Methods to connect free-standing soft neural probes to active electronic devices with high channel count interface

Abstract

Methods of fabricating soft probes, such as soft neural probes are provided. The fabrication methods entail fabrication of soft probes, such as free-standing soft neural probes, on a fabrication substrate and methods of releasing the fabricated neural probes from the substrate without damage. The methods may involve deposition of alternating layers of insulating flexible polymer, such as an elastomer, and conductive or semiconductive material.

Description

METHODS TO CONNECT FREE-STANDING SOFT NEURAL PROBES TO ACTIVE ELECTRONIC DEVICES WITH HIGH CHANNEL COUNT INTERFACECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] A PCT Request Form is filed concurrently with this specification as part of the present application. Each application that the present application claims benefit of or priority to as identified in the concurrently filed PCT Request Form is incorporated by reference herein in their entireties and for all purposes.BACKGROUND

[0002] Implantable neural probes (e.g., electrodes or electrode arrays) that are capable of recording electrophysiological signals and / or stimulating activity in the brain have found wide application in basic biology, neurological disease diagnostics, and treatment. For example, stereotactic electroencephalograph (sEEG) electrodes are widely used for detecting epilepsy origination regions in the brain and Deep Brain Stimulation (DBS) electrodes are used to treat, inter alia, Parkinson’s Disease, pain, and Essential Tremors. These implantable neural probes, however, are usually fabricated from relatively rigid materials like metal, silicon, or plastics. The mismatch in mechanical properties (e.g., stiffness) between the soft brain tissue and stiffer probe material often causes damage in the targeted brain region and such damage is usually accompanied by an inflammatory response and often the formation of fibroses, and / or tissue necrosis.

[0003] With developments in material science and advanced manufacturing techniques, soft brain probes have been developed that can record from and / or stimulate brain tissue, just like their traditional hard material counterparts. The softness and flexibility of such brain probes ensures a better interface with the brain tissue, with less inflammatory response, and therefore these soft probes have garnered significant interest for bio-medical applications, especially those contingent on chronic, or long-term, neural experiments. However, most commercial electronic devices, comprising one or more integrated circuits (ICs) arranged on a printed circuit board (PCB), are made with hard materials, and there is an existing challenge in connecting the soft brain probes to the rigid backend electronics. Moreover, the desire for minimally invasive surgery and high-bandwidth recording / stimulation of brain activity requires that the connection between the soft neuralprobe and the back-end electronics occupies a small footprint that engages a large number of electrical contacts. These considerations make the connection problem even more challenging.

[0004] The background description provided herein is for the purposes 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.SUMMARY

[0005] Methods of fabricating soft probes, such as soft neural probes, are provided. The fabrication methods entail fabrication of soft probes, such as free-standing soft neural probes, on a fabrication substrate and methods of releasing the fabricated neural probes from the substrate without damage. The methods may involve deposition of alternating layers of insulating flexible polymer, such as an elastomer, and conductive or semiconductive material. This method allows for the seamless integration of soft neural probes which causes less damage in the brain and hard electronics which provide superior signal processing power.

[0006] Various embodiments provided herein may include, but need not be limited to, one or more of the following:

[0007] Embodiment 1 : A method of preparing a free-standing soft neural probe electrically connected to an active electronic device, said method comprising:

[0008] a) providing a fabrication substrate 103 comprising a fabrication material 102 and a fracture zone 105;

[0009] b) depositing a layer of sacrificial material 104 over a portion of said fabrication substrate;

[0010] c) depositing an insulating flexible polymer layer 106a over said sacrificial layer material and over a portion of said fabrication substrate 103;

[0011] d) depositing a layer of conductive or semiconductive material 108a on said polymer layer 106 and said fabrication substrate 103 where:

[0012] said conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes;

[0013] each of said one or more electrodes is disposed over at least a portion of said sacrificial layer material and a region of said fabrication substrate that is not coveredwith said sacrificial layer material; and

[0014] said conductive or semiconductive material forms one or more connection pads 110 on a region of said fabrication substrate that is not coated with said sacrificial layer and said one electrode or plurality of electrodes is each electrically coupled to at least one of said connection pads;

[0015] e) optionally repeating steps (c) and (d) to added alternating layers of polymer and conductive or semiconductive material 108 where said polymer reveals at least a portion of said connection pad(s) 110 and insulates said electrode(s) 108 and said connection pads 110 from subsequently applied conductive or semiconductive material layer(s); and

[0016] f) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material where said final layer reveals at least a portion of said connection pad(s) 110; thereby forming a soft neural probe comprising one or more electrodes disposed between layers of said polymer and disposed on said fabrication substrate.

[0017] Embodiment 2: The method of embodiment 1 further comprising:

[0018] providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components 118;

[0019] bonding said substrate 107 to said fabrication substrate 103;

[0020] wire bonding each of said one or more connection pads 110 to one or more of said contact pads 114 to form wire bond(s) 120 between said connection pads 110 and said contact pads 114;

[0021] removing the sacrificial layer material 104; and

[0022] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components.

[0023] Embodiment 3: The method of embodiment 1 further comprising:

[0024] providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where each of said one or more contact pads 114 is electrically coupled to said one or more active or passive electronic components;

[0025] flip chip bonding each of said one or more connection pads 110 to one or moreof said contact pads 114 to form flip chip bond(s) 122 between said connection pads 110 and said contact pads 114;

[0026] removing the sacrificial layer material 104; and

[0027] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components.

[0028] Embodiment 4: The method of embodiment 3, further comprising bonding said substrate 107 to said fabrication substrate 103.

[0029] Embodiment 5: The method according to any one of embodiments 3-4, further comprising adding a fill to the flip-chip bonding pad region to enforce bonding between substrate 103 and 107.

[0030] Embodiment 6: The method of embodiment 1 further comprising:

[0031] providing one or more active or passive electronic components 118 bearing one or more contact pads 114, where each of said one or more contact pads 114 is electrically coupled to said one or more active or passive electronic components 118;

[0032] flip chip bonding each of said one or more connection pads 110 to one or more of said contact pads 114 to form flip chip bond(s) 122 between said connection pads 110 and said contact pads 114;

[0033] removing the sacrificial layer material 104; and

[0034] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components.

[0035] Embodiment 7 : The method of embodiment 6, further comprising bonding said one or more active or passive electronic components 118 to said fabrication substrate 103.

[0036] Embodiment 8: The method according to any one of embodiments 6-7, further comprising adding a fill to the flip-chip bonding pad region to enforce bonding said one or more active or passive electronic components 118 and said fabrication substrate 103.

[0037] Embodiment 9: The method of embodiment 1 further comprising:

[0038] providing said fabrication substrate with a through-hole 112 at each of said connection pads 110;

[0039] providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where each of said one or more contact pads 114 is electrically coupled to said one or more active orpassive electronic components;

[0040] juxtaposing said substrate 107 to said fabrication substrate 103;

[0041] depositing a conductor into each of said through-holes 110 to form an electrical connection 124 between said connection pads 110 and said contact pads 114;

[0042] removing the sacrificial layer material 104; and

[0043] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components 118.

[0044] Embodiment 10: The method of embodiment 9, further comprising bonding said substrate 107 to said fabrication substrate 103.

[0045] Embodiment 11: The method of embodiment 1 further comprising:

[0046] providing said fabrication substrate with a through-hole 112 at each of said connection pads 110;

[0047] providing one or more active or passive electronic components 118 bearing one or more contact pads 114, where each of said one or more contact pads 114 is electrically coupled to said one or more active or passive electronic components 118;

[0048] juxtaposing said one or more active or passive electronic components 118 to said fabrication substrate 103;

[0049] depositing a conductor into each of said through-holes 110 to form an electrical connection 124 between said connection pads 110 and said contact pads 114;

[0050] removing the sacrificial layer material 104; and

[0051] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components 118.

[0052] Embodiment 12: The method of embodiment 11, further comprising bonding said one or more active or passive electronic components 118 to said fabrication substrate 103.

[0053] Embodiment 13: The method according to any one of embodiments 1-12, wherein the sacrificial layer is omitted and a pick up tool is used to peel the soft neural probe from the fabrication substrate.

[0054] Embodiment 14: A method of preparing a free-standing soft neural probe electrically connected to an active electronic device, said method comprising:

[0055] a) providing a fabrication substrate 103 comprising a first region comprising a fabrication material 102 and a second region comprising a sacrificial material 104;

[0056] b) depositing an insulating flexible polymer layer 106a on said substrate where said polymer layer is disposed over at least a portion of said first region and over at least a portion of said second region;

[0057] c) depositing a conductive or semiconductive material 108a on said polymer layer 106 and said fabrication substrate 103 where:

[0058] said conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes;

[0059] each of said one or more electrodes is disposed over at least a portion of said sacrificial layer material and a region of said fabrication substrate that is not covered with said sacrificial layer material; and

[0060] said conductive or semiconductive material forms one or more connection pads 110 on a region of said fabrication substrate that is not coated with said sacrificial layer and said one electrode or plurality of electrodes is each electrically coupled to at least one of said connection pads;

[0061] d) optionally repeating steps (b) and (c) to added alternating layers of polymer and conductive or semiconductive material 108 where said polymer reveals at least a portion of said connection pad(s) 110 and insulates said electrode(s) 108 and said connection pads 110 from subsequently applied conductive or semiconductive material layer(s); and

[0062] e) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material where said final layer reveals at least a portion of said connection pad(s) 110;

[0063] thereby forming a soft neural probe comprising one or more electrodes disposed between layers of said polymer and disposed on said fabrication substrate.

[0064] Embodiment 15: The method of embodiment 14 further comprising:

[0065] providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components;

[0066] bonding said substrate 107 to said fabrication substrate 103;

[0067] wire bonding each of said one or more connection pads 110 to one or more of said contact pads 114 to form wire bond(s) 120 between said connection pads 110 and said contact pads 114;

[0068] removing the sacrificial layer material 104 comprising the second region of saidfabrication substrate 103; and

[0069] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components.

[0070] Embodiment 16: The method of embodiment 14 further comprising:

[0071] providing one or more active or passive electronic components 118 bearing one or more contact pads 114, where each of said one or more contact pads 114 is electrically coupled to said one or more active or passive electronic components 118;

[0072] bonding said one or more active or passive electronic components 118 to said fabrication substrate 103;

[0073] wire bonding each of said one or more connection pads 110 to one or more of said contact pads 114 to form wire bond(s) 120 between said connection pads 110 and said contact pads 114;

[0074] removing the sacrificial layer material 104 comprising the second region of said fabrication substrate 103; and

[0075] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components.

[0076] Embodiment 17: The method of embodiment 14 further comprising:

[0077] providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where each of said one or more contact pads 114 is electrically coupled to said one or more active or passive electronic components;

[0078] flip chip bonding each of said one or more connection pads 110 to one or more of said contact pads 114 to form flip chip bond(s) 122 between said connection pads 110 and said contact pads 114;

[0079] removing the sacrificial layer material 104 comprising the second region of said fabrication substrate 103; and

[0080] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components.

[0081] Embodiment 18: The method of embodiment 17, further comprising bonding said substrate 107 to said fabrication substrate 103.

[0082] Embodiment 19: The method of embodiment 14 further comprising:

[0083] providing one or more active or passive electronic components 118 bearing one or more contact pads 114, where each of said one or more contact pads 114 is electrically coupled to said one or more active or passive electronic components 118;

[0084] flip chip bonding each of said one or more connection pads 110 to one or more of said contact pads 114 to form flip chip bond(s) 122 between said connection pads 110 and said contact pads 114;

[0085] removing the sacrificial layer material 104 comprising the second region of said fabrication substrate 103; and

[0086] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components 118.

[0087] Embodiment 20: The method of embodiment 19, further comprising bonding said one or more active or passive electronic components 118 to said fabrication substrate 103.

[0088] Embodiment 21: The method of embodiment 14 further comprising:

[0089] providing said fabrication substrate with a through-hole 110 at each of said connection pads 110;

[0090] providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where each of said one or more contact pads 114 is electrically coupled to said one or more active or passive electronic components;

[0091] bonding said substrate 107 to said fabrication substrate 103;

[0092] depositing a conductor into each of said through-holes 110 to form an electrical connection 124 between said connection pads 110 and said contact pads 114;

[0093] removing the sacrificial layer material 104 comprising the second region of said fabrication substrate 103; and

[0094] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components 118.

[0095] Embodiment 22: The method of embodiment 14 further comprising:

[0096] providing said fabrication substrate with a through-hole 110 at each of said connection pads 110;

[0097] providing one or more active or passive electronic components 118 bearing one or more contact pads 114, where each of said one or more contact pads 114 is electricallycoupled to said one or more active or passive electronic components 118;

[0098] bonding said one or more active or passive electronic components 118 to said fabrication substrate 103;

[0099] depositing a conductor into each of said through-holes 110 to form an electrical connection 124 between said connection pads 110 and said contact pads 114;

[0100] removing the sacrificial layer material 104 comprising the second region of said fabrication substrate 103; and

[0101] fracturing said fabrication substrate 103 at said fracture zone 105 to provide said free-standing soft neural probe electrically connected to said one or more active or passive electronic components 118.

[0102] Embodiment 23: A method of preparing a free-standing soft neural probe electrically connected to an active electronic device, said method comprising:

[0103] a) providing a fabrication substrate 103 where said fabrication substrate comprises an integrated circuit 502 and one or more connection pads 110, where said connection pad(s) 110 are electrically connected to at least one circuit element 504 comprising said integrated circuit;

[0104] b) depositing a layer of sacrificial material 104 over a portion of said fabrication substrate;

[0105] c) depositing an insulating flexible polymer layer 106a over said sacrificial layer material and over at least a portion of said fabrication substrate 103;

[0106] d) depositing a layer of conductive or semiconductive material 108 on said polymer layer 106 and said fabrication substrate 103 where:

[0107] said conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes 108a;

[0108] each of said one or more electrodes is disposed over at least a portion of said sacrificial layer material and a region of said fabrication substrate that is not covered with said sacrificial layer material; and

[0109] said conductive or semiconductive material forms an electrical connection with one or more of said connection pads 110;

[0110] e) optionally repeating steps (c) and (d) to added alternating layers of polymer and conductive or semiconductive material 108 where said polymer reveals at least a portion of said connection pad(s) 110 and insulates said electrode(s) 108 and said connection pads 110 from subsequently applied conductive or semiconductive material layer(s); and

[0111] f) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material where said final layer reveals at least a portion of said connection pad(s) 110; thereby forming a soft neural probe comprising one or more electrodes disposed between layers of said polymer and disposed on said fabrication substrate.

[0112] Embodiment 24: The method of embodiment 23, wherein a circuit element comprising said integrated circuit comprises an element selected from the group consisting of an amplifier, a preamplifier, a multiplexer, an analog-to-digital converter (ADC), a digital-to-analog converter (DAC), power management circuit, a microcontroller, an impedance matching circuit, an interconnect, a signal splitter, and a wireless data transmission module.

[0113] Embodiment 25: The method according to any one of embodiments 23-24, wherein said method comprises removing said sacrificial material 104 thereby freeing terminal region(s) of said electrodes from the fabrication substrate.

[0114] Embodiment 26: The method according to any one of embodiments 23-25, wherein said fabrication substrate 103 comprises a fracture zone 105.

[0115] Embodiment 27: The method of embodiment 26, wherein said method comprises fracturing said fabrication substrate at the fracture zone 105.

[0116] Embodiment 28: The method according to any one of embodiments 23-27, wherein said integrated circuit comprises output pads, leads, or pins 508.

[0117] Embodiment 29: The method according to any one of embodiments 23-28, wherein said integrated circuit is disposed on a support.

[0118] Embodiment 30: The method of embodiment 29, wherein said support comprises a circuit board (e.g., a printed circuit board (PCB).

[0119] Embodiment 31 : The method according to any one of embodiments 29-30, wherein said support comprises output pads, leads, or pins 510.

[0120] Embodiment 32: The method according to any one of embodiments 1-31, wherein:

[0121] a plurality of neural probes are fabricated on a single fabrication substrate 103; and

[0122] said substrate is diced into smaller pieces each with one or multiple neural probes on each piece.

[0123] Embodiment 33: The method according to any one of embodiments 1-32, wherein said polymer comprises a material selected from the group consisting of afluorinated elastomer, polyimide, polydimethylsiloxane (PDMS), parylene-C, and epoxy resin (e.g., SU-8).

[0124] Embodiment 34: The method according to any one of embodiments 1-33, wherein said layer(s) of polymer 106 comprise a fluorinated elastomer.

[0125] Embodiment 35 : The method of embodiment 34, wherein said fluorinated elastomer is a fluorinated elastomer that is not perfluorinated.

[0126] Embodiment 36: The method of embodiment 35, wherein said fluorinated elastomer is partially fluorinated.

[0127] Embodiment 37: The method of embodiment 36, wherein:

[0128] said fluorinated 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; and / or

[0129] said 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

[0130] said fluorinated elastomer is greater than or equal to 25% fluorinated and less than 100% fluorinated.

[0131] Embodiment 38: The method of embodiment 37, wherein said fluorinated elastomer is selected from the group consisting of poly(l,l,l,3,3,3-hexafluoroisopropyl acrylate) (PHFIPA), and / or poly [2-(perfluorohexyl)ethyl] acrylate.

[0132] Embodiment 39: The method of embodiment 35, wherein said fluorinated elastomer is a perfluorinated elastomer.

[0133] Embodiment 40: The method of embodiment 39, wherein said perfluorinated elastomer is selected from the group consisting of perfluoropoly ether (PFPE), polytetrafluoroethylene (PTFE), perfluoropoly ether dimethylacrylate (PFPE-DMA), fluorinated ethylene -propylene (FEP), perfluoroalkoxy polymer (PF A), poly chloro trifluoroethylene (PCTFE) .

[0134] Embodiment 41: The method of embodiment 39, wherein said perfluorinated elastomer comprises a perfluoropolyether.

[0135] Embodiment 42: The method of embodiment 41, wherein the perfluoropolyether has a weight- average molecular weight above 8 kDa.

[0136] Embodiment 43: The method of embodiment 42, wherein, wherein the perfluoropolyether has a weight- average molecular weight above 20 kDa.

[0137] Embodiment 44: The method according to any one of embodiments 41-43, wherein said perfluorinated elastomer is a copolymer.

[0138] Embodiment 45 : The method of embodiment 44, wherein said perfluorinatedelastomer is tetrafluoroethylene propylene (TFE).

[0139] Embodiment 46: The method of embodiment 39, said perfluorinated elastomer comprises perfluoropoly ether (PFPE).

[0140] Embodiment 47: The method according to any one of embodiments 1-46, wherein said layer(s) of elastomer range in thickness from about to about 0.5 pm to 5 pm.

[0141] Embodiment 48: The method according to any one of embodiments 1-47, wherein one or more of said layers of elastomer material 106 are patterned to provide open regions to provide contact with a tissue at one or more discrete locations along the surface of one or more electrodes formed by the conductive or semiconductive material 108.

[0142] Embodiment 49: The method according to any one of embodiments 1-48, wherein one or more of said layers of polymer material 106 are patterned to encapsulate one or more electrodes formed by said conducive or semiconductive material 108 to provide one or more capacitive electrodes.

[0143] Embodiment 50: The method according to any one of embodiments 1-49, wherein said layers of elastomer material 108 are deposited by an additive semiconductor fabrication process.

[0144] Embodiment 51: The method of embodiment 50, wherein said additive semiconductor fabrication process is selected from the group consisting of spincoating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), wherein said process is optionally combined with photolithographic patterning.

[0145] Embodiment 52: The method according to any one of embodiments 1-49, wherein said sacrificial material 104 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 (e.g., OmniCoat).

[0146] Embodiment 53: The method of embodiment 52, wherein said sacrificial material comprises a water soluble polymer selected from the group consisting of poly(acrylic acid), dextran, poly(methacrylic acid), poly (acrylamide), poly(ethylene imine), poly(vinyl alcohol), poly(ethylene oxide), chitosan, and sucrose.

[0147] Embodiment 54: The method according to any one of embodiments 1-53, wherein said sacrificial material 104 is deposited by an additive semiconductor fabrication process.

[0148] Embodiment 55: The method of embodiment 54, wherein said additivesemiconductor fabrication process is selected from the group consisting of spincoating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), thermal oxidation, wherein said process is optionally combined with photolithographic patterning.

[0149] Embodiment 56: The method according to any one of embodiments 1-55, wherein said sacrificial material is removed by etching and / or dissolution.

[0150] 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 HC1 and FeCh in solution.

[0151] Embodiment 58: The method of embodiment 56, wherein the sacrificial layer comprises SiCT. and the SiCT is removed from the substrate with HF.

[0152] 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).

[0153] 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.

[0154] Embodiment 61: The method according to any one of embodiments 1-60, wherein said conductive or semiconductive material 108 comprises a metal or metal alloy, a metal oxide or nitride, a conductive polymer, a semiconductor, and / or graphene.

[0155] Embodiment 62: The method of embodiment 61, wherein said conductive or semiconductive material 108 comprises a metal or metal alloy.

[0156] Embodiment 63: The method of embodiment 62, wherein said 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, conducting oxides or nitrides thereof, and alloys thereof.

[0157] Embodiment 64: The method of embodiment 62, wherein said conductive or semiconductive material 108 comprises titanium nitride or platinum-iridium alloy.

[0158] Embodiment 65: The method of embodiment 62, wherein said conductive or semiconductive material 108 comprises gold.

[0159] Embodiment 66: The method according to any one of embodiments 1-63, wherein said conductive or semiconductive material 108 forms a single electrode.

[0160] Embodiment 67: The method according to any one of embodiments 1-63, wherein said conductive or semiconductive material 108 is patterned to form a pluralityof electrodes.

[0161] Embodiment 68: The method of embodiment 67, wherein said conductive or semiconductive material 108 forms a plurality of electrodes that are electrically isolated from each other and / or that are independently addressable.

[0162] Embodiment 69: The method according to any one of embodiments 1-68, wherein said layers of conductive or semiconductor material 108 form 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.

[0163] Embodiment 70: The method according to any one of embodiments 1-69, wherein said layer(s) of conductive or semiconductor material 108 range in thickness from about to about 20 nm to 1 pm.

[0164] Embodiment 71: The method according to any one of embodiments 69-70, wherein the layers of conductive or semiconductive material 108 form a plurality of electrodes having an electrode number density of greater than or equal to 10"5electrodes / micron2, greater than or equal to 10"4electrodes / micron2, greater than or equal to 10"3electrodes / micron2, greater than or equal to 10"2electrodes / micron2, greater than or equal to 101electrodes / micron2, or greater, and / or less than or equal to 101electrodes / micron2, less than or equal to 100 electrodes / micron2, less than or equal to 101electrodes / micron2, or less.

[0165] Embodiment 72: The method according to any one of embodiments 1-71, wherein said layer(s) of conductive or semiconductor material 108 form electrodes having an average length that ranges from about 1mm up to about 20 mm.

[0166] Embodiment 73: The method according to any one of embodiments 1-72, wherein said layer(s) of conductive or semiconductor material 108 form electrodes having an average width that ranges from about 100 nm up to about 100 pm.

[0167] Embodiment 74: The method according to any one of embodiments 1-72, wherein said layer(s) of conductive or semiconductor material 108 form features (e.g., electrodes) that are separated by a minimal distance at or below 30 micrometers, or at or below 20 micrometers, or at or below 10 micrometers, or at or below 5 micrometers, or at or below 2 micrometers, or below.

[0168] Embodiment 75: The method according to any one of embodiments 1-74, wherein said conductive or semiconductive material 108, comprises an adhesion layer.

[0169] Embodiment 76: The method of embodiment 75, wherein said conductive orsemiconductive material 108 comprises an adhesion layer comprising a material selected from the group consisting of aluminum, aluminum oxide, tungsten, niobium, chrome, titanium.

[0170] Embodiment 77: The method of embodiment 76, wherein the adhesion layer comprises aluminum, titanium, chromium.

[0171] Embodiment 78: The method according to any one of embodiments 1-77, wherein said conductive or semiconductive material 108 and / or said adhesion layer is deposited by an additive semiconductor fabrication process.

[0172] Embodiment 79: The method of embodiment 77, wherein said additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), wherein said process is optionally combined with photolithographic patterning.

[0173] Embodiment 80: The method according to any one of embodiments 1-79, wherein said polymer material 106 is treated with an inert gas plasma before deposition of said conductive or semiconductive material 108.

[0174] Embodiment 81 : The method of embodiment 80, wherein said inert gas plasma comprises an argon or nitrogen plasma.

[0175] Embodiment 82: The method according to any one of embodiments 1-81, wherein one or more of said connection pads 110 are treated to a bumping procedure to form metal bumps on said pads.

[0176] Embodiment 83: The method of embodiment 82, wherein said bumping procedure comprises electroplating or metal deposition.

[0177] Embodiment 84: The method according to any one of embodiments 82-83, wherein said bumps comprises a metal selected from the group consisting of solder, Au, and Ir, In, Cu.

[0178] Embodiment 85: The method according to any one of embodiments 1-84, wherein said active or passive electronic component(s) 118 comprise an active or passive electronic component selected from the group consisting of an amplifier, a preamplifier, a multiplexer, an analog-to-digital converter (ADC), a digital-to-analog converter (DAC), power management circuit, micro-controller, and wireless data transmission module.

[0179] Embodiment 86: The method according to any one of claims 1-85, wherein said active or passive electronic component(s) contains I / O pads on the neural probes and corresponding contact on the electronics, the I / Os and corresponding contacts pads willhave a same pitch size of, or below, 2 millimeters, or of, or below, 1 millimeters, or of, or below, 500 micrometers, or of, or below, 200 micrometers, or of, or below, 100 micrometers, or of, or below, 50 micrometers, or of, or below, 20 micrometers, or of, or below, 10 micrometers, or of, or below, 5 micrometers, or of, or below, 2 micrometers.

[0180] Embodiment 87: The method according to any one of claims 1-86, wherein said active or passive electronic component(s) contains I / O pads on the neural probes and corresponding contact on the electonics , the I / Os and corresponding contacts pads will have 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 connections.

[0181] Embodiment 88: The method according to any one of embodiments 1-87, wherein said method comprises treating the neural probe to temporarily increase probe stiffness during insertion into a tissue or organ.

[0182] Embodiment 89: The method of embodiment 88, wherein said treating comprises coating said neural probe with a bioabsorbable stiffening agent.

[0183] Embodiment 90: The method of embodiment 89, wherein said stiffening agent comprises a material selected from the group consisting of dextran, glucose, polyethylene glycol (PEG), gelatin.

[0184] Embodiment 91: The method of embodiment 88, wherein said treating wherein said treating comprises freezing said neural probe.

[0185] Embodiment 92: The method according to any one of embodiments 1-89, wherein said method comprises sterilizing said neural probe.

[0186] Embodiment 93: The method of embodiment 90, wherein said 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.

[0187] Embodiment 94: The method of embodiment 93, wherein said method comprises exposure to ethylene oxide.

[0188] Embodiment 95 : A flexible neural probe made by a method according to any one of embodiments 1 -94.

[0189] Embodiment 96: A kit comprising a container containing a flexible neural probe of embodiment 95.

[0190] Embodiment 97: The kit of embodiment 96, wherein said kit comprises instructional materials teaching the use of said neural probe.Definitions

[0191] As used herein, the term “about” is understood to account for minor increases and / or decreases beyond a recited value, which changes do not significantly impact the desired function of the parameter beyond the recited value(s). In some cases, “about” encompasses + / -10% of any recited value. As used herein, this term modifies any recited value, range of values, or endpoints of one or more ranges.

[0192] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0193] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than 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 open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0194] 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” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0195] As used herein in the specification and in the claims, the phrase “at least one,” in reference 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 and every element specifically listed within thelist of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a nonlimiting 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”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, 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); etc.

[0196] 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.

[0197] In the claims, as well as in the specification above, 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 the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0198] The term “free-standing” refers to the property of an object that does not have the support of an substrate, and can be manipulated and deformed freely within the media it resides in (e.g air, water).

[0199] The term “flexible” refers to the physical property of a material being able to be bent without breaking at certain dimensions, it does not imply about the Young’s modulus of the material and stretchability.

[0200] The term “soft” refers to the physical property of a material that deforms or yields readily to pressure or weight. These materials usually have a Young’s modulus of less than 1G Pa and can be stretched up to 5% without breaking.

[0201] The term "probe" refers to a structure comprising one or a plurality of electrodes configured delivering a signal to or receiving a signal from a biological tissue,e.g., the brain or other neurological tissue, the heart or other organs.

[0202] The term “neural probe” refers to a structure comprising one or a plurality of electrodes configured delivering a signal to or receiving a signal from the brain or other neurological tissue such as in the peripheral nervous system. In various embodiments the neural probe comprises one or a plurality of flexible electrodes, e.g., microelectrodes, deposited on or in one or more flexible polymer layer(s).

[0203] An "electrode" refers to a conductive element configured to conduct charge from a first point to a second point. In various embodiments an electrode can comprise one or more "tip(s)" or “contact area(s)", a conductor region, and a terminal region. In certain embodiments the tip(s) are configured for contact with a tissue, e.g., brain or other neural tissue, while the contact areas are configured to facilitate electrical connection to one or more electrical components.

[0204] A "fracture zone" in, for example, a fabrication substrate, refers to a region of the substrate that has been treated so that under mechanical or chemical stress the substrate preferentially fractures at the location of the fracture zone. 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 a mechanical stress, e.g., bending or pulling. In certain embodiments the fracture zone comprises a region of the substrate that is chemically treated or fabricated from a different material, e.g., a sacrificial material, so when chemically treated, e.g., with a solvent or etchant, the substrate preferentially fractures at that location. In certain embodiments, the fracture zone is materially the same as the rest of the fabrication substrate but is positioned relative to the deposited neural probe to facilitate cutting of the substrate at that region.

[0205] The term “flexible polymer”, or “polymer”, refers to any polymeric material that can be bent without breaking down and can resume to its original shape after the deformation. This flexible polymer material can be an inherently elastomer, namely a natural or synthetic polymer that is able to resume its original shape when a large deformation is applied. In certain embodiments an elastomeric polymer refers to a polymer or copolymer that, free of diluents, retracts to less than 1.5 times its original length within one minute after being stretched at room temperature to twice its original length and held for one minute before release. This flexible polymer can also be a plastic material or resin material, that in the bulk form factor is hard and brittle, but then made into thin films with a thickness less than 10 pm, it can be bent without breaking.

[0206] A “fluoropolymer” is a fluorocarbon-based polymer with multiple carbonfluorine bonds. Illustrative fluoropolymers include, but are not limited to PVF (polyvinylfluoride), PVDF (polyvinylidene fluoride), PTFE (polytetrafluoroethylene), PCTFE (polychlorotrifluoroethylene), PFA, MFA (perfluoroalkoxy polymer), FEP (fluorinated ethylene -propylene), ETFE (polyethylenetetrafluoroethylene), ECTFE (polyethylenechlorotrifluoroethylene), FFPM / FFKM (Perfluorinated Elastomer [Perfluoroelastomer]), FPM / FKM (Fluoroelastomer [Vinylidene Fluoride based copolymers]), FEPM (Fluoroelastomer [Tetrafluoroethylene-Propylene]), PFPE (Perfluoropoly ether), PFSA (Perfluorosulfonic acid), and the like.

[0207] A perfluoropolymer is a polymer derived from another by replacing all (or most) of the hydrogen atoms by those of fluorine. Typically, a perfluoropolymer is a polymer wherein the carbon atoms within all or a portion of the polymer are only bound to fluorine and / or other heteroatoms, rather than hydrogen. A perflurorelastomer is an elastomer where the carbon atoms within all or a portion of the elastomer are only bound to fluorine and / or other heteroatoms, rather than hydrogen.

[0208] The term “adhesive polymer” as used herein, refers to an organic polymer such as OMNICOAT.

[0209] The term “physiological conditions” as used herein, refers to conditions typical inside the body of a mammal, e.g., conditions simulating those under which the (normal) functions of a cell, organ, or tissue can be expressed. Illustrative physiological conditions can comprise approximately neutral pH (e.g., pH 7.0-7.4), salinity of about 9- 10% e.g., about 0.1 to about 0.2 M NaCl or about 0.15 M NaCl), temperature ranging from about 96 °F to 104°F (~35°C to ~ 40°C) and the like. A typical temperature, for humans is about 37 °C.

[0210] The term “stably bonded” when referring to a multi-layered article e.g., as described herein, indicates that the layers typically do 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 for at least 2 years.

[0211] The terms "subject," "individual," and "patient" may be used interchangeablyand refer to humans, as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0212] A “capacitive electrode” is an insulated electrode that does not make ohmic contact with tissues or body fluids.

[0213] The term "integrated circuit" refers to group of electronic circuits or devices and their connections that are small and are produced in or on a small slice of material e.g., silicon) or in whole a wafer format.

[0214] A "circuit element" or "integrated circuit element" refers to a component of an integrated circuit. The element can be a device comprising the integrated circuit, including but not limited to, a preamplifier, a multiplexer, a voltage regulator, analog to digital converter (ADC), digital to analog converter (DAC), microcontroller, field programmable gate array (FPGA), transceiver, signal conditioner, or memory device, or a connection / interconnect to a device comprising the integrated circuit.

[0215] These and other aspects are described further below with reference to the drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0216] Figure 1A illustrates additive fabrication of soft neural probes on a fabrication substrate with a layer of sacrificial material below the electrode(s) 108a. . . .

[0217] Figures IB- IF illustrate various methods of releasing the flexible electrodes comprising a neural probe and making electrical connections to one or more active or passive electronic components.

[0218] Figure 2A illustrates additive fabrication of soft neural probes on a fabrication substrate 103 where the fabrication substrate itself comprises a region formed by a sacrificial material 104.

[0219] Figure 2B illustrates methods of releasing the flexible electrodes comprising a neural probe and making electrical connections to one or more active or passive electronic components.

[0220] Figure 3 illustrates a cross-section of a neural probe in fabrication according tovarious methods described herein. As illustrated the cross-section provide a fabrication substrate 103, a layer of sacrificial material 104 disposed on top of the fabrication substrate, a layer of flexible polymer 106 various layers of which can be designated 106a, 106b, 106c, etc. a layer of conductive or semiconductive material 108 that can form various layers of electrodes (108a, 108b, 108c, etc.) as illustrated, where the layer of conductive or semiconductive material further comprises a layer of adhesion material 109.

[0221] Figure 4 illustrates one embodiment of a method that involves removal of a sacrificial material 104 followed by fracture of a fabrication substrate 103.

[0222] Figures 5A and 5B illustrate neural probes fabricated on a substrate comprising an integrated circuit. Figure 5A) One neural probe fabricated on an integrated circuit. Figure 5B) Neural probes fabricated on integrated circuits where the integrated circuits are disposed on a support (e.g., a PCB). It will be recognized that in various embodiments, the integrated circuit can not only be a small piece of a wafer, but also a whole silicon wafer.

[0223] Figures 6A and 6B illustrate strategies for using neural probes fabricated in an integrated circuit. Figure 6A) The part of integrated circuit underneath the sacrificial layer does not contain any useful circuit, it is just removed after elimination of the sacrificial layer. Figure 6B) The released neural probe is lifted up (e.g., 90 degrees), so it’s almost perpendicular to the ASIC / PCB from the side view. Then it is flipped upside down the neural probe is inserted on or into the target tissue (e.g. , brain). If the probe is long enough, the ASIC / PCB side can still remain outside of the skull.DETAILED DESCRIPTION

[0224] In the following description, numerous specific details are set forth 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 to not unnecessarily obscure the disclosed embodiments. While the disclosed embodiments will be described in conjunction with the specific embodiments, it will be understood that it is not intended to limit the disclosed embodiments.

[0225] In various embodiments methods are provided for the fabrication of soft neural probes (e.g., electrodes) and interconnection of these soft neural probes with hard electronic components (e.g., PCB boards, IC chips, or a combination of both etc.). These methods ensure the flexibility of the final free-standing neural probe and provide for highdensity electrical connections with hard electronics.

[0226] In general, as explained below, the methods typically involve fabrication of one or a plurality of neural probes (e.g., electrodes) disposed on a fabrication substrate where at least a portion of the probe(s) are also disposed on (or encapsulate within) a highly elastic polymer. Subsequent decoupling or removal of the fabrication substrate under a portion of the probe(s) leaves highly flexible probes electrically connected to one or more connection pads and / or associated electronics. This fabrication method is described in more detail below.

[0227] A high channel count interface can be formed by using advanced fabrication methods like photolithography, or metal deposition to define miniature sized high density electrodes. However, these advanced fabrication methods usually can only be used on hard materials, which is how most of the conventional probes are made, which may cause chronic damage in the brain. The methods described herein facilitate use of advanced fabrication techniques to produce neural probes with soft material, yet still have them connect to hard electronics.Additive fabrication of soft neural probes on a fabrication substrate

[0228] One illustrative, but non-limiting, method of fabricating a substrate with one or a plurality of electrodes is illustrated in Figure 1A. As illustrated therein the method can involve: a) providing a fabrication substrate 103 comprising a fabrication material 102 and a fracture zone 105, there may be through hole vias 112 for electrical connection already embedded in the fabrication substrate; 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 said fabrication substrate 103; d) depositing a layer of conductive or semiconductive material 108 on the polymer layer 106 and said fabrication substrate 103 where:

[0229] The conductive or semiconductive material is patterned to form one electrode 108a or is patterned to form a plurality of electrodes 108a . . . 108n and one or more connection pads 110;

[0230] each of the one or more electrodes is disposed over at least a portion of said sacrificial layer material and a region of said fabrication substrate that is not covered with the sacrificial layer material; and

[0231] the conductive or semiconductive material 108 forms one or more connectionpads 110 on a region of that fabrication substrate that is not coated with the sacrificial layer and the one electrode or plurality of electrodes is each electrically coupled to at least one of the connection pads.

[0232] This provides a fabrication substrate 103 with a first layer comprising one or more electrodes 108 electrically coupled to at least one connection pad 110 where a portion of the electrode(s) is disposed over the sacrificial material 104. In various embodiments the procedure can be repeated one or more times to add alternating layers of polymer 106 and conductive or semiconductive material 108 where the polymer is deposited so that it reveals at least a portion of the connection pad(s) 110 and insulates the electrode(s) 108a. . . and the conductive pads 110a. . . from subsequently applied conductive or semiconductive material layer(s).

[0233] Once the desired number of alternating layers of electrodes 108a. . . and polymer 106 are formed a final layer of polymer material can be applied to encapsulate the top layer of conductive or semiconductive material where final layer reveals at least a portion of said connection pad(s) 110a. . . ; thereby forming a soft neural probe comprising one or more electrodes 108a. . . disposed between layers of said polymer and disposed on said fabrication substrate 103.

[0234] It will be recognized that in certain embodiments, this fabrication procedure can produce a single neural probe (one electrode or an electrode array) disposed on the fabrication substrate, while in certain other embodiments, a plurality of neural probes (each one electrode or electrode array) can be produced on a single substrate which can later be separated from each other as desired.

[0235] The various layers, e.g., sacrificial material 104, conductive or semiconductive material 108, and polymer 106 can be deposited by any convenient method.Release of flexible electrode elements and coupling to electronics

[0236] One method of releasing the flexible neural probe e.g., comprising one or more electrode(s)) and coupling it to electronics or other elements is shown in Figure IB. As shown therein, in certain embodiments, the method can comprise providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components 118; bonding substrate 107 to the fabrication substrate 103; wire bonding each of the one ormore connection pads 110 to one or more of the contact pads 114 to form wire bond(s) 120 between the connection pads 110 and the contact pads 114; removing the sacrificial layer material 104; and fracturing the fabrication substrate 103 at the fracture zone 105 to provide a free-standing soft neural probe 100 (e.g., comprising one or a plurality of electrodes) electrically connected to an electronic device (e.g., to one or more of the active or passive electronic components, e.g., as illustrated in Figure 4.

[0237] Yet another method of releasing the flexible neural probe (comprising, e.g., one or more electrode(s)) and coupling the neural probe (electrode(s)) to electronics or other elements is shown in Figure 1C. As shown therein, in certain embodiments, the method can comprise providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where 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 flip chip bond(s) 122 between the connection pads 110 and said contact pads 114; removing the sacrificial layer material 104; and fracturing the fabrication substrate 103 at the fracture zone 105 to provide a freestanding soft neural probe 100 (e.g., comprising one or a plurality of electrodes) electrically connected to an electronic device e.g., to one or more of the active or passive electronic components). In certain embodiments this method can further comprise bonding the substrate 107 to the fabrication substrate 103. In certain embodiments the method can further comprise adding a fill (e.g., an epoxy resin) to the flip-chip bonding pad region to enforce bonding between substrate 103 and 107.

[0238] In another illustrative, but non-limiting approach, the method can proceed as described above, but instead of flip chip bonding of the neural probe (electrode(s)) to pads on a substrate that also carries one or more electronic components, the flip chip bonding can occur to one or more electronic components directly. This is illustrated in Figure ID. As shown therein, in certain embodiments, the method can comprise providing one or more active or passive electronic components 118 bearing one or more contact pads 114, where 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 flip chip bond(s) 122 between the connection pads 110 and the contact pads 114; removing the sacrificial layer material 104; and fracturing the fabrication substrate 103 at the fracture zone 105 to provide a free-standing soft neural probe 100 (e.g., comprising one or a plurality ofelectrodes) electrically connected to an electronic device {e.g., to one or more of the active or passive electronic components). In certain embodiments this method can further comprise bonding the substrate 107 to the fabrication substrate 103. In certain embodiments the method can further comprise adding a fill to the flip-chip bonding pad region to enforce bonding between substrate 103 and 107.

[0239] Still yet another method of releasing the flexible neural probe (comprising, e.g., one or more electrode(s)) and coupling the neural probe (electrode(s)) to electronics or other elements is shown in Figure IE. As shown therein, in certain embodiments, the method can further comprise providing the fabrication substrate with a through-hole vias 112 at each of the connection pads 110 or, in certain embodiments, as an alternative to the connection pads 110; providing a substrate 107 comprising a support 116 bearing one or more contact pads 114 and one or more active or passive electronic components 118, where 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 to the fabrication substrate 103; depositing a conductor into each of the through-holes 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 electrodes (connection pads 110) and the contact pads 114; removing the sacrificial layer material 104; and fracturing the fabrication substrate 103 at the fracture zone 105 to provide a free-standing soft neural probe 100 {e.g., comprising one or a plurality of electrodes) electrically connected to an electronic device e.g., to one or more of the active or passive electronic components). In certain embodiments the conductor deposited into each of the through holes is 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.

[0240] In another illustrative, but non-limiting approach, the method can proceed as described above, but instead of depositing a conductor into each of the through-holes 110 to form an electrical connection 124 between the connection pads 110 and the contact pads 114, on a substrate that also carries one or more electronic components, the bonding can occur to one or more contact pads that are integrated with one or more electronic components. This is illustrated in Figure IF. As shown therein, in certain embodiments, the method can comprise providing the fabrication substrate with a through-hole via 112 at each of the connection pads 110; providing one or more active or passive electronic components 118 bearing one or more contact pads 114, where each of the one or more contact pads 114 is electrically coupled to the one or more active or passive electroniccomponents 118; juxtaposing the one or more active or passive electronic components 118 to the fabrication substrate 103; depositing a conductor into each of the through-holes 110 to form an electrical connection 124 between the connection pads 110 and the contact pads 114; removing the sacrificial layer material 104; and fracturing the fabrication substrate 103 at the fracture zone 105 to provide a free-standing soft neural probe 100 (e.g., comprising one or a plurality of electrodes) electrically connected to an electronic device e.g., to one or more of the active or passive electronic components).

[0241] In certain embodiments in any of the foregoing methods the sacrificial layer is omitted and a pick up tool can be used to peel the soft neural probe from the fabrication substrate.Additive fabrication of soft neural probes on a "hybrid" fabrication substrate where the substrate comprises a region formed from a sacrificial material

[0242] In certain embodiments in any of the foregoing methods, the sacrificial 104 material deposited on the fabrication substrate 103 can be eliminated and the fabrication substrate itself can be a "hybrid" fabrication substrate that comprises a region formed from the sacrificial material 104. In such instances the fracture zone 105 can be omitted. In such embodiments, removal of the sacrificial material 104 comprising the fabrication substrate e.g., by selective etching or dissolution) effectively releases the neural probe.

[0243] This is illustrated, in Figures 2A and 2B. Thus, for example, in certain embodiments, the method comprises:

[0244] a) providing a fabrication substrate 103 comprising a first region comprising a fabrication material 102 and a second region comprising a sacrificial material 104;

[0245] b) depositing an insulating flexible polymer layer 106a on the substrate where the polymer layer is disposed over at least a portion of the first region and over at least a portion of the second region;

[0246] c) depositing a conductive or semiconductive material 108a on the polymer layer 106 and the fabrication substrate 103 where:

[0247] the conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes;

[0248] each of the one or more electrodes is disposed over at least a portion of the sacrificial layer material and a region of the fabrication substrate that is not covered with the sacrificial layer material; and

[0249] the conductive or semiconductive material forms one or more connection pads 110 on a region of the fabrication substrate that is not coated with the sacrificial layer and the one electrode or plurality of electrodes is each electrically coupled to at least one of the connection pads;

[0250] d) optionally repeating steps (b) and (c) to added alternating layers of polymer and conductive or semiconductive material 108 where the polymer reveals at least a portion of the connection pad(s) 110 and insulates the electrode(s) 108 and the connection pads 110 from subsequently applied conductive or semiconductive material layer(s); and

[0251] e) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material where the final layer reveals at least a portion of the connection pad(s) 110; thereby forming a soft neural probe comprising one or more electrodes disposed between layers of the polymer and disposed on the fabrication substrate.

[0252] Release of the flexible electrode elements and coupling to electronics then occurs where 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 consequently no fracturing of the fabrication substrate is required. Accordingly, the fabrication substrate 103 need not incorporate a fraction zone 105.

[0253] In various embodiments, the wire bonding, flip chip bonding and the deposition of a conductor into the through-holes 110 can proceed as described above and illustrated in Figures IB to IF, and / or Figure 2B.Additive fabrication of soft neural probes on a fabrication substrate where the fabrication substrate comprises an integrated circuit

[0254] In another embodiment, the fabrication substrate can comprise an integrated circuit 502, e.g., as illustrated in Figures 5 A and 5B. A portion of the integrated circuit is covered with a sacrificial material 104 and alternating layers of insulating polymer 106 and conducting or semiconducting material 108.

[0255] Thus, in one illustrative, but non-limiting embodiment, the fabrication method can comprises a) providing a fabrication substrate 103 where the fabrication substrate comprises an integrated circuit 502 and one or more connection pads 110, where the connection pad(s) 110 are electrically connected to at least one circuit element 504 comprising said integrated circuit e.g., as illustrated in Figure 5A); b) depositing a layerof 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) depositing a layer of conductive or semiconductive material 108 on the polymer layer 106 and the fabrication substrate 103 where:

[0256] the conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes 108a;

[0257] each of the one or more electrodes is disposed over at least a portion of the sacrificial layer material and a region of said fabrication substrate that is not covered with said sacrificial layer material; and

[0258] the conductive or semiconductive material forms an electrical connection with one or more of said connection pads 110;

[0259] e) optionally repeating steps (c) and (d) to added alternating layers of polymer and conductive or semiconductive material 108 where the polymer reveals at least a portion of the connection pad(s) 110 and insulates said electrode(s) 108 and said connection pads 110 from subsequently applied conductive or semiconductive material layer(s); and f) applying a final layer of polymer material to encapsulate the top layer of conductive or semiconductive material where said final layer reveals at least a portion of said connection pad(s) 110; thereby forming a soft neural probe comprising one or more electrodes disposed between layers of said polymer and disposed on said fabrication substrate.

[0260] In certain embodiments a circuit element comprising the integrated circuit comprises an element selected from the group consisting of an amplifier, a preamplifier, a multiplexer, an analog-to-digital converter (ADC), a digital-to-analog converter (DAC), power management circuit, a micro-controller, an impedance matching circuit, an interconnect, a signal conditioner, and power regulation circuit, a wireless data transmission module, and the like.

[0261] In various embodiments the deposited polymer encapsulated electrodes are freed from the fabrication substrate by removing the sacrificial material 104 thereby freeing terminal region(s) of said electrodes from the fabrication substrate. The neural probe can be used in this format, e.g., by flipping the electrodes away from the underlying substrate see, e.g., Figure 6B). In certain embodiments the fabrication substrate can further comprise a fracture zone 105 and the substrate underlying the neural probe electrodes can be fractured away from the substrate / integrated circuit thereby freeing the electrodes.

[0262] In certain embodiments, e.g., as illustrated in Figure 6 A part of integrated circuit underneath the sacrificial layer does not contain any useful circuit, and it is just fractured away or cut off after removing the sacrificial layer. In a second approach, e.g., as illustrated in Figure 6B, the released neural probe is lifted up {e.g., to 90 degree), so it’s almost perpendicular to the integrated circuit from the side view. Then it can be flipped upside down and inserted into the target tissue probe, if the probe is long enough, the integrated circuit (and support described below) can still stay outside of the skull. In certain embodiments the length of the electrodes and freestanding neural probe can vary according to need, our current small animal design is 10mm and we can expand to 40mm for human applications.

[0263] In certain embodiments, instead of a sacrificial material 104 being deposited on the fabrication substrate, the sacrificial material can itself form a part of a hybrid substrate comprising a region of sacrificial material and an integrated circuit. After formation of the neural probe, the sacrificial material is removed leaving just the integrated circuit with attached neural probe(s).

[0264] In certain embodiments, e.g., as illustrated in Figure 5B, the fabrication substrate can comprise a plurality of integrated circuits thereby facilizing the simultaneous fabrication of a plurality of nanoprobes thereon. In certain embodiments the neural probes can then be separated from each other for use.

[0265] In certain embodiments the integrated circuit(s) 502 each comprise one or more output pads, leads, or pins 508 that facilitate output of a signal that is processed by the integrated circuit.

[0266] In certain embodiments, e.g., as illustrated in Figure 5B, in certain embodiments the integrated circuit 502 can be disposed on a support 506. In certain embodiments the support can comprise a circuit board e.g., a printed circuit board (PCB). In certain embodiments the support can comprise output pads, leads, or pins 510. In one non-liming embodiment schematically illustrated in Figure 5B, signals (e.g., neural signals are picked at the electrodes (108a, represented by circles), then pass through the thin interconnects onto the small squares 110 (illustrated by arrow "1" in Figure 5B). The neural probe together with the thin interconnects and small squares are post-fabricated on top of the integrated circuit. The contact pads 110 (illustrated by the small squares) are input pads for the integrated circuit, the signal from the electrodes 108a goes down into the integrated circuit where it is processed {e.g., amplified, multiplexed, etc.). The processed signal is delivered to the output pads 508 (illustrated by arrow "2" in Figure 5B). and end up in theIC output pads 508 which are the medium squares. The output signal from the output pads 508 can then travel through wire-bonds 512 from the integrated circuit output pads 508 (illustrated by medium squares) to the connection pads, pins, or leads 510 on a support (e.g., PCB) 506 (illustrated by large square pads). This PCB can then be easily connected to any downstream electronics for data acquisition. It will be recognized that the wire bonds can readily be substituted with flip-chip bonds, or any other suitable method of forming electrical connections.

[0267] The foregoing fabrication method on an integrated circuit is illustrative and nonlimiting. Using the teachings provided herein numerous other methods of fabricating neural probes on an integrated circuit will be available to one of skill in the art.Fabrication substrate 103

[0268] In various embodiments any of a number of materials and / or devices can serve as a fabrication substrate.

[0269] In various embodiments the fabrication substrate 103 simply comprises a material that provides support for deposition of the layer(s) of polymer 106 and conductive or semiconductive material 108. In certain embodiments the fabrication is a "functional substrate" that can comprise a circuit, a device, or a portion thereof where the substrates functionally interact with the fabricated neural probe. In certain embodiments the neural probe overlaps a portion of a circuit comprising the substrate.

[0270] In various embodiments the fabrication substrate 103 may comprise any suitable material. For example, in certain embodiments the substrate may comprise one or more conductor(s) e.g., a metal conductor), silicon e.g., a silicon wafer), a semiconductor substrate, and the like. According to certain embodiments, the substrate may comprise silicon, germanium, gallium arsenide, or combinations thereof. In certain embodiments the substrate may comprises a group IV elemental semiconductor, (C, Si, Ge, Sn), a group IV compound semiconductor, a Group VI elemental semiconductor, (S, Se, Te), a III-V semiconductor, a II-VI semiconductor, a I-VII semiconductor, a IV- VI semiconductor, a V-VI semiconductor, a II- V semiconductor, a I-III-VI2 semiconductor, a semiconductor oxide, and organic semiconductor, and the like.

[0271] In certain embodiments the fabrication substrate 103 comprises one or more electronic components and / or a printed circuit board (PCB). In certain embodiments the fabrication substrate 103 comprises an active or passive electronic component. Illustrativeactive or passive electronic components include, but are not limited to an amplifier, a preamplifier, an impedance-matching circuit, a multiplexer, an analog-to-digital converter (ADC), a digital-to-analog converter (DAC), power management circuit, a microcontroller, a wireless data transmission module, and the like.

[0272] In certain embodiments the fabrication substrate 103 comprises a substrate on which a single neural probe is fabricated. In other embodiments the fabrication substrate 103 comprises a substrate on which a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, or more) neural probes are fabricated. In certain embodiments where a plurality of neural probes is to be fabricated on a single fabrication substrate the substrate can be modified to facilitate separation of the completed neural probes from each other. Thus, for example, in certain embodiments the fabrication substrate can comprise fracture zones e.g., a scored or perforated region) disposed between the regions on which the neural probes are fabricated to facilitate mechanical separation of the neural probes from each other. In certain embodiments the fabrication substrate can comprise zones formed from a sacrificial material disposed between the regions on which the neural probes are fabricated to facilitate separation of the neural probes from each other by simple dissolution of the sacrificial material.Sacrificial materials and dissolution methods

[0273] As indicated above, in various embodiments, the methods described herein involve depositing one or more layers of a sacrificial material 104. A sacrificial material typically is a material that can be selectively removed (e.g., dissolved) without damage to and / or substantial alteration of surrounding or overlapping structures.

[0274] Materials suitable for use as sacrificial materials / layers in microfabrication methods are well known to those of skill in the art. Illustrative sacrificial materials include, but are not limited to chromium, chromium oxide, nickel, gold, silicon, silicon oxide, a water-soluble polymer, and an adhesive polymer (e.g., OMNICOAT®).

[0275] Various sacrificial materials can be deposited by any of a number of methods well known to those of skill 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(s) of the sacrificial material layer(s).

[0276] Such sacrificial materials are readily removed after application by use of suitable solvents. For example, nickel can be removed from the substrate with an HCI / FcCF mixer solution. SiO2 can be removed from the substrate with HF. OMNICOAT® can be removed from a substrate with tetramethylammonium hydroxide (TMAH).

[0277] In certain embodiments the sacrificial materials can comprise one or more water soluble polymers. Water-soluble polymers have two attractive characteristics for this application: 1) They can be deposited conveniently by spin-coating, and the solvent removed at a low temperature (95-150°), and 2) the resulting layer can be dissolved in water; no corrosive reagents or organic solvents are required. This technique is therefore compatible with a number of fragile materials, such as organic polymers, metal oxides and metals — materials that might be damaged during typical surface micromachining processes. The carboxylic acid groups of one illustrative polymer, e.g., poly(acrylic acid) (PAA), can be transformed by reversible ion-exchange from water-soluble (Na+ counterion) to water-insoluble (Ca2+counterion) forms. The use of PAA and dextran polymers as sacrificial materials is a useful technique for the fabrication of microstructures.

[0278] Examples of suitable water soluble sacrificial materials include, but are not limited to poly(acrylic acid), dextran, poly(methacrylic acid), poly (acrylamide), poly(ethylene imine), poly(vinyl alcohol), poly(ethylene oxide), chitosan, and sucrose. Numerous water soluble polymeric sacrificial materials are known to those of skill in the art (see, e.g., Linder et al. (2005) Small, 1(7): 730-736, and references therein).

[0279] The foregoing examples of sacrificial materials for use in the methods described herein are illustrative and non-limiting. Using the teaching provided herein, numerous other suitable sacrificial materials will be recognized by one of skill in the art.Polymer material / layer(s) 106Materials

[0280] As explained above the methods of fabricating a neural probe described herein involve depositing one or more layers of flexible polymer materials 106. Flexible polymer materials are polymers that can maintain integration or return to their original shape after large deformation, although some materials does not have property in the bulk form factor, when they are made into thin films with a thickness less than 10 pm then can be bent without breaking. Theses materials can be elastomers, plastics or resins. For instance, insome embodiments, the flexible polymer may exhibit a moderate Young’s modulus. For example, in certain embodiments, the elastomer has an elastic modulus above 10 MPa, above 100 MPa, above 1 GPa, above 10 GPa, or higher.

[0281] In certain embodiments the flexible polymer used in the methods described herein comprises commercial plastic or expoxy cross-linked polymeric resins, e.g such as SU-8 and Bisphenol A diglycidyl ether, polyimide, linear low-density polyethylene, high density polyethylene, polystyrene, polypropylene, polyvinylchloride.

[0282] As explained above the methods of fabricating a neural probe described herein involve depositing one or more layers of polymer 106. Elastomers are polymers that are characterized by weak intermolecular forces and consequently viscoelasticity. For instance, in some embodiments, the elastomer may exhibit a low elastic modulus. For example, in certain embodiments, the elastomer has an elastic modulus below 10 MPa, below 5 MPa, below 2 MPa, below 1 MPa, or lower. In some embodiments, the elastomer can exhibit a high elastic tensile deformation. For example, in some embodiments, the elastomer can 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 below 1 MPa and can exhibit elastic tensile deformation at or above 20% strain. The elastic modulus and / or the elastic tensile deformation may be determined by any suitable method. For example, the elastic modulus and the elastic tensile deformation could be measured using a tensile tester.

[0283] 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 fluorinated elastomer that is partially fluorinated. In certain embodiments the elastomer is a fluorinated elastomer that is greater than or equal to 25%, or greater than or equal to 50%, or greater than or equal to 75% or more 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 said second fluorinated elastomer is greater than or equal to 25% fluorinated and less than 100% fluorinated.

[0284] In certain embodiments the elastomer comprises a fluorinated elastomer selected from the group consisting of poly(l,l,l,3,3,3-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 dimethylacrylate (PFPE-DMA), fluorinated ethylene-propylene (FEP), perfluoroalkoxy polymer (PFA), poly chloro trifluoroethylene (PCTFE). In certain embodiments the elastomer comprises a perfluoropolyether. In certain embodiments the elastomer comprises a copolymer. In certain embodiments the elastomer is or comprises tetrafluoroethylene propylene (TFE). In certain embodiments the elastomer comprises or is perfluoropolyether (PFPE).

[0285] 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(l,l,l,3,3,3-hexafluoroisopropyl acrylate) (PHFIPA) or poly[2- (perfluorohexyl)ethyl] acrylate (PPFHEA). The polymer may also be a copolymer (e.g., between two or more fluorinated elastomers, including both these polymers and the perfluorinated elastomers described above.

[0286] In certain embodiments the elastomer comprises a polymer that has an average molecular weight above about 8 kDa, or an average molecular weight above about 10 kDa, or an average molecular weight above about 12 kDa, or an average molecular weight above about 14 kDa, or an average molecular weight above about 16 kDa, or an average molecular weight above about 18 kDa, or an average molecular weight above about 20 kDa.

[0287] In some embodiments, the elastomer has a molecular weight prior to crosslinking e.g., a weight average molecular weight) that is less than or equal to 1000 kDa, 500 kDa, 200 kDa, 100 kDa, 50 kDa, 40 kDa, 30 kDa, 20 kDa, 15 kDa, 10 kDa, 8 kDa, 5 kDa, or less and / or weight average molecular weight of the polymer, according to certain embodiments, is greater than or equal to 1 kDa, 2 kDa, 3 kDa, 4 kDa, 5 kDa, 8 kDa, 10 kDa, 15 kDa, 20 kDa, 30 kDa, 40 kDa, or greater. Combinations of these ranges are possible. For instance, in certain embodiments, the weight average molecular weight of the polymer may be greater than or equal to 1 kDa and less than or equal to 8 kDa, according to certain embodiments. According to other embodiments, the weight average molecular weight of the polymer may be greater than 20 kDa. The weight average molecular weight of the polymer may be determined by any suitable method, e.g., by gel permeation chromatography.

[0288] The foregoing elastomers {e.g., fluoropolymers) are illustrative and non-limiting. Using the teaching provided herein numerous other elastomers suitable for use in the methods described herein will be available to one of skill in the art.Polymer deposition methods

[0289] The polymer layer(s) 106 can be deposited using any of a number of thin film coating techniques well known to those of skill in the art. Such methods include, but are not limited to liquid chemical deposition, spin coating, spray coating, casting, vacuum polymer deposition, physical vapor deposition (PVD) and various chemical vapor deposition (CVD, PECVD, etc.). Methods of depositing polymers on substrates are well known to those of skill in the art (see, e.g., Martin et al. (2010) Handbook of Deposition Technologies for Films and Coatings: Science, Applications and Technology, Third Edition, William Andrew Pub (ISBN 978-0-8155-2031-3).

[0290] In one illustrative, but non-limiting embodiments the polymer layer(s) 106 are deposited using chemical vapor deposition (CVD) methods. Chemical Vapor Deposition (CVD) methods significantly augment the capabilities of traditional surface modification techniques for designing polymeric surfaces. In CVD polymerization, monomer(s) are delivered to the surface in a vapor phase and then undergo simultaneous polymerization and thin film formation. By eliminating the need to dissolve macromolecules, CVD enables insoluble polymers to be coated and prevents solvent damage to the substrate. Since de-wetting and surface tension effects are absent, CVD coatings conform to the geometry of the underlying substrate. Hence, CVD polymers can be readily applied to virtually any substrate: organic, inorganic, rigid, flexible, planar, three-dimensional, dense, or porous. CVD methods integrate readily with other vacuum processes used to fabricate patterned surfaces and devices. Typically, CVD film growth proceeds from the substrate up, allowing for interfacial engineering, real-time monitoring, thickness control, and the synthesis of films with graded composition.

[0291] Two specific methods of CVD polymerization that closely translate solution chemistry to vapor deposition are initiated chemical vapor deposition (iCVD) and oxidative chemical vapor deposition (oCVD). In iCVD, a variant of hot filament CVD, the deposition rate is enhanced, and chemical functionalities of the polymer’s constituents are maintained by including a thermally labile initiator in the feed stream. Due to the low energy required when using an initiator, delicate substrates can be coated. In oCVD, infusible, electrically conductive films are formed directly on the substrate of interest as the oxidant and monomer are introduced into the reactor simultaneously.

[0292] Methods of chemical vapor deposition of polymer films are provided in detail, for example, by Asatekin et al. (2010) Materials Today, 13(5): 26-33 and referencestherein.Thicknesses

[0293] In certain embodiments, the polymer layer(s) 106 have a thickness of 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(s) have 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(s) have a thickness of 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(s) have a thickness of greater than or equal to 300 nanometers and less than or equal to 2000 nanometers.

[0294] In certain embodiments the thickness of the polymer layer(s) ranges from about 0.5pm, or from about 1 pm, or from about 2 pm up to about 10 pm or up to about 5 pm, or up to about 4 pm, or up to about 3 pm.

[0295] It will be recognized that in certain embodiments, all of the polymer layers are the same thickness. In other embodiments, different polymer layers can have different thicknesses. For example, in certain embodiments, the outside polymer layers can be thicker than the polymer layers disposed between the layers of conductors or semiconducting material.

[0296] As in indicated above, in various embodiment the polymer layer(s) 106 are deposited and patterned to cover and / or separate different layers of conductive or semiconductive material 108 thereby insulating different conducive or semiconductive layers from each. Typically, the polymer is deposited / patterned to reveal at least a portion of the connection pad(s) 110 and insulates the electrode(s) 108 and the connection pads 110 from subsequently applied conductive or semiconductive material layer(s). In certain embodiments the polymer layer(s) are patterned to expose one or more discrete locationson the electrodes to provide contact points with a tissue. In certain embodiments the tips of the electrodes are exposed and / or in certain embodiments, one or more discrete location(s) an electrode are exposed.Polymer modification and / or functionalization

[0297] In certain embodiments the polymer layers 106 described herein can be functionalized or otherwise modified. Methods of chemically functionalizing polymers are well known to those of skill in the art (see, e.g., Pinson & Thiry (2019) Surface Modification of Polymers: Methods and Applications, Wiley Inc.). In various embodiments such functionalization can improve mechanical and / or chemical properties of the polymer.

[0298] It has also been surprisingly recognized that treatment of the polymer (e.g., fluorinated elastomer) may advantageously facilitate deposition of material onto the surface of the polymer, in some embodiments. Moreover, it was surprisingly discovered that treatment of a fluorinated elastomer (e.g., a perfluoropolymer) with a plasma can greatly facilitate the deposition and stable binding of subsequently layers to that fluoropolymer without adverse consequences to the chemical and physical properties of the fluoropoly mer(s). In this regard, without being bound to a particular theory, it is noted that the elastomer “surface” is like a viscous liquid, which has heretofore made metal deposition difficult or impossible (metal particles simply diffuse through the thin film, instead of forming a dense metal layer on the surface). It is believed the plasma treatment on the elastomer can increase the surface energy and allow evaporation of a dense metal layer". In effect it is believed that the plasma essentially turns the first few nanometers of fluorinated elastomer surface into a more rigid version of itself that can support particle deposition (e.g., metal deposition) while not altering the overall mechanical / chemical properties of the structure.

[0299] Accordingly, in various embodiments the polymer layer(s) 106 can be treated with a plasma, e.g., prior to deposition of subsequent layers. In various embodiments the plasma comprises a plasma formed from an inert gas (e.g., argon, helium, neon, krypton, xenon, etc. . In certain embodiments the plasma comprises an argon or a nitrogen plasma.

[0300] In various embodiments treatment of the polymer may advantageously prepare a surface of the polymer for interaction with additional materials. For example, in certain embodiments treatment of the fluorinated polymer may introduce reactive, charged, and / orpolarized sites on the surface of the fluorinated elastomer that can form chemical or physical bonds with subsequently deposited materials.

[0301] The treatment of the polymer using plasma formed from an inert gas can, in some embodiments, advantageously exclude oxygen from the treated polymer. This may prevent the reaction of oxygen with the treated surface, advantageously enhancing the ability of the polymer to adhere to other materials. As a result, arbitrarily thick and / or multilayered articles comprising polymers (e.g., perfluorinated elastomers) may be fabricated in certain embodiments. Similarly, arbitrarily thick and / or multilayered articles comprising fluorinated elastomers may be fabricated. Fabrication of multilayered articles comprising fluorinated elastomers as described herein may provide a substantial advantage for the preparation of articles comprising a high number density of electrodes. For example, as described herein, fabricating additional rows of electrodes on a sensor may comprise fabricating additional layers of a device.

[0302] In some embodiments, after the formation of the (plasma) treated polymer e.g., perfluoropoly ether), additional material is deposited onto the treated polymer. In various embodiments, the deposited additional material may comprise a conductive material, a semiconductive material, or other material(s). For example, in some embodiments, the deposited additional material may comprise a metal or metal alloy. The ability to deposit conductive material(s) is advantageous, because it can be used to fabricate portions of electronic circuits e.g., sensors). For example, conductive materials may be used to fabricate electrodes.

[0303] 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.

[0304] According to certain embodiments, polymers may be deposited onto treated polymers via solution processing. Due to the hydrophobic nature of the fluorinated (e.g., perfluorinated) polymers, according to some embodiments, the polymer(s) 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, owing to their hydrophobicity. Fluorinated elastomers may experience a low volumetric swelling during solution processing of additional materials. In certain embodiments, the perfluorinated elastomer may experience a volumetric swelling of 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 to0.2%, or less, in some embodiments. For example, the fluorinated elastomer (e.g., perfluorinated elastomer) may experience a volumetric swelling of 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. According to certain embodiments, the low volumetric swelling of the fluorinated elastomer may advantageously preserve a pattern with a high spatial resolution, which nonetheless comprises multiple layers of chemically distinct polymers. More generally, fluorinated elastomers may, advantageously, preserve a pattern with a high spatial resolution, which nonetheless comprises multiple layers of chemically distinct polymers as a result of their low volumetric swelling.

[0305] In certain embodiments the deposited additional material may be additional polymer (e.g., additional layer(s) of a fluorinated elastomer). This may result in a thicker layer of the polymer. In some embodiments, the polymer layer, has a minimum thickness of at least 0.3 micrometers, at least 0.5 micrometers, at least 0.7 micrometers, or more. In some embodiments, the fluorinated elastomer layer has a minimum thickness of less than or equal to 3 micrometers, less than or equal to 2.5 micrometers, less than or equal to 2 micrometers, less than or equal to 1 micrometer. 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 micrometers and less than or equal to 3 micrometers.

[0306] 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 the perfluorinated elastomer may result in a thicker layer of the perfluorinated elastomer. In some embodiments, the perfluorinated elastomer layer, has a minimum thickness of at least 0.3 micrometers, at least 0.5 micrometers, at least 0.7 micrometers, or more exhibits a high degree of crosslinking. In some embodiments, the perfluorinated elastomer layer has a minimum thickness of less than or equal to 3 micrometers, less than or equal to 2.5 micrometers, less than or equal to 2 micrometers, less than or equal to 1 micrometers. 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 micrometers and less than or equal to 3 micrometers.

[0307] The foregoing examples of polymeric materials for use in the methods described herein are illustrative and non-limiting. Using the teaching provided herein, numerous other suitable polymeric materials will be recognized by one of skill in the art.Conductive / semiconductive material laver(s) 108 - Electrodes Conductive / semiconductive Materials

[0308] In certain embodiments the layer(s) of conductive or semiconductive material 108 comprise 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, conducting oxides or nitrides thereof, and alloys thereof. In certain embodiments the conductive or semiconductive material 108 comprises titanium nitride or platinum-iridium alloy. In certain embodiments the conductive or semiconductive material 108 comprises gold.

[0309] In certain embodiments the conductive or semiconductive material 108 comprises a conductive polymer without heteroatoms, e.g., poly(fluorene)s, polyphenylenes, polypyrenes, polyazulenes, polynaphthalenes, and the like.

[0310] In certain embodiments the conductive or semiconductive material 108 comprises a nitrogen-containing conductive polymer, e.g., conductive polymers in which nitrogen (N) is in the aromatic cycle, e.g., poly(pyrrole)s (PPY), polycarbazoles, polyindoles, polyazepines, and the like, or in which the nitrogen is outside the aromatic cycle, e.g., polyanilines (PANI), and the like. In certain embodiments the conductive or semiconductive material 108 comprises a sulfur-containing conductive polymer, e.g., conductive polymers in which sulfur (S) is in the aromatic cycle, e.g., poly(thiophene)s (PT), poly(3,4-ethylenedioxythiophene) (PEDOT), and the like or in which sulfur is outside the aromatic cycle, e.g., poly(p-phenylene sulfide) (PPS), and the like. In certain embodiments In certain embodiments the conductive or semiconductive material 108 comprises a conductive polymer such as poly(acetylene)s (PAC), poly (p -phenylene vinylene) (PPV), and the like.

[0311] In certain embodiments the conductive or semiconductive material 108 comprises graphene.Adhesion laver(s) 109

[0312] In certain embodiments bonding between the layer(s) of conductive or semiconductive material 108 and subsequently applied layers (e.g., layer(s) of polymeric material 106) can be facilitated by the incorporation of an adhesion layer, e.g., as illustrated in Figure 3. Thus, for example, in certain embodiments the layer(s) of conductive or semiconductive material 108 can further comprises an adhesion layer 109. While in Figure 3 the adhesion layer 109 is shown only on top of the layer of conductive or semiconductive material 108 it will be recognized that in certain embodiments, the adhesion layer 109 can be below the layer of conductive or semiconductive material 108 to facilitate adhesion to the layer below (e.g., layer of polymer 106 below), or the adhesion layer 109 can be provided both on top of and below the layer of conductive or semiconductive material.

[0313] Materials suitable for adhesion layers are well known to those of skill in the art and include, but are not limited to aluminum, aluminum oxide, tungsten, niobium, chrome, titanium, and the like. It is noted that in certain embodiments, the adhesion layer may be conducting, or semiconducting, or non-conductive. In one illustrative but non-limiting embodiment the layer(s) of conductive or semiconductive material 108 can comprise a gold conducting layer deposited on an aluminum adhesion layer, an aluminum adhesion layer deposited on a gold conducting layer, or a gold conducting layer deposited between two aluminum adhesion layers.Conductive / semiconductor material 108 deposition

[0314] Methods of depositing and patterning the conductive or semiconductive material 108 are well known to those of skill 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.

[0315] In some embodiments, one or more layers comprising the conductive or semiconductive material 108 may be patterned e.g., by a mask), a resist, or by other methods well known to those of skill in the art. Thus, for example, one common approach to selectively patterning a surface with a conductor or semiconductor involves masking the areas of the surface that is to be free of the conductive or semiconductive material so that the solution or gas phase comprising conductive or semiconductive material cannot come in contact with those areas. This is readily accomplished by coating the substratewith a masking material {e.g., a polymer resist) and selectively etching the resist off of areas that are to be coupled. Alternatively photoactivatable resist can be applied to the surface and selectively activated {e.g., via UV light) in areas that are to be protected. Such "photolithographic" 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, and the like). In addition, the resist can be patterned on the surface simply by contact printing the resist onto the surface.

[0316] In other approaches, the surface is uniformly contacted with the conductive or semiconductive material. The molecules can then be selectively etched off the surface in areas that are to be molecule free. Etching methods are well known to those of skill in the art and include, but are not limited to plasma etching, laser etching, acid etching, and the like.

[0317] Other approaches involve contact printing of the conductive or semiconductive material, e.g., using an inkjet printer or a contact print head shaped to selectively deposit the conductive or semiconductive material(s) in desired regions {see e.g., U.S. Patent 6,221,653).Electrode configuration

[0318] 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 that are electrically isolated from each other and / or that are independently addressable. In certain embodiments the layer(s) of conductive or semiconductor material 108 form 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 electrodes, at least about 5,000, or at least about 10,000 electrodes.

[0319] In certain embodiments where the conductive or semiconductive material 108 is patterned to form a plurality of electrodes those electrodes have an electrode number density {e.g., number of electrodes per unit area of a projected surface of the neural probe). In some embodiments, the electrodes have an electrode number density of greater than orequal to 10’5electrodes / micron2, greater than or equal to 10’4electrodes / micron2, greater than or equal to 10"3electrodes / micron2, greater than or equal to 10"2electrodes / micron2, greater than or equal to 10"1electrodes / micron2, or greater. In some embodiments, the electrodes have an electrode number density of less than or equal to 101electrodes / micron2, less than or equal to 100 electrodes / micron2, less than or equal to 101electrodes / micron2, or less. Combinations of these ranges are possible. For example, in some embodiments, the electrodes have an electrode number density of greater than or equal to 10"5electrodes / micron2and less than or equal to 101electrodes / micron2.

[0320] In certain embodiments the method provided herein allow patterning of, e.g., electrodes at high resolution. Thus, for example, in certain embodiments, the minimal distance between pattern features e.g., between two electrodes) is at or below 30 micrometers, or at or below 20 micrometers, or at or below 10 micrometers, or at or below 5 micrometers, or at or below 2 micrometers, or below.

[0321] In certain embodiments the layer(s) of conductive or semiconductive material 108 range in thickness from about 20nm, or from about 20 nm, or from about 30 nm, or from about 40 nm, or from about 50 nm, or from about 60 nm, or from about 70 nm, or from about 80 nm, or from about 90 nm, or from about 100 nm up toa bout 1 pm, or up to about 900 nm, or up to about 800 nm, or up to about 700 nm, or up to about 600 nm, or up to about 500 nm, or up to about 400 nm, or up to about 300 nm, or up to about 200 nm, or up to about 150 nm.

[0322] In certain embodiments the layer(s) of conductive or semiconductive material 108 form electrodes having an average length that ranges from about 1 mm, or from about 2 mm, or from about 3mm, or from about 4mm or from about 5 mm or from about 6mm, or from about 7mm, or from about 8mm up to about 20 mm, or up to about 18 mm, or up to about 16 mm, or up to about 14 mm, or up to about 12 mm.

[0323] In certain embodiments the layer(s) of conductive or semiconductive material 108 form electrodes having an average width that ranges from about 100 nm, or from about 200 nm, or from about 500 nm, or from about 800 nm, or from about 1 pm, or from about 5 pm, or from about 10 pm, or from about 20 pm up to about 100 pm, or up to about 80 pm, or up to about 60 pm, or up to about 50 pm, or up to about 40 pm, or up to about 30 pm, or up to about 20 pm.Treatment of contact pads

[0324] In various embodiments the contact pads 114 are treated to facilitate formation of electrical connections. In certain embodiments the contact pads 114 are treated to a bumping procedure effectively increasing the rugosity and surface area of the contact pads. In certain embodiments the bumping procedure comprises electroplating or metal deposition to form bumps on the contact pads. In certain embodiments the bumps comprises a metal selected from the group consisting of solder, Au, and Ir, In, Cu.I / O contact pads and packaging method

[0325] As indicated above, in various embodiments, the contacts pads on the neural probe are made with metal, include Au, Pt, Ti, Cu, Al. When neural probe is fabricated on a plain Si substrate, the I / O pads (input / output circuits) have a pitch between 20 pm and 2 mm, and it uses wire-bonding or flip chip bonding or mechanical direct contact to form connections to the external electronic components e.g PCB, ICs. When the neural probe is fabricated on a substrate with active electronics (e.g a CMOS wafer), the I / O pads have a pitch between 2 pm and 200 pm, and it uses post-fabrication methods ( e.g lithography, metal deposition, lift off, wet etching, dry etching) to form connections to the active electronics in the substrate.

[0326] In certain embodiments the methods provided herein further comprise sterilizing the neural probes. Methods of effectively sterilizing the neural 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.

[0327] In certain embodiments, particularly after sterilization, the neural probes can be packaged into sterile packaging. Illustrative, but non-limiting examples of sterile 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 processing (see, e.g., QSEAL® Pre-validated Sterile Packaging). In certain embodiments single or double barrier package configurations involving foam, polyurethane, shelf boxes and other protective packaging materials can be utilized. In certain embodiments thepackaging provides an inert gas e.g., argon) inside the package.Implantation of the neural probe

[0328] In some embodiments, at least a portion of a neural probe described herein is implanted in a subject. For example, in various embodiments, part or the entire neural probe may be implanted in a subject. For example, in certain embodiments, the neural probe may be implanted in the brain or other nervous tissue, spinal cord, heart, peripheral muscle, and the like. In some embodiments, the neural probe is configured for long-term residence inside a subject, e.g., the neural probe is stable under physiological conditions. In certain embodiments the neural probe may be configured for long-term contact with the surface of a brain or for partial or full implantation in the brain of subject.

[0329] Accordingly, in certain embodiments the neural probe(s), in use, are partially or full implanted in a target tissue, e.g., brain tissue. Methods of implanting neural probes are described, for example, in PCT Publication No: PCT / US2022 / 019430. As described therein, in certain embodiments, a frame and / or shuttle can be used to guide and position the neural probe(s) at or in a target tissue {e.g., brain tissue).

[0330] In certain embodiments implantation of the neural probe(s) can be facilitated by temporarily increasing the stiffness of the neural probe(s)). In one illustrative, but nonlimiting approach the neural probe is coated with a bioabsorbable stiffening agent. Illustrative bioabsorbable stiffening agents include, but are not limited to dextran, glucose, polyethylene glycol (PEG), gelatin, and the like. In certain embodiments the neural probe(s) can be stiffened by freezing.Kits

[0331] In certain embodiments kits are provided for use of the neural probes described herein. In certain embodiments the kits comprise one or more containers containing neural probes fabricated according to any of the methods described herein. In certain embodiments the containers provide sterile packaging for sterile neuroprobes. In certain embodiments the kits further comprise a shuttle and / or a frame to facilitate implantation of a neural probe described herein.

[0332] In certain embodiments the kits can further comprise instructional / informational materials. In certain embodiments the instructional materials teach the use of the neuralprobe(s) contained in the kit for receiving electrical signals form a target tissue (e.g., brain or other neural tissue) for transmitting a signal to a target tissue. In certain embodiments the instructional materials provide instructions for implantation of the neural probe(s) into a target tissue.

[0333] While the instructional materials typically comprise written or printed materials they are not limited to such. 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 discs, tapes, cartridges, chips), optical media (e.g. , CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.

[0334] 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

CLAIMSWhat is claimed is:

1. A method of preparing a soft probe electrically connected to an active electronic device, said method comprising: a) providing a fabrication substrate comprising a fabrication material and a fracture zone; b) depositing a layer of sacrificial material over a portion of said fabrication substrate; c) depositing an insulating flexible polymer layer over the layer of sacrificial material and over a portion of said fabrication substrate; d) depositing a layer of conductive or semiconductive material on said polymer layer and said fabrication substrate wherein: said conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes; each of said one or more electrodes is disposed over at least a portion of the layer of sacrificial material and a region of said fabrication substrate that is not covered with said sacrificial material; and said conductive or semiconductive material forms one or more connection pads on a region of said fabrication substrate that is not coated with the layer of sacrificial material and said one electrode or plurality of electrodes is each electrically coupled to at least one of said connection pads; e) optionally repeating steps (c) and (d) to added alternating layers of polymer and conductive or semiconductive material wherein said polymer reveals at least a portion of said connection pad(s) and insulates said electrode(s) and said connection pads from subsequently applied conductive or semiconductive material layer(s); and f) applying a final layer of polymer material to encapsulate a top layer of conductive or semiconductive material where said final layer reveals at least a portion of said connection pad(s); thereby forming a soft probe comprising one or more electrodes disposed between layers of said polymer and disposed on said fabrication substrate.

2. The method of claim 1, further comprising: providing a substrate comprising a support bearing one or more contact pads and one or more active or passive electronic components, wherein each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; bonding said substrate to said fabrication substrate; wire bonding each of said one or more connection pads to one or more of said contact pads to form wire bond(s) between said connection pads and said contact pads; removing the layer of sacrificial material; and fracturing said fabrication substrate at said fracture zone to provide said soft probe electrically connected to said one or more active or passive electonic components.

3. The method of claim 2, further comprising: providing a substrate comprising a support bearing one or more contact pads and one or more active or passive electronic components, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; flip chip bonding each of said one or more connection pads to one or more of said contact pads to form flip chip bond(s) between said connection pads and said contact pads; removing the layer of sacrificial material; and fracturing said fabrication substrate at said fracture zone to provide said soft probe electrically connected to said one or more active or passive electronic components.

4. The method of claim 3, further comprising bonding said substrate to said fabrication substrate.

5. The method according to any one of claims 3-4, further comprising adding a fill to a flip chip bonding pad region to enforce bonding between said fabrication substrate and said substrate.

6. The method of claim 2, further comprising: providing one or more active or passive electronic components bearing one or more contact pads, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; flip chip bonding each of said one or more connection pads to one or more of said contact pads to form flip chip bond(s) between said connection pads and said contact pads; removing the sacrificial material; and fracturing said fabrication substrate at said fracture zone to provide said soft probe electrically connected to said one or more active or passive electronic components.

7. The method of claim 6, further comprising bonding said one or more active or passive electronic components to said fabrication substrate.

8. The method according to any one of claims 6-7, further comprising adding a fill to a flip chip bonding pad region to enforce bonding said one or more active or passive electronic components and said fabrication substrate.

9. The method of claim 2, further comprising: providing said fabrication substrate with a through-hole at each of said connection pads; providing a substrate comprising a support bearing one or more contact pads and one or more active or passive electronic components, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; juxtaposing said substrate to said fabrication substrate; depositing a conductor into each of said through-holes to form an electrical connection between said connection pads and said contact pads; removing the sacrificial material; and fracturing said fabrication substrate at said fracture zone to provide said soft probe electrically connected to said one or more active or passive electronic components.

10. The method of claim 9, further comprising bonding said substrate to said fabrication substrate.

11. The method of claim 2, further comprising: providing said fabrication substrate with a through-hole at each of said connection pads; providing one or more active or passive electronic components bearing one or more contact pads, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; juxtaposing said one or more active or passive electronic components to said fabrication substrate; depositing a conductor into each of said through-holes to form an electrical connection between said connection pads and said contact pads; removing the layer of sacrificial material; and fracturing said fabrication substrate at said fracture zone to provide said soft probe electrically connected to said one or more active or passive electronic components.

12. The method of claim 2, further comprising bonding said one or more active or passive electronic components to said fabrication substrate.

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

14. A method of preparing a free-standing soft neural probe electrically connected to an active electronic device, said method comprising: a) providing a fabrication substrate comprising a first region comprising a fabrication material and a second region comprising a sacrificial material; b) depositing an insulating flexible polymer layer on said substrate wherein said polymer layer is disposed over at least a portion of said first region and over at least a portion of said second region; c) depositing a conductive or semiconductive material on said polymer layer and said fabrication substrate wherein:said conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes; each of said one or more electrodes is disposed over at least a portion of said sacrificial material and a region of said fabrication substrate that is not covered with said sacrificial material; and said conductive or semiconductive material forms one or more connection pads on a region of said fabrication substrate that is not coated with said sacrificial material and said one electrode or plurality of electrodes is each electrically coupled to at least one of said connection pads; d) optionally repeating steps (b) and (c) to added alternating layers of polymer and conductive or semiconductive material wherein said polymer reveals at least a portion of said connection pad(s) and insulates said electrode(s) and said connection pads from subsequently applied conductive or semiconductive material layer(s); and e) applying a final layer of polymer material to encapsulate a top layer of conductive or semiconductive material where said final layer reveals at least a portion of said connection pad(s); thereby forming a soft neural probe comprising one or more electrodes disposed between layers of said polymer and disposed on said fabrication substrate.

15. The method of claim 14, further comprising: providing a substrate comprising a support bearing one or more contact pads and one or more active or passive electronic components, wherein each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; bonding said substrate to said fabrication substrate; wire bonding each of said one or more connection pads to one or more of said contact pads to form wire bond(s) between said connection pads and said contact pads; removing the sacrificial material comprising the second region of said fabrication substrate; and fracturing said fabrication substrate at a fracture zone to provide said freestanding soft neural probe electrically connected to said one or more active or passive electronic components.

16. The method of claim 14, further comprising: providing one or more active or passive electronic components bearing one or more contact pads, wherein each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; bonding said one or more active or passive electronic components to said fabrication substrate; wire bonding each of said one or more connection pads to one or more of said contact pads to form wire bond(s) between said connection pads and said contact pads; removing the sacrificial material comprising the second region of said fabrication substrate; and fracturing said fabrication substrate at a fracture zone to provide said freestanding soft neural probe electrically connected to said one or more active or passive electronic components.

17. The method of claim 14, further comprising: providing a substrate comprising a support bearing one or more contact pads and one or more active or passive electronic components, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; flip chip bonding each of said one or more connection pads to one or more of said contact pads to form flip chip bond(s) between said connection pads and said contact pads; removing the sacrificial material comprising the second region of said fabrication substrate; and fracturing said fabrication substrate at a fracture zone to provide said freestanding soft neural probe electrically connected to said one or more active or passive electronic components.

18. The method of claim 7, further comprising bonding said substrate to said fabrication substrate.

19. The method of claim 14, further comprising: providing one or more active or passive electronic components bearing one or more contact pads, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; flip chip bonding each of said one or more connection pads to one or more of said contact pads to form flip chip bond(s) between said connection pads and said contact pads; removing the sacrificial material comprising the second region of said fabrication substrate; and fracturing said fabrication substrate at a fracture zone to provide said freestanding soft neural probe electrically connected to said one or more active or passive electronic components.

20. The method of claim 19, further comprising bonding said one or more active or passive electronic components to said fabrication substrate.

21. The method of claim 14, further comprising: providing said fabrication substrate with a through-hole at each of said connection pads; providing a substrate comprising a support bearing one or more contact pads and one or more active or passive electronic components, wherein each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; bonding said substrate to said fabrication substrate; depositing a conductor into each of said through-holes to form an electrical connection between said connection pads and said contact pads; removing the sacrificial material comprising the second region of said fabrication substrate; and fracturing said fabrication substrate at a fracture zone to provide said freestanding soft neural probe electrically connected to said one or more active or passive electronic components.

22. The method of claim 14, further comprising: providing said fabrication substrate with a through-hole at each of said connection pads;providing one or more active or passive electronic components bearing one or more contact pads, where each of said one or more contact pads is electrically coupled to said one or more active or passive electronic components; bonding said one or more active or passive electronic components to said fabrication substrate; depositing a conductor into each of said through-holes to form an electrical connection between said connection pads and said contact pads; removing the sacrificial material comprising the second region of said fabrication substrate; and fracturing said fabrication substrate at a fracture zone to provide said freestanding soft neural probe electrically connected to said one or more active or passive electronic components.

23. A method of preparing a free-standing soft neural probe electrically connected to an active electronic device, said method comprising: a) providing a fabrication substrate wherein said fabrication substrate comprises an integrated circuit and one or more connection pads, where said connection pad(s) are electrically connected to at least one circuit element comprising said integrated circuit; b) depositing a layer of sacrificial material over a portion of said fabrication substrate; c) depositing an insulating flexible polymer layer over the layer of sacrificial material and over at least a portion of said fabrication substrate; d) depositing a layer of conductive or semiconductive material on said insulating flexible polymer layer and said fabrication substrate wherein: said conductive or semiconductive material is patterned to form one electrode or is patterned to form a plurality of electrodes; each of said one or more electrodes is disposed over at least a portion of said layer of sacrificial material and a region of said fabrication substrate that is not covered with said layer of sacrificial material; and said conductive or semiconductive material forms an electrical connection with one or more of said connection pads; e) optionally repeating steps (c) and (d) to added alternating layers of polymer and conductive or semiconductive material wherein said polymer reveals atleast a portion of said connection pad(s) and insulates said electrode(s) and said connection pads from subsequently applied conductive or semiconductive material layer(s); and f) applying a final layer of polymer material to encapsulate a top layer of conductive or semiconductive material where said final layer reveals at least a portion of said connection pad(s); thereby forming a soft neural probe comprising one or more electrodes disposed between layers of said polymer and disposed on said fabrication substrate.

24. The method of claim 23, wherein a circuit element comprising said integrated circuit comprises an element selected from the group consisting of an amplifier, a preamplifier, a multiplexer, an analog-to-digital converter (ADC), a digital-to-analog converter (DAC), power management circuit, a micro-controller, an impedance matching circuit, an interconnect, a signal splitter, and a wireless data transmission module.

25. The method according to any one of claims 23-24, wherein said method comprises removing said layer of sacrificial material thereby freeing terminal region(s) of said electrodes from the fabrication substrate.

26. The method according to any one of claims 23-25, wherein said fabrication substrate comprises a fracture zone.

27. The method of claim 26, wherein said method comprises fracturing said fabrication substrate at the fracture zone.

28. The method according to any one of claims 23-27, wherein said integrated circuit comprises output pads, leads, or pins.

29. The method according to any one of claims 23-28, wherein said integrated circuit is disposed on a support.

30. The method of claim 29, wherein said support comprises a circuit board.

31. The method according to any one of claims 29-30, wherein said support comprises output pads, leads, or pins.

32. The method according to any one of claims 1-31, wherein:a plurality of neural probes are fabricated on a single fabrication substrate; and said substrate is diced into smaller pieces each with one or multiple neural probes on each piece.

33. The method according to any one of claims 1-32, wherein said polymer comprises a material selected from the group consisting of a fluorinated elastomer, polyimide, polydimethylsiloxane, parylene-C, and epoxy resin.

34. The method according to any one of claims 1-33, wherein said layer(s) of polymer comprise a fluorinated elastomer.

35. The method of claim 34, wherein said fluorinated elastomer is a fluorinated elastomer that is not perfluorinated.

36. The method of claim 35, wherein said fluorinated elastomer is partially fluorinated.

37. The method of claim 36, wherein: said fluorinated elastomer is greater than or equal to 25% fluorinated and less than 100% fluorinated.

38. The method of claim 35, wherein said fluorinated elastomer is selected from the group consisting of poly(l,l,l,3,3,3-hexafluoroisopropyl acrylate) (PHFIPA), and poly[2-(perfluorohexyl)ethyl]acrylate.

39. The method of claim 34, wherein said fluorinated elastomer is a perfluorinated elastomer.

40. The method of claim 39, wherein said perfluorinated elastomer is selected from the group consisting of perfluoropolyether (PFPE), polytetrafluoroethylene (PTFE), perfluoropolyether dimethylacrylate (PFPE-DMA), fluorinated ethylene-propylene (FEP), perfluoroalkoxy polymer (PF A), and polychlorotrifluoroethylene (PCTFE).

41. The method of claim 39, wherein said perfluorinated elastomer comprises a perfluoropolyether.

42. The method of claim 41, wherein the perfluoropolyether has a weight-average molecular weight above 8 kDa.

43. The method of claim 41, wherein the perfluoropolyether has a weight-average molecular weight above 20 kDa.

44. The method according to any one of claims 41-43, wherein said perfluorinated elastomer is a copolymer.

45. The method of claim 44, wherein said perfluorinated elastomer is tetrafluoroethylene propylene (TFE).

46. The method of claim 39, wherein said perfluorinated elastomer comprises perfluoropoly ether (PFPE).

47. The method according to any one of claims 1-46, wherein said layer(s) of polymer range in thickness from about to about 0.5 pm to 5 pm.

48. The method according to any one of claims 1-47, wherein one or more of said layers of polymer material are patterned to provide open regions to provide contact with a tissue at one or more discrete locations along the surface of one or more electrodes formed by the conductive or semiconductive material.

49. The method according to any one of claims 1-48, wherein one or more of said layers of polymer material are patterned to encapsulate one or more electrodes formed by said conducive or semiconductive material to provide one or more capacitive electrodes.

50. The method according to any one of claims 1-49, wherein said layers of polymer material are deposited by an additive semiconductor fabrication process.

51. The method of claim 50, wherein said additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), wherein said process is optionally combined with photolithographic patterning.

52. The method according to any one of claims 1-49, wherein said 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 said sacrificial material comprises a water soluble polymer selected from the group consisting of poly(acrylic acid), dextran, poly (methacrylic acid), poly (acrylamide), poly (ethylene imine), poly (vinyl alcohol), poly(ethylene oxide), chitosan, and sucrose.

54. The method according to any one of claims 1-53, wherein said sacrificial material is deposited by an additive semiconductor fabrication process.

55. The method of claim 54, wherein said 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 said process is optionally combined with photolithographic patterning.

56. The method according to any one of claims 1-55, wherein said sacrificial material is removed by etching and / or dissolution.

57. The method of claim 56, wherein the sacrificial layer comprises nickel and the nickel is removed from the substrate with a mixture of HC1 and FeC h in solution.

58. The method of claim 56, wherein the sacrificial layer comprises SiCT. and the SiO2 is removed from the substrate with HF.

59. The method of claim 56, wherein the sacrificial layer comprises an adhesive polymer and the adhesive polymer is removed with 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 according to any one of claims 1-60, wherein said 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 said conductive or semiconductive material comprises a metal or metal alloy.

63. The method of claim 62, wherein said 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, conducting oxides or nitrides thereof, and alloys thereof.

64. The method of claim 62, wherein said conductive or semiconductive material comprises titanium nitride or platinum-iridium alloy.

65. The method of claim 62, wherein said conductive or semiconductive material comprises gold.

66. The method according to any one of claims 1-65, wherein said conductive or semiconductive material forms a single electrode.

67. The method according to any one of claims 1-65, wherein said conductive or semiconductive material is patterned to form a plurality of electrodes.

68. The method of claim 67, wherein said conductive or semiconductive material forms a plurality of electrodes that are electrically isolated from each other and / or that are independently addressable.

69. The method according to any one of claims 1-68, wherein said layers of conductive or semiconductor material form at least about 10 electrodes.

70. The method according to any one of claims 1-69, wherein said layer(s) of conductive or semiconductor material range in thickness from about to about 20 nm to 1 pm.

71. The method according to any one of claims 69-70, wherein the layers of conductive or semiconductive material form a plurality of electrodes having an electrode number density of less than or equal to 101electrodes / micron2.

72. The method according to any one of claims 1-71, wherein said layer(s) of conductive or semiconductor material form electrodes having an average length that ranges from about 1mm up to about 20 mm.

73. The method according to any one of claims 1-72, wherein said layer(s) of conductive or semiconductor material form electrodes having an average width that ranges from about 100 nm up to about 100 pm.

74. The method according to any one of claims 1-72, wherein said layer(s) of conductive or semiconductor material form features that are separated by a minimal distance at or below 30 micrometers, or at or below 20 micrometers, or at or below 10 micrometers, or at or below 5 micrometers, or at or below 2 micrometers, or below.

75. The method according to any one of claims 1-74, wherein said conductive or semiconductive material comprises an adhesion layer.

76. The method of claim 75, wherein said conductive or semiconductive material comprises an adhesion layer comprising a material selected from the group consisting of aluminum, aluminum oxide, tungsten, niobium, chrome, and titanium.

77. The method of claim 76, wherein the adhesion layer comprises aluminum, titanium, or chromium.

78. The method according to any one of claims 1-77, wherein said conductive or semiconductive material and / or said adhesion layer is deposited by an additive semiconductor fabrication process.

79. The method of claim 78, wherein said additive semiconductor fabrication process is selected from the group consisting of spin coating, casting, chemical vapor deposition (CVD), physical vapor deposition (PVD), and wherein said additive semiconductor fabrication process is optionally combined with photolithographic patterning.

80. The method according to any one of claims 1-79, wherein said polymer material is treated with an inert gas plasma before deposition of said conductive or semiconductive material.

81. The method of claim 80, wherein said inert gas plasma comprises an argon or nitrogen plasma.

82. The method according to any one of claims 1-81, wherein one or more of said connection pads are treated to a bumping procedure to form metal bumps on said pads.

83. The method of claim 82, wherein said bumping procedure comprises electroplating or metal deposition.

84. The method according to any one of claims 82-83, wherein said bumps comprises a metal selected from the group consisting of solder, Au, Ir, In, and Cu.

85. The method according to any one of claims 1-84, wherein said active or passive electronic component(s) comprise an active or passive electronic component selected from the group consisting of an amplifier, a preamplifier, a multiplexer, an analog-to- digital converter (ADC), a digital-to-analog converter (DAC), power management circuit, micro-controller, and wireless data transmission module.

86. The method according to any one of claims 1-85, wherein said active or passive electronic component(s) contains I / O pads on the neural probes and corresponding contact on the electronics, the I / Os and corresponding contacts pads will have a same pitch size of, or below, 2 millimeters.

87. The method according to any one of claims 1-86, wherein said active or passive electronic component(s) contains I / O pads on the neural probes and corresponding contact on the electronics , the I / Os and corresponding contacts pads will have at least about 10 connections.

88. The method according to any one of claims 1-87, wherein said 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 said treating comprises coating said neural probe with a bioabsorbable stiffening agent.

90. The method of claim 89, wherein said bioabsorbable stiffening agent comprises a material selected from the group consisting of dextran, glucose, polyethylene glycol (PEG), and gelatin.

91. The method of claim 89, wherein said treating comprises freezing said neural probe.

92. The method according to any one of claims 1-91, wherein said method comprises sterilizing said neural probe.

93. The method of claim 92, wherein said sterilizing comprises a method selected from the group consisting of by exposure to radiation, chemical sterilization, and autoclaving.

94. The method of claim 93, wherein said method comprises exposure to ethylene oxide.

95. A flexible neural probe made by a method according to any one of claims 1-94.

96. A kit comprising a container containing a flexible neural probe of claim 95.

97. The kit of claim 96, wherein said kit comprises instructional materials teaching the use of said neural probe.

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