.g. Si, GaAs, Ge, or an insulating material, such as e.g. pyrex, silica, mica, SiC, diamond, sapphire, or any other suitable substrate.
  • a membrane 18 is then deposited onto the substrate.
  • the membrane 18 may e.g.
  • the metal may, for example, be Au, Pt, Al, Ta, ITO, carbon or any other suitable metal, or may e.g. comprise a conducting or semiconducting polymer, such as e.g. poly(3,4- ethylenedioxythiophene) or PEDOT, a semiconductor material such as e.g. Si, or an insulating material such as e.g. SiO 2 , Si 3 N 4 , SiC, Ta 2 O 5 , AI 2 O 3 , polycarbonate, polyethylene, parylene C or any other suitable insulating material.
  • a conducting or semiconducting polymer such as e.g. poly(3,4- ethylenedioxythiophene) or PEDOT
  • a semiconductor material such as e.g. Si
  • an insulating material such as e.g. SiO 2 , Si 3 N 4 , SiC, Ta 2 O 5 , AI 2 O 3 , polycarbonate, polyethylene, parylene C or any other suitable insulating material
  • the membrane 18 may comprise combinations of the above-described materials, wherein with combinations is meant stacks of layers of materials or materials classes as described above, such as e.g. SiO 2 on top of a Si layer.
  • the membrane 18 may have a thickness of between 100 nm and 10 ⁇ m. In other embodiments, however, the membrane 18 thickness may be between 10 ⁇ m and 100 ⁇ m.
  • standard processing techniques should be used which allow very accurate ( ⁇ 10 nm) control over the thickness of the layers forming the membrane 18. With very accurate control is meant that the position of the nanopore 13 can be determined with an accuracy of less than 10 nm.
  • Suitable methods for the deposition of the membrane 18 may be epitaxial methods (e.g. Molecular Beam Epitaxy (MBE), Metal Organic Chemical Vapour Deposition (MOCVD), Metal Organic Molecular Beam Epitaxy (MOMBE), ...) or vapour-deposition techniques, (e.g. Atomic Layer Deposition (ALD), Chemical Vapour deposition (CVD), plasma- assisted chemical vapour deposition (e.g. PECVD), vacuum evaporation, sputtering etc).
  • ALD Atomic Layer Deposition
  • CVD Chemical Vapour deposition
  • PECVD plasma- assisted chemical vapour deposition
  • vacuum evaporation e.g. sputtering etc.
  • wafer bonding and ion-implantation techniques may be used, such as e.g. in bonded Silicon On Insulator and Selective Implantation of oxygen SOI (SIMOX-SOI), which both yield layer stacks of silicon on oxide forming the thin membrane 18.
  • SIMOX-SOI Selective Implantation of oxygen SOI
  • the substrate is locally removed at those positions where a nanopore 13 is or will be extending through the membrane 18, or in other words, in the vicinity of an intersection of a nanopore 13 and the bottom surface of the membrane 18.
  • 'vicinity 1 is meant an area of the bottom surface comprising at least the zone where the nanopore 13 intersects the membrane bottom surface, and possibly but not necessarily larger. This may be done by e.g. bulk micromachining.
  • the wafer may first be thinned by a standard IC thinning method such as e.g. grinding, plasma etching
  • the wafer may also be polished, for example by Chemical Mechanical Polishing (CMP).
  • CMP Chemical Mechanical Polishing
  • the substrate should be etched away locally. Suitable etching methods may, for example, be ion milling, reactive ion etching (RIE), deep reactive ion etching, sputtering or wet etching.
  • RIE reactive ion etching
  • the definition of said pore through said membrane can occur before or after the bulk micromachining. Definition of at least one nanopore 13 through the membrane 18 may be performed before or after the bulk micromachining step, leading to a defined etch pattern.
  • the nanopore 13 may be defined by IC-compatible fabrication methods and may preferably be defined lithographically, either through optical lithography (UV, deep UV, extreme UV), electron-beam lithography, X-ray lithography, focused ion beam lithography or nano-imprint lithography, because lithographic processes allow for accurate determination with a deviation of less than 10 nm.
  • definition of the at least one nanopore 13 is meant the definition of the position of the nanopore 13 in the membrane 18.
  • the actual conformation or formation of the nanopore 13 through the membrane 18 depends on the further processing (see below).
  • a hole is etched through the membrane 18 based on the defined etch pattern.
  • the hole may be etched throughout the entire membrane 18 in one processing step, while in other embodiments according to the invention, the hole may be etched throughout the entire membrane 18 using at least two subsequent etching steps.
  • the etching process for forming the holes in the membrane 18 may be combined with the deposition of conductive, e.g.
  • the inner surface of the nanopore 13 may also be modified after pore-formation.
  • the inner surface may be morphologically altered, for example changed from amorphous to crystalline or vice versa, made porous, or having its micro-scale morphology changed, by rinsing a chemical fluid through the nanopore, or by melting and condensing the inner surface.
  • the inner surface of the nanopore 13 may be changed by depositing a layer with accurately determined thickness into the nanopore 13. This deposition can occur either epitaxially (e.g. MBE, MOCVD, MOMBE) or non-epitaxially (e.g. CVD, ). In a preferred embodiment, a self-limiting, layer- by-layer process is used, as in Atomic layer deposition. In another embodiment, the surface of the nanopore 13 is changed by a combination of these steps. Thereafter, the third electrode 16 is deposited onto the membrane (18), extending into the nanopore 13. This may be performed by, for example, evaporation, epitaxy, sputtering or another method yielding accurate control over the layer thickness inside the nanopore 13.
  • a self-limiting, monolayer-by-monolayer process may be used, as e.g. in atomic layer deposition.
  • the third electrode 16 may comprise a metal such as e.g. Au, Al, Ag, Pt, Cu, a degenerate semiconductor or an alloy.
  • the conductivity of the third electrode 16 should be such, that the electrode forms an equipotential surface.
  • the third electrode 16 may extend over the entire inner surface 20 of the nanopore 13. In another embodiment, this third electrode 16 does not extend throughout the entire nanopore 13.
  • the present invention furthermore includes a computer program product which provides, when executed on a computing device, the functionality of a method for determining the voltage to be applied to the third electrode 16 when using the nanofluidic device 10 according to the present invention.
  • the method comprises in a first step, loading a pre-determined relationship between the applied voltage and the flow of charge carriers through at least one nanopore 13 through the membrane 18.
  • the flow of charge carriers required for a particular application is determined. Combination of the first step with the second step then yields the required voltage to be applied to the third electrode 16 which is integrated in the nanopore 13.
  • the present invention includes a data carrier such as a CD- ROM or a diskette which stores the above computer program product in a machine readable form and which executes the method for determining the voltage to be applied to the third electrode 16 when executed on a computing device.
  • a data carrier such as a CD- ROM or a diskette which stores the above computer program product in a machine readable form and which executes the method for determining the voltage to be applied to the third electrode 16 when executed on a computing device.
  • a data carrier such as a CD- ROM or a diskette which stores the above computer program product in a machine readable form and which executes the method for determining the voltage to be applied to the third electrode 16 when executed on a computing device.
  • such software is often offered on the Internet or a company Intranet for download, hence the present invention includes transmitting the computer program product according to the present invention over a local or wide area network.
  • the computing device may include one of a microprocessor and an FPGA. It is to be understood that although preferred embodiments, specific constructions and configurations, as well as materials, have been discussed herein for devices according to the present invention, various changes or modifications in form and detail may be made without departing from the scope and spirit of this invention.

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Abstract

L'invention concerne un dispositif nanofluidique de régulation du flux de porteurs de charge à travers un nanopore d'une membrane de manière à former un canal qui relie le premier côté de la membrane au second côté opposé de la membrane; l'invention concernant par ailleurs un procédé de fabrication de ce dispositif. Ce dispositif comprend une première électrode placée sur le premier côté de la membrane, une deuxième électrode placée sur le second côté de la membrane et une troisième électrode intégrée dans le nanopore. L'application de tensions appropriées aux première, deuxième, et troisième électrodes permet de modifier la répartition des potentiels à l'intérieur du nanopore et, par conséquent, de réguler le flux des porteurs de charge.
PCT/BE2005/000102 2004-06-28 2005-06-28 Dispositif de regulation du flux de porteurs de charge a travers un nanopore dans une membrane et procede de fabrication de ce dispositif WO2006000064A2 (fr)

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GB0414390A GB0414390D0 (en) 2004-06-28 2004-06-28 Device and method for controlling the charge distribution in a nanopore
GB0414390.5 2004-06-28
US58446204P 2004-06-29 2004-06-29
US60/584,462 2004-06-29

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US20140318964A1 (en) * 2011-11-14 2014-10-30 Brigham Young University Two-Chamber Dual-Pore Device
US8980073B2 (en) 2011-03-04 2015-03-17 The Regents Of The University Of California Nanopore device for reversible ion and molecule sensing or migration
US9598281B2 (en) 2011-03-03 2017-03-21 The Regents Of The University Of California Nanopipette apparatus for manipulating cells
CN115275003A (zh) * 2022-07-18 2022-11-01 北京大学 一种液-液界面型忆阻器及兴奋型神经突触器件

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WO2002035580A2 (fr) * 2000-10-24 2002-05-02 Molecular Electronics Corporation Dispositifs moleculaires a trois bornes a commande par champ

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US9598281B2 (en) 2011-03-03 2017-03-21 The Regents Of The University Of California Nanopipette apparatus for manipulating cells
US10513434B2 (en) 2011-03-03 2019-12-24 The Regents Of The University Of California Nanopipette apparatus for manipulating cells
US8980073B2 (en) 2011-03-04 2015-03-17 The Regents Of The University Of California Nanopore device for reversible ion and molecule sensing or migration
CN105044170A (zh) * 2011-03-04 2015-11-11 加利福尼亚大学董事会 用于可逆的离子和分子感测或迁移的纳米孔装置
US10345260B2 (en) 2011-03-04 2019-07-09 The Regents Of The University Of California Nanopore device for reversible ion and molecule sensing or migration
US11243188B2 (en) 2011-03-04 2022-02-08 The Regents Of The University Of California Nanopore device for reversible ion and molecule sensing or migration
US11709148B2 (en) 2011-03-04 2023-07-25 The Regents Of The University Of California Nanopore device for reversible ion and molecule sensing or migration
US20140318964A1 (en) * 2011-11-14 2014-10-30 Brigham Young University Two-Chamber Dual-Pore Device
US9696277B2 (en) * 2011-11-14 2017-07-04 The Regents Of The University Of California Two-chamber dual-pore device
US11054390B2 (en) 2011-11-14 2021-07-06 The Regents Of The University Of California Two-chamber dual-pore device
CN115275003A (zh) * 2022-07-18 2022-11-01 北京大学 一种液-液界面型忆阻器及兴奋型神经突触器件
CN115275003B (zh) * 2022-07-18 2024-04-30 北京大学 一种液-液界面型忆阻器及兴奋型神经突触器件

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