WO2023196962A2 - Réseau de nanofibres à électrodes multiples biodégradable - Google Patents

Réseau de nanofibres à électrodes multiples biodégradable Download PDF

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Publication number
WO2023196962A2
WO2023196962A2 PCT/US2023/065513 US2023065513W WO2023196962A2 WO 2023196962 A2 WO2023196962 A2 WO 2023196962A2 US 2023065513 W US2023065513 W US 2023065513W WO 2023196962 A2 WO2023196962 A2 WO 2023196962A2
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Prior art keywords
nanofiber
electrode
conductive layer
biodegradable
inkjet printing
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WO2023196962A3 (fr
Inventor
Tetsuhiko Teshima
Bernhard Wolfrum
Nouran ADLY
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NTT Research Inc
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NTT Research Inc
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/263—Bioelectric electrodes therefor characterised by the electrode materials
    • A61B5/265—Bioelectric electrodes therefor characterised by the electrode materials containing silver or silver chloride
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/263—Bioelectric electrodes therefor characterised by the electrode materials
    • A61B5/268—Bioelectric electrodes therefor characterised by the electrode materials containing conductive polymers, e.g. PEDOT:PSS polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/25—Bioelectric electrodes therefor
    • A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
    • A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
    • A61B5/293—Invasive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/369—Electroencephalography [EEG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4058—Detecting, measuring or recording for evaluating the nervous system for evaluating the central nervous system
    • A61B5/4064—Evaluating the brain
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K71/00—Manufacture or treatment specially adapted for the organic devices covered by this subclass
    • H10K71/60—Forming conductive regions or layers, e.g. electrodes
    • H10K71/611—Forming conductive regions or layers, e.g. electrodes using printing deposition, e.g. ink jet printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0209—Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
    • A61B2562/0215—Silver or silver chloride containing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/04—Arrangements of multiple sensors of the same type
    • A61B2562/043—Arrangements of multiple sensors of the same type in a linear array
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/04—Arrangements of multiple sensors of the same type
    • A61B2562/046—Arrangements of multiple sensors of the same type in a matrix array

Definitions

  • Biodegradable electrodes have been used for gathering electrical data from and/or for providing electrical signals to biological media such as cells.
  • biodegradable electrodes may be surgically implanted in the brain to monitor electrical activity of the brain and/or to provide electrical stimulation to the brain.
  • the biodegradable electrodes may be absorbed by the body (or any other biological medium) after a predetermined period of time. Multiple biodegradable electrodes may form a multielectrode array.
  • a biodegradable nanofiber electrode may be provided.
  • the biodegradable nanofiber electrode may comprise a nanofiber substrate; a conductive layer inkjet printed on the nanofiber substrate; and a passivation layer inkjet printed on the conductive layer, wherein the passivation layer partially covers the conductive layer forming electrical contact pads on non-covered portions.
  • a method of fabricating a biodegradable nanofiber electrode may comprise fabricating a nanofiber substrate; inkjet printing the conductive layer on a nanofiber substrate; and forming electrical contact pads by selectively inkjet printing a passivation layer on the conductive layer, the passivation layer partially covering the conductive layer.
  • FIG. 1 shows an example of a biodegradable nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 2A shows a flow diagram of an illustrative method of fabricating a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 2B shows structures generated by the steps of the method of fabricating the nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 2C shows a flow diagram of an illustrative method of printing a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 2D shows a printhead performing the steps of the method printing the nanofiber electrode, according to example embodiments of this disclosure
  • FIG. 3 shows an illustrative chart showing a control of jettability of an inkjet ink that may be used to print one or more layers of a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 4A shows a chart of illustrative impedances of electrode arrays printed on silk nanofiber substrate, according to example embodiments of this disclosure.
  • FIG. 4B shows a chart of illustrative phases of electrode arrays printed on a silk nanofiber substrate, according to example embodiments of this disclosure.
  • FIG. 5A shows an illustrative nanofiber electrode array, according to some embodiments of this disclosure, according to example embodiments of this disclosure.
  • FIG. 5B shows an illustrative nanofiber electrode array, according to example embodiments of this disclosure.
  • FIG. 5C shows an illustrative nanofiber electrode array, according to example embodiments of this disclosure.
  • FIG. 6A shows a flow diagram of an example method of fabricating a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 6B shows corresponding structures generated by the steps of the method of fabricating the nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 6C shows a flow diagram of an example method of fabricating a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 6D shows corresponding structures generated by the steps of the method of fabricating the nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 7 shows a chart showing impedances of an electrode array with carbon as conductive layer and printed silk as a passivation layer, according to example embodiments of this disclosure.
  • FIG. 8 shows a chart illustrating long term variations of impedances of an electrode array at 1 KHz with different annealing methods, according to example embodiments of this disclosure.
  • FIG. 9 shows an illustrative nanofiber electrode array, according to example embodiments of this disclosure.
  • FIG. 10 shows illustrative environment, according to example embodiments of this disclosure.
  • FIG. 11 shows an example usage of a nanofiber electrode as a drug delivery device, according to example embodiments of this disclosure.
  • FIG. 12 shows an example chart illustrating a drug delivery property of a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 13 shows an example chart illustrating a drug delivery property of a nanofiber electrode, according to example embodiments of this disclosure.
  • FIGS. 14A-14C show example charts illustrating the properties of a silk nanofiber electrode array on a biological medium, according to example embodiments of this disclosure.
  • Embodiments disclosed herein provide flexible and biodegradable nanofiber electrodes and multielectrode nanofiber arrays that may be fabricated relatively inexpensively compared to traditional fabrication methods.
  • the electrodes may be printed using printing technology such as, but not limited to, inkjet printing.
  • a polymer electrode may be printed on a nanofiber substrate.
  • a passivation layer may be printed over the polymer electrode.
  • the passivation layer may partially cover the polymer electrode exposing at least a portion thereof as an electrical contact with the polymer electrode.
  • the printed layers may then be photocured.
  • the electrodes and electrode arrays fabricated using the embodiments disclosed herein may be suitable for human body use.
  • the materials for the different layers may be nontoxic biomass based materials (non-limiting examples are described below).
  • the electrodes and electrode arrays may further provide good electrical conductivity while being inert (e.g., not oxidizing within the human body).
  • the electrodes or electrode arrays may not rust (an example effect of oxidization) within the human body.
  • different examples of the passivation layers may provide robust electrolyte leakage protection.
  • the electrochemical window provided by the electrodes and electrode arrays e.g., between -1.5V and +1.5 V, may be suited for performing measurements on the human body.
  • the electrodes and electrode arrays have exhibited a monotonic impedance response and approximately constant phase response across a range of frequencies, thereby allowing for measurements within the human body while reducing frequency selective noise (e.g., noise introduced by non-monotonic frequency response and variable phase response.
  • frequency selective noise e.g., noise introduced by non-monotonic frequency response and variable phase response.
  • Manufacturers can fine tune the time for biological absorption — or biodegradability — of the electrodes and electrode arrays. For example, manufacturers may select different materials for the layers and print layers with different geometries based on the desired biodegradability. Furthermore, manufactures may have a controlled photocuring (e.g., for a predetermined duration) of the printed layers, where the photocuring may fine tune the biodegradability. The combination of printing and photocuring, allows a manufacturer to finely tune the time for biological absorption — or biodegradability.
  • inkjet printing may be used for fabricating the electrodes and electrode arrays. Such approach reduces the overall cost of conventional fabrication process, as well as simplifying a conventionally complex fabrication process. Additionally, by utilizing inkjet printing, for example, the present approach may support rapid prototyping. In other words, by utilizing inkjet printing, multiple prototypes can be generated, deployed, and tested relatively inexpensively.
  • FIG. 1 shows an example of a biodegradable nanofiber electrode 100, according to example embodiments of this disclosure.
  • the nanofiber electrode 100 may include a nanofiber substrate 102, a conductive polymer 104, and a passivation layer 106.
  • one or more of nanofiber substrate 102, conductive polymer 104, and passivation layer 106 may be biodegradable.
  • the biodegradability of nanofiber substrate 102, conductive polymer 104, and/or passivation layer 106 may be finely tuned using the example embodiments disclosed herein. The fine tuning may be based on, for example, a selection of materials, geometry (e.g., size) of the layers, duration of photocuring the materials are subjected to.
  • the nanofiber substrate 102 may be formed from fibers with diameters in the nanometer range.
  • the nanofiber substrate 102 may be formed from polymer nanofibers generated using electrospinning techniques. For example, during electrospinning, electrical force may be used to draw threads of polymer solutions and/or melt polymer up to a desired fiber diameter (e.g., in nanometers).
  • the nanofiber substrate 102 may be formed from nanofibers extracted from biomass.
  • the nanofiber substrate 102 may be generated by printing (e.g., inkjet printing as described with reference to FIG. 2C below).
  • the nanofiber substrate 102 may be generated filtration techniques, such as using a filter membrane.
  • the nanofiber substrate 102 may be generated using spin-coating.
  • the biodegradability of the nanofiber substrate 102 may be tuned by utilizing, for example, photocuring techniques.
  • the biodegradability of the nanofiber substrate may be tuned by altering the physical and/or chemical properties of the nanofiber substrate 102 may be altered (e.g., using photocuring) such that the nanofiber substrate 102 may be biologically absorbed after a desired time.
  • a microelectrode array based on the nanofiber substrate 102 implanted in the human brain may be tuned, using these techniques, to biodegrade within two days to eleven days based on the functionality and use of the microelectrode array.
  • the nanofiber substrate 102 may be tuned to not biodegrade or be absorbed for a relatively longer amount of time.
  • the polymer electrode 104 may be formed on top of the nanofiber substrate 102. In some embodiments, the polymer electrode 104 may be printed on the nanofiber substrate 102. The printing may use nano-carbon inks. Some non-limiting examples of the nano-carbon inks may include carbon nanotubes (CNT), carbon black, or graphene.
  • CNT carbon nanotubes
  • the CNT’s may provide good electrochemical performance while being mechanically robust.
  • the electrical conductivity provided by CNT may be approximately 3.3* 10 4 S/m (Siemen per meter).
  • Graphene may have a superior electrochemical performance.
  • the electrical conductivity provided by graphene may be approximately 2* 10 5 S/m.
  • the printing of the polymer electrode 104 may use inks formed from metal-based nanoparticles.
  • the metal-based nanoparticles include silver (Ag), platinum (Pt), or gold (Au).
  • Silver is relatively cheap while providing excellent electrical conductivity of approximately 6.3* 10 7 S/m.
  • Platinum has good electrical conductivity of approximately 9.4* 10 6 S/m while being chemically inert.
  • platinum has a wide electrochemical window (i.e., electrode electrical potential range between which the substance, here platinum, is neither oxidized nor reduced).
  • Gold has a good electrical conductivity of approximately 4.1* 10 7 S/m while also being chemically inert. Gold too has a wide electrochemical window.
  • the printing may use conductive polymer inks.
  • the conductive polymers may include poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), polyaniline, polythiophene, polyacetylene, or polypyrrole.
  • PEDOT:PSS generally has a good electrochemical performance while being flexible and soft.
  • the electrical conductivity of PEDOT:PSS may be approximately 900 S/m.
  • the polymer electrode 104 may be used to generate the polymer electrode 104.
  • the materials and/or combinations thereof may be chosen based on the desired level of flexibility, electrochemical properties, electrical conductivity, and/or durability of the polymer electrode 104 and/or the electrode array.
  • the polymer electrode 104 may also be biodegradable. In some embodiments, the biodegradability of polymer electrode 104 may be tuned using chemical, curing, and/or photochemical processes.
  • the passivation layer 106 may be formed on top of the polymer electrode 104.
  • the passivation layer 106 may insulate the polymer electrode 104 from the biological medium (e.g., cell) that the polymer electrode 104 is deployed to.
  • the passivation layer 106 may leave gaps (e.g., non-covered portions) on the polymer electrode 104 to provide electrical contacts a and b (also referred to as contact pads) on the polymer electrode 104.
  • the electrical contacts a and b may be used to provide electricity to the polymer electrode 104 (e.g., to electrically stimulate the biological media) or detect electricity on the polymer electrode 104 (e.g., to measure electrical parameters of the biological media).
  • the passivation layer 106 may be formed from an insulative polymer such as polyacrylate (PA) ink and/or polyimide (PI) ink.
  • PA polyacrylate
  • PI polyimide
  • Each of the PA and PI inks may provide a very good insulation to the polymer electrode 104 from the biological media.
  • each of the PA and PI inks may be long lasting within the biological medium (e.g., inside the human body).
  • the passivation layer 106 may be formed from biomass materials such as silk or chitin.
  • biomass materials such as silk or chitin.
  • the biomass materials may be tuned to be biodegradable within a desired time window (e.g., between two and eleven days).
  • nanofiber substrate 102 The aforementioned materials for the nanofiber substrate 102, polymer electrode 104, and passivation layer 106 are provided just as examples and should not be considered limiting. Other materials may be used for desired flexibility and tunability of biodegradability. Therefore, any type of materials in any of the layers providing the desired flexibility and biodegradability should be considered within the scope of this disclosure.
  • nanofiber electrodes 100 may be used to form a biodegradable nanofiber electrode array discussed below in more detail in conjunction with FIGS. 5A-5C.
  • FIG. 2A shows a flow diagram of an illustrative method 200 of fabricating a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 2B shows structures generated by the steps of the method 200, according to example embodiments of this disclosure.
  • the fabrication method 200 may generally be less expensive and more convenient compared to traditional mask based photolithography fabrication processes. It should also be understood that the steps of the method 200 are just for illustration and processes with alternate, additional, or fewer number of steps should also be considered within the scope of this disclosure.
  • the method may begin at step 202 where the nanofiber substrate 102 may be fabricated.
  • the fabrication may include any type of depositing, printing, and/or layering technology that may generate a single-layer structure 210, shown in FIG. 2B, with a layer of the nanofiber substrate 102.
  • the polymer electrode 104 may be fabricated on top of the nanofiber substrate 102. This fabrication step may include any type of depositing, printing, and/or layering technology. Step 204 may generate a two-layered structure 220 shown in FIG. 2B.
  • the passivation layer 106 may be fabricated on top of the polymer electrode 104. This fabrication step may include any type of depositing, printing, and/or layering technology. Step 206 may generate three-layered structure 230 shown in FIG. 2B. The passivation layer 106 may have gaps exposing the underlying polymer electrodes. These gaps may form electrical contacts a and b.
  • FIG. 2C shows a flow diagram of an illustrative method 250 of printing a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 2D shows a printhead 208 performing the steps of the method 250, according to example embodiments of this disclosure.
  • the printhead 208 may be based on any type of technology, such as inkjet printing, aerosol jet printing, and/or dip-pen printing. It should be understood that these technologies are intended just as examples and should not be considered limiting. Because the nanofiber substrate 102 does not use more expensive photolithography and masks, the printing-based fabrication is less expensive and more convenient compared to traditional techniques.
  • the method 250 may begin at step 252, where the printhead 208 may print the nanofiber substrate 102.
  • the printhead 208 may deposit an ink 206, for example, while moving across successive locations, to generate the nanofiber substrate 102 (forming the structure 210).
  • the printhead 208 may print the polymer electrode 104 on the nanofiber substrate 102.
  • the printhead 208 may use an ink 210 to print the polymer electrode 104 (forming structure 220).
  • the printhead 208 may print the passivation layer 106 on the polymer electrode 104.
  • the printhead 208 may use an ink 212 to print the passivation layer 106 (forming structure 230).
  • the printhead 208 may print the passivation layer 106 to leave gaps on the polymer electrode 104 forming the electrical contacts a and b.
  • the printing of the nanofiber substrate 102, polymer electrode 104, and the passivation layer 106 may therefore use a relatively simple and inexpensive printing process, for example, inkjet printing. This printing process is therefore less expensive and yet more convenient compared to traditional photolithography using masks.
  • various parameters of the printing may be controlled for printing several layers with desired properties.
  • the minimum distance of movement of the printhead 208 may be controlled. In some embodiments, the minimum distance of movement may be approximately 5 pm.
  • the viscosity of the ink may be controlled to generate a desired droplet size.
  • different materials for example, in the form of inks, may be loaded into the printer, which may then use to the loaded materials sequentially to fabricate the different layers. The jettabilities of the different inks is described below in reference in FIG. 3.
  • FIG. 3 shows an illustrative chart 300 showing a control of jettability of an inkjet ink that may be used to print one or more layers of a nanofiber electrode, according to example embodiments of this disclosure.
  • t/: nozzle diameter
  • p density of the ink
  • y: surface tension of the ink
  • tuning of one or more of the parameters may be used to land anywhere in the chart 300 (five example positions in the chart 300 are illustrated in FIG. 3). Therefore, the desired level of jettability may be achieved for different types of inks of the materials for printing one or more layers of the nanofiber electrodes. Inkjet printing therefore offers a larger flexibility in controlling the properties of the printed layers.
  • FIG. 4A shows a chart 402 of illustrative impedances of electrode arrays printed on silk nanofiber substrate, according to example embodiments of this disclosure.
  • the chart 402 shows impedances of two electrode arrays.
  • a first impedance 406 may be associated with a first electrode array.
  • a second impedance 408 may be associated with a second electrode array.
  • both of the impedances 406 and 408 are monotonic across different frequencies — a desired impedance property for the electrode arrays to be used in a biological medium.
  • a monotonic impedance may not affect the measurements when the measurement frequencies are varied, thereby reducing a potential noise in the measurements. In other words, the measurements may become frequency agnostic because of the monotonic impedance.
  • FIG. 4B shows a chart 404 of illustrative phases of electrode arrays printed on a silk nanofiber substrate, according to example embodiments of this disclosure.
  • the chart 404 shows phases of two electrode arrays, same as the two electrode arrays described in FIG. 4A.
  • a first phase 410 may be associated with the first electrode array.
  • a second phase 412 may be associated with the second electrode array.
  • both of the phases 410 and 412 are relatively stable — a desired property for electrode arrays to be used in a biological medium.
  • a relative stable phase may make measurements phase-agnostic. In other words, measurement signals of different frequencies may not introduce phase change associated noise.
  • FIG. 5 A shows an illustrative nanofiber electrode array 500a, according to example embodiments of this disclosure.
  • the nanofiber electrode array 500a may be fabricated from a silk substrate 502a.
  • a polymer electrode 510a may be printed using an ink comprising silver and carbon forming a silver portion 504a and a carbon portion 506a.
  • a silk passivation layer 508a may be printed on top of the polymer electrode 510
  • FIG. 5B shows an illustrative nanofiber electrode array 500b, according to example embodiments of this disclosure.
  • the nanofiber electrode array 500b may be fabricated from a silk substrate 502b.
  • a polymer electrode 510b may be printed using an ink comprising silver and carbon forming a silver portion 504b and carbon portion 506b.
  • a silk passivation layer 508b may be printed on top of the polymer electrode 510b.
  • the embodiments of printing may be used to generate nanofiber electrode array 500b with a different geometry of the polymer electrode 510b compared to polymer electrode 510a in the nanofiber electrode array 500a.
  • the carbon portion 506b of the polymer electrode 510b is relatively thinner than the carbon portion 506a of the polymer electrode 510a.
  • FIG. 5C shows an illustrative nanofiber electrode array 500c, according to example embodiments of this disclosure.
  • the nanofiber electrode array 500c may be fabricated from a silk substrate 502c.
  • a polymer electrode 510c may be printed using an ink comprising silver and carbon forming a silver portion 504c and a carbon portion 506c.
  • a silk passivation layer 508c may be printed on top of the polymer electrode 510c.
  • the polymer electrode 510c as a different geometry than the polymer electrodes 510a and 510c.
  • This difference in geometry between the polymer electrodes 510a, 510b, and 510c can be easily and inexpensively achieved in the printing embodiments because the difference may entail sending different instructions to the printhead.
  • a separate mask for each geometry has to be formed, which is both cumbersome and expensive.
  • the difference in geometry allows for fine tuning of the biodegradability of the electrode arrays 500a, 500b, and 500c.
  • FIG. 6A shows a flow diagram of an example method 600 of fabricating a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 6B shows corresponding structures generated by the steps of the method 600, according to example embodiments of this disclosure. It should be understood that the steps shown in FIG. 6A and described herein are merely intended as examples and should not be considered limiting. Accordingly, methods with additional, alternative, and fewer number of steps should also be considered within the scope of this disclosure.
  • the method 600 may begin at step 601 where a silver layer 604 may be printed on a silk nanofiber substrate 602.
  • the silver layer 604 may form a conductive part of the nanofiber electrode.
  • the silk nanofiber substrate 602 and the silver layer 604 may form a structure 610.
  • method 600 may include step 603a.
  • a silk passivation layer 606 may be printed on top of the silver layer 604, generating the structure 620a.
  • FIG. 6C shows a flow diagram of an example method 650 of fabricating a nanofiber electrode, according to example embodiments of this disclosure.
  • FIG. 6D shows corresponding structures generated by the steps of the method 650, according to example embodiments of this disclosure. It should be understood that the steps shown in FIG. 6C and described herein are merely intended as examples and should not be considered limiting. Accordingly, methods with additional, alternative, and fewer number of steps should also be considered within the scope of this disclosure.
  • the method 650 may begin at step 601 where the silver layer 604 may be printed on the silk nanofiber substrate 602.
  • the silver layer 604 may form a conductive part of the nanofiber electrode.
  • the silk nanofiber substrate 602 and the silver layer 604 may form the structure 610.
  • method 650 may include step 603b.
  • a carbon layer 608 and a silk passivation layer 606 may be printed on top of the silver layer 604.
  • the silk passivation layer 606 and the carbon layer 608 may be printed sequentially.
  • the silk passivation layer 606 and the carbon layer 608 may be formed by a silk-carbon nanocomposite and printed simultaneously.
  • the conductive part may be formed by a combination of a silver layer 604 and a carbon layer 608.
  • the silver layer 604 may provide good electrical conductivity
  • the carbon layer 608 may provide a good electrochemical window and inertness. For instance, cell cultures may be grown on the relatively inert carbon layer 608 with a good electrochemical window.
  • FIG. 7 shows a chart 700 showing impedances of an electrode array with carbon as a conductive layer and printed silk as a passivation layer, according to example embodiments of this disclosure.
  • the illustrative chart 700 shows the impedances as the microelectrode array is annealed with water.
  • the chart 700 shows the change in impedances through a course of eleven days with a predetermined about of annealing time (e.g., 4 hours of annealing).
  • the impedances are monotonic across the frequency range, a desired property for an electrode array to be used in a biological medium.
  • FIG. 8 shows a chart 800 illustrating long term variations of impedances of an electrode array at 1 KHz with different annealing methods, according to example embodiments of this disclosure.
  • the impedances are fairly consistent for a period of time (e.g., eleven days) despite multiple annealing. Therefore, the electrode arrays fabricated using the embodiments disclosed herein may be fairly robust (e.g., not disintegrating or degrading instantaneously) when deployed to a biological medium, while having a tunable level of biodegradability.
  • FIG. 9 shows an illustrative nanofiber electrode array 900, according to example embodiments of this disclosure.
  • the nanofiber electrode array 900 may be formed of individual electrodes, one of which has been labeled as 902.
  • a biological medium e.g., cells
  • FIG. 10 shows illustrative environment 1000, according to example embodiments.
  • Illustrative environment 1000 may include nanofiber electrode arrays with cell cultures positioned thereon.
  • environment 1000 may include nanofiber electrode arrays 1002a, 1002b, and 1002c and cultured HL-1 (cardiac muscle) cell cultures 1004a, 1004b, and 1004c.
  • HL-1 cardiac muscle
  • Each of cell culture 1004a, 1004b, and 1004c may be positioned on corresponding nanofiber electrode arrays 1002a, 1002b, and 1002c, respectively.
  • the nanofiber electrode arrays 1002a, 1002b, and 1002c may measure electrical properties of the cell cultures 1004a, 1004b, and 1004c, respectively.
  • the nanofiber electrode arrays 1002a, 1002b, and 1002c may provide electrical stimulation to
  • Nanofiber electrodes and nanofiber electrode arrays fabricated using the embodiments disclosed herein may be flexible, biocompatible, and biodegradable, and yet provide desired level of conductivity. Furthermore, the electrodes and the electrode arrays may be fabricated by low-cost inkjet printing method. Because of the usage of biological materials (e.g., chitin, chitosan, etc.), the electrodes and electrode arrays may provide good affinity to human body or any other types of biological media. In addition to providing measuring electrical activity, nanofiber electrodes and nanofiber electrode arrays may also be deployed as drug delivery devices.
  • biological materials e.g., chitin, chitosan, etc.
  • the electrodes and electrode arrays may provide good affinity to human body or any other types of biological media.
  • nanofiber electrodes and nanofiber electrode arrays may also be deployed as drug delivery devices.
  • FIG. 11 shows an example usage of a nanofiber electrode as a drug delivery device, according to example embodiments of this disclosure.
  • a silk-carbon nanocomposite 1108, which may be used as a passivation layer on top of a carbon electrode (not shown), may have a nanostructure 1110.
  • the silk-carbon nanocomposite 1108 may include carbon nanoparticles 1104 within a silk substrate 1114.
  • the silk-carbon nanocomposite 1108 may be electro-responsive, e.g., may change its properties in response to receiving an electrical voltage.
  • a drug 1102 may be printed (e.g., using the printing embodiments described in reference to FIGS.
  • the drug 1102 passes through the silk-carbon nanocomposite 1108 and onto the biological structure (e.g., cell, tissue) that the silk-carbon nanocomposite 1108 is attached to.
  • the biological structure e.g., cell, tissue
  • FIG. 12 shows an example chart 1200 illustrating a drug delivery property of a nanofiber electrode, according to example embodiments of this disclosure.
  • the chart is based on an electrode that has a layer of a test compound (e.g., methylene blue) printed thereon. Then, a silver-carbon nanocomposite film as printed to cover the test compound layer. The nanocomposite with all the printed layer was immersed in phosphate-buffered saline and subjected to different voltage pulses for different durations. UV absorbance spectroscopy was then used to analyze the solution, showing the much of the test compound had been released. As shown in the chart 1200, no drug compound was detected under 0.15 V, and a plateau was reached after 0.3 V.
  • a test compound e.g., methylene blue
  • a same type of nanocomposite e.g., with the test compound layer
  • no test compound was released, thus indicating that the release mechanism may be based on applying the electrical stimulation.
  • FIG. 13 shows an example chart 1300 illustrating a drug delivery property of a nanofiber electrode, according to example embodiments of this disclosure.
  • a test medium e.g., phosphate-buffered saline solution
  • FIGS. 14A-14C show example charts 1402, 1404, 1406, 1408, 1410 illustrating the properties of a silk nanofiber electrode array on a biological medium, according to example embodiments of this disclosure.
  • cardiomyocyte-like HL-1 cells were cultured for a few days on the silk nanofiber electrode array to generate a confluent cell layer.
  • An initiation of spontaneous contractions confirmed that the printed silk nanofiber electrode array was compatible with a layer of active cells.
  • the cells’ action potential was monitored locally via an amperometric recording with an amplification system that had the capacity to record on up to 64 channels at 10 kHz sampling rate per channel.
  • an activity (expressed both as measured electrical activity and spikes calculated based on the measured electrical activity) by the cells is shown as 1403 (as measured by the nanofiber electrode array). Then the cells were stimulated using noradrenaline, a catecholamine, which induces a sympathetic response. The stimulated cells showed increased activity, shown as 1405, as measured by the nanofiber electrode array. For example, an addition of 2 microliter of lOmM of noradrenaline led to a rise in the spontaneous action potential firing rate from 1.3 Hz to 1.8 Hz. Once the measurements had been complete, sodium dodecyl sulfate was added to terminate all the cells, and the measurements after addition show no activity (shown as 1407).
  • a nanofiber electrode array was printed using a silk substrate. Biological cells were cultured on the nanofiber electrode array and a recording of the cellular activity was performed using the nanofiber electrode array. The recording is shown in chart 1404. A zoomed-in portion of the chart 1404 is shown in chart 1406, which shows a spike.
  • nanofiber electrode arrays were inkjet printed with noradrenaline containing ink between a carbon electrode (e.g., used for recording) and an electro-responsive silk- carbon composite layer in a sandwich type design (e.g., as described above).
  • HL-1 cells were then cultured on these printed structures without any noradrenaline in the medium resulting in an irregular beating pattern.
  • Chart 1408 shows the irregular beating pattern as 1409. Then, a voltage was applied — which may trigger the release of noradrenaline — and beating patterns increased significantly, shown as 1411 in chart 1408.
  • chart 1408 shows beating pattern 1413 without the application of the volage pulse and beating pattern 1415 after the application of the voltage pulse. Therefore, there may be no significant increase in the beating pattern in this control because there is no noradrenaline to be released by the application of the voltage pulse.
  • This experimentation therefore may provide the proof of concept of using the embodiments as a drug delivery device in addition to (or as an alternate to) a measurement/stimulation device.
  • the amount of drug release may be tuned by modulating the voltage simulation, thereby offering a dosage control flexibility.
  • the silk-carbon nanocomposite has demonstrated a monotonic increase in the cumulative release with the applied pulse voltage, thereby making the embodiments of nanofiber electrodes and nanofiber electrode arrays as viable candidates for a long term yet temporally precise drug delivery system.

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Abstract

Dans certains modes de réalisation, une électrode à nanofibres biodégradables peut être fournie. L'électrode à nanofibres biodégradables peut comprendre un substrat de nanofibres ; un jet d'encre de couche conductrice imprimé sur le substrat de nanofibres ; et un jet d'encre de couche de passivation imprimé sur la couche conductrice, la couche de passivation recouvrant partiellement la couche conductrice formant des plots de contact électrique sur des parties non couvertes.
PCT/US2023/065513 2022-04-08 2023-04-07 Réseau de nanofibres à électrodes multiples biodégradable Ceased WO2023196962A2 (fr)

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