WO2017157874A1 - Dispositif photovoltaïque destiné à la stimulation de cellules et/ou de réactions électrochimiques - Google Patents

Dispositif photovoltaïque destiné à la stimulation de cellules et/ou de réactions électrochimiques Download PDF

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WO2017157874A1
WO2017157874A1 PCT/EP2017/055886 EP2017055886W WO2017157874A1 WO 2017157874 A1 WO2017157874 A1 WO 2017157874A1 EP 2017055886 W EP2017055886 W EP 2017055886W WO 2017157874 A1 WO2017157874 A1 WO 2017157874A1
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layer
semiconductor
platelets
metal
metal layer
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PCT/EP2017/055886
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August Dorn
Daniel Diedrich
Robert Blick
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Universität Hamburg Arbeitsstelle Für Wissens- Und Technologietransfer
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Priority to DE112017001412.3T priority Critical patent/DE112017001412T5/de
Publication of WO2017157874A1 publication Critical patent/WO2017157874A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/20Applying electric currents by contact electrodes continuous direct currents
    • A61N1/205Applying electric currents by contact electrodes continuous direct currents for promoting a biological process
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • AHUMAN NECESSITIES
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    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/326Applying electric currents by contact electrodes alternating or intermittent currents for promoting growth of cells, e.g. bone cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/0616Skin treatment other than tanning
    • AHUMAN NECESSITIES
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    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/062Photodynamic therapy, i.e. excitation of an agent
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    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/0622Optical stimulation for exciting neural tissue
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/0624Apparatus adapted for a specific treatment for eliminating microbes, germs, bacteria on or in the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/067Radiation therapy using light using laser light
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    • C12MAPPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M25/00Means for supporting, enclosing or fixing the microorganisms, e.g. immunocoatings
    • C12M25/06Plates; Walls; Drawers; Multilayer plates
    • C12M25/08Plates; Walls; Drawers; Multilayer plates electrically charged
    • CCHEMISTRY; METALLURGY
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    • C12M35/00Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
    • C12M35/02Electrical or electromagnetic means, e.g. for electroporation or for cell fusion
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    • C12N5/00Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06Animal cells or tissues; Human cells or tissues
    • C12N5/0602Vertebrate cells
    • C12N5/0618Cells of the nervous system
    • C12N5/0619Neurons
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    • H01L31/00Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof
    • H01L31/0248Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof characterised by their semiconductor bodies
    • H01L31/0352Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof characterised by their semiconductor bodies characterised by their shape or by the shapes, relative sizes or disposition of the semiconductor regions
    • H01L31/035272Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof characterised by their semiconductor bodies characterised by their shape or by the shapes, relative sizes or disposition of the semiconductor regions characterised by at least one potential jump barrier or surface barrier
    • H01L31/035281Shape of the body
    • HELECTRICITY
    • H01ELECTRIC ELEMENTS
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    • H01L31/00Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof
    • H01L31/04Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof adapted as photovoltaic [PV] conversion devices
    • H01L31/06Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof adapted as photovoltaic [PV] conversion devices characterised by potential barriers
    • H01L31/07Semiconductor devices sensitive to infrared radiation, light, electromagnetic radiation of shorter wavelength or corpuscular radiation and specially adapted either for the conversion of the energy of such radiation into electrical energy or for the control of electrical energy by such radiation; Processes or apparatus specially adapted for the manufacture or treatment thereof or of parts thereof; Details thereof adapted as photovoltaic [PV] conversion devices characterised by potential barriers the potential barriers being only of the Schottky type
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00Materials characterised by their function or physical properties
    • A61L2400/12Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N2005/0658Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0659Radiation therapy using light characterised by the wavelength of light used infrared
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N2005/0658Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662Visible light
    • CCHEMISTRY; METALLURGY
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    • C12N2529/00Culture process characterised by the use of electromagnetic stimulation
    • C12N2529/10Stimulation by light
    • HELECTRICITY
    • H01ELECTRIC ELEMENTS
    • H01LSEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L2924/00Indexing scheme for arrangements or methods for connecting or disconnecting semiconductor or solid-state bodies as covered by H01L24/00
    • H01L2924/10Details of semiconductor or other solid state devices to be connected
    • H01L2924/11Device type
    • H01L2924/12Passive devices, e.g. 2 terminal devices
    • H01L2924/1203Rectifying Diode
    • H01L2924/12032Schottky diode
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02EREDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E10/00Energy generation through renewable energy sources
    • Y02E10/50Photovoltaic [PV] energy

Definitions

  • Photovoltaic device for stimulation of cells and/or electrochemical reactions
  • the invention relates to devices for stimulating cells and/or electrochemical reactions and to methods for fabricating such devices.
  • the devices are driven by
  • US 2008/300 663 Al discloses untethered micro or nanoscale probes that may be dispersed within tissue to be individually addressed through external electromagnetic radiation to create local electrical currents used for direct stimulation, alteration of cellular potentials, or the release or modification of contained or attached chemical compounds.
  • the device may additionally be the active ingredient of a disinfecting or sterilizing agent, or of a medicament. Further advantageous embodiments of the device, system and method are detailed in the respective dependent claims.
  • the inventors have developed a device for stimulation of at least one cell, and/or for stimulation of at least one electrochemical reaction.
  • This device comprises at least one semiconductor that is configured to convert electromagnetic radiation into a charge separation, or, in other words, into charges being separated. This charge separation provides the stimulus.
  • the cell is most preferably a neuron with a bi-lipid membrane.
  • the semiconductor comprises any chemical reaction that is tied to the flowing of an electric current.
  • the voltage associated with the charge separation is the driving force for the flow of such a current.
  • the semiconductor is planar, and the device further comprises a planar metal layer.
  • This metal layer forms a Schottky barrier (Schottky junction), and/or a metal-insulator-semiconductor, MIS, junction, with the semiconductor layer.
  • the semiconductor layer and/or the metal layer is configured to bind to a cell on contact, and/or configured to repel the cell on contact so that the semiconductor binds to the cell, in order to promote oriented or non-oriented binding to the cell, and/or configured to promote the electrochemical reaction when the device is exposed to a solvent.
  • the metal layer forms a Schottky barrier solar cell, SBSC, with the semiconductor.
  • the metal layer, and/or the semiconductor is configured to bind to a bi-lipid membrane of the cell.
  • Schottky barriers and MIS junctions Compared with the p-n junctions used in the previous art, Schottky barriers and MIS junctions have a lower open circuit voltage of at most 900 mV. However, this can produce a sufficiently large potential for any type of cellular stimulation.
  • the main advantage of Schottky barriers and MIS junctions is that they are very simple to produce. Consequently, they are easier to miniaturize. This means that in a fixed array of many such devices that is brought into contact with one or more cells, the devices can be arranged in a much smaller spacing, yielding more contact points and an improved spatial resolution. Where the devices are autonomous units that are diffused into a network of cells, especially into a network of neurons, those units can be made smaller, so as to facilitate their penetration deep into this three-dimensional network.
  • the metal layer has two more advantages that add to said miniaturization. First, it reflects the light and produces plasmon effects at the interface to the semiconductor, improving the efficiency of the conversion between the external electromagnetic radiation and the charge separation. For example, solar power conversion efficiencies above 20 % have been reported for silicon SBSCs, and with laser excitation in the spectral range between S00 nm and 800 nm, external quantum efficiencies exceeding 80 % can be achieved. Second, the additional function of the metal layer as a binding element to a cell on contact allows even very small devices to bind to the cell in a self-organized way without an extra component for such binding adding to the bulk of the device. There is a further attraction between the metal layer and the potential difference at the surface of a bi-lipid membrane that forms part of a cell.
  • the device further comprises a p-n junction, and/or a second Schottky barrier, and/or a second metal-insulator-semiconductor junction, in series with the first Schottky barrier and/or metal-insulator-semiconductor junction.
  • this increases the open circuit voltage.
  • Higher open circuit voltages can be desirable to improve the ability of the device to polarize a cell.
  • higher open circuit voltages also enable electrochemical processes, which do not take place at lower voltages. This can provide the device with a cytotoxic property when illuminated, so that the device has a further use as a disinfecting or sterilizing agent.
  • each junction When there are multiple junctions, each junction will provide its own depletion region. These depletion regions may be separated by additional tunnel junctions, akin to multi-junction solar cells.
  • the junctions can be made of the same or of different semiconductor materials. In contrast to multi-junction solar cells, it is not necessary to use different semiconductors with different band gaps, since the primary goal is to increase the open circuit voltage, rather than to improve the power conversion efficiency of light from a broad-band emitter such as the sun.
  • the metal layer is divided into a plurality of separate electrodes, which are located on the surface of the semiconductor. If the semiconductor is irradiated with electromagnetic radiation in the area of the junction with the metal layer, this will produce excitons consisting of an electron and a hole. One of these carriers will be drawn into the metal layer, while the other one will be drawn to the other face of the semiconductor.
  • a reference point for the voltage corresponding to the charge separation may be set by fixing this other face of the semiconductor at a specific potential, for example, by connecting this other face to a ground potential by means of an ohmic contact.
  • the solvent may be at the ground potential, and the voltage on the metal layer may be applied to the cell with respect to this ground potential.
  • the polarity of the voltage induced by the charge separation depends on the semiconductor and the type of doping, as well as on the work function of the metal layer. Depending on this polarity, irradiation of the semiconductor will result in either a stimulation or an inhibition of cellular activity, particularly neural activity.
  • a network comprising multiple cells may attach itself to the many electrodes of the device in a self-organized way.
  • the behavior of the cell network can then be studied by irradiating the semiconductor in one or more places where it forms a junction with the metal layer. Stimulation or inhibition of cellular activity may be monitored by any suitable means, for example, voltage- or calcium-sensitive dyes or electrically contacted electrodes.
  • a semiconductor, which is topped with the metal layer may, for example, be irradiated through its bottom face. For example, the absorption of silicon is rather weak, so enough of the light will reach the junction with the metal layer.
  • the localization of the irradiation may be further enhanced in an advantageous embodiment of the invention where at least one electrode comprises an aperture for passing the electromagnetic radiation into the semiconductor.
  • At least one electrode is partially covered by an insulating layer, and the part of the electrode not covered by the insulating layer is configured to bind to the bi-lipid membrane of the cell on contact.
  • the insulating layer may be configured to inhibit the attachment of cells to it, so that the cells will only attach to the part of the electrode not covered by the insulating layer. For example, this may be used to prevent the optical path to an aperture in the electrode from being obstructed by an attached cell.
  • the insulating layer may be transparent for the electromagnetic radiation that is used to excite the semiconductor, and/or it may comprise an aperture that corresponds to the aperture in the metal layer below.
  • the semiconductor comprises at least one platelet that is coated on one face with the metal layer.
  • platelet is by itself not limited to particular shapes. Rather, this term only implies that there is a planar top face, a planar bottom face, and a circumferential side face that is more or less line-shaped or band-shaped.
  • the platelet may, for example, have a circular, elliptic, polygonal or star shape.
  • the platelets are meant to be used as autonomous units that can be spread over a two-dimensional network of cells, particularly neurons, or diffused deep into a three- dimensional network of cells. They can be individually or collectively addressed with electromagnetic radiation, e.g., by a laser. Each platelet may preferably be a disc that is substantially circular or elliptic, so as to avoid sharp corners or edges of polygonal shapes that might snag inside a three-dimensional network of cells, particularly neurons. There may be other applications where such snagging is advantageous and/or desired.
  • the platelet Since either the top face or the bottom face of the platelet is metallic, the platelet is Janus-faced. This means that when a platelet is viewed in a microscope or other apparatus, it can be distinguished which face is being viewed. For example, when a plurality of autonomous platelets is diffused into a network of cells, it can be monitored whether the platelets have properly attached themselves to the cells with their metallic or semiconductor face, depending on which polarity is desired.
  • the platelet may have a diameter R between 20 nm and 20 ⁇ , preferably between 80 nm and 20 ⁇ , more preferably between 200 nm and 20 ⁇ and most preferably between 1 ⁇ m and 10 ⁇ . These ranges are motivated by several different effects.
  • the platelet should on average cover at least one voltage gated Na + and K + ion channel and assuming an ion channel density of about 60 Na + and 18 K + per 1 ⁇ 2 , this would require a platelet diameter above roughly 0,3 m. In practice, however, a platelet diameter exceeding the diameter of the focal point of the laser of about 200- S00 nm is also favorable. A larger platelet diameter also allows for the platelet orientation on the membrane to be determined in an optical microscope.
  • the platelet may have a thickness D between S nm and S ⁇ , preferably between 20 nm and 5 ⁇ and more preferably between 500 nm and S ⁇ .
  • a thickness D between S nm and S ⁇ , preferably between 20 nm and 5 ⁇ and more preferably between 500 nm and S ⁇ .
  • at least one dimension of the platelet be larger than about 80 nm.
  • the main impact of the thickness of the semiconductor is on the efficiency for the absorption of the incident electromagnetic radiation. For example, if the semiconductor is silicon, satisfactory absorption at excitation wavelengths below 550 nm can be expected for a silicon layer thickness between 500 nm and 5 ⁇ m. Silicon is a semiconductor with an indirect band gap, which places a limit on the efficiency of the absorption. Semiconductors with a direct band gap absorb light more efficiently, so they may be thinner.
  • Platelets with diameters ranging from 1 ⁇ to 10 ⁇ and with thicknesses ranging from 20 nm to 5 ⁇ can be produced using standard optical lithography. Smaller diameters can be achieved with the use of electron-beam, nano-imprint or stencil lithography. Rods with diameters below 30 nm can be fabricated by the vapor-liquid- solid synthesis of silicon nanowires capped with gold catalyst particles, which can subsequently be removed from the growth substrate by sonication.
  • the platelet is configured to be hydrophilic. This facilitates the dispersion of a plurality of platelets in a biocompatible polar solvent for biological applications, especially for distribution across a two-dimensional or three-dimensional network of cells.
  • An overall hydrophilic nature of the faces of the platelet may, for example, be achieved by means of hydrophilic native oxides of the semiconductor or the metal, or by means of suitable ligand coatings.
  • the platelets may be charge stabilized, e.g., using citric acid.
  • Non-polar solvents which are not biocompatible, may be advantageous for non- biological applications. If a plurality of platelets is to be d spersed in a non-polar solvent, the platelets are preferably hydrophobic.
  • the metal layer or of the semiconductor layer is functionalized with a ligand coating to promote oriented attachment of the semiconductor and/or of the metal layer to the cell, especially to the bi-lipid membrane.
  • a ligand coating to promote oriented attachment of the semiconductor and/or of the metal layer to the cell, especially to the bi-lipid membrane.
  • the ligand may, for example, be poly-L-lysin.
  • the ligands in the coating may comprise positively charged end groups, which are attracted to the negatively charged glycocalyx in the bi-lipid membrane of a neuron.
  • the ligand coating comprises a thiol, and the most preferred thiol is 11 -amini- 1 -undecanethiol, AUT.
  • AUT provides a synergistic effect in combination with gold as the metal, as it selectively attaches to gold via gold-thiol bonds.
  • the complementary charging between the gold surface and the neuron promotes the platelets to adhere to the neuron in the desired orientation.
  • randomly oriented attachment could also be useful in some cases. Since it is possible to determine the orientation of a platelet through an optical microscope, it would be possible to de- or repolarize cells by choosing suitably bound platelets. In this case, the entire surface of the platelet can be functionalized to promote binding to the cell.
  • the metal layer comprises one or more of gold, platinum, silver, aluminum, titanium, a transparent conducting oxide, and a conducting polymer.
  • These materials are non-toxic and relatively resistant to the aggressive biological fluids in a network of cells, particularly neurons.
  • the noble metals have the additional advantage that their combination with, e.g., silicon can generate potentials above 0.6 V, which is sufficient for any type of cellular stimulation.
  • the metal layer may comprise a first sub-layer of a first metal that is configured to bind to the cell on contact and a second sub-layer of a second metal, which is applied between said first sub-layer and the semiconductor as an adhesion layer.
  • the adhesion of gold to silicon may be promoted by a titanium adhesion layer.
  • the metal layer may comprise a first sub-layer that is configured to bind to the cell on contact and a third sub-layer of a third metal that coats at least partial area of the first sub-layer, so as to inhibit the binding to the cell in the coated area.
  • This can be used to fine-tune the area of the metal layer that will attach to the bi-lipid membrane of a cell.
  • the gold layer may be limited to attach to the bi-lipid membrane only with its circumferential side face.
  • the exact position in which the platelet will attach itself inside the bi-lipid membrane may be tailored according to the concrete need for stimulation or inhibition of cellular activity.
  • the semiconductor comprises silicon or germanium.
  • the main advantage of silicon is that silicon-on-insulator (SOI) substrates, which are a very convenient feedstock for the production of platelets, are available commercially.
  • SOI silicon-on-insulator
  • Germanium on the other hand, has a lower band gap, which is favorable for longer excitation wavelengths in the bio-window around 800 nm.
  • Other advantageous semiconductors are, for example the large
  • bandgap semiconductors diamond and BN as well as the direct bandgap
  • semiconductors GaN, SiC, ZnO, ZnS, ZnSe and ZnTe, and transition metal oxides are examples of semiconductors GaN, SiC, ZnO, ZnS, ZnSe and ZnTe, and transition metal oxides.
  • the semiconductor layer may face the metal layer on one face and face an insulating layer on the other face.
  • This insulating layer may, for example, be an oxide of the semiconductor.
  • Such an oxide may inhibit the attachment of the bi- lipid membrane of a cell, which further promotes attachment of an autonomous platelet to the cell in the right orientation, namely with the metal layer facing the cell.
  • the invention also provides a system for the stimulation of a plurality of points in a network of cells, particularly neurons, wherein this network may be two-dimensional or three-dimensional.
  • the system comprises a plurality of platelets according to the invention dispersed in a solvent.
  • the solvent may, for example, be water or another polar solvent that is biocompatible.
  • the platelets may comprise driving means that use the charge separation as an energy source.
  • driving means may, for example, comprise one or more flagella motors.
  • the driving means may aid the diffusion of the platelets into the network of neurons.
  • the platelets may also comprise means for communication between two or more platelets, and/or a mechanical link between two or more platelets. This allows for a tunable degree of coordination between the stimuli delivered by different platelets.
  • the invention also provides a method for the fabrication of the platelets.
  • the feedstock for this method is a semiconductor-on-insulator substrate that comprises at least the semiconductor layer, an insulating layer and a base layer.
  • the base layer may, for example, consist of the same material as the semiconductor layer, and optionally differ from the material of the semiconductor layer in that the base layer is not doped.
  • the metal layer of the platelets is applied to at least part of the semiconductor-on- insulator substrate and patterned to the shape of the platelets by means of
  • lithography Any suitable kind of lithography may be used.
  • the metal layer may first be applied across the whole of the substrate and subsequently removed in the areas not belonging to the platelets, i.e., areas not covering the platelets.
  • the substrate may, for example, be masked before application of the metal layer, so that the metal layer attaches to the substrate only in the areas belonging to the platelets.
  • Positive or negative lithography may be used.
  • a photoresist that is used for the patterning may be applied either before or after deposition of the metal layer. If a photoresist is selectively applied onto the semiconductor in the areas not belonging to the platelets, a subsequently applied metal layer will attach to the semiconductor-on-insulator substrate only in the areas belonging to the platelets. The metal may be removed from the areas not belonging to the platelets by lift-off of the photoresist. The remaining metal in the areas belonging to the platelets may then serve as an etching mask for the etching of the semiconductor layer. At least the semiconductor layer is etched away in the areas not belonging to the platelets, i.e., the areas not covering the platelets.
  • This may, for example, be performed after the fabrication of the metal in the shape of the platelets.
  • the patterning of the platelets and the etching away of the semiconductor layer may advantageously be combined to speed up and simplify the fabrication.
  • one single patterned layer of photoresist may be used as a mask for the combined etching of both the semiconductor and the metal layer in the areas not belonging to the platelets.
  • the platelets are detached from the substrate. Any suitable means may be used for this detaching.
  • the remaining semiconductor platelets may only be weakly bound to the insulating layer, so that they may be lifted off by a physical process, such as sonication or delamination.
  • Sonication detaches the platelets by means of vibration, while delamination may, for example, use a shear force applied between the platelets and the substrate, and/or a bending force applied to the substrate.
  • the platelets may be also detached chemically. Therefore, the detaching of the platelets from the substrate may specifically comprise a detaching from the base layer, a detaching from the insulating layer, or both.
  • the etching of the semiconductor is dry etching.
  • This may advantageously be combined with lithography, so that only one patterning step is necessary: After a full metal layer has been applied to the substrate, a photoresist may be applied only in the areas covering the platelets. In all other areas, the photoresist is removed. In the subsequent dry etching, both the metal layer and the semiconductor layer are removed, save for the areas that belong to the platelets and are protected by the photoresist.
  • the material of the base layer may be different from the material of the
  • the etching also removes the insulating layer in the areas not belonging to the platelets.
  • the detaching comprises wet etching of the insulating layer. This etching may, for example, be done using hydrofluoric acid.
  • the insulating layer is then a sacrificial layer.
  • SOI semiconductor-on-insulator
  • the detached platelets may then be functionalized with ligands and dispersed in a solvent, e.g., water or another aqueous solvent.
  • a solvent e.g., water or another aqueous solvent.
  • Another method for the fabrication of a plurality of platelet devices comprises: applying a sacrificial layer to at least part of a base layer that serves as a substrate;
  • the photoresist layer may be applied before the sacrificial layer; it then serves as a mask for the deposition of the sacrificial layer as well.
  • the photoresist layer may also double as the sacrificial layer.
  • the pattern in the photoresist layer is not required to continue through to the substrate. The pattern only needs to provide some topographic contrast between areas belonging to the platelets and areas not belonging to the platelets.
  • the sacrificial layer may be any layer that can readily be eroded by any suitable means without compromising the integrity of the semiconductor and the metal.
  • the sacrificial layer may be etchable by an etchant that attacks neither the semiconductor nor the metal.
  • the sacrificial layer may, for example, also be a photoresist or other polymer layer that can be lifted off using a solvent, which attacks neither the semiconductor nor the metal.
  • the sacrificial layer may, for example, also be configured to be a mechanically weak link between the semiconductor and the baser layer, so that when a mechanical force is applied between the semiconductor and the base layer, the sacrificial layer will erode before the semiconductor or the metal layer breaks.
  • An erosion of the sacrificial layer does not require a full removal of the sacrificial layer. Rather, it is sufficient to compromise the integrity the sacrificial layer just enough so that it can no longer hold the platelets in place.
  • the shape and size of the platelets can be defined by a lithographic process such as optical- or UV-lithography, electron-beam lithography, nano-imprint lithography, stencil lithography, or other in conjunction with any combination of thin film deposition, lift-off, and/or vertical etching, e.g. by dry etching, ion etching, wet chemical etching, or other.
  • the platelets can either be released from the substrate by a physical process such as sonication or delamination, or by removing the sacrificial layer.
  • the sacrificial layer can be removed with the use of solvents, wet chemical etching, vapor etching, or other.
  • the use of photovoltaic nano-platelets to polarize cells is also useful for studying cancer cells and cancer treatment. Cancer cells are known to have electrical and mechanical properties, which differ from healthy tissue, and cancer cells often have a lower polarization than regular cells. The polarization of cancer cells is therefore thought to be a useful regulator for cancer, and research indicates that this is indeed the case.
  • the proposed photovoltaic devices can be used to increase the polarization of cancer cells and can thus be a valuable tool in cancer research and cancer therapy.
  • the photo voltages induced in the micro- or nano-scale platelets can have cytotoxic effects stemming from electrochemical reactions and heating.
  • the production of triplet oxygen is known to have cytotoxic effects, which is exploited in photodynamic therapy.
  • Important advantages of photovoltaic platelets over other substances typically used in photodynamic therapy is their high chemical stability, lower photobleaching, low dark toxicity, and additional means for targeting tissue through size and surface functionalization of the platelets.
  • the invention therefore also provides a disinfecting or sterilizing agent.
  • This agent comprises a plurality of platelet devices according to the invention, and/or a system of such platelet devices dispersed in a solvent, as its active ingredient.
  • the platelets are dispersed in water or are applied to a surface (which is covered by a thin water film under ambient conditions) and exposed to electromagnetic radiation.
  • the disinfection/sterilizing effect is caused by heating and electrochemical reactions, e.g. leading to the production of reactive oxygen species such as singlet oxygen, or other.
  • the invention also provides a medicament for the treatment of cancer or skin illnesses.
  • This medicament comprises a plurality of platelet devices according to the invention, and/or a system of such platelet devices dispersed in a solvent, as its active ingredient.
  • the photovoltaic platelets are dispersed in a solvent, which can be applied to the region of interest.
  • the surfaces of the platelets can be chemically functionalized to specifically bind to targeted tissue, cells, or other moieties.
  • side specific functionalization of the platelets is possible to promote oriented attachment.
  • a preferred mechanism is linking platelets to cancer cells or tumors via antibodies or antibody-fragments. Size selective targeting is also possible based on size dependent kinetics, if the platelets are introduced into the bloodstream or tissue. Illumination by electromagnetic radiation can be carried out with a laser, a LED, a broad-band light source such as thermal or halogen lamp, ambient lighting, or other.
  • a preferred wavelength range for illumination is between 650nm-950nm, the so-called biological window of tissue.
  • the therapeutic effect is caused by electrochemical reactions (e.g. the production of reactive oxygen species) cell polarization, and/or heating.
  • the platelets can also serve as a tool for cancer research, to study cancer cells analog to the method described for cells, particularly for neurons.
  • Skin illnesses include, but are not limited to skin cancer, acne, herpes, warts, scabies, and eczema. They may be treated by applying the platelets to the affected tissue, e.g. through application of a solution in which they are dispersed. Subsequent
  • illumination by electromagnetic radiation can be carried out with a laser, a LED, a broad-band light source such as thermal or halogen lamp, ambient lighting, or other.
  • the therapeutic effect is caused by electrochemical reactions, cell polarization, and/or heating.
  • Figure 1 Embodiment of the device 1 with multiple electrodes 61 on the
  • Figure 2 Embodiment of the device 1 configured as an autonomous unit with semiconductor 3 shaped as a platelet 31.
  • Figure 3 Dependence of the width Wo of the depletion zone 38 on the doping density Nd (a); dependence of the absorption A on the thickness D of the platelet 31 for silicon as the semiconductor layer (b).
  • Figure 4 Multiple autonomous devices 1 attached to a neuron 2 in various places.
  • Figure 5 Fabrication of devices 1 forming a system 10 from a semiconductor-on- insulator substrate 35 as feedstock.
  • Figure 6 Exemplary implementation manners of the fabrication method shown in Figure 5.
  • Figure 7 Fabrication of devices 1 without a semiconductor-on-insulator substrate 35.
  • Figure 1 shows a first exemplary embodiment of the device 1 according to the invention.
  • Figure la is a top view from an angled perspective.
  • the metal layer 6 is divided into a plurality of separate electrodes 61a-61f, which are located on the surface of a semiconductor substrate 3, e.g. silicon.
  • Figure lb shows a sectional view of the area where one electrode 61a-61f is applied to the silicon substrate 3, forming a local Schottky barrier 7 with the silicon 3.
  • the silicon substrate 3 is connected to a ground potential by means of an ohmic contact 37.
  • Each electrode 61a-61f has an aperture 62 through which laser light 4 can pass through into the silicon 3.
  • the electrode 61a-61f is partially covered by an insulating layer 63 that extends across the top face of the silicon substrate 3.
  • the insulating layer 63 limits the attachment of the bi-lipid membrane 21 of the neuron 2 to the part 64 of the electrode 61a-61f that is not covered by the insulating layer 63.
  • the insulating layer 63 is transparent, so as to let laser light 4 pass to the aperture 62 and on to the silicon 3.
  • the laser light 4 can be focused onto the aperture 62 by means of an objective that is mounted on a piezo stage with the two planar coordinate axes x and y as degrees of freedom.
  • excitons 39 that consist of an electron 38a and a hole 38b are generated.
  • the electron 38a moves upwards to the electrode 61a-61f, while the hole 38b moves downwards to the ground potential via the ohmic contact 37.
  • the Schottky barrier 7 forms a depletion zone 38, which induces charge separation 5.
  • Charge separation leads to a potential difference, which is equivalent to a voltage between the electrode 61 a-61f and ground potential. This voltage can either stimulate or inhibit activity of the neuron 2, depending on the polarity.
  • Figure 2 shows a second exemplary embodiment of the device 1.
  • Figure 2a is a perspective view.
  • the semiconductor 3 is a platelet 31 with diameter R that is covered by the metal layer 6.
  • the top face of the metal layer 6 is functionalized with a ligand coating 69.
  • a depletion zone 38 will form that is adjacent to the bottom face of the metal layer 6 and extends downwards through only a part of the total thickness D of the platelet 31.
  • Figure 2b is a sectional view of the device 1 in its state where it is attached to the bi- lipid membrane 21 of a cell 2.
  • the semiconductor platelet 31 is n- doped.
  • Figure 2d shows an example of how the construction of the metal layer 6 as a bi- layer of a first layer 65 and a third layer 67 that completely coats the first layer 65 influences the attachment of the device 1 to the bi-lipid layer 21.
  • the area 68 coated by the layer 67 is the complete plane of the first layer 65.
  • the first layer 65 is made of gold
  • the third layer 67 is made of titanium.
  • the ligand coating 69 comprises 11-amini-l-undecanethiol, AUT, that selectively binds to the gold in the first layer 65 by means of gold-thiol bonds. Consequently, when the device 1 is exposed to a solution of the ligand coating 69 during manufacture, the ligand coating 69 will stick only to the exposed circumferential side face of the first layer 65.
  • the device 1 will attach itself to the bi-lipid membrane 21 only by means of this circumferential side face, which will be in the middle of the bi-lipid membrane 21.
  • Figure 2e shows how a change in the composition of the metal layer 6 affects the attachment of the device 1 within the bi-lipid membrane 21.
  • the first layer 65 is thinner, while the third layer 67 is thicker than in the example shown in Figure 2d.
  • the third layer 67 only covers a partial area 68 of the first layer 65. Consequently, ligands of the ligand coating 69 will attach not only to the circumferential side face of the first layer 65, but also to its bottom face that faces the bi-lipid membrane 21. The net effect of this is that the device 11 will penetrate less deep into the bi-lipid membrane 21 because all the ligands attached to the first layer 65 will have found counterparts in the bi-lipid membrane 21 at an earlier time.
  • Figure 3a shows the dependence of the width WD of the depletion zone 38 on the doping density Nd for different pairs of silicon platelets 31 and metal layers 6.
  • literature values for corresponding Schottky barrier heights ⁇ are listed.
  • the width WD of the depletion zone should be smaller than the thickness D of the platelet 31 , so as to make the Schottky barrier height reach its equilibrium value and maximize the open circuit voltage. From Figure 3a, it appears that doping levels above 2*10 15 cm '3 should be most suitable.
  • a thin adhesion layer 66 between the gold and silicon e.g. aluminum or titanium with a thickness of 2-5 nm, could be needed to prevent delamination of the gold layer. The adhesion layer 66 would likely also dominate the resulting Schottky barrier height and open circuit voltage. It is not shown in Figure 3a.
  • Figure 3b shows the absorption A of the silicon platelet 31 as a function of the thickness D of the platelet 31 for different laser wavelengths. It appears that at excitation wavelengths below 550 nm, a layer thickness between 0.5 and 3 ⁇ shows satisfactory absorption.
  • Figure 4 shows a neuron 2 with autonomous devices 1 attached in various places.
  • the neuron 2 comprises a cell nucleus 24, a soma 25, an axon 26 and a dendrite 27.
  • a specific functional area of the neuron 2 can be stimulated or inhibited by focusing a laser beam 4 on the specific device 1 present in that area.
  • Figure 5 illustrates the fabrication of devices 1 and a system 10.
  • a silicon-on- insulator substrate 35 that comprises a doped silicon layer 3, a silicon dioxide layer 32 and an undoped silicon base layer 33 is the feedstock for the fabrication.
  • a metal layer 6 is applied on top of the silicon layer 3.
  • this metal layer 6 is then patterned 110 and segmented into islands that correspond to the platelets 31 that are to be fabricated.
  • selective dry etching 120 that attacks the semiconductor layer 3 and the insulating layer 32, but not the metal layer 6, pillars of metal layer 6 on top of semiconductor platelets 31 on top of insulating layer 32 are left free-standing on the silicon base layer 33.
  • FIG. 6 further details two possible implementation manners of the first
  • Figure 6a shows the first implementation manner.
  • the metal layer 6 is deposited on the semiconductor-on-insulator substrate 35 that comprises a base layer 33, an insulating layer 32 and the actual semiconductor 3 on top.
  • a photoresist layer 50 is applied onto the metal layer 6 selectively in the areas belonging to the platelets 31.
  • the photoresist layer 50 is an etching mask for a subsequent vertical etching. This vertical etching removes the metal layer 6 in the areas not belonging to the platelets 31, and is therefore the second sub-step 110b of the patterning 110.
  • the vertical etching etches away 120 the semiconductor 3 in the areas not belonging to the platelets 31.
  • the etching 120 forms the semiconductor 3 into the platelets 31. After this etching 120, the photoresist is removed 125. In the final step 130, the platelets 31 are detached 130 from the substrate 35 to form independent devices 1.
  • Figure 6b shows the second implementation manner. In contrast to Figure 6a, the order of the steps 100 and 110a is reversed.
  • the first sub-step 110a of the patterning 110 namely the applying of the photoresist 50, is performed before the metal layer 6 is applied 100.
  • the second sub-step 110b of the patterning 110 namely the removal of the metal in the areas not belonging to the platelets 31, is effected by lift-off of the photoresist layer 50, rather than by the vertical etching.
  • the vertical etching 120 of the semiconductor 3 is configured not to attack the metal layer 6, but rather to use the metal layer 6 as an etching mask to form the platelets 31 out of the semiconductor 3.
  • the detaching 130 of the platelets 31 from the substrate 35 to form independent devices 1 may be performed in the same way as in the first implementation manner.
  • Figure 7 further details three possible implementation manners of the second embodiment of the fabrication method. Compared with the first embodiment detailed in Figure 6, this embodiment can be used also with semiconductors 3 for which no semiconductor-on-insulator substrate 35 is readily available. In addition, no equipment for vertical etching is required. This comes at the price that more work is required to deposit the semiconductor and the sacrificial layer.
  • Figure 7a details the first implementation manner. First, in step 210, the sacrificial layer 36 is applied to the base layer 33 that serves as the substrate. In step 220a, a photoresist layer 50 is applied and structured by means of lithography with a pattern corresponding to the platelets 31.
  • the photoresist layer 50 serves a mask for the subsequent depositing 220b of the semiconductor 3 platelets 31 including the metal layer 6.
  • the semiconductor 3 and the metal 6 are deposited across the whole surface, but the photoresist layer SO will keep them from coming into contact with the sacrificial layer 36 in the areas not belonging to the platelets 31.
  • the semiconductor 3 and the metal 6 in the areas not belonging to the platelets 31 are removed by lift-off of the photoresist layer 50.
  • step 240 the platelets 31 are detached by erosion of the sacrificial layer 36 to form independent devices 1.
  • Figure 7b details the second implementation manner. Compared with Figure 7a, the order of the steps 210 and 220a has been reversed.
  • the semiconductor layer 50 therefore serves as a mask for the deposition of the sacrificial layer 36 as well.
  • the semiconductor 3 and the metal 6 are removed in the areas not belonging to the platelets 31 in step 230, no sacrificial layer 36 remains in these areas.
  • the platelets 31 are not on a flat sacrificial layer 36 that extends across the whole base layer 36. Rather, the platelets 31 are linked to the base layer 33 by means of freestanding pedestals of the material of the sacrificial layer 36. This makes it easier to erode the sacrificial layer 36 in step 240 by means of under-etching.
  • Figure 7c details the third implementation manner.
  • the photoresist layer 50 doubles as the sacrificial layer 36. Therefore, the applying 220a of the photoresist layer 50 is also the applying 210 of the sacrificial layer 36 onto the base layer 33.
  • the pattern in the photoresist layer 50 that corresponds to the platelets 31 does not extend through the whole thickness of the photoresist layer 50 on to the base layer 33. Rather, the photoresist layer 50 merely provides some topographic contrast between areas belonging to the platelets 31 and areas not belonging to the platelets 31.
  • the removing 230 of the semiconductor 3 and the metal 6 in the areas not belonging to the platelets 31 is effected by means of a partial lift-off of the photoresist layer 50.
  • the platelets 31 are then liberated in step 240 by a complete lift-off of the photoresist layer 50.
  • steps 230 and 240 into one single lift-off step.
  • the disks 31 will then be mixed with scrap
  • steps 230 and 240 ensures that this scrap is removed and a solution containing only finished devices 1 as solid ingredients is obtained.
  • the disclosure of the present invention also includes the following Examples:
  • Example 1 A device for stimulation of at least one cell, and/or for stimulation of at least one electrochemical reaction, comprising at least one semiconductor that is configured to convert electromagnetic radiation into a charge separation, wherein the semiconductor is planar and the device further comprises a planar metal layer, wherein the metal layer forms a Schottky barrier, and/or a metal-insulator- semiconductor junction, with the semiconductor layer, the semiconductor and/or the metal layer is configured to bind to a cell on contact, and/or configured to repel the cell on contact, in order to promote oriented or non-oriented binding to the cell, and/or configured to promote the electrochemical reaction when the device is in contact with a solvent.
  • Example 2 The device of Example 1, wherein the metal layer is divided into a plurality of separate electrodes, which are located on the surface of the
  • Example 3 The device of Example 2, wherein at least one electrode comprises an aperture for passing the electromagnetic radiation into the semiconductor.
  • Example 4 The device of Example 2 or 3, wherein at least one electrode is partially covered by an insulating layer and the part of the electrode not covered by the insulating layer is configured to bind to the bi-lipid membrane of the cell on contact.

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Abstract

L'invention concerne un dispositif (1) destiné à la stimulation d'au moins une cellule (2) et/ou destiné à la stimulation d'au moins une réaction électrochimique, comprenant au moins un semi-conducteur (3) qui est conçu pour convertir un rayonnement électromagnétique (4) en une séparation de charge (5). Le semi-conducteur (3) est planaire et le dispositif comprend en outre une couche métallique plane (6), la couche métallique (6) formant une barrière de Schottky (7), et/ou une jonction semi-conducteur-isolant métallique, avec la couche semi-conductrice (3), le semi-conducteur et/ou la couche métallique est conçu pour se lier à une cellule (2) lorsqu'ils entrent en contact, et/ou conçu pour repousser la cellule (2) lorsqu'ils entrent en contact afin de favoriser une liaison orientée ou non orientée à la cellule, et/ou conçu pour favoriser la réaction électrochimique lorsque le dispositif (1) est en contact avec un solvant (11). Le semi-conducteur (3) comprend au moins une plaquette (31) présentant une face supérieure plane, une face inférieure plane, et une face latérale circonférentielle qui est plus ou moins en forme de ligne ou en forme de bande, soit la face supérieure, soit la face inférieure de la plaquette (31) étant revêtue de la couche métallique (6). L'invention concerne un système (10) destiné à la stimulation d'une pluralité de points dans un réseau de cellules, comprenant une pluralité de dispositifs (1) dispersée dans un solvant (11). L'invention concerne des procédés (100-140, 210-240) destinés à la fabrication d'une pluralité de dispositifs (1). L'invention concerne également un agent désinfectant ou stérilisant, et un médicament, comportant une pluralité de dispositifs en tant que principe actif.
PCT/EP2017/055886 2016-03-18 2017-03-14 Dispositif photovoltaïque destiné à la stimulation de cellules et/ou de réactions électrochimiques WO2017157874A1 (fr)

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