CN120712055A - Method for connecting a standalone soft neural probe to an active electronic device with a high channel count interface - Google Patents

Abstract

Methods for fabricating soft probes, such as soft neural probes, are provided. The fabrication methods entail fabricating the soft probe, such as a freestanding soft neural probe, on a fabrication substrate and releasing the fabricated neural probe from the substrate without damaging it. The methods may involve depositing alternating layers of an insulating, flexible polymer, such as an elastomer, and layers of a conductive or semiconductive material.

Description

Method for connecting a free-standing soft nerve probe to an active electronic device with a high channel count interface

Cross Reference to Related Applications

PCT request tables are filed concurrently with the present description as part of the present application. Each application (as indicated in the PCT request list filed concurrently herewith) for which the application is claimed with rights or priority is hereby incorporated by reference in its entirety and for all purposes.

Background

Implantable neural probes (e.g., electrodes or electrode arrays) capable of recording electrophysiological signals and/or stimulating brain activity have been widely used in basic biology, neurological disease diagnosis and treatment. For example, stereotactic electroencephalogram (sEEG) electrodes are widely used to detect epileptic origin areas in the brain, and Deep Brain Stimulation (DBS) electrodes are particularly useful for treating parkinson's disease, pain, and essential tremors. However, these implantable nerve probes are typically made of a relatively rigid material such as metal, silicon, or plastic. Mismatch in mechanical properties (e.g., stiffness) between soft brain tissue and harder probe material often causes damage to the targeted brain region, and such damage is often accompanied by inflammatory reactions, and often by the formation of fibrosis and/or tissue necrosis.

With the development of material science and advanced manufacturing techniques, soft brain probes have been developed that can record and/or stimulate brain tissue from brain tissue just as conventional hard material probes. The softness and flexibility of such brain probes ensures better interfaces with brain tissue with less inflammatory reactions, and thus, these soft probes have attracted considerable interest in biomedical applications, especially those applications that rely on chronic or long-term neural experiments. However, most commercial electronic devices including one or more Integrated Circuits (ICs) arranged on a Printed Circuit Board (PCB) are made of hard materials and present challenges in connecting the brain probe to the rigid back-end electronics. Furthermore, the desire for minimally invasive surgery and high bandwidth recording/stimulation of brain activity requires that the connection between the soft nerve probe and the back-end electronics occupy a small footprint that can engage a large number of electrical contacts. These considerations make the connection problem even more challenging.

The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.

Disclosure of Invention

Methods of making soft probes, such as soft nerve probes, are provided. The fabrication method entails fabricating soft probes, such as free-standing soft nerve probes, on a fabrication substrate, and releasing the fabricated nerve probes from the substrate without damage. The method may involve depositing alternating layers of insulating flexible polymer, such as elastomer, and conductive or semiconductive material. This approach allows for seamless integration of soft neural probes with less damage to the brain and hard electronics that provide superior signal processing capabilities.

Various embodiments provided herein may include, but are not limited to, one or more of the following:

embodiment 1 a method of preparing a free-standing soft nerve probe electrically connected to an active electronic device, the method comprising:

a) Providing a fabrication substrate, the fabrication substrate 103 comprising a fabrication material 102 and a fracture zone 105;

b) Depositing a layer of sacrificial material 104 over a portion of the fabrication substrate;

c) Depositing an insulating flexible polymer layer 106a over the sacrificial layer material and over a portion of the fabrication substrate 103;

d) Depositing a layer 108a of conductive or semiconductive material on the polymer layer 106 and the fabrication substrate 103, wherein:

the conductive or semiconductive material is patterned to form one electrode or patterned to form a plurality of electrodes;

Each of the one or more electrodes being disposed over at least a portion of the sacrificial layer material and an area of the fabrication substrate not covered with the sacrificial layer material, and

The conductive or semiconductive material forms one or more connection pads 110 on the area of the fabrication substrate not coated with the sacrificial layer, and the electrode or electrodes are each electrically coupled to at least one of the connection pads;

e) Optionally repeating steps (c) and (d) to add alternating layers of polymer and layers of conductive or semiconductive material 108, wherein the polymer reveals at least a portion of the connection pad 110 and insulates the electrode 108 and the connection pad 110 from subsequently applied layers of conductive or semiconductive material, and

F) A final layer of polymeric material is applied to encapsulate the top layer of conductive or semiconductive material, wherein the final layer reveals at least a portion of the connection pads 110, thereby forming soft nerve probes comprising one or more electrodes disposed between the polymeric layers and on the fabrication substrate.

Embodiment 2 the method of embodiment 1, further comprising:

Providing a substrate 107 comprising a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components 118;

Bonding the substrate 107 to the fabrication substrate 103;

Wire bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a wire bond 120 between the connection pad 110 and the contact pad 114;

removing the sacrificial layer material 104, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components.

Embodiment 3 the method of embodiment 1, further comprising:

Providing a substrate 107 comprising a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components;

Flip chip bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a flip chip bond 122 between the connection pad 110 and the contact pad 114;

removing the sacrificial layer material 104, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components.

Embodiment 4 the method of embodiment 3, further comprising bonding the substrate 107 to the fabrication substrate 103.

Embodiment 5 the method of any of embodiments 3-4, further comprising adding filler to the flip chip bond pad region to force bonding between substrates 103 and 107.

Embodiment 6 the method of embodiment 1, further comprising:

Providing one or more active or passive electronic components 118 supporting one or more contact pads 114, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components 118;

Flip chip bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a flip chip bond 122 between the connection pad 110 and the contact pad 114;

removing the sacrificial layer material 104, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components.

Embodiment 7 the method of embodiment 6, further comprising bonding the one or more active or passive electronic components 118 to the fabrication substrate 103.

Embodiment 8 the method of any of embodiments 6 to 7, further comprising adding filler to the flip chip bond pad region to force bonding of the one or more active or passive electronic components 118 to the fabrication substrate 103.

Embodiment 9 the method of embodiment 1, further comprising:

providing the fabrication substrate having a via 112 at each of the connection pads 110;

Providing a substrate 107 comprising a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components;

Juxtaposing the substrate 107 with the fabrication substrate 103;

Depositing conductors into each of the vias 110 to form electrical connections 124 between the connection pads 110 and the contact pads 114;

removing the sacrificial layer material 104, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components 118.

Embodiment 10 the method of embodiment 9, further comprising bonding the substrate 107 to the fabrication substrate 103.

Embodiment 11 the method of embodiment 1, further comprising:

providing the fabrication substrate having a via 112 at each of the connection pads 110;

Providing one or more active or passive electronic components 118 supporting one or more contact pads 114, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components 118;

juxtaposing the one or more active or passive electronic components 118 with the fabrication substrate 103;

Depositing conductors into each of the vias 110 to form electrical connections 124 between the connection pads 110 and the contact pads 114;

removing the sacrificial layer material 104, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components 118.

Embodiment 12 the method of embodiment 11, further comprising bonding the one or more active or passive electronic components 118 to the fabrication substrate 103.

Embodiment 13 the method of any one of embodiments 1 to 12, wherein the sacrificial layer is omitted and a pick-up tool is used to peel the soft nerve probe from the fabrication substrate.

Embodiment 14 a method of preparing a free-standing soft nerve probe electrically connected to an active electronic device, the method comprising:

a) Providing a fabrication substrate 103, the fabrication substrate comprising a first region comprising a fabrication material 102 and a second region comprising a sacrificial material 104;

b) Depositing an insulating flexible polymer layer 106a on the substrate, wherein the polymer layer is disposed over at least a portion of the first region and over at least a portion of the second region;

c) Depositing a conductive or semiconductive material 108a on the polymer layer 106 and the fabrication substrate 103, wherein:

the conductive or semiconductive material is patterned to form one electrode or patterned to form a plurality of electrodes;

Each of the one or more electrodes being disposed over at least a portion of the sacrificial layer material and an area of the fabrication substrate not covered with the sacrificial layer material, and

The conductive or semiconductive material forms one or more connection pads 110 on the area of the fabrication substrate not coated with the sacrificial layer, and the electrode or electrodes are each electrically coupled to at least one of the connection pads;

d) Optionally repeating steps (b) and (c) to add alternating layers of polymer and layers of conductive or semiconductive material 108, wherein the polymer reveals at least a portion of the connection pad 110 and insulates the electrode 108 and the connection pad 110 from subsequently applied layers of conductive or semiconductive material, and

E) Applying a final layer of polymeric material to encapsulate the top layer of conductive or semiconductive material, wherein the final layer reveals at least a portion of the connection pads 110;

thereby forming a soft nerve probe comprising one or more electrodes disposed between layers of the polymer and disposed on the fabrication substrate.

Embodiment 15 the method of embodiment 14, further comprising:

Providing a substrate 107 comprising a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components;

Bonding the substrate 107 to the fabrication substrate 103;

Wire bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a wire bond 120 between the connection pad 110 and the contact pad 114;

removing the sacrificial layer material 104 constituting the second region of the production substrate 103, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components.

Embodiment 16 the method of embodiment 14, further comprising:

Providing one or more active or passive electronic components 118 supporting one or more contact pads 114, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components 118;

bonding the one or more active or passive electronic components 118 to the fabrication substrate 103;

Wire bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a wire bond 120 between the connection pad 110 and the contact pad 114;

removing the sacrificial layer material 104 constituting the second region of the production substrate 103, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components.

Embodiment 17 the method of embodiment 14, further comprising:

Providing a substrate 107 comprising a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components;

Flip chip bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a flip chip bond 122 between the connection pad 110 and the contact pad 114;

removing the sacrificial layer material 104 constituting the second region of the production substrate 103, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components.

Embodiment 18 the method of embodiment 17 further comprising bonding the substrate 107 to the fabrication substrate 103.

Embodiment 19 the method of embodiment 14, further comprising:

Providing one or more active or passive electronic components 118 supporting one or more contact pads 114, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components 118;

Flip chip bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a flip chip bond 122 between the connection pad 110 and the contact pad 114;

removing the sacrificial layer material 104 constituting the second region of the production substrate 103, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components 118.

Embodiment 20 the method of embodiment 19, further comprising bonding the one or more active or passive electronic components 118 to the fabrication substrate 103.

Embodiment 21 the method of embodiment 14, further comprising:

Providing the fabrication substrate having a via 110 at each of the connection pads 110;

Providing a substrate 107 comprising a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components;

Bonding the substrate 107 to the fabrication substrate 103;

Depositing conductors into each of the vias 110 to form electrical connections 124 between the connection pads 110 and the contact pads 114;

removing the sacrificial layer material 104 constituting the second region of the production substrate 103, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components 118.

Embodiment 22 the method of embodiment 14, further comprising:

Providing the fabrication substrate having a via 110 at each of the connection pads 110;

Providing one or more active or passive electronic components 118 supporting one or more contact pads 114, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components 118;

bonding the one or more active or passive electronic components 118 to the fabrication substrate 103;

Depositing conductors into each of the vias 110 to form electrical connections 124 between the connection pads 110 and the contact pads 114;

removing the sacrificial layer material 104 constituting the second region of the production substrate 103, and

The fabrication substrate 103 is broken at the break zone 105 to provide the free-standing soft neural probes electrically connected to the one or more active or passive electronic components 118.

Embodiment 23a method of preparing a free-standing soft nerve probe electrically connected to an active electronic device, the method comprising:

a) Providing a fabrication substrate 103, wherein the fabrication substrate comprises an integrated circuit 502 and one or more connection pads 110, wherein the connection pads 110 are electrically connected to at least one circuit element 504 constituting the integrated circuit;

b) Depositing a layer of sacrificial material 104 over a portion of the fabrication substrate;

c) Depositing an insulating flexible polymer layer 106a over the sacrificial layer material and over at least a portion of the fabrication substrate 103;

d) A layer 108 of conductive or semiconductive material is deposited over the polymer layer 106 and the fabrication substrate 103, wherein:

the conductive or semiconductive material is patterned to form one electrode or patterned to form a plurality of electrodes 108a;

Each of the one or more electrodes being disposed over at least a portion of the sacrificial layer material and an area of the fabrication substrate not covered with the sacrificial layer material, and

The conductive or semiconductive material forms an electrical connection with one or more of the connection pads 110;

e) Optionally repeating steps (c) and (d) to add alternating layers of polymer and layers of conductive or semiconductive material 108, wherein the polymer reveals at least a portion of the connection pad 110 and insulates the electrode 108 and the connection pad 110 from subsequently applied layers of conductive or semiconductive material, and

F) A final layer of polymeric material is applied to encapsulate the top layer of conductive or semiconductive material, wherein the final layer reveals at least a portion of the connection pads 110, thereby forming soft nerve probes comprising one or more electrodes disposed between the polymeric layers and on the fabrication substrate.

Embodiment 24 the method of embodiment 23 wherein the circuit elements comprising the integrated circuit comprise elements selected from the group consisting of amplifiers, preamplifiers, multiplexers, analog-to-digital converters (ADCs), digital-to-analog converters (DACs), power management circuits, microcontrollers, impedance matching circuits, interconnects, signal splitters, and wireless data transfer modules.

Embodiment 25 the method of any of embodiments 23-24, wherein the method comprises removing the sacrificial material 104, thereby releasing the terminal regions of the electrodes from the fabrication substrate.

Embodiment 26 the method of any of embodiments 23 to 25 wherein the fabrication substrate 103 comprises a fracture zone 105.

Embodiment 27 the method of embodiment 26, wherein the method comprises fracturing the fabrication substrate at the fracture zone 105.

Embodiment 28 the method of any of embodiments 23 to 27 wherein the integrated circuit comprises an output pad, pinout or pin 508.

Embodiment 29 the method of any of embodiments 23-28, wherein the integrated circuit is disposed on a support.

Embodiment 30 the method of embodiment 29, wherein the support comprises a circuit board (e.g., a Printed Circuit Board (PCB)).

Embodiment 31 the method of any of embodiments 29 to 30, wherein the support comprises an output pad, pinout or pin 510.

Embodiment 32 the method of any one of embodiments 1 to 31, wherein:

is fabricated on a single fabrication substrate 103, and

The substrate is cut into smaller pieces each having one or more nerve probes on each piece.

Embodiment 33 the method of any of embodiments 1-32 wherein the polymer comprises a material selected from the group consisting of fluorinated elastomers, polyimides, polydimethylsiloxane (PDMS), parylene-C, and epoxy resins (e.g., SU-8).

Embodiment 34 the method of any of embodiments 1-33, wherein the polymer layer 106 comprises a fluorinated elastomer.

Embodiment 35 the method of embodiment 34, wherein the fluorinated elastomer is a fluorinated elastomer that has not been perfluorinated.

Embodiment 36 the method of embodiment 35, wherein the fluorinated elastomer is partially fluorinated.

Embodiment 37 the method of embodiment 36, wherein:

the fluorinated elastomer is greater than or equal to 25%, or greater than or equal to 50%, or greater than or equal to 75% or greater fluorinated, and/or

The fluorinated elastomer is less than 100%, or less than or equal to 90%, or less than or equal to 75%, or less than or equal to 50% or less fluorinated, and/or

The fluorinated elastomer is greater than or equal to 25% fluorinated and less than 100% fluorinated.

Embodiment 38 the method of embodiment 37 wherein the fluorinated elastomer is selected from the group consisting of poly (1, 3-hexafluoroisopropyl acrylate) (PHFIPA) and/or poly [2- (perfluorohexyl) ethyl ] acrylate.

Embodiment 39 the method of embodiment 35, wherein the fluorinated elastomer is a perfluorinated elastomer.

Embodiment 40 the method of embodiment 39 wherein the perfluorinated elastomer is selected from the group consisting of perfluoropolyether (PFPE), polytetrafluoroethylene (PTFE), perfluoropolyether dimethacrylate (PFPE-DMA), fluorinated ethylene-propylene (FEP), perfluoroalkoxy Polymer (PFA), and Polytrifluoroethylene (PCTFE).

Embodiment 41 the method of embodiment 39, wherein the perfluorinated elastomer includes a perfluoropolyether.

Embodiment 42 the method of embodiment 41 wherein the perfluoropolyether has a weight average molecular weight of greater than 8 kDa.

Embodiment 43 the method of embodiment 42, wherein the perfluoropolyether has a weight average molecular weight of greater than 20 kDa.

Embodiment 44 the method of any one of embodiments 41 to 43, wherein the perfluorinated elastomer is a copolymer.

Embodiment 45 the method of embodiment 44, wherein the perfluorinated elastomer is tetrafluoroethylene propylene (TFE).

Embodiment 46 the method of embodiment 39, the perfluorinated elastomer includes a perfluoropolyether (PFPE).

Embodiment 47 the method of any one of embodiments 1 to 46, wherein the elastomeric layer has a thickness in a range of about 0.5 μm to about 5 μm.

Embodiment 48 the method of any of embodiments 1 to 47 wherein one or more of the elastomeric material layers 106 are patterned to provide open areas to provide contact with tissue at one or more discrete locations along the surface of one or more electrodes formed from the conductive or semiconductive material 108.

Embodiment 49 the method of any of embodiments 1 to 48 wherein one or more of the layers of polymeric material 106 are patterned to encapsulate one or more electrodes formed from the conductive or semiconductive material 108 to provide one or more capacitive electrodes.

Embodiment 50 the method of any one of embodiments 1 to 49, wherein the layer of elastomeric material 108 is deposited by an additive semiconductor manufacturing process.

Embodiment 51 the method of embodiment 50 wherein the additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical Vapor Deposition (CVD), physical Vapor Deposition (PVD), wherein the process is optionally combined with photolithographic patterning.

Embodiment 52 the method of any of embodiments 1-49 wherein the sacrificial material 104 comprises a material selected from the group consisting of chromium, chromium oxide, nickel, gold, silicon oxide, a water-soluble polymer, and an adhesive polymer (e.g., omniCoat).

Embodiment 53 the method of embodiment 52 wherein the sacrificial material comprises a water-soluble polymer selected from the group consisting of poly (acrylic acid), dextran, poly (methacrylic acid), poly (acrylamide), poly (ethyleneimine), poly (vinyl alcohol), poly (ethylene oxide), chitosan, and sucrose.

Embodiment 54 the method of any of embodiments 1-53 wherein the sacrificial material 104 is deposited by an additive semiconductor fabrication process.

Embodiment 55 the method of embodiment 54 wherein the additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical Vapor Deposition (CVD), physical Vapor Deposition (PVD), thermal oxidation, wherein the process is optionally combined with photolithographic patterning.

Embodiment 56 the method of any of embodiments 1-55, wherein the sacrificial material is removed by etching and/or dissolution.

Embodiment 57 the method of embodiment 56 wherein the sacrificial layer comprises nickel and the nickel is removed from the substrate with a mixture of HCl and FeCl ₃ in solution.

Embodiment 58 the method of embodiment 56 wherein the sacrificial layer comprises SiO ₂ and the SiO ₂ is removed from the substrate with HF.

Embodiment 59 the method of embodiment 56, wherein the sacrificial layer comprises an adhesive polymer (e.g., omniCoat) and the adhesive polymer is removed with tetramethylammonium hydroxide (TMAH).

Embodiment 60 the method of embodiment 56, wherein the sacrificial layer comprises a water-soluble polymer and the water-soluble polymer is removed with water.

Embodiment 61 the method of any of embodiments 1-60 wherein the conductive or semiconductive material 108 comprises a metal or metal alloy, metal oxide or nitride, conductive polymer, semiconductor, and/or graphene.

Embodiment 62 the method of embodiment 61 wherein the conductive or semiconductive material 108 comprises a metal or metal alloy.

Embodiment 63 the method of embodiment 62, wherein the conductive or semiconductive material 108 comprises a metal selected from the group consisting of gold, nickel, platinum, iridium, chromium, tungsten, tantalum, tin, nichrome, titanium, copper, rhodium, rhenium, silver, stainless steel, palladium, aluminum, zirconium, conductive oxides or nitrides thereof, and alloys thereof.

Embodiment 64 the method of embodiment 62, wherein the conductive or semiconductive material 108 comprises titanium nitride or a platinum iridium alloy.

Embodiment 65 the method of embodiment 62 wherein the conductive or semiconductive material 108 comprises gold.

Embodiment 66 the method of any of embodiments 1-63, wherein the conductive or semiconductive material 108 forms a single electrode.

Embodiment 67 the method of any of embodiments 1-63 wherein the conductive or semiconductive material 108 is patterned to form a plurality of electrodes.

Embodiment 68 the method of embodiment 67 wherein the conductive or semiconductive material 108 forms a plurality of electrodes that are electrically isolated from each other and/or that are independently addressable.

Embodiment 69 the method of any one of embodiments 1 to 68 wherein the layer of conductive or semiconductor material 108 forms at least about 10, or at least about 20, or at least about 50, or at least about 100, or at least about 250, or at least about 500, or at least about 1000, or at least about 10,000, or at least about 100,000, or at least about 1,000,000 electrodes.

Embodiment 70 the method of any of embodiments 1-69 wherein the layer of conductive or semiconductor material 108 has a thickness in the range of about 20nm to about 1 μm.

Embodiment 71 the method of any of embodiments 69 to 70 wherein the layer of conductive or semiconductive material 108 forms a plurality of electrodes having an electrode number density of greater than or equal to 10 ^-5 electrodes/micrometer ², greater than or equal to 10 ^-4 electrodes/micrometer ², greater than or equal to 10 ^-3 electrodes/micrometer ², greater than or equal to 10 ^-2 electrodes/micrometer ², greater than or equal to 10 ^-1 electrodes/micrometer ² or greater and/or less than or equal to 10 ¹ electrodes/micrometer ², less than or equal to 100 electrodes/micrometer ², less than or equal to 10 ^-1 electrodes/micrometer ² or less.

Embodiment 72 the method of any of embodiments 1-71 wherein the layer of conductive or semiconductive material 108 forms an electrode having an average length in the range of about 1mm up to about 20 mm.

Embodiment 73 the method of any of embodiments 1-72 wherein the layer of conductive or semiconductive material 108 forms an electrode having an average width in a range of about 100nm up to about 100 μm.

Embodiment 74 the method of any of embodiments 1-72 wherein the layer of conductive or semiconductive material 108 forms features (e.g., electrodes) separated by a minimum distance at or below 30 microns, or at or below 20 microns, or at or below 10 microns, or at or below 5 microns, or at or below 2 microns, or less.

Embodiment 75 the method of any of embodiments 1 to 74 wherein the conductive or semiconductive material 108 comprises an adhesion layer.

Embodiment 76 the method of embodiment 75 wherein the conductive or semiconductive material 108 comprises an adhesion layer comprising a material selected from the group consisting of aluminum, aluminum oxide, tungsten, niobium, chromium, titanium.

Embodiment 77 the method of embodiment 76, wherein the adhesion layer comprises aluminum, titanium, chromium.

Embodiment 78 the method of any one of embodiments 1 to 77, wherein the conductive or semiconductive material 108 and/or the adhesion layer is deposited by an additive semiconductor fabrication process.

Embodiment 79 the method of embodiment 77, wherein the additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical Vapor Deposition (CVD), physical Vapor Deposition (PVD), and wherein the additive semiconductor fabrication process is optionally combined with photolithographic patterning.

Embodiment 80 the method of any of embodiments 1-79 wherein the polymeric material 106 is treated with an inert gas plasma prior to the deposition of the conductive or semiconductive material 108.

Embodiment 81 the method of embodiment 80 wherein the inert gas plasma comprises an argon or nitrogen plasma.

Embodiment 82 the method of any one of embodiments 1-81 wherein one or more of the connection pads 110 are treated in a bumping procedure to form metal bumps on the pads.

Embodiment 83 the method of embodiment 82, wherein the bumping procedure comprises electroplating or metal deposition.

Embodiment 84 the method of any of embodiments 82-83, wherein the bump comprises a metal selected from the group consisting of solder, au, and Ir, in, cu.

Embodiment 85 the method of any of embodiments 1-84, wherein the active or passive electronic component 118 comprises an active or passive electronic component selected from the group consisting of an amplifier, a pre-amplifier, a multiplexer, an analog-to-digital converter (ADC), a digital-to-analog converter (DAC), a power management circuit, a microcontroller, and a wireless data transfer module.

Embodiment 86 the method of any of embodiments 1 to 85 wherein the active or passive electronic component contains an I/O pad on the nerve probe and a corresponding contact on an electronic device, the I/O pad and corresponding contact pad will have the same pitch size of 2 millimeters or less than 2 millimeters, or 1 millimeter or less than 1 millimeter, or 500 micrometers or less than 500 micrometers, or 200 micrometers or less than 200 micrometers, or 100 micrometers or less than 100 micrometers, or 50 micrometers or less than 50 micrometers, or 20 micrometers or less than 20 micrometers, or 10 micrometers or less than 10 micrometers, or 5 micrometers or less than 5 micrometers, or 2 micrometers or less than 2 micrometers.

Embodiment 87 the method of any of embodiments 1 to 86, wherein the active or passive electronic component contains an I/O pad on the nerve probe and a corresponding contact on the electronic device, the I/O pad and the corresponding contact pad will have at least about 10 connections, or at least about 20, or at least about 50, or at least about 100, or at least about 250, or at least about 500, or at least about 1000, or at least about 10,000, or at least about 100,000, or at least about 1,000,000 connections.

Embodiment 88 the method of any one of embodiments 1 to 87, wherein the method comprises treating the nerve probe to temporarily increase probe hardness during insertion into a tissue or organ.

Embodiment 89 the method of embodiment 88, wherein the disposing comprises coating the nerve probe with a bioabsorbable sclerosant.

Embodiment 90 the method of embodiment 89, wherein the hardener comprises a material selected from the group consisting of dextran, glucose, polyethylene glycol (PEG), gelatin.

Embodiment 91 the method of embodiment 88, wherein the treating comprises freezing the nerve probe.

Embodiment 92 the method of any one of embodiments 1 to 89, wherein the method comprises sterilizing the nerve probe.

Embodiment 93 the method of embodiment 90 wherein the sterilizing comprises a method selected from the group consisting of by exposure to radiation (e.g., ionizing radiation or ultraviolet light), chemical sterilization (e.g., exposure to ethylene oxide, etc.), and/or autoclaving.

Embodiment 94 the method of embodiment 93, wherein the method comprises exposure to ethylene oxide.

Embodiment 95 a flexible nerve probe made by the method of any one of embodiments 1-94.

Embodiment 96: a kit comprising a container containing the flexible nerve probe of embodiment 95.

Embodiment 97 the kit of embodiment 96, wherein the kit comprises a teaching material that teaches use of the nerve probe.

Definition of the definition

As used herein, the term "about" should be understood to take into account minor increases and/or decreases beyond the stated value, such changes do not significantly affect the desired function of the parameter beyond the stated value. In some cases, "about" encompasses +/-10% of any stated value. As used herein, the term modifies any Chen Shuzhi, ranges of values, or endpoints of one or more ranges.

As used herein in the specification and claims, the indefinite articles "a" and "an" are to be understood as meaning "at least one" unless clearly indicated to the contrary.

As used herein in the specification and claims, the phrase "and/or" should be understood to mean "either or both" of the elements so joined (i.e., elements that in some cases exist in combination and in other cases exist separately). Other elements may optionally be present in addition to the elements specifically identified by the "and/or" clause, whether related or unrelated to those elements specifically identified, unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to "a and/or B" when used in conjunction with an open language such as "comprising" may refer to a without B (optionally including elements other than B), may refer to B without a (optionally including elements other than a) in another embodiment, may refer to both a and B (optionally including other elements) in yet another embodiment, and the like.

As used herein in the specification and in the claims, "or" should be understood to have the same meaning as "and/or" as defined above. For example, when separating items in a list, "or" and/or "should be construed as inclusive, i.e., including at least one of a plurality of elements or a list of elements, but also including more than one of a plurality of elements or a list of elements, and optionally including additional unlisted items. Only if an opposite term (such as "or" only one of the terms "or" when used in the claims) is explicitly indicated, will be meant to include exactly one element of the plurality of elements or in the list of elements. In general, the term "or" as used herein should be interpreted as indicating an exclusive alternative (i.e., "one or the other, but not both") only if there is an exclusive term (such as "either one of", only one of ", or exactly one of", as used herein. "consisting essentially of" when used in the claims shall have their ordinary meaning in the art of patent law.

As used herein in the specification and claims, the phrase "at least one" when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each element specifically listed within the list of elements and not excluding any combination of elements in the list of elements. This definition also allows that elements may optionally be present other than the specifically identified elements within the list of elements referred to by the phrase "at least one," whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of A and B" (or equivalently, "at least one of A or B," or equivalently, "at least one of A and/or B") may refer to at least one, optionally including more than one A, and optionally including elements other than B, may refer to at least one, optionally including more than one B, and optionally including elements other than A, in another embodiment may refer to at least one, optionally including more than one A and at least one, optionally including more than one B (and optionally including other elements), in yet another embodiment may refer to at least one, optionally including more than one B (and optionally including other elements), and the like.

Use of ordinal terms such as "first," "second," "third," etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

In the claims, as well as in the foregoing specification, all transitional phrases (such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and the like) are to be understood to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in section 2111.03 of the U.S. patent office patent examination protocol handbook.

The term "freestanding" refers to the property that an object has no support for a substrate and can be freely manipulated and deformed within the medium (e.g., air, water) in which it is located.

The term "flexible" refers to the physical property of a material that is capable of bending in a particular dimension without breaking, which does not imply the Young's modulus and stretchability of the material.

The term "soft" refers to the physical property of a material to deform or yield easily due to pressure or weight. These materials typically have young's modulus less than 1GPa and can be stretched up to 5% without breaking.

The term "probe" refers to a structure comprising one or more electrodes configured to deliver signals to or receive signals from biological tissue (e.g., brain or other neural tissue, heart or other organ).

The term "neural probe" refers to a structure that includes one or more electrodes configured to deliver signals to or receive signals from the brain or other nervous system tissue (such as in the peripheral nervous system). In various embodiments, the nerve probe includes one or more flexible electrodes, e.g., microelectrodes, deposited on or within one or more flexible polymer layers.

An "electrode" refers to a conductive element configured to conduct an electrical charge from a first point to a second point. In various embodiments, the electrode may include one or more "tips" or "contact regions," conductor regions, and terminal regions. In certain embodiments, the tip is configured for contact with tissue (e.g., brain or other neural tissue), and the contact region is configured to facilitate electrical connection with one or more electrical components.

For example, making a "fracture zone" in a substrate refers to a region of the substrate that has been treated such that the substrate fractures preferentially at the location of the fracture zone under mechanical or chemical stress. In certain embodiments, the fracture zone comprises a region of the substrate that is scored or perforated to facilitate fracture at that location when the substrate is subjected to mechanical stress (e.g., bending or pulling). In certain embodiments, the fracture zone comprises a region of the substrate that is chemically treated or made of a different material (e.g., a sacrificial material), so that the substrate fractures preferentially at that location when chemically treated, e.g., with a solvent or etchant. In certain embodiments, the fracture zone is the same in material as the remainder of the fabrication substrate, but is positioned relative to the deposited nerve probe to facilitate cutting the substrate at that zone.

The term "flexible polymer" or "polymer" refers to any polymeric material that can be bent without breaking and that can return to its original shape after deformation. Such flexible polymeric materials may be inherently elastomeric, i.e., natural or synthetic polymers capable of recovering their original shape when subjected to large deformations. In certain embodiments, an elastomeric polymer refers to a polymer or copolymer that is free of diluent, is stretched to twice its original length at room temperature, and retracts to less than 1.5 times its original length within one minute after one minute of release. Such flexible polymers may also be plastic materials or resin materials whose bulk form factor is hard and brittle, but which can be folded without breaking after being made into films having a thickness of less than 10 μm.

"Fluoropolymer" is a fluorocarbon-based polymer having multiple carbon-fluorine bonds. Exemplary fluoropolymers include, but are not limited to, PVF (polyvinyl fluoride), PVDF (polyvinylidene fluoride), PTFE (polytetrafluoroethylene), PCTFE (polychlorotrifluoroethylene), PFA, MFA (perfluoroalkoxy polymer), FEP (fluorinated ethylene-propylene), ETFE (polytetrafluoroethylene), ECTFE (polyethylene chlorotrifluoroethylene), FFPM/FFKM (perfluorinated elastomer [ perfluoroelastomer ]), FPM/FKM (fluoroelastomer [ vinylidene fluoride copolymer ]), FEPM (fluoroelastomer [ tetrafluoroethylene-propylene ]), PFPE (perfluoropolyether), PFSA (perfluorosulfonic acid), and the like.

A perfluoropolymer is a polymer that is derived from another polymer by substituting all (or most) of the hydrogen atoms with fluorine atoms. Typically, perfluoropolymers are polymers in which carbon atoms in all or a portion of the polymer are bonded to fluorine and/or other heteroatoms only, rather than hydrogen. Perfluoroelastomers are elastomers in which carbon atoms within all or a portion of the elastomer are bonded only to fluorine and/or other heteroatoms, rather than hydrogen.

The term "adhesive polymer" as used herein refers to an organic polymer, such as OMNICOAT.

The term "physiological condition" as used herein refers to typical conditions in a mammalian body, e.g. conditions that mimic those conditions that may express the (normal) function of a cell, organ or tissue. Exemplary physiological conditions may include approximately neutral pH (e.g., pH 7.0 to 7.4), salinity of about 9% to 10% (e.g., about 0.1M to about 0.2M NaCl or about 0.15M NaCl), temperature in the range of about 96°f to 104°f (about 35 ℃ to about 40 ℃), and the like. Typical temperatures for humans are about 37 ℃.

When referring to a multi-layer article (e.g., as described herein), the term "stably bonded" indicates that the layer typically does not delaminate under physiological conditions (e.g., when implanted into a tissue or organ of a mammal). Typically, when the layers are stably bonded, they remain bonded under physiological conditions for at least 1 week, or at least 2 weeks, or at least 3 weeks, or at least 1 month, or at least 2 months, or at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 1 year, or at least 1.5 years, or at least 2 years.

The terms "subject," "individual," and "patient" are used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cows, ungulates, rabbits, etc.). In various embodiments, the subject may be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a doctor or other health worker in a hospital, as an outpatient, or other clinical setting. In certain embodiments, the subject may not be under the care or prescription of a doctor or other health worker.

A "capacitive electrode" is an insulated electrode that does not make ohmic contact with tissue or body fluids.

The term "integrated circuit" refers to a group of electronic circuits or devices and their connections that are small and are produced in or on a small piece of material (e.g., silicon) or in the form of an entire wafer.

"Circuit element" or "integrated circuit element" refers to a component of an integrated circuit. The element may be a device that forms an integrated circuit including, but not limited to, a preamplifier, a multiplexer, a voltage regulator, an analog to digital converter (ADC), a digital to analog converter (DAC), a microcontroller, a Field Programmable Gate Array (FPGA), a transceiver, a signal conditioner, or a memory device or a connection/interconnection with a device that forms an integrated circuit.

These and other aspects are further described below with reference to the drawings.

Drawings

Fig. 1A illustrates additive fabrication of a soft neural probe on a fabrication substrate, with a layer of sacrificial material under electrode 108a.

Fig. 1B-1F illustrate various methods of releasing a flexible electrode that constitutes a nerve probe and making electrical connection with one or more active or passive electronic components.

Fig. 2A illustrates additive fabrication of soft neural probes on a fabrication substrate 103, where the fabrication substrate itself includes regions formed by sacrificial material 104.

Fig. 2B illustrates a method of releasing the flexible electrodes that make up the nerve probe and making electrical connection with one or more active or passive electronic components.

Fig. 3 illustrates a cross-section of a neural probe in fabrication, according to various methods described herein. As shown, the cross-section provides a fabrication substrate 103, a sacrificial material layer 104 disposed atop the fabrication substrate, a flexible polymer layer 106 (where the various layers may be labeled 106a, 106b, 106c, etc.), a conductive or semiconductive material 108 (which may form the various electrode layers (108 a, 108b, 108c, etc., as shown)), wherein the conductive or semiconductive material layer further comprises an adhesion material layer 109.

Fig. 4 illustrates one embodiment of a method involving removal of sacrificial material 104 followed by breaking of fabrication substrate 103.

Fig. 5A and 5B illustrate a neural probe fabricated on a substrate including an integrated circuit. Fig. 5A) a nerve probe fabricated on an integrated circuit. Fig. 5B) a plurality of nerve probes fabricated on an integrated circuit, wherein the integrated circuit is disposed on a support (e.g., PCB). It will be appreciated that in various embodiments, the integrated circuit may be not only a small piece of a wafer, but also the entire silicon wafer.

Fig. 6A and 6B illustrate strategies for using neural probes fabricated in an integrated circuit. The portion of the integrated circuit under the sacrificial layer of fig. 6A) does not contain any useful circuitry, but is removed only after the sacrificial layer is eliminated. Fig. 6B) the released nerve probe is lifted (e.g., 90 degrees) so that it is nearly perpendicular to the ASIC/PCB from a side view. The nerve probe is then turned upside down and inserted onto or into the target tissue (e.g., brain). If the probe is long enough, the ASIC/PCB side can still remain outside the skull.

Detailed Description

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the presented embodiments. The disclosed embodiments may be practiced without some or all of these specific details. In other instances, well known process operations have not been described in detail in order not to unnecessarily obscure the disclosed embodiments. Although the disclosed embodiments have been described in connection with specific embodiments, it will be understood that they are not intended to limit the disclosed embodiments.

In various embodiments, methods of fabricating soft neural probes (e.g., electrodes) and interconnecting these soft neural probes with hard electronic components (e.g., PCB boards, IC chips, or a combination of both, etc.) are provided. These methods ensure flexibility of the final free-standing nerve probe and provide high density electrical connection with hard electronics.

In general, as explained below, the method typically involves fabricating one or more nerve probes (e.g., electrodes) disposed on a fabrication substrate, wherein at least a portion of the probes are also disposed on (or encapsulated within) a highly elastic polymer. The fabrication substrate under a portion of the probes is then decoupled or removed, leaving the highly flexible probes electrically connected to one or more connection pads and/or associated electronics. This method of fabrication is described in more detail below.

Micro-sized high density electrodes may be defined by using advanced fabrication methods (e.g., photolithography or metal deposition) to form high channel count interfaces. However, these advanced fabrication methods are generally only applicable to hard materials, most of which are made of hard materials, which may cause chronic damage to the brain. The methods described herein facilitate the use of advanced fabrication techniques to produce nerve probes from soft materials, but they can still be connected to hard electronics.

Additive fabrication of soft neural probes on fabrication substrates

An exemplary but non-limiting method of fabricating a substrate with one or more electrodes is shown in fig. 1A. As shown therein, the method may include a) providing a fabrication substrate 103 including a fabrication material 102 and a fracture region 105, in which a via 112 for electrical connection may have been embedded, b) depositing a sacrificial material layer 104 over a portion of the fabrication substrate, c) depositing an insulating flexible polymer layer 106a over the sacrificial material and over a portion of the fabrication substrate 103, d) depositing a conductive or semiconductive material layer 108 over the polymer layer 106 and the fabrication substrate 103, wherein:

The conductive or semiconductive material is patterned to form one electrode 108a, or is patterned to form a plurality of electrodes 108 a..108n and one or more connection pads 110;

one or more electrodes each disposed over at least a portion of the sacrificial layer material and an area of the fabrication substrate not covered with the sacrificial layer material, and

The conductive or semiconductive material 108 forms one or more connection pads 110 on the area of the fabrication substrate not coated with the sacrificial layer, and the electrode or electrodes are each electrically coupled to at least one of the connection pads.

This provides fabrication substrate 103 with a first layer comprising one or more electrodes 108 electrically coupled to at least one connection pad 110, wherein a portion of the electrodes are disposed over sacrificial material 104. In various embodiments, this procedure may be repeated one or more times to add alternating layers of polymer 106 and layers of conductive or semiconductive material 108, wherein the polymer is deposited such that it reveals at least a portion of the connection pad 110 and insulates the electrode 108 a..and the conductive pad 110 a..from subsequently applied layers of conductive or semiconductive material.

Once the desired number of alternating electrode layers 108a and polymer layers 106 are formed, a final layer of polymer material may be applied to encapsulate a top layer of conductive or semiconductive material, wherein the final layer reveals at least a portion of the connection pads 110a, thereby forming a soft nerve probe comprising one or more electrodes 108a disposed between the polymer layers and on the fabrication substrate 103.

It will be appreciated that in certain embodiments, the fabrication protocol may produce a single nerve probe (one electrode or electrode array) disposed on a fabrication substrate, while in certain other embodiments, multiple nerve probes (one electrode or electrode array each) may be produced on a single substrate, which may later be separated from one another as desired.

The various layers may be deposited by any convenient method, such as sacrificial material 104, conductive or semiconductive material 108, and polymer 106.

Releasing flexible electrode elements and coupling to electronic devices

One method of releasing a flexible nerve probe (e.g., including one or more electrodes) and coupling it to an electronic device or other element is shown in fig. 1B. As shown therein, in certain embodiments, the method may include providing a substrate 107 including a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components 118, bonding the substrate 107 to a fabrication substrate 103, wire-bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a wire bond 120 between the connection pad 110 and the contact pad 114, removing the sacrificial layer material 104, and breaking the fabrication substrate 103 at a break zone 105 to provide a free-standing soft neural probe 100 (e.g., including one or more electrodes) electrically connected to an electronic device (e.g., electrically connected to one or more of the active or passive electronic components, as shown in fig. 4).

Yet another method of releasing the flexible nerve probe (including, for example, one or more electrodes) and coupling the nerve probe (electrode) to an electronic device or other element is shown in fig. 1C. As shown therein, in certain embodiments, the method may include providing a substrate 107 including a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components, flip-chip bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a flip-chip bond 122 between the connection pad 110 and the contact pad 114, removing the sacrificial layer material 104, and breaking the fabrication substrate 103 at a break region 105 to provide a free-standing soft neural probe 100 (e.g., including one or more electrodes) electrically connected to an electronic device (e.g., one or more of the active or passive electronic components). In certain embodiments, such a method may further comprise bonding the substrate 107 to the fabrication substrate 103. In certain embodiments, the method may further include adding a filler (e.g., epoxy) to the flip chip bond pad region to force bonding between the substrates 103 and 107.

In another exemplary but non-limiting method, the method can be performed as described above, but rather than flip-chip bonding the nerve probe (electrode) to a pad on a substrate that also carries one or more electronic components, the one or more electronic components can be flip-chip bonded directly. This is shown in fig. 1D. As shown therein, in certain embodiments, the method may include providing one or more active or passive electronic components 118 supporting one or more contact pads 114, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components 118, flip-chip bonding each of the one or more connection pads 110 to one or more of the contact pads 114 to form a flip-chip bond 122 between the connection pad 110 and the contact pad 114, removing the sacrificial layer material 104, and breaking the fabrication substrate 103 at the break region 105 to provide a free-standing soft neural probe 100 (e.g., including one or more electrodes) electrically connected to an electronic device (e.g., electrically connected to one or more of the active or passive electronic components). In certain embodiments, such a method may further comprise bonding the substrate 107 to the fabrication substrate 103. In certain embodiments, the method may further include adding filler to the flip chip bond pad region to force bonding between substrates 103 and 107.

Yet another method of releasing the flexible nerve probe (including, for example, one or more electrodes) and coupling the nerve probe (electrode) to an electronic device or other element is shown in fig. 1E. As shown therein, in certain embodiments, the method may further include providing a fabrication substrate having vias 112 at the or each of the alternatives to the connection pads 110 in certain embodiments, providing a substrate 107 including a support 116 supporting one or more contact pads 114 and one or more active or passive electronic components 118, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components, juxtaposing the substrate 107 with the fabrication substrate 103, depositing conductors into each of the vias 110 to form an electrical connection 124 between the connection pads 110 and the contact pads 114, e.g., to provide an electrical connection between the electrode (connection pads 110) and the contact pads 114, removing the sacrificial layer material 104, and breaking the substrate fabrication 103 at the break zone 105 to provide a free-standing soft nerve probe 100 (e.g., including one or more electrodes) electrically connected to the electronic device (e.g., to one or more of the active or passive electronic components). In certain embodiments, the conductors deposited into each of the vias are sufficient to bond the substrate 107 to the fabrication substrate 103. In certain embodiments, the substrate 107 is further bonded to the fabrication substrate 103.

In another exemplary but non-limiting method, the method may be performed as described above, but rather than depositing conductors into each of the vias 110 to form electrical connections 124 between connection pads 110 and contact pads 114 on a substrate that also carries one or more electronic components, the method may be bonded to one or more contact pads integrated with one or more electronic components. This is shown in fig. 1F. As shown therein, in certain embodiments, the method may include providing a fabrication substrate having a via 112 at each of the connection pads 110, providing one or more active or passive electronic components 118 supporting one or more contact pads 114, wherein each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electronic components 118, juxtaposing the one or more active or passive electronic components 118 with the fabrication substrate 103, depositing a conductor into each of the via 110 to form an electrical connection 124 between the connection pad 110 and the contact pad 114, removing the sacrificial layer material 104, and fracturing the fabrication substrate 103 at a fracture zone 105 to provide a free-standing soft neural probe 100 (e.g., including one or more electrodes) electrically connected to an electronic device (e.g., one or more of the active or passive electronic components).

In certain embodiments, in any of the foregoing methods, the sacrificial layer is omitted and a pick-up tool may be used to peel the soft nerve probe from the fabrication substrate.

Additive fabrication of soft nerve probes on a "hybrid" fabrication substrate in which the substrate includes regions formed of sacrificial material

In certain embodiments, sacrificial material 104 deposited on fabrication substrate 103 may be eliminated in any of the foregoing methods, and the fabrication substrate itself may be a "hybrid" fabrication substrate that includes areas formed by sacrificial material 104. In such examples, the fracture zone 105 may be omitted. In such embodiments, removal of sacrificial material 104 comprising the fabrication substrate (e.g., by selective etching or dissolution) effectively releases the nerve probe.

This is shown in fig. 2A and 2B. Thus, for example, in certain embodiments, the method comprises:

a) Providing a fabrication substrate 103, the fabrication substrate comprising a first region comprising a fabrication material 102 and a second region comprising a sacrificial material 104;

b) Depositing an insulating flexible polymer layer 106a on the substrate, wherein the polymer layer is disposed over at least a portion of the first region and over at least a portion of the second region;

c) Depositing a conductive or semiconductive material 108a on the polymer layer 106 and the fabrication substrate 103, wherein:

the conductive or semiconductive material is patterned to form one electrode or patterned to form a plurality of electrodes;

one or more electrodes each disposed over at least a portion of the sacrificial layer material and the area of the fabrication substrate not covered with the sacrificial layer material, and

Forming one or more connection pads 110 on the area of the fabrication substrate not coated with the sacrificial layer, and each of the electrode or electrodes being electrically coupled to at least one of the connection pads;

d) Optionally repeating steps (b) and (c) to add alternating layers of polymer and layers of conductive or semiconductive material 108, wherein the polymer reveals at least a portion of the connection pad 110 and insulates the electrode 108 and connection pad 110 from subsequently applied layers of conductive or semiconductive material, and

E) A final layer of polymeric material is applied to encapsulate the top layer of conductive or semiconductive material, wherein the final layer reveals at least a portion of the connection pads 110, thereby forming soft nerve probes comprising one or more electrodes disposed between the layers of polymeric material and on the fabrication substrate.

Then, releasing the flexible electrode element and coupling it to the electronic device occurs, wherein instead of removing the sacrificial material 104 on top of the fabrication substrate 103, the sacrificial material 104 forming the hybrid substrate is removed and thus, no breaking of the fabrication substrate is required. Thus, the substrate 103 need not be fabricated with the fracture zone 105 incorporated.

In various embodiments, wire bonding, flip chip bonding, and depositing conductors into vias 110 may be performed as described above and shown in fig. 1B-1F and/or fig. 2B.

Additive fabrication of soft neural probes on fabrication substrates where fabrication substrates include integrated circuits

In another embodiment, fabricating the substrate may include an integrated circuit 502, for example, as shown in fig. 5A and 5B. A portion of the integrated circuit is covered with sacrificial material 104 and alternating layers of insulating polymer 106 and conductive or semiconductive material 108.

Thus, in one exemplary but non-limiting embodiment, the fabrication method can include a) providing a fabrication substrate 103, wherein the fabrication substrate includes an integrated circuit 502 and one or more connection pads 110, wherein the connection pads 110 are electrically connected to at least one circuit element 504 (e.g., as shown in FIG. 5A) making up the integrated circuit, b) depositing a sacrificial material layer 104 over a portion of the fabrication substrate, c) depositing an insulating flexible polymer layer 106a over the sacrificial material and over at least a portion of the fabrication substrate 103, d) depositing a conductive or semiconductive material layer 108 over the polymer layer 106 and the fabrication substrate 103, wherein:

the conductive or semiconductive material is patterned to form one electrode or patterned to form a plurality of electrodes 108a;

One or more electrodes each disposed over at least a portion of the sacrificial layer material and the area of the fabrication substrate not covered with the sacrificial layer material, and

A conductive or semiconductive material forms an electrical connection with one or more of the connection pads 110;

e) Optionally repeating steps (c) and (d) to add alternating layers of polymer and layers of conductive or semiconductive material 108, wherein the polymer reveals at least a portion of the connection pads 110 and insulates the electrodes 108 and the connection pads 110 from subsequently applied layers of conductive or semiconductive material, and f) applying a final layer of polymer material to encapsulate a top layer of conductive or semiconductive material, wherein the final layer reveals at least a portion of the connection pads 110, thereby forming soft nerve probes comprising one or more electrodes disposed between the layers of polymer and on the fabrication substrate.

In certain embodiments, the circuit elements comprising the integrated circuit include elements selected from the group consisting of amplifiers, preamplifiers, multiplexers, analog-to-digital converters (ADCs), digital-to-analog converters (DACs), power management circuits, microcontrollers, impedance matching circuits, interconnects, signal conditioners, and power conditioning circuits, wireless data transfer modules, and the like.

In various embodiments, the deposited polymer encapsulated electrode is detached from the fabrication substrate by removing sacrificial material 104, thereby detaching the terminal areas of the electrode from the fabrication substrate. The nerve probe may be used in this form, for example, by flipping the electrode away from the underlying substrate (see, e.g., fig. 6B). In some embodiments, the fabrication substrate may also include a break zone 105, and the substrate under the neuroprobe electrode may be broken away from the substrate/integrated circuit, thereby disengaging the electrode.

In some embodiments, for example, as shown in fig. 6A, the portion of the integrated circuit under the sacrificial layer does not contain any useful circuitry, and it is only broken or cut away after the sacrificial layer is removed. In a second method, for example, as shown in fig. 6B, the released nerve probe is lifted (e.g., to 90 degrees), so that it is nearly perpendicular to the integrated circuit from a side view. It can then be flipped upside down and inserted into the target tissue probe, and if the probe is long enough, the integrated circuit (and the support described below) can still remain outside the skull. In certain embodiments, the length of the electrodes and freestanding nerve probes can be varied as desired, with current small animal designs being 10mm, and for human applications, can be extended to 40mm.

In some embodiments, rather than depositing sacrificial material 104 on a fabrication substrate, the sacrificial material itself may form a portion of a hybrid substrate that includes regions of sacrificial material and integrated circuits. After the nerve probe is formed, the sacrificial material is removed, leaving only the integrated circuit with the nerve probe attached.

In certain embodiments, for example, as shown in fig. 5B, fabricating the substrate may include a plurality of integrated circuits, thereby facilitating the simultaneous fabrication of a plurality of nanoprobes thereon. In certain embodiments, the nerve probes may then be separated from each other for use.

In certain embodiments, integrated circuits 502 each include one or more output pads, pinouts, or pins 508 that facilitate the output of signals processed by the integrated circuits.

In certain embodiments, for example, as shown in fig. 5B, in certain embodiments, integrated circuit 502 may be disposed on support 506. In certain embodiments, the support may include a circuit board (e.g., a Printed Circuit Board (PCB)), in certain embodiments, the support may include an output pad, lead or pin 510. In one non-limiting embodiment, schematically shown in fig. 5B, a signal (e.g., a neural signal) is picked up at an electrode (108 a, represented by circles) and then passed through a fine interconnect to a small square 110 (shown by arrow "1" in fig. 5B.) the neural probe is post-fabricated on top of the integrated circuit along with the fine interconnect and small square contact pad 110 (shown by small square) is an input pad of the integrated circuit into which the signal from electrode 108a is processed (e.g., amplified, multiplexed, etc.) and finally reaches IC output pad 508, which is an output signal from output pad 508 in the middle square may then travel from output pad 508 (shown by small square) to lead pad 506 or any other suitable way to be picked up by wire bond 512, or connected to a suitable lead wire (e.g., flip chip) may be easily realized in place of this way of being connected to the PCB.

The foregoing fabrication methods on an integrated circuit are illustrative and not limiting. Numerous other methods of fabricating neural probes on integrated circuits will be available to those skilled in the art using the teachings provided herein.

Fabrication of substrate 103

In various embodiments, any of a variety of materials and/or devices may be used as the fabrication substrate.

In various embodiments, the fabrication substrate 103 includes only the materials that provide support for the deposited polymer layer 106 and the conductive or semiconductive material layer 108. In certain embodiments, the article is a "functional substrate" that may comprise a circuit, a device, or a portion thereof, wherein the substrate functionally interacts with the fabricated nerve probe. In certain embodiments, the nerve probe overlaps a portion of the circuitry comprising the substrate.

In various embodiments, the fabrication substrate 103 may comprise any suitable material. For example, in certain embodiments, the substrate may include one or more conductors (e.g., metal conductors), silicon (e.g., silicon wafers), semiconductor substrates, and the like. According to certain embodiments, the substrate may comprise silicon, germanium, gallium arsenide, or combinations thereof. In certain embodiments, the substrate may include a group IV element semiconductor (C, si, ge, sn), a group IV compound semiconductor, a group VI element semiconductor (S, se, te), a III-V semiconductor, a II-VI semiconductor, an I-VII semiconductor, a IV-VI semiconductor, a V-VI semiconductor, a II-V semiconductor, an I-III-VI2 semiconductor, a semiconductor oxide, an organic semiconductor, and the like.

In certain embodiments, the fabrication substrate 103 includes one or more electronic components and/or Printed Circuit Boards (PCBs). In certain embodiments, the fabrication substrate 103 includes active or passive electronic components. Exemplary active or passive electronic components include, but are not limited to, amplifiers, preamplifiers, impedance matching circuits, multiplexers, analog-to-digital converters (ADCs), digital-to-analog converters (DACs), power management circuits, microcontrollers, wireless data transmission modules, and the like.

In certain embodiments, fabricating the substrate 103 comprises fabricating a substrate on which individual nerve probes are fabricated. In other embodiments, fabricating the substrate 103 includes fabricating a substrate of a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, or more) of nerve probes thereon. In certain embodiments in which multiple nerve probes are to be fabricated on a single fabrication substrate, the substrate may be modified to facilitate separation of the completed nerve probes from each other. Thus, for example, in certain embodiments, fabricating the substrate can include breaking areas (e.g., scored or perforated areas) disposed between areas on which the nerve probes are fabricated to facilitate mechanical separation of the nerve probes from each other. In certain embodiments, the fabrication substrate may include regions formed of a sacrificial material disposed between regions on which the nerve probes are fabricated to facilitate separation of the nerve probes from one another by simply dissolving the sacrificial material.

Sacrificial material and dissolution method

As indicated above, in various embodiments, the methods described herein involve depositing one or more layers of sacrificial material 104. The sacrificial material is typically a material that can be selectively removed (e.g., dissolved) without damaging and/or significantly altering the surrounding or overlying structure.

Materials suitable for use as sacrificial materials/layers in microfabrication methods are well known to those skilled in the art. Exemplary sacrificial materials include, but are not limited to, chromium oxide, nickel, gold, silicon oxide, water soluble polymers and adhesive polymers (e.g.,)。

The various sacrificial materials may be deposited by any of a variety of methods well known to those skilled in the art. Such methods include, but are not limited to, spin coating, casting, chemical Vapor Deposition (CVD), physical Vapor Deposition (PVD), and the like. In various embodiments, the deposition process is optionally combined with photolithographic patterning to provide the desired pattern of the sacrificial material layer.

Such sacrificial materials are easily removed after application by use of a suitable solvent. For example, a mixed solution of HCl/FeCl ₃ may be used to remove nickel from a substrate. HF may be used to remove SiO ₂ from the substrate. Removal of tetramethylammonium hydroxide (TMAH) from a substrate

In certain embodiments, the sacrificial material may comprise one or more water-soluble polymers. Water-soluble polymers have two attractive properties in this application, 1) they can be conveniently deposited by spin coating and the solvent removed at low temperatures (95 ° to 150 °), and 2) the resulting layers are soluble in water and do not require corrosive reagents or organic solvents. Thus, this technique is compatible with a wide variety of fragile materials (such as organic polymers, metal oxides, and metals), i.e., materials that may be damaged during typical surface micromachining processes. The carboxylic acid groups of an exemplary polymer, e.g., poly (acrylic acid) (PAA), can be converted from a water soluble (na+ counterion) to a water insoluble (Ca ²⁺ counterion) form by reversible ion exchange. The use of PAA and dextran polymers as sacrificial materials is a useful technique for making microstructures.

Examples of suitable water-soluble sacrificial materials include, but are not limited to, poly (acrylic acid), dextran, poly (methacrylic acid), poly (acrylamide), poly (ethyleneimine), poly (vinyl alcohol), poly (ethylene oxide), chitosan, and sucrose. Numerous water-soluble polymeric sacrificial materials are known to those skilled in the art (see, e.g., linder et al (2005) Small,1 (7): pages 730 to 736, and references therein).

The foregoing examples of sacrificial materials for use in the methods described herein are illustrative and not limiting. Numerous other suitable sacrificial materials will be recognized by those skilled in the art using the teachings provided herein.

Polymeric material/layer 106

Material

As explained above, the methods of making the nerve probes described herein involve depositing one or more layers of flexible polymeric material 106. Flexible polymeric materials are polymers that maintain their bulk or return to their original shape after large deformation, and although some materials do not possess the properties of bulk form factor, they can be folded without breaking when formed into films having a thickness of less than 10 μm. These materials may be elastomers, plastics or resins. For example, in some embodiments, the flexible polymer may exhibit a medium young's modulus. For example, in certain embodiments, the elastomer has an elastic modulus of greater than 10MPa, greater than 100MPa, greater than 1GPa, greater than 10GPa, or greater.

In certain embodiments, the flexible polymers used in the methods described herein include commercial plastics or epoxy cross-linked polymer resins, such as SU-8 and bisphenol a diglycidyl ether, polyimide, linear low density polyethylene, high density polyethylene, polystyrene, polypropylene, polyvinyl chloride, for example.

As explained above, the methods of making the nerve probes described herein involve depositing one or more layers of polymer 106. Elastomers are polymers characterized by weak intermolecular forces and thus viscoelasticity. For example, in some embodiments, the elastomer may exhibit a low modulus of elasticity. For example, in certain embodiments, the elastomer has an elastic modulus of less than 10MPa, less than 5MPa, less than 2MPa, less than 1MPa, or less. In some embodiments, the elastomer may exhibit high elastic stretch deformation. For example, in some embodiments, the elastomer may exhibit elastic tensile deformation at or above 20% strain, 30% strain, 50% strain, or 100% strain. In some embodiments, combinations of these mechanical properties are possible. For example, in some embodiments, the elastomer has an elastic modulus of less than 1MPa and may exhibit elastic tensile deformation at or above 20% strain. The modulus of elasticity and/or elastic tensile set may be determined by any suitable method. For example, tensile testing machines may be used to measure elastic modulus and elastic tensile deformation.

In certain embodiments, the elastomer used in the methods described herein comprises a fluorinated elastomer. In certain embodiments, the elastomer is a fluorinated elastomer that is not perfluorinated. In certain embodiments, the elastomer is a partially fluorinated elastomer. In certain embodiments, the elastomer is greater than or equal to 25%, or greater than or equal to 50%, or greater than or equal to 75% or more fluorinated elastomer, and/or the fluorinated elastomer is less than 100%, or less than or equal to 90%, or less than or equal to 75%, or less than or equal to 50% or less fluorinated, and/or the second fluorinated elastomer is greater than or equal to 25% fluorinated and less than 100% fluorinated.

In certain embodiments, the elastomer comprises a fluorinated elastomer selected from the group consisting of poly (1, 3-hexafluoroisopropyl acrylate) (PHFIPA) and or poly [2- (perfluorohexyl) ethyl ] acrylate. In certain embodiments, the elastomer comprises an elastomer selected from the group consisting of perfluoropolyether (PFPE), polytetrafluoroethylene (PTFE), perfluoropolyether dimethacrylate (PFPE-DMA), fluorinated ethylene-propylene (FEP), perfluoroalkoxy Polymer (PFA), and Polytrifluoroethylene (PCTFE). In certain embodiments, the elastomer comprises a perfluoropolyether. In certain embodiments, the elastomer comprises a copolymer. In certain embodiments, the elastomer is or includes tetrafluoroethylene propylene (TFE). In certain embodiments, the elastomer comprises or is a perfluoropolyether (PFPE).

In various embodiments, the elastomer may comprise any of a variety of suitable fluorinated elastomers. For example, in some embodiments, the polymer may be poly (1, 3-hexafluoroisopropyl acrylate) (PHFIPA) or poly [2- (perfluorohexyl) ethyl ] acrylate (PPFHEA). The polymer may also be a copolymer (e.g., a copolymer between two or more fluorinated elastomers, including both these polymers and the perfluorinated elastomers described above).

In certain embodiments, the elastomer comprises a polymer having an average molecular weight of greater than about 8kDa, or greater than about 10kDa, or greater than about 12kDa, or greater than about 14kDa, or greater than about 16kDa, or greater than about 18kDa, or greater than about 20 kDa.

In some embodiments, the elastomer has a molecular weight (e.g., weight average molecular weight) of less than or equal to 1000kDa, 500kDa, 200kDa, 100kDa, 50kDa, 40kDa, 30kDa, 20kDa, 15kDa, 10kDa, 8kDa, 5kDa or less, and/or according to certain embodiments, the weight average molecular weight of the polymer is greater than or equal to 1kDa, 2kDa, 3kDa, 4kDa, 5kDa, 8kDa, 10kDa, 15kDa, 20kDa, 30kDa, 40kDa or greater, prior to crosslinking. Combinations of these ranges are possible. For example, in certain embodiments, according to certain embodiments, the weight average molecular weight of the polymer can be greater than or equal to 1kDa and less than or equal to 8kDa. According to other embodiments, the weight average molecular weight of the polymer may be greater than 20kDa. The weight average molecular weight of the polymer may be determined by any suitable method (e.g., by gel permeation chromatography).

The foregoing elastomers (e.g., fluoropolymers) are illustrative and not limiting. Numerous other elastomers suitable for use in the methods described herein will be available to those skilled in the art using the teachings provided herein.

Polymer deposition process

The polymer layer 106 may be deposited using any of a variety of thin film coating techniques well known to those skilled in the art. Such methods include, but are not limited to, liquid phase chemical deposition, spin coating, spray coating, casting, vacuum polymer deposition, physical Vapor Deposition (PVD), and various chemical vapor depositions (CVD, PECVD, etc.). Methods of depositing polymers on a substrate are well known to those skilled in the art (see, e.g., martin et al, third edition (2010)Handbook of Deposition Technologies for Films and Coatings:Science,Applications and Technology,, WILLIAM ANDREW Pub (ISBN 978-0-8155-2031-3).

In one exemplary but non-limiting embodiment, the polymer layer 106 is deposited using a Chemical Vapor Deposition (CVD) method. Chemical Vapor Deposition (CVD) methods significantly enhance the ability of conventional surface modification techniques to design polymer surfaces. In CVD polymerization, monomers are delivered to a surface in the gas phase and then polymerization and film formation are performed simultaneously. CVD enables the coating of insoluble polymers and prevents solvents from damaging the substrate by eliminating the need to dissolve macromolecules. The CVD coating conforms to the geometry of the underlying substrate because of the absence of dewetting and surface tension effects. Thus, the CVD polymer can be easily applied to almost any substrate, organic, inorganic, rigid, flexible, planar, three-dimensional, dense, or porous. CVD methods are easily integrated with other vacuum processes used to fabricate patterned surfaces and devices. Typically, CVD film growth proceeds upward from the substrate, allowing for interfacial engineering, real-time monitoring, thickness control, and synthesis of films with graded composition.

Two specific CVD polymerization methods that convert solution chemistry tightly to vapor deposition are Initiated Chemical Vapor Deposition (iCVD) and oxidized chemical vapor deposition (oCVD). In iCVD (i.e., a variation of hot filament CVD), the deposition rate is increased and the chemical functionality of the components of the polymer is maintained by including a thermally labile initiator in the feed stream. Because of the low energy required when using an initiator, precision substrates can be coated. In opcvd, an unmelted conductive film is formed directly on a substrate of interest when an oxidizing agent and a monomer are simultaneously introduced into a reactor.

Methods of chemical vapor deposition of polymer films are provided in detail by, for example, asatekin et al (2010) MATERIALS TODAY,13 (5): pages 26 to 33, and references therein.

Thickness of (L)

In certain embodiments, the polymer layer 106 has a thickness greater than or equal to 50 nanometers, greater than or equal to 100 nanometers, greater than or equal to 200 nanometers, greater than or equal to 300 nanometers, greater than or equal to 400 nanometers, greater than or equal to 500 nanometers, or greater. According to certain embodiments, the polymer layer has a thickness of less than or equal to 5000 nanometers, less than or equal to 4000 nanometers, less than or equal to 3000 nanometers, less than or equal to 2000 nanometers, less than or equal to 1000 nanometers, less than or equal to 500 nanometers, or less. Combinations of these ranges are possible. For example, in certain embodiments, the polymer layer has a thickness greater than or equal to 50 nanometers and less than or equal to 5000 nanometers. As another example, according to some embodiments, the polymer layer has a thickness greater than or equal to 300 nanometers and less than or equal to 2000 nanometers.

In certain embodiments, the thickness of the polymer layer is in the range of about 0.5 μm, or about 1 μm, or about 2 μm up to about 10 μm, or up to about 5 μm, or up to about 4 μm, or up to about 3 μm.

It will be appreciated that in certain embodiments, the thickness of all polymer layers is the same. In other embodiments, different polymer layers may have different thicknesses. For example, in certain embodiments, the outer polymer layer may be thicker than the polymer layer disposed between the layers of conductor or semiconductor material.

Patterning

As indicated above, in various embodiments, the polymer layer 106 is deposited and patterned to cover and/or separate the different layers of conductive or semiconductive material 108, thereby insulating the different conductive or semiconductive layers from one another. Typically, the polymer is deposited/patterned to reveal at least a portion of the connection pads 110 and to insulate the electrodes 108 and connection pads 110 from a subsequently applied layer of conductive or semiconductive material. In certain embodiments, the polymer layer is patterned to expose one or more discrete locations on the electrode to provide points of contact with tissue. In certain embodiments, the tip of the electrode is exposed, and/or in certain embodiments, one or more discrete locations of the electrode are exposed.

Polymer modification and/or functionalization

In certain embodiments, the polymer layer 106 described herein may be functionalized or otherwise modified. Methods of chemically functionalizing polymers are well known to those skilled in the art (see, e.g., pinson and Thiry (2019) Surface Modification of Polymers: methods and Applications, wiley Inc.). In various embodiments, such functionalization may improve the mechanical and/or chemical properties of the polymer.

It has also surprisingly been recognized that in some embodiments, disposing of the polymer (e.g., fluorinated elastomer) may advantageously facilitate deposition of the material onto the surface of the polymer. Furthermore, it has surprisingly been found that treating fluorinated elastomers (e.g., perfluoropolymers) with plasma can greatly facilitate subsequent layer deposition and stable bonding to the fluoropolymer without adversely affecting the chemical and physical properties of the fluoropolymer. In this regard, without being bound by a particular theory, it is noted that the elastomeric "surface" resembles a viscous liquid, which thus makes metal deposition difficult or impossible (metal particles diffuse only through the film, rather than forming a dense metal layer on the surface). It is believed that plasma treatment of the elastomer can increase the surface energy and allow evaporation of the dense metal layer. Indeed, it is believed that the plasma essentially converts the first few nanometers of the fluorinated elastomer surface into a more rigid version of the supportable particle deposition itself (e.g., metal deposition) without altering the overall mechanical/chemical properties of the structure.

Thus, in various embodiments, the polymer layer 106 may be treated with plasma, for example, prior to deposition of subsequent layers. In various embodiments, the plasma includes a plasma formed from an inert gas (e.g., argon, helium, neon, krypton, xenon, etc.). In certain embodiments, the plasma comprises an argon or nitrogen plasma.

In various embodiments, disposing of the polymer may advantageously prepare the surface of the polymer for interaction with other materials. For example, in certain embodiments, disposing of the fluorinated polymer may introduce reactive, charged, and/or polarized sites on the surface of the fluorinated elastomer that may form chemical or physical bonds with subsequently deposited materials.

In some embodiments, treating the polymer with a plasma formed from an inert gas may advantageously exclude oxygen from the treated polymer. This may prevent oxygen from reacting with the treated surface, advantageously enhancing the ability of the polymer to adhere to other materials. Thus, in certain embodiments, any thick and/or multi-layer article comprising a polymer (e.g., perfluorinated elastomer) may be fabricated. Similarly, any thick and/or multi-layer article comprising a fluorinated elastomer may be made. Fabrication of a multilayer article comprising a fluorinated elastomer as described herein can provide significant advantages for the preparation of articles comprising high number density electrodes. For example, as described herein, fabricating additional rows of electrodes on the sensor may include fabricating additional layers of the device.

In some embodiments, after the (plasma) treated polymer (e.g., perfluoropolyether) is formed, additional material is deposited onto the treated polymer. In various embodiments, the deposited additional material may include a conductive material, a semiconductive material, or other materials. For example, in some embodiments, the deposited additional material may include a metal or metal alloy. The ability to deposit conductive material is advantageous because it can be used to fabricate portions of an electronic circuit (e.g., a sensor). For example, conductive materials may be used to fabricate the electrodes.

In some embodiments, the additional material is a polymer. In certain embodiments, the polymer is not a perfluorinated elastomer. In some embodiments, the additional material is not a fluorinated elastomer. In certain embodiments, the additional material is a photoresist.

According to certain embodiments, the polymer may be deposited onto the treated polymer via solution treatment. Because of the hydrophobicity of fluorinated (e.g., perfluorinated) polymers, according to some embodiments, the polymers do not swell in the presence of non-fluorinated solvents. Similarly, in some embodiments, fluorinated elastomers may not swell in the presence of non-fluorinated solvents due to their hydrophobicity. During solution processing of the additional material, the fluorinated elastomer may experience low volume swelling. In certain embodiments, the perfluorinated elastomer may experience less than or equal to 5%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, less than or equal to 0.2%, or in some embodiments less volume swelling. For example, a fluorinated elastomer (e.g., a perfluorinated elastomer) may experience less than or equal to 5%, less than or equal to 2%, less than or equal to 1%, less than or equal to 0.5%, less than or equal to 0.2%, or less volume swelling. According to certain embodiments, the low volume swelling of the fluorinated elastomer may advantageously maintain a pattern with high spatial resolution, which nevertheless comprises multiple layers of chemically different polymers. More generally, fluorinated elastomers can advantageously retain patterns with high spatial resolution, which nevertheless comprise multiple layers of chemically different polymers due to their low volume swelling.

In certain embodiments, the deposited additional material may be an additional polymer (e.g., an additional layer of fluorinated elastomer). This may result in a thicker layer of polymer. In some embodiments, the polymer layer has a minimum thickness of at least 0.3 microns, at least 0.5 microns, at least 0.7 microns, or greater. In some embodiments, the fluorinated elastomer layer has a minimum thickness of less than or equal to 3 microns, less than or equal to 2.5 microns, less than or equal to 2 microns, less than or equal to 1 micron. Combinations of these ranges are possible. For example, according to certain embodiments, the fluorinated elastomer layer has a minimum thickness of at least 0.3 microns and less than or equal to 3 microns.

In some embodiments, the deposited additional material is an additional layer of perfluorinated elastomer. In certain embodiments, where the initial layer is a perfluorinated elastomer, depositing an additional layer of perfluorinated elastomer may result in a thicker layer of perfluorinated elastomer. In some embodiments, the perfluorinated elastomer layer has a minimum thickness of at least 0.3 microns, at least 0.5 microns, at least 0.7 microns, or greater, exhibiting high crosslinking. In some embodiments, the perfluorinated elastomer layer has a minimum thickness of less than or equal to 3 microns, less than or equal to 2.5 microns, less than or equal to 2 microns, less than or equal to 1 micron. Combinations of these ranges are possible. For example, according to certain embodiments, the perfluorinated elastomer layer has a minimum thickness of at least 0.3 microns and less than or equal to 3 microns.

The foregoing examples of polymeric materials for use in the methods described herein are illustrative and not limiting. Numerous other suitable polymeric materials will be recognized by those skilled in the art using the teachings provided herein.

Layer 108 of conductive/semiconductive material-electrode

Conductive/semiconductive material

In certain embodiments, the layer of conductive or semiconductive material 108 comprises a metal or metal alloy, a metal oxide or nitride, a conductive polymer, a semiconductor, and/or graphene. In certain embodiments, the conductive or semiconductive material 108 comprises a metal or metal alloy. In certain embodiments, the conductive or semiconductive material 108 comprises a metal selected from the group consisting of gold, platinum, iridium, chromium, tungsten, tantalum, tin, nichrome, titanium, copper, rhodium, rhenium, silver, stainless steel, palladium, aluminum, zirconium, conductive oxides or nitrides thereof, and alloys thereof. In certain embodiments, the conductive or semiconductive material 108 comprises titanium nitride or a platinum iridium alloy. In certain embodiments, the conductive or semiconductive material 108 comprises gold.

In certain embodiments, the conductive or semiconductive material 108 comprises a conductive polymer without heteroatoms, such as poly (fluorene), polyphenyl, polypyrene, polyazulene, polynaphthalene, and the like.

In certain embodiments, the conductive or semiconductive material 108 comprises a nitrogen-containing conductive polymer, for example, a conductive polymer in which nitrogen (N) is in an aromatic ring (e.g., poly (pyrrole) (PPY), polycarbazole, polybenzazole, polyazepine, etc.), or a conductive polymer in which nitrogen is outside an aromatic ring (e.g., polyaniline (PANI), etc.). In certain embodiments, the conductive or semiconductive material 108 comprises a sulfur-containing conductive polymer, for example, a conductive polymer in which sulfur (S) is in an aromatic ring (e.g., poly (thiophene) (PT), poly (3, 4-ethylenedioxythiophene) (PEDOT), etc.), or a conductive polymer in which sulfur is outside an aromatic ring (e.g., poly (p-phenylene sulfide) (PPS), etc.). In certain embodiments, the conductive or semiconductive material 108 comprises a conductive polymer, such as poly (acetylene) (PAC), poly (p-phenylvinyl) (PPV), or the like.

In certain embodiments, the conductive or semiconductive material 108 comprises graphene.

Adhesive layer 109

In certain embodiments, bonding between the layer of conductive or semiconductive material 108 and a subsequently applied layer (e.g., the layer of polymeric material 106) may be facilitated by the incorporation of an adhesion layer, for example, as shown in fig. 3. Thus, for example, in certain embodiments, the layer of conductive or semiconductive material 108 may also include an adhesion layer 109. Although in fig. 3, the adhesion layer 109 is shown only atop the conductive or semiconductive material layer 108, it will be appreciated that in certain embodiments the adhesion layer 109 may be below the conductive or semiconductive material layer 108 to facilitate adhesion to an underlying layer (e.g., an underlying polymer layer 106), or the adhesion layer 109 may be disposed both atop and below the conductive or semiconductive material layer.

Suitable materials for the adhesion layer are well known to those skilled in the art and include, but are not limited to, aluminum oxide, tungsten, niobium, chromium, titanium, and the like. It should be noted that in certain embodiments, the attachment layer may be conductive, semiconductive, or nonconductive. In one exemplary but non-limiting embodiment, the conductive or semiconductive material layer 108 may comprise a gold conductive layer deposited on an aluminum adhesion layer, an aluminum adhesion layer deposited on a gold conductive layer, or a gold conductive layer deposited between two aluminum adhesion layers.

Deposition of conductive/semiconductive material 108

Methods of depositing and patterning the conductive or semiconductive material 108 are well known to those skilled in the art. Such methods include, but are not limited to, spin coating, ion plating, sputter deposition, cathodic arc deposition, chemical Vapor Deposition (CVD), molecular vapor deposition, and the like.

In some implementations, one or more layers comprising the conductive or semiconductive material 108 can be patterned (e.g., through a mask, resist, or other methods well known to those skilled in the art). Thus, for example, one common method of selectively patterning a surface having a conductor or semiconductor involves masking areas of the surface that are free of conductive or semiconductive material such that a solution or gas phase containing the conductive or semiconductive material cannot make contact with those areas. This can be easily achieved by coating the substrate with a masking material (e.g., a polymer resist) and selectively etching the resist away from the areas to be coupled. Alternatively, a photo-activated resist may be applied to the surface and selectively activated (e.g., via UV light) in the area to be protected. Such "lithographic" methods are well known in the semiconductor industry (see, e.g., van Zant (2000) Microchip Fabrication: A PRACTICAL Guide to Semiconductor Processing; nishi and Doering(2000)Handbook of Semiconductor Manufacturing Technology;Xiao(2000)Introduction to Semiconductor Manufacturing Technology;Campbell(1996)The Science and Engineering of Microelectronic Fabrication(Oxford Series in Electrical Engineering),Oxford University Press,, etc.). In addition, the resist may be patterned on the surface simply by contact printing the resist onto the surface.

In other methods, the surface is uniformly contacted with a conductive or semiconductive material. Molecules can then be selectively etched away from the surface in areas that will be free of molecules. Etching methods are well known to those skilled in the art and include, but are not limited to, plasma etching, laser etching, acid etching, and the like.

Other methods involve contact printing of conductive or semiconductive materials, for example, using an inkjet printer or a shaped contact printhead to selectively deposit the conductive or semiconductive material in desired areas (see, e.g., U.S. patent 6,221,653).

Electrode arrangement

In certain embodiments, the conductive or semiconductive material 108 forms a single electrode. In certain embodiments, the conductive or semiconductive material 108 is patterned to form a plurality of electrodes. In certain embodiments, the plurality of electrodes are electrically isolated from each other and/or are independently addressable. In certain embodiments, the layer of conductive or semiconductive material 108 forms at least about 10, or at least about 20, or at least about 50, or at least about 100, or at least about 250, or at least about 500, at least about 1000, at least about 5,000, or at least about 10,000 electrodes.

In certain embodiments in which the conductive or semiconductive material 108 is patterned to form a plurality of electrodes, those electrodes have an electrode number density (e.g., the number of electrodes per unit area of the projection surface of the nerve probe). In some embodiments, the electrode has greater than or equal to 10 ^-5 electrodes per micrometer ², greater than or equal to 10 ^-4 electrodes per micrometer ², Greater than or equal to 10 ^-3 electrodes/micrometer ², greater than or equal to 10 ^-2 electrodes/micrometer ², an electrode number density of greater than or equal to 10 ^-1 electrodes/micron ² or greater. In some embodiments, the electrode has an electrode number density of less than or equal to 10 ¹ electrodes/micrometer ², less than or equal to 100 electrodes/micrometer ², less than or equal to 10 ^-1 electrodes/micrometer ², or less. combinations of these ranges are possible. For example, in some embodiments, the electrode has an electrode number density greater than or equal to 10 ^-5 electrodes/micrometer ² and less than or equal to 10 ¹ electrodes/micrometer ².

In certain embodiments, the methods provided herein allow for patterning of, for example, electrodes with high resolution. Thus, for example, in certain embodiments, the minimum distance between pattern features (e.g., between two electrodes) is at or below 30 microns, or at or below 20 microns, or at or below 10 microns, or at or below 5 microns, or at or below 2 microns, or less.

In certain embodiments, the thickness of the layer of conductive or semiconductive material 108 is in the range of about 20nm, or about 30nm, or about 40nm, or about 50nm, or about 60nm, or about 70nm, or about 80nm, or about 90nm, or about 100nm up to about 1 μm, or up to about 900nm, or up to about 800nm, or up to about 700nm, or up to about 600nm, or up to about 500nm, or up to about 400nm, or up to about 300nm, or up to about 200nm, or up to about 150nm.

In certain embodiments, the layer of conductive or semiconductive material 108 forms an electrode having an average length in the range of about 1mm, or about 2mm, or about 3mm, or about 4mm, or about 5mm, or about 6mm, or about 7mm, or about 8mm up to about 20mm, or up to about 18mm, or up to about 16mm, or up to about 14mm, or up to about 12mm.

In certain embodiments, the layer of conductive or semiconductive material 108 forms an electrode having an average width in the range of about 100nm, or about 200nm, or about 500nm, or about 800nm, or about 1 μm, or about 5 μm, or about 10 μm, or about 20 μm up to about 100 μm, or up to about 80 μm, or up to about 60 μm, or up to about 50 μm, or up to about 40 μm, or up to about 30 μm, or up to about 20 μm micrometers.

Handling of contact pads

In various embodiments, the contact pads 114 are treated to facilitate the formation of electrical connections. In certain embodiments, the contact pads 114 are treated in accordance with a bumping procedure, effectively increasing the roughness and surface area of the contact pads. In certain embodiments, the bumping procedure includes electroplating or metal deposition to form bumps on the contact pads. In certain embodiments, the bump comprises a metal selected from the group consisting of solder, au, and Ir, in, cu.

I/O contact pad and packaging method

As indicated above, in various embodiments, the contact pads on the nerve probe are made of metal, including Au, pt, ti, cu, al. When the nerve probe is fabricated on a common Si substrate, the I/O pads (input/output circuits) have a pitch between 20 μm and 2mm, and they form connections with external electronic components (e.g., PCB, IC) using wire bonding, or flip chip bonding, or mechanical direct contact. When the nerve probe is fabricated on a substrate (e.g., CMOS wafer) with active electronics, the I/O pads have a pitch of between 2 μm and 200 μm and post fabrication methods (e.g., lithography, metal deposition, lift-off, wet etching, dry etching) are used to form connections to the active electronics in the substrate.

Sterilizing and/or packaging nerve probes

In certain embodiments, the methods provided herein further comprise sterilizing the nerve probe. Methods for effectively sterilizing nerve probes include, but are not limited to, exposure to radiation (e.g., ionizing radiation or ultraviolet light), chemical sterilization (e.g., exposure to ethylene oxide, etc.), and/or autoclaving.

In certain embodiments, particularly after sterilization, the nerve probe may be packaged in a sterile package. Illustrative but non-limiting examples of aseptic packaging systems include pre-validated packaging trays, lids, and pouches formed from materials for gamma, ethylene oxide (EtO), and/or electron beam (e-beam) sterilization processes (see, e.g.Pre-validated sterile packaging). In certain embodiments, single or double layer barrier packaging configurations involving foams, polyurethane, shelving boxes, and other protective packaging materials may be utilized. In certain embodiments, the package provides an inert gas (e.g., argon) inside the package.

Implantation of nerve probe

In some embodiments, at least a portion of the nerve probes described herein are implanted in a subject. For example, in various embodiments, part or all of the nerve probe may be implanted in the subject. For example, in certain embodiments, the nerve probe may be implanted in brain or other neural tissue, spinal cord, heart, peripheral muscle, and the like. In some embodiments, the nerve probe is configured for long-term residence in a subject, e.g., the nerve probe is stable under physiological conditions. In certain embodiments, the nerve probe may be configured for prolonged contact with a surface of the brain, or for partial or total implantation in the brain of a subject.

Thus, in certain embodiments, the nerve probe is partially or fully implanted in a target tissue (e.g., brain tissue) at the time of use. Methods of implanting nerve probes are described, for example, in PCT publication No. PCT/US 2022/019430. As described therein, in certain embodiments, a frame and/or shuttle may be used to guide and position a nerve probe at or in a target tissue (e.g., brain tissue).

In certain embodiments, implantation of the nerve probe may be facilitated by temporarily increasing the stiffness of the nerve probe. In one exemplary but non-limiting method, the nerve probe is coated with a bioabsorbable sclerosant. Exemplary bioabsorbable sclerosants include, but are not limited to, dextran, glucose, polyethylene glycol (PEG), gelatin, and the like. In certain embodiments, the nerve probe may be hardened by freezing.

Kit of parts

In certain embodiments, kits for using the nerve probes described herein are provided. In certain embodiments, the kit includes one or more receptacles containing nerve probes made according to any one of the methods described herein. In certain embodiments, the container provides a sterile package for the sterile nerve probe. In certain embodiments, the kit further comprises a shuttle and/or frame to facilitate implantation of the nerve probes described herein.

In certain embodiments, the kit may further comprise a teaching/informational material. In certain embodiments, the teaching material teaches the use of a nerve probe contained in a kit to receive an electrical signal from a target tissue (e.g., brain or other nerve tissue) for transmitting the signal to the target tissue. In certain embodiments, the teaching material provides teaching for implanting the nerve probe into the target tissue.

Although instructional materials typically include written or printed materials, they are not limited thereto. Any medium capable of storing such instructions and communicating them to an end user is contemplated herein. Such media include, but are not limited to, electronic storage media (e.g., magnetic disks, tapes, cartridges, chips), optical media (e.g., CD-ROM), and the like. Such media may include addresses of internet websites providing such instructional materials.

It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims (97)

1. A method for preparing a soft probe electrically connected to an active electronic device, the method comprising: a) providing a fabrication substrate, wherein the fabrication substrate comprises a fabrication material and a fracture region; b) depositing a layer of sacrificial material over a portion of the fabrication substrate; c) depositing an insulating, flexible polymer layer over the layer of sacrificial material and over a portion of the fabrication substrate; d) depositing a layer of conductive or semiconductive material on the polymer layer and the fabrication substrate, wherein: The conductive or semiconductive material is patterned to form an electrode or is patterned to form a plurality of electrodes; Each of the one or more electrodes is disposed over at least a portion of the sacrificial material layer and an area of the fabrication substrate not covered with the sacrificial material; and The conductive or semiconductive material forms one or more connection pads on the fabrication substrate in an area not coated with the sacrificial material layer, and the one electrode or the plurality of electrodes are each electrically coupled to at least one of the connection pads; e) optionally repeating steps (c) and (d) to add alternating layers of polymer and conductive or semiconductive material, wherein the polymer exposes at least a portion of the connection pad and insulates the electrode and the connection pad from subsequently applied layers of conductive or semiconductive material; and f) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material, wherein the final layer exposes at least a portion of the connection pad; thereby forming a soft probe comprising one or more electrodes disposed between the layers of polymer and disposed on the fabrication substrate. 2. The method according to claim 1, further comprising: providing a substrate comprising a support supporting one or more contact pads and one or more active or passive electronic components, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; bonding the substrate to the fabrication substrate; wire bonding each of the one or more connection pads to one or more of the contact pads to form a wire bond between the connection pad and the contact pad; removing the sacrificial material layer; and The fabrication substrate is fractured at the fracture region to provide the soft probe electrically connected to the one or more active or passive electronic components. 3. The method according to claim 2, further comprising: providing a substrate comprising a support supporting one or more contact pads and one or more active or passive electronic components, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; flip chip bonding each of the one or more connection pads to one or more of the contact pads to form a flip chip bond between the connection pad and the contact pad; removing the sacrificial material layer; and The fabrication substrate is fractured at the fracture region to provide the soft probe electrically connected to the one or more active or passive electronic components. The method of claim 3 , further comprising bonding the substrate to the fabrication substrate. 5. The method according to any one of claims 3 to 4, further comprising adding a filler to a flip chip bond pad area to force bonding between the fabrication substrate and the substrate. 6. The method according to claim 2, further comprising: providing one or more active or passive electronic components supporting one or more contact pads, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; flip chip bonding each of the one or more connection pads to one or more of the contact pads to form a flip chip bond between the connection pad and the contact pad; removing the sacrificial material; and The fabrication substrate is fractured at the fracture region to provide the soft probe electrically connected to the one or more active or passive electronic components. 7. The method of claim 6, further comprising bonding the one or more active or passive electronic components to the fabrication substrate. 8. The method according to any one of claims 6 to 7, further comprising adding a filler to a flip chip bond pad area to force bonding of the one or more active or passive electronic components to the fabrication substrate. 9. The method according to claim 2, further comprising: providing the fabrication substrate having a through hole at each of the connection pads; providing a substrate comprising a support supporting one or more contact pads and one or more active or passive electronic components, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; juxtaposing the substrate with the fabrication substrate; depositing a conductor into each of the through-holes to form an electrical connection between the connection pad and the contact pad; removing the sacrificial material; and The fabrication substrate is fractured at the fracture region to provide the soft probe electrically connected to the one or more active or passive electronic components. 10. The method of claim 9, further comprising bonding the substrate to the fabrication substrate. 11. The method according to claim 2, further comprising: providing the fabrication substrate having a through hole at each of the connection pads; providing one or more active or passive electronic components supporting one or more contact pads, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; juxtaposing the one or more active or passive electronic components with the fabrication substrate; depositing a conductor into each of the through-holes to form an electrical connection between the connection pad and the contact pad; removing the sacrificial material layer; and The fabrication substrate is fractured at the fracture region to provide the soft probe electrically connected to the one or more active or passive electronic components. 12. The method of claim 2, further comprising bonding the one or more active or passive electronic components to the fabrication substrate. 13. The method according to any one of claims 1 to 12, wherein the sacrificial material layer is omitted and a pick-up tool is used to peel the soft probe from the fabrication substrate. 14. A method for preparing a standalone soft neural probe electrically connected to an active electronic device, the method comprising: a) providing a fabrication substrate, the fabrication substrate comprising a first region and a second region, the first region comprising a fabrication material, and the second region comprising a sacrificial material; b) depositing an insulating flexible polymer layer on the substrate, wherein the polymer layer is disposed over at least a portion of the first region and over at least a portion of the second region; c) depositing a conductive or semiconductive material on said polymer layer and said fabrication substrate, wherein: The conductive or semiconductive material is patterned to form an electrode or is patterned to form a plurality of electrodes; Each of the one or more electrodes is disposed over at least a portion of the sacrificial material and an area of the fabrication substrate not covered with the sacrificial material; and The conductive or semiconductive material forms one or more connection pads on the fabrication substrate in areas not coated with the sacrificial material, and the electrode or electrodes are each electrically coupled to at least one of the connection pads; d) optionally repeating steps (b) and (c) to add alternating layers of polymer and conductive or semiconductive material, wherein the polymer exposes at least a portion of the connection pad and insulates the electrode and the connection pad from subsequently applied layers of conductive or semiconductive material; and e) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material, wherein the final layer exposes at least a portion of the connection pads; thereby forming a soft neural probe comprising one or more electrodes disposed between the layers of polymer and disposed on the fabrication substrate. 15. The method according to claim 14, further comprising: providing a substrate comprising a support supporting one or more contact pads and one or more active or passive electronic components, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; bonding the substrate to the fabrication substrate; wire bonding each of the one or more connection pads to one or more of the contact pads to form a wire bond between the connection pad and the contact pad; removing the sacrificial material constituting the second region of the fabrication substrate; and The fabrication substrate is fractured at a fracture region to provide the freestanding soft neural probe electrically connected to the one or more active or passive electronic components. 16. The method according to claim 14, further comprising: providing one or more active or passive electronic components supporting one or more contact pads, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; bonding the one or more active or passive electronic components to the fabrication substrate; wire bonding each of the one or more connection pads to one or more of the contact pads to form a wire bond between the connection pad and the contact pad; removing the sacrificial material constituting the second region of the fabrication substrate; and The fabrication substrate is fractured at a fracture region to provide the freestanding soft neural probe electrically connected to the one or more active or passive electronic components. 17. The method according to claim 14, further comprising: providing a substrate comprising a support supporting one or more contact pads and one or more active or passive electronic components, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; flip chip bonding each of the one or more connection pads to one or more of the contact pads to form a flip chip bond between the connection pad and the contact pad; removing the sacrificial material constituting the second region of the fabrication substrate; and The fabrication substrate is fractured at a fracture region to provide the freestanding soft neural probe electrically connected to the one or more active or passive electronic components. 18. The method of claim 7, further comprising bonding the substrate to the fabrication substrate. 19. The method according to claim 14, further comprising: providing one or more active or passive electronic components supporting one or more contact pads, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; flip chip bonding each of the one or more connection pads to one or more of the contact pads to form a flip chip bond between the connection pad and the contact pad; removing the sacrificial material constituting the second region of the fabrication substrate; and The fabrication substrate is fractured at a fracture region to provide the freestanding soft neural probe electrically connected to the one or more active or passive electronic components. 20. The method of claim 19, further comprising bonding the one or more active or passive electronic components to the fabrication substrate. 21. The method according to claim 14, further comprising: providing the fabrication substrate having a through hole at each of the connection pads; providing a substrate comprising a support supporting one or more contact pads and one or more active or passive electronic components, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; bonding the substrate to the fabrication substrate; depositing a conductor into each of the through-holes to form an electrical connection between the connection pad and the contact pad; removing the sacrificial material constituting the second region of the fabrication substrate; and The fabrication substrate is fractured at a fracture region to provide the freestanding soft neural probe electrically connected to the one or more active or passive electronic components. 22. The method according to claim 14, further comprising: providing the fabrication substrate having a through hole at each of the connection pads; providing one or more active or passive electronic components supporting one or more contact pads, wherein each of the one or more contact pads is electrically coupled to the one or more active or passive electronic components; bonding the one or more active or passive electronic components to the fabrication substrate; depositing a conductor into each of the through-holes to form an electrical connection between the connection pad and the contact pad; removing the sacrificial material constituting the second region of the fabrication substrate; and The fabrication substrate is fractured at a fracture region to provide the freestanding soft neural probe electrically connected to the one or more active or passive electronic components. 23. A method of preparing a standalone soft neural probe electrically connected to an active electronic device, the method comprising: a) providing a fabrication substrate, wherein the fabrication substrate comprises an integrated circuit and one or more connection pads, wherein the connection pads are electrically connected to at least one circuit element constituting the integrated circuit; b) depositing a layer of sacrificial material over a portion of the fabrication substrate; c) depositing an insulating, flexible polymer layer over the layer of sacrificial material and over at least a portion of the fabrication substrate; d) depositing a layer of conductive or semiconductive material on the insulating flexible polymer layer and the fabrication substrate, wherein: The conductive or semiconductive material is patterned to form an electrode or is patterned to form a plurality of electrodes; Each of the one or more electrodes is disposed over at least a portion of the sacrificial material layer and an area of the fabrication substrate not covered with the sacrificial material layer; and The conductive or semiconductive material forms an electrical connection with one or more of the connection pads; e) optionally repeating steps (c) and (d) to add alternating layers of polymer and conductive or semiconductive material, wherein the polymer exposes at least a portion of the connection pad and insulates the electrode and the connection pad from subsequently applied layers of conductive or semiconductive material; and f) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material, wherein the final layer exposes at least a portion of the connection pads; thereby forming a soft neural probe comprising one or more electrodes disposed between the layers of polymer and disposed on the fabrication substrate. 24. The method of claim 23, wherein the circuit elements comprising the integrated circuit include elements selected from the group consisting of: an amplifier, a preamplifier, a multiplexer, an analog-to-digital converter (ADC), a digital-to-analog converter (DAC), a power management circuit, a microcontroller, an impedance matching circuit, an interconnect, a signal splitter, and a wireless data transmission module. 25. A method according to any one of claims 23 to 24, wherein the method comprises removing the layer of sacrificial material, thereby freeing the terminal region of the electrode from the fabrication substrate. 26. The method of any one of claims 23 to 25, wherein the fabrication substrate comprises a fracture zone. 27. The method of claim 26, wherein the method comprises fracturing the substrate at the fracture region. 28. A method according to any one of claims 23 to 27, wherein the integrated circuit comprises output pads, pins or leads. 29. A method according to any one of claims 23 to 28, wherein the integrated circuit is provided on a support. 30. The method of claim 29, wherein the support comprises a circuit board. 31. The method of any one of claims 29 to 30, wherein the support comprises an output pad, a lead or a pin. 32. The method according to any one of claims 1 to 31, wherein: fabricating multiple neural probes on a single fabrication substrate; and The substrate is cut into smaller pieces, each having one or more neural probes on each piece. 33. The method of any one of claims 1 to 32, wherein the polymer comprises a material selected from the group consisting of: a fluorinated elastomer, a polyimide, polydimethylsiloxane, parylene-C, and an epoxy resin. 34. The method of any one of claims 1 to 33, wherein the polymer layer comprises a fluorinated elastomer. 35. The method of claim 34, wherein the fluorinated elastomer is a fluorinated elastomer that is not perfluorinated. 36. The method of claim 35, wherein the fluorinated elastomer is partially fluorinated. 37. The method of claim 36, wherein: The fluorinated elastomer is greater than or equal to 25% fluorinated and less than 100% fluorinated. 38. The method of claim 35, wherein the fluorinated elastomer is selected from the group consisting of poly(1,1,1,3,3,3-hexafluoroisopropyl acrylate) (PHFIPA) and poly[2-(perfluorohexyl)ethyl]acrylate. 39. The method of claim 34, wherein the fluorinated elastomer is a perfluorinated elastomer. 40. The method of claim 39, wherein the perfluorinated elastomer is selected from the group consisting of perfluoropolyether (PFPE), polytetrafluoroethylene (PTFE), perfluoropolyether dimethacrylate (PFPE-DMA), fluorinated ethylene-propylene (FEP), perfluoroalkoxy polymer (PFA), and polychlorotrifluoroethylene (PCTFE). 41. The method of claim 39, wherein the perfluorinated elastomer comprises a perfluoropolyether. 42. The method of claim 41, wherein the perfluoropolyether has a weight average molecular weight greater than 8 kDa. 43. The method of claim 41, wherein the perfluoropolyether has a weight average molecular weight greater than 20 kDa. 44. The method of any one of claims 41 to 43, wherein the perfluorinated elastomer is a copolymer. 45. The method of claim 44, wherein the perfluorinated elastomer is tetrafluoroethylene propylene (TFE). 46. The method of claim 39, wherein the perfluorinated elastomer comprises perfluoropolyether (PFPE). 47. The method of any one of claims 1 to 46, wherein the polymer layer has a thickness in the range of about 0.5 μm to about 5 μm. 48. A method according to any one of claims 1 to 47, wherein one or more of the layers of polymeric material are patterned to provide open areas to provide contact with tissue at one or more discrete locations along the surface of one or more electrodes formed from the conductive or semiconductive material. 49. A method according to any one of claims 1 to 48, wherein one or more of the layers of polymeric material are patterned to encapsulate one or more electrodes formed from the conductive or semiconductive material, thereby providing one or more capacitive electrodes. 50. The method of any one of claims 1 to 49, wherein the layer of polymer material is deposited by an additive semiconductor fabrication process. 51. The method of claim 50, wherein the additive semiconductor fabrication process is selected from the group consisting of: spin coating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), wherein the process is optionally combined with photolithographic patterning. 52. The method of any one of claims 1 to 49, wherein the sacrificial material comprises a material selected from the group consisting of chromium, chromium oxide, nickel, gold, silicon, silicon oxide, a water soluble polymer, and an adhesive polymer. 53. The method of claim 52, wherein the sacrificial material comprises a water-soluble polymer selected from the group consisting of poly(acrylic acid), dextran, poly(methacrylic acid), poly(acrylamide), poly(ethyleneimine), poly(vinyl alcohol), poly(ethylene oxide), chitosan, and sucrose. 54. The method of any one of claims 1 to 53, wherein the sacrificial material is deposited by an additive semiconductor fabrication process. 55. The method of claim 54, wherein the additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), thermal oxidation, wherein the process is optionally combined with photolithographic patterning. 56. The method of any one of claims 1 to 55, wherein the sacrificial material is removed by etching and/or dissolving. 57. The method of claim 56, wherein the sacrificial layer comprises nickel and the nickel is removed from the substrate using a mixture of HCl and _FeCl3 in solution. 58. The method of claim 56, wherein the sacrificial layer comprises _SiO2 , and the _SiO2 is removed from the substrate using HF. 59. The method of claim 56, wherein the sacrificial layer comprises an adhesive polymer, and the adhesive polymer is removed using tetramethylammonium hydroxide (TMAH). 60. The method of claim 56, wherein the sacrificial layer comprises a water-soluble polymer, and the water-soluble polymer is removed with water. 61. The method of any one of claims 1 to 60, wherein the conductive or semiconductive material comprises a metal or metal alloy, a metal oxide or nitride, a conductive polymer, a semiconductor and/or graphene. 62. The method of claim 61, wherein the conductive or semiconductive material comprises a metal or a metal alloy. 63. The method of claim 62, wherein the conductive or semiconductive material comprises a metal selected from the group consisting of gold, platinum, iridium, chromium, tungsten, tantalum, tin, nickel, titanium, copper, rhodium, rhenium, silver, stainless steel, palladium, aluminum, zirconium, conductive oxides or nitrides thereof, and alloys thereof. 64. The method of claim 62, wherein the conductive or semiconductive material comprises titanium nitride or a platinum-iridium alloy. 65. The method of claim 62, wherein the conductive or semiconductive material comprises gold. 66. The method of any one of claims 1 to 65, wherein the conductive or semiconductive material forms a single electrode. 67. A method according to any one of claims 1 to 65, wherein the conductive or semiconductive material is patterned to form a plurality of electrodes. 68. The method of claim 67, wherein the conductive or semiconductive material forms a plurality of electrodes that are electrically isolated from each other and/or independently addressable. 69. The method of any one of claims 1 to 68, wherein the layer of conductive or semiconductive material forms at least about 10 electrodes. 70. The method of any one of claims 1 to 69, wherein the layer of conductive or semiconductive material has a thickness in the range of about 20 nm to about 1 μm. 71. The method of any one of claims 69 to 70, wherein the layer of conductive or semiconductive material forms a plurality of electrodes having an electrode number density less than or equal to 10 ^{<-1 >} electrodes/micrometer ^<2> . 72. The method of any one of claims 1 to 71, wherein the layer of conductive or semiconductive material forms an electrode having an average length in the range of about 1 mm up to about 20 mm. 73. The method of any one of claims 1 to 72, wherein the layer of conductive or semiconductive material forms an electrode having an average width in the range of about 100 nm up to about 100 μm. 74. A method according to any one of claims 1 to 72, wherein the layer of conductive or semiconductive material forms features separated by a minimum distance that is at or below 30 microns, or at or below 20 microns, or at or below 10 microns, or at or below 5 microns, or at or below 2 microns, or less. 75. A method according to any one of claims 1 to 74, wherein the conductive or semiconductive material comprises an adhesion layer. 76. The method of claim 75, wherein the conductive or semiconductive material comprises an adhesion layer comprising a material selected from the group consisting of: aluminum, aluminum oxide, tungsten, niobium, chromium, and titanium. 77. The method of claim 76, wherein the adhesion layer comprises aluminum, titanium, or chromium. 78. The method of any one of claims 1 to 77, wherein the conductive or semiconductive material and/or the adhesion layer is deposited by an additive semiconductor fabrication process. 79. The method of claim 78, wherein the additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), and wherein the additive semiconductor fabrication process is optionally combined with photolithographic patterning. 80. A method according to any one of claims 1 to 79, wherein the polymer material is treated with an inert gas plasma prior to deposition of the conductive or semiconductive material. 81. The method of claim 80, wherein the inert gas plasma comprises argon or nitrogen plasma. 82. The method of any one of claims 1 to 81, wherein one or more of the connection pads are subjected to a bumping procedure to form metal bumps on the pads. 83. The method of claim 82, wherein the bump formation procedure comprises electroplating or metal deposition. 84. The method of any one of claims 82 to 83, wherein the bump comprises a metal selected from the group consisting of solder, Au, Ir, In, and Cu. 85. The method of any one of claims 1 to 84, wherein the active or passive electronic components comprise active or passive electronic components selected from the group consisting of: amplifiers, preamplifiers, multiplexers, analog-to-digital converters (ADCs), digital-to-analog converters (DACs), power management circuits, microcontrollers, and wireless data transmission modules. 86. A method according to any one of claims 1 to 85, wherein the active or passive electronic components contain I/O pads on the neural probe and corresponding contacts on the electronic device, and the I/O pads and corresponding contact pads will have the same pitch size of 2 mm or less. 87. A method according to any one of claims 1 to 86, wherein the active or passive electronic component contains I/O pads on the neural probe and corresponding contacts on the electronic device, and the I/O pads and corresponding contact pads will have at least about 10 connections. 88. The method of any one of claims 1 to 87, wherein the method comprises treating the neural probe to temporarily increase probe stiffness during insertion into a tissue or organ. 89. The method of claim 88, wherein the treating comprises coating the neural probe with a bioabsorbable hardening agent. 90. The method of claim 89, wherein the bioabsorbable sclerosing agent comprises a material selected from the group consisting of dextran, glucose, polyethylene glycol (PEG), and gelatin. 91. The method of claim 89, wherein the treating comprises freezing the neural probe. 92. The method of any one of claims 1 to 91, wherein the method comprises sterilizing the neural probe. 93. The method of claim 92, wherein the sterilization comprises a method selected from the group consisting of: by exposure to radiation, chemical sterilization, and autoclaving. 94. The method of claim 93, wherein the method comprises exposure to ethylene oxide. 95. A flexible neural probe made by the method according to any one of claims 1 to 94. 96. A kit comprising a container housing the flexible neural probe according to claim 95. 97. The kit of claim 96, wherein the kit includes instructional materials teaching the use of the neural probe.