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- 238000000034 method Methods 0.000 claims 55
- 239000000758 substrate Substances 0.000 claims 33
- 210000004027 cell Anatomy 0.000 claims 23
- 239000004020 conductor Substances 0.000 claims 17
- 238000000151 deposition Methods 0.000 claims 16
- -1 polydimethylsiloxane Polymers 0.000 claims 16
- 210000002569 neuron Anatomy 0.000 claims 15
- 230000008021 deposition Effects 0.000 claims 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 8
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 8
- 239000004205 dimethyl polysiloxane Substances 0.000 claims 8
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims 8
- 229920000747 poly(lactic acid) Polymers 0.000 claims 8
- 229920000139 polyethylene terephthalate Polymers 0.000 claims 8
- 239000005020 polyethylene terephthalate Substances 0.000 claims 8
- 239000004626 polylactic acid Substances 0.000 claims 8
- 238000005520 cutting process Methods 0.000 claims 5
- 239000011521 glass Substances 0.000 claims 5
- 239000000463 material Substances 0.000 claims 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 4
- 208000003098 Ganglion Cysts Diseases 0.000 claims 4
- 239000002202 Polyethylene glycol Substances 0.000 claims 4
- 229920000954 Polyglycolide Polymers 0.000 claims 4
- 239000004642 Polyimide Substances 0.000 claims 4
- 239000004793 Polystyrene Substances 0.000 claims 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims 4
- 208000005400 Synovial Cyst Diseases 0.000 claims 4
- 238000005266 casting Methods 0.000 claims 4
- 210000003169 central nervous system Anatomy 0.000 claims 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 claims 4
- 210000003061 neural cell Anatomy 0.000 claims 4
- 210000001428 peripheral nervous system Anatomy 0.000 claims 4
- 229920003207 poly(ethylene-2,6-naphthalate) Polymers 0.000 claims 4
- 229920000052 poly(p-xylylene) Polymers 0.000 claims 4
- 229920001223 polyethylene glycol Polymers 0.000 claims 4
- 239000011112 polyethylene naphthalate Substances 0.000 claims 4
- 239000004633 polyglycolic acid Substances 0.000 claims 4
- 229920001721 polyimide Polymers 0.000 claims 4
- 229920002223 polystyrene Polymers 0.000 claims 4
- 229920002635 polyurethane Polymers 0.000 claims 4
- 239000004814 polyurethane Substances 0.000 claims 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims 4
- 235000012239 silicon dioxide Nutrition 0.000 claims 4
- 239000000377 silicon dioxide Substances 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 claims 3
- 229910052751 metal Inorganic materials 0.000 claims 3
- 239000002184 metal Substances 0.000 claims 3
- 230000002025 microglial effect Effects 0.000 claims 3
- 210000004498 neuroglial cell Anatomy 0.000 claims 3
- 210000004248 oligodendroglia Anatomy 0.000 claims 3
- 230000002093 peripheral effect Effects 0.000 claims 3
- 210000004116 schwann cell Anatomy 0.000 claims 3
- 239000010935 stainless steel Substances 0.000 claims 3
- 229910001220 stainless steel Inorganic materials 0.000 claims 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 claims 2
- 230000036982 action potential Effects 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 2
- 229910021393 carbon nanotube Inorganic materials 0.000 claims 2
- 239000002041 carbon nanotube Substances 0.000 claims 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 2
- 229910052737 gold Inorganic materials 0.000 claims 2
- 239000010931 gold Substances 0.000 claims 2
- 229910021389 graphene Inorganic materials 0.000 claims 2
- 239000006193 liquid solution Substances 0.000 claims 2
- 239000002905 metal composite material Substances 0.000 claims 2
- 230000001537 neural effect Effects 0.000 claims 2
- 210000000276 neural tube Anatomy 0.000 claims 2
- 229920000642 polymer Polymers 0.000 claims 2
- 230000000717 retained effect Effects 0.000 claims 2
- 229910052710 silicon Inorganic materials 0.000 claims 2
- 239000010703 silicon Substances 0.000 claims 2
- 229910052709 silver Inorganic materials 0.000 claims 2
- 239000004332 silver Substances 0.000 claims 2
- 230000000638 stimulation Effects 0.000 claims 2
- 238000007740 vapor deposition Methods 0.000 claims 2
- 206010001497 Agitation Diseases 0.000 claims 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims 1
- 229910045601 alloy Inorganic materials 0.000 claims 1
- 239000000956 alloy Substances 0.000 claims 1
- 230000003376 axonal effect Effects 0.000 claims 1
- 230000028600 axonogenesis Effects 0.000 claims 1
- 239000006285 cell suspension Substances 0.000 claims 1
- 239000002131 composite material Substances 0.000 claims 1
- 238000010894 electron beam technology Methods 0.000 claims 1
- 238000000313 electron-beam-induced deposition Methods 0.000 claims 1
- 238000009713 electroplating Methods 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910001000 nickel titanium Inorganic materials 0.000 claims 1
- HLXZNVUGXRDIFK-UHFFFAOYSA-N nickel titanium Chemical compound [Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ti].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni].[Ni] HLXZNVUGXRDIFK-UHFFFAOYSA-N 0.000 claims 1
- 238000010899 nucleation Methods 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- 238000007650 screen-printing Methods 0.000 claims 1
- 230000035945 sensitivity Effects 0.000 claims 1
- 230000000946 synaptic effect Effects 0.000 claims 1
- 239000010936 titanium Substances 0.000 claims 1
- 229910052719 titanium Inorganic materials 0.000 claims 1
- 229910052720 vanadium Inorganic materials 0.000 claims 1
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 claims 1
- 239000011701 zinc Substances 0.000 claims 1
- 229910052725 zinc Inorganic materials 0.000 claims 1
Description
本出願は、２０１９年１１月１５日に出願された米国特許仮出願第６２／９３５，９８７号及び２０２０年９月２７日に出願された米国特許仮出願第６２／０８３，９７６号の利益を主張し、その全体が参照により本明細書に組み込まれる。
政府支援条項
本発明は、米国国立科学財団によって授与されたＮＳＦ ＲＥＵ助成金番号 ＮＳＦ－ＥＥＣ １５６０００７、米国国立科学財団によって授与されたＮＳＦ ＩＵＣＲＣ ＭＩＳＴセンター助成金番号 ＮＳＦ－ＩＩＰ １４３９６８０、および米国国立衛生研究所によって授与されたＳＢＩＲ資金調達１Ｒ４３ ＥＳ０２９８８６－０１の下で政府支援を受けてなされた。政府は、本発明において一定の権利を有する。
This application has the benefit of U.S. Provisional Patent Application No. 62/935,987, filed on November 15, 2019, and U.S. Provisional Patent Application No. 62/083,976, filed on September 27, 2020. and is incorporated herein by reference in its entirety.
Government support clause
This invention is supported by NSF REU Grant No. NSF-EEC 1560007 awarded by the National Science Foundation, NSF IUCRC MIST Center Grant No. NSF-IIP 1439680 awarded by the National Science Foundation, and the National Institutes of Health. Made with government support under SBIR funding 1R43 ES029886-01. The Government has certain rights in this invention.
Claims (96)
平面導電性シートに複数の切り欠きを形成することと、
複数のマイクロニードルが前記平面導電性シートに対して直角に延びるように、前記複数の切り欠きで材料を移行させることと、
前記平面導体シートを切断し、前記複数のマイクロニードルを前記平面シートから切り離し、切り離された複数のマイクロニードルを製造することと、
前記切り離された複数のマイクロニードルを上面、下面、及び前記上面と下面の間にある縁面を備える透明な平面基板体に固定することと、
を含み、
一又は複数の導電性トレースが前記縁面と、前記下面又は上面の一方又は双方に蒸着され、
前記切り離された複数のマイクロニードルが前記導体トレース上に固定されることにより、前記複数のマイクロニードルのうち少なくとも一つのマイクロニードルと前記複数一又は複数の導電性トレースのうち少なくとも一つのトレースが導電的に接続される、
ことを特徴とする方法。 A method of manufacturing a three-dimensional microelectrode array (3D MEA), the method comprising:
Forming a plurality of notches in a planar conductive sheet;
transferring material in the plurality of cutouts such that the plurality of microneedles extend perpendicularly to the planar conductive sheet;
Cutting the planar conductor sheet and separating the plurality of microneedles from the planar sheet to produce a plurality of separated microneedles;
fixing the plurality of separated microneedles to a transparent flat substrate body having an upper surface, a lower surface, and an edge surface between the upper surface and the lower surface;
including;
one or more conductive traces are deposited on the edge surface and one or both of the bottom or top surface;
By fixing the plurality of separated microneedles on the conductor trace, at least one microneedle among the plurality of microneedles and at least one trace among the one or more conductive traces are connected. conductively connected,
A method characterized by:
ことを特徴とする請求項１記載の方法。 The planar conductive substrate is composed of a metal, a polymer-metal composite, a conductive silicon composite, or a conductive glass.
2. A method according to claim 1, characterized in that:
ことを特徴とする請求項２記載の方法。 The metal includes stainless steel, titanium, zinc, magnesium nitinol, vanadium or combinations and alloys thereof.
3. A method according to claim 2, characterized in that:
ことを特徴とする請求項１～３のいずれかに記載の方法。 the transparent planar substrate comprises glass or a transparent polymer;
The method according to any one of claims 1 to 3, characterized in that:
ことを特徴とする請求項１～４のいずれかに記載の方法。 The microneedles are at an angle of 60° or more, 70° or 80° with respect to the planar conductive sheet.
The method according to any one of claims 1 to 4, characterized in that:
ことを特徴とする請求項５記載の方法。 The microneedle has an angle of 80° or more,
6. The method according to claim 5, characterized in that:
ことを特徴とする請求項１～６のいずれかに記載の方法。 further comprising depositing an insulating layer on the plurality of microneedles;
The method according to any one of claims 1 to 6, characterized in that:
ことを特徴とする請求項７記載の方法。 The insulating layer is made of parylene, polydimethylsiloxane (PDMS), SU-8, silicon dioxide, polyimide, polyurethane, polylactic acid, polyglycolic acid, polylactic acid glycolic acid, polyvinyl alcohol, polystyrene, polyethylene glycol, polyethylene terephthalate, polyethylene terephthalate. containing glycol, polyethylene naphthalate, or a combination thereof, and is deposited so that a portion of the plurality of microelectrodes is exposed, and a portion of the microelectrode is covered with the insulating layer.
8. The method according to claim 7, characterized in that:
ことを特徴とする請求項７又は８記載の方法。 the insulating layer is deposited by narrow area precision drop casting;
The method according to claim 7 or 8, characterized in that.
ことを特徴とする請求項１～９のいずれかに記載の方法。 Following the fixing step, the method further comprises placing cells on the plurality of microneedles.
The method according to any one of claims 1 to 9, characterized in that:
ことを特徴とする請求項１０記載の方法。 The cells include electrogenic cells.
11. The method according to claim 10.
ことを特徴とする請求項１１記載の方法。 further comprising sensing electrophysiological signals from the electrogenic cells.
12. The method according to claim 11, characterized in that:
導電性材料を前記少なくとも一つの開口部を通して前記透明な平面基板体に蒸着することと、
を更に備える、
ことを特徴とする請求項１～１１のいずれかに記載の方法。 Before fixing the plurality of separated microneedles to the transparent flat substrate, at least one opening is formed so that the mask covers at least one of the upper surface or the lower surface and a part of the edge surface. applying a mask comprising a portion to the transparent planar substrate;
depositing a conductive material onto the transparent planar substrate through the at least one opening;
further comprising;
The method according to any one of claims 1 to 11, characterized in that:
ことを特徴とする請求項１３記載の方法。 The deposition is performed by electron beam deposition, resistance deposition, laser deposition, screen printing, or electroplating.
14. The method according to claim 13, characterized in that:
ことを特徴とする請求項１３又は１４記載の方法。 the masked transparent planar substrate body is held at an angle during deposition such that the conductive material is deposited on the edge surface;
The method according to claim 13 or 14, characterized in that.
ことを特徴とする請求項１５記載の方法。 the transparent planar substrate body is held at an angle by an angled deposition rig comprising a base and a bracket portion fixed at right angles to the base;
16. The method according to claim 15, characterized in that:
導電性材料を前記少なくとも一つの開口部を通して前記透明な平面基板体に蒸着することであって、前記導電性材料は前記縁面に蒸着され、前記透明な平面基板は蒸着の方向に対して角度をつけて保持されることと、を備える、
ことを特徴とする方法。 covering a transparent planar substrate with a mask having at least one opening, the transparent planar substrate having a top surface, a bottom surface, and at least one edge surface between the top surface and the bottom surface; the at least one opening overlaps the edge surface;
depositing a conductive material onto the transparent planar substrate body through the at least one opening, the conductive material being deposited on the edge surface, and the transparent planar substrate being oriented at an angle relative to the direction of deposition; and being held with a
A method characterized by:
ことを特徴とする請求項１８記載の方法。 holding the transparent planar substrate comprises associating the transparent planar substrate with an angle deposition;
19. The method according to claim 18, characterized in that:
ことを特徴とする請求項１９記載の方法。 The angled deposition uses an angled deposition rig comprising a base and a bracket fixed at right angles to the base.
20. The method according to claim 19, characterized in that:
複数のマイクロニードルを上面、下面、及び前記上面と下面の間にある縁面を備え、前記下面又は上面の一方又は双方に一又は複数の導電性トレースが蒸着された透明な平面基板体に固定することと、
少なくとも一つのフレーム部材を前記透明な平面基板に取り付けることであって、前記少なくとも一つのフレーム部材は、前記縁面が挿入される少なくとも一つの溝と、その中に画定され前記上面から前記下面に広がる少なくとも一つのチャネルを備えることと、
導電性材料を前記少なくとも一つのチャネルに蒸着し、前記導電性材料が前記少なくとも一つのトレースと導電的に接続するようにすることと、を備える、
ことを特徴とする方法。 A method of manufacturing a three-dimensional microelectrode array (3D MEA), the method comprising:
A plurality of microneedles are fixed to a transparent planar substrate body having an upper surface, a lower surface, and an edge surface between the upper surface and the lower surface, and having one or more conductive traces deposited on one or both of the lower surface and the upper surface. to do and
attaching at least one frame member to the transparent planar substrate, the at least one frame member having at least one groove defined therein into which the edge surface is inserted and extending from the upper surface to the lower surface; comprising at least one channel extending;
depositing a conductive material in the at least one channel such that the conductive material is in conductive connection with the at least one trace;
A method characterized by:
ことを特徴とする請求項２１記載の方法。 The plurality of microneedles are composed of a metal polymer metal composite, silicon and/or conductive glass,
22. A method according to claim 21, characterized in that.
ことを特徴とする請求項２１又は２２記載の方法。 The transparent planar substrate includes glass.
23. The method according to claim 21 or 22, characterized in that:
前記平面導電性シートに対して直角に延びるように、前記複数の切り欠きで材料を移行させることと、
前記平面導体シートを切断し、前期複数のマイクロニードルを前期平面シートから切り離し、切り離された複数のマイクロニードルを製造することと、
によって、前記固定ステップの前に前記複数のマイクロニードルを製造する、
ことを特徴とする請求項２１～２３のいずれかに記載の方法。 Forming a plurality of notches in a planar conductive sheet;
transferring material in the plurality of cutouts so as to extend perpendicularly to the planar conductive sheet;
Cutting the planar conductor sheet and separating the plurality of microneedles from the planar sheet to produce a plurality of separated microneedles;
manufacturing the plurality of microneedles before the fixing step, by
The method according to any one of claims 21 to 23, characterized in that:
ことを特徴とする請求項２４記載の方法。 The plurality of microneedles are at an angle of 60° or more, 70° or 80° with respect to the planar conductive sheet.
25. The method according to claim 24, characterized in that:
ことを特徴とする請求項２４記載の方法。 The plurality of microneedles are at an angle of 80° or more,
25. A method according to claim 24, characterized in that:
ことを特徴とする請求項２１～２６のいずれかに記載の方法。 further comprising depositing an insulating layer on the plurality of microneedles;
The method according to any one of claims 21 to 26, characterized in that:
ことを特徴とする請求項２７記載の方法。 The insulating layer is made of parylene, polydimethylsiloxane (PDMS), SU-8, silicon dioxide, polyimide, polyurethane, polylactic acid, polyglycolic acid, polylactic acid glycolic acid, polyvinyl alcohol, polystyrene, polyethylene glycol, polyethylene terephthalate, polyethylene terephthalate. contains glycol, polyethylene naphthalate, or a combination thereof, and is deposited so that a portion of the plurality of microelectrodes is exposed, and a portion of the microelectrode is covered with the insulating layer.
28. A method according to claim 27, characterized in that.
ことを特徴とする請求項２７又は２８記載の方法。 the insulating layer is deposited by narrow area precision drop casting;
29. A method according to claim 27 or 28, characterized in that.
ことを特徴とする請求項２１～２９のいずれかに記載の方法。 Following the fixing step, the method further comprises placing cells on the plurality of microneedles.
The method according to any one of claims 21 to 29, characterized in that:
ことを特徴とする請求項３０記載の方法。 the cell is an electrogenic cell,
31. The method of claim 30.
ことを特徴とする請求項３１記載の方法。 further comprising sensing electrophysiological signals from the electrogenic cells.
32. A method according to claim 31, characterized in that.
前記透明な平面基板体に蒸着される複数の導電性トレースと、
ステンレス鋼で構成される複数の微細加工３Ｄマイクロニードルであって、前記複数の３Ｄマイクロニードルのうち少なくとも一つのマイクロニードルが前記複数の導電性トレースのうち少なくとも一つと導電的に接続するように前記透明な平面基板体に取り付けられる複数の微細加工３Ｄマイクロニードルと、
を備え、
任意で、前記透明な平面基板体と関連付けられた少なくとも一つのフレーム部材であって、前記少なくとも一つのフレーム部材は、前記縁面が挿入される少なくとも一つの溝と、その中に画定され前記上面から前記下面に広がる少なくとも一つのチャネルと、前記少なくとも一つのチャネル内に蒸着されることで、前記複数の導電性トレースのうち少なくとも一つとの導電的な接続を提供する導電性材料と、を備える少なくとも一つのフレーム部材を備える、
ことを特徴とする３Ｄ ＭＥＡ。 a transparent planar substrate body comprising an upper surface, a lower surface, and an edge surface between the upper surface and the lower surface;
a plurality of conductive traces deposited on the transparent planar substrate;
a plurality of microfabricated 3D microneedles constructed of stainless steel, wherein at least one microneedle of the plurality of 3D microneedles is in conductive connection with at least one of the plurality of conductive traces; a plurality of microfabricated 3D microneedles attached to a transparent flat substrate;
Equipped with
Optionally, at least one frame member associated with the transparent planar substrate body, the at least one frame member having at least one groove defined therein into which the edge surface is inserted and the upper surface a conductive material deposited within the at least one channel to provide conductive connection with at least one of the plurality of conductive traces. comprising at least one frame member;
3D MEA is characterized by:
複数のマイクロニードルが前記平面導電性シートに対して直角に延びるように、前記複数の切り欠きで材料を移行させることと、
前記平面導体シートを切断し、前期複数のマイクロニードルを前記平面シートから切り離し、切り離された複数のマイクロニードルを製造することと、
によって、前記複数の微細加工３Ｄマイクロニードルが製造される、
ことを特徴とする請求項３４記載の３Ｄ ＭＥＡ。 Forming a plurality of notches in a planar conductive sheet;
transferring material in the plurality of cutouts such that the plurality of microneedles extend perpendicularly to the planar conductive sheet;
Cutting the planar conductor sheet and separating the plurality of microneedles from the planar sheet to produce a plurality of separated microneedles;
The plurality of microfabricated 3D microneedles are manufactured by,
35. The 3D MEA according to claim 34.
ことを特徴とする請求項３４又は３５記載の３Ｄ ＭＥＡ。 Further comprising an insulating layer on the plurality of microneedles so that a portion of the plurality of microneedles is exposed and a portion of the microneedle is covered thereby.
36. The 3D MEA according to claim 34 or 35.
ことを特徴とする請求項３６記載の３Ｄ ＭＥＡ。 The insulating layer is made of parylene, polydimethylsiloxane (PDMS), SU-8, silicon dioxide, polyimide, polyurethane, polylactic acid, polyglycolic acid, polylactic acid glycolic acid, polyvinyl alcohol, polystyrene, polyethylene glycol, polyethylene terephthalate, polyethylene terephthalate. composed of glycol, polyethylene naphthalate, or a combination thereof;
37. The 3D MEA according to claim 36.
ことを特徴とする請求項３６又は３７記載の３Ｄ ＭＥＡ。 the insulating layer is deposited by narrow area precision drop casting;
38. The 3D MEA according to claim 36 or 37.
ことを特徴とする請求項３４～３８のいずれかに記載の３Ｄ ＭＥＡ。 further comprising cells disposed on the plurality of microneedles;
39. The 3D MEA according to any one of claims 34 to 38.
ことを特徴とする請求項３９記載の３Ｄ ＭＥＡ。 the cell is an electrogenic cell,
40. The 3D MEA according to claim 39.
ことを特徴とする請求項３９記載の３Ｄ ＭＥＡ。 The conductive material includes silver, gold, graphene or carbon nanotubes.
40. The 3D MEA according to claim 39.
前記透明な平面基板体の前記縁面と、前記上面又は下面の一方又は双方に蒸着される複数の導電性トレースと、
ステンレス鋼で構成される複数の微細加工３Ｄマイクロニードルであって、前記複数の３Ｄマイクロニードルのうち少なくとも一つのマイクロニードルが前記複数の導電性トレースのうち少なくとも一つと導電的に接続するように前記透明な平面基板体に取り付けられる複数の微細加工３Ｄマイクロニードルと、
を備える、
ことを特徴とする３Ｄ ＭＥＡ。 a transparent planar substrate body comprising an upper surface, a lower surface, and an edge surface between the upper surface and the lower surface;
a plurality of conductive traces deposited on the edge surface and one or both of the top or bottom surface of the transparent planar substrate body;
a plurality of microfabricated 3D microneedles constructed of stainless steel, wherein at least one microneedle of the plurality of 3D microneedles is in conductive connection with at least one of the plurality of conductive traces; a plurality of microfabricated 3D microneedles attached to a transparent flat substrate;
Equipped with
3D MEA is characterized by:
複数のマイクロニードルが前記平面導電性シートに対して直角に延びるように、前記複数の切り欠きで材料を移行させることと、
前記平面導体シートを切断し、前期複数のマイクロニードルを前記平面シートから切り離し、切り離された複数のマイクロニードルを製造することと、
によって、前記複数の微細加工３Ｄマイクロニードルが製造される、
ことを特徴とする請求項４２記載の３Ｄ ＭＥＡ。 Forming a plurality of notches in a planar conductive sheet;
transferring material in the plurality of cutouts such that the plurality of microneedles extend perpendicularly to the planar conductive sheet;
Cutting the planar conductor sheet and separating the plurality of microneedles from the planar sheet to produce a plurality of separated microneedles;
The plurality of microfabricated 3D microneedles are manufactured by,
43. The 3D MEA according to claim 42.
ことを特徴とする請求項４２又は４３記載の３Ｄ ＭＥＡ。 Further comprising an insulating layer on the plurality of microneedles so that a portion of the plurality of microneedles is exposed and a portion of the microneedle is covered thereby.
44. The 3D MEA according to claim 42 or 43.
ことを特徴とする請求項４４記載の３Ｄ ＭＥＡ。 The insulating layer is made of parylene, polydimethylsiloxane (PDMS), SU-8, silicon dioxide, polyimide, polyurethane, polylactic acid, polyglycolic acid, polylactic acid glycolic acid, polyvinyl alcohol, polystyrene, polyethylene glycol, polyethylene terephthalate, polyethylene terephthalate. containing glycol, polyethylene naphthalate, or a combination thereof;
45. The 3D MEA according to claim 44.
ことを特徴とする請求項４４又は４５記載の３Ｄ ＭＥＡ。 the insulating layer is deposited by narrow area precision drop casting;
46. The 3D MEA according to claim 44 or 45.
ことを特徴とする請求項４２～４６のいずれかに記載の３Ｄ ＭＥＡ。 further comprising cells disposed on the plurality of microneedles;
47. The 3D MEA according to any one of claims 42 to 46.
ことを特徴とする請求項４７記載の３Ｄ ＭＥＡ。 the cell is an electrogenic cell,
48. The 3D MEA according to claim 47.
ことを特徴とする請求項３４記載の３Ｄ ＭＥＡ。 The conductive material includes silver, gold, graphene or carbon nanotubes.
35. The 3D MEA according to claim 34.
ことを特徴とする請求項４２～４９のいずれかに記載の３Ｄ ＭＥＡ。 The transparent planar substrate body includes glass.
50. The 3D MEA according to any one of claims 42 to 49.
ことを特徴とする請求項４２～５０のいずれかに記載の３Ｄ ＭＥＡ。 further comprising a culture well associated with the transparent planar substrate such that a liquid solution may be retained over the plurality of microneedles;
51. The 3D MEA according to any one of claims 42 to 50.
ことを特徴とする請求項３４～４１のいずれかに記載の３Ｄ ＭＥＡ。 further comprising a culture well associated with the transparent planar substrate such that a liquid solution may be retained over the plurality of microneedles;
42. The 3D MEA according to any one of claims 34 to 41.
起電性細胞から電気生理学的信号を検知することと、
を備える、
ことを特徴とする方法。 Obtaining the 3D MEA according to claim 48;
detecting electrophysiological signals from electrogenic cells;
Equipped with
A method characterized by:
起電性細胞から電気生理学的信号を検知することと、
を含む、
ことを特徴とする方法。 Obtaining the 3D MEA according to claim 40;
detecting electrophysiological signals from electrogenic cells;
including,
A method characterized by:
前記縁面、前記上面又は下面、もしくはその組み合わせに蒸着される複数の導電性トレースと、
複数の微細加工３Ｄマイクロニードルであって、前記複数の３Ｄマイクロニードルのうち少なくとも一つのマイクロニードルが前記複数の導電性トレースのうち少なくとも一つと導電的に接続するように前記透明な平面基板体に取り付けられ、前記複数の微細加工３Ｄマイクロニードルは、３Ｄマイクロニードルの第１のセットを備え、第１の幅寸法と第１の長さ寸法を有する第１部分と、３Ｄマイクロニードルの第２のセットを備え、第２の幅寸法と第２の長さ寸法を有する第２部分とを備える組立体において提供され、前記第２の幅寸法は前記第１の幅寸法より大きく、前記第１の長さ寸法は前記第２の長さ寸法より大きく、そして、任意で、前記複数の微細加工３Ｄマイクロニードルは、導電的に分離されている複数の微細加工３Ｄマイクロニードルと、
を備える、
ことを特徴とする３Ｄ ＭＥＡ。 a transparent planar substrate body comprising an upper surface, a lower surface, and an edge surface between the upper surface and the lower surface;
a plurality of conductive traces deposited on the edge surface, the top or bottom surface, or a combination thereof;
a plurality of microfabricated 3D microneedles on the transparent planar substrate body such that at least one microneedle of the plurality of 3D microneedles is in conductive connection with at least one of the plurality of conductive traces; attached, the plurality of microfabricated 3D microneedles comprising a first set of 3D microneedles, a first portion having a first width dimension and a first length dimension, and a second portion of the 3D microneedles. a second portion having a second width dimension and a second length dimension, the second width dimension being greater than the first width dimension; a length dimension is greater than the second length dimension, and optionally, the plurality of microfabricated 3D microneedles are electrically conductively separated;
Equipped with
3D MEA is characterized by:
ことを特徴とする請求項５５記載の３Ｄ ＭＥＡ。 The first set comprises about 8 3D microelectrodes and the second set comprises about 2 3D microelectrodes.
56. The 3D MEA according to claim 55.
ことを特徴とする請求項５５記載の３Ｄ ＭＥＡ。 The first width dimension is about 10-500 μm, the first length dimension is about 10-500 μm, the second width dimension is about 10-500 μm, and the second length dimension is about 10-500 μm. is about 10 to 500 μm,
56. The 3D MEA according to claim 55.
ことを特徴とする請求項５５～５７のいずれかに記載の３Ｄ ＭＥＡ。 The first portion and the second portion form a geometric shape in which the first portion corresponds to a neural tube of a neuron and the second portion corresponds to a ganglion of a neuron.
58. The 3D MEA according to any one of claims 55 to 57.
ことを特徴とする請求項５５～５８のいずれかに記載の３Ｄ ＭＥＡ。 further comprising one or more cells arranged on the plurality of microneedles,
59. The 3D MEA according to any one of claims 55 to 58.
ことを特徴とする請求項５９記載の３Ｄ ＭＥＡ。 The one or more cells include one or more nerve cells,
60. The 3D MEA according to claim 59.
ことを特徴とする請求項６０記載の３Ｄ ＭＥＡ。 The one or more neural cells include peripheral nervous system neurons, central nervous system neurons, Schwann cells, oligodendrocytes, microglial cells, glial cells, other peripheral or central nervous support cells, or combinations thereof.
61. The 3D MEA according to claim 60.
ことを特徴とする請求項１記載の方法。 The plurality of detached microneedles comprises a first set of 3D microneedles, a first portion having a first width dimension and a first length dimension, and a second set of 3D microneedles. , a second portion having a second width dimension and a second length dimension, the second width dimension being greater than the first width dimension, and the first length dimension being larger than the second length dimension. greater than a length dimension, and optionally further comprising conductively separating the plurality of 3D microneedles.
2. A method according to claim 1, characterized in that:
ことを特徴とする請求項２１記載の方法。 The plurality of 3D microneedles comprises a first set of 3D microneedles, the first portion having a first width dimension and a first length dimension, a second set of 3D microneedles, and a first portion having a first width dimension and a first length dimension. a second portion having a second width dimension and a second length dimension, the second width dimension being greater than the first width dimension, and the first length dimension being the second length dimension; larger than the dimension, and optionally further comprising conductively separating the plurality of 3D microneedles.
22. A method according to claim 21, characterized in that.
ことを特徴とする請求項３４～５２のいずれかに記載の３Ｄ ＭＥＡ。 The plurality of 3D microneedles comprises a first set of 3D microneedles, the first portion having a first width dimension and a first length dimension, a second set of 3D microneedles, and a first portion having a first width dimension and a first length dimension. a second portion having a second width dimension and a second length dimension, the second width dimension being greater than the first width dimension, and the first length dimension being the second length dimension; the plurality of microfabricated 3D microneedles, and optionally further comprising conductively separating the plurality of micromachined 3D microneedles;
53. The 3D MEA according to any one of claims 34 to 52.
ことを特徴とする請求項６４記載の３Ｄ ＭＥＡ。 The first portion and the second portion form a geometric shape in which the first portion corresponds to a neural tube of a neuron and the second portion corresponds to a ganglion of a neuron.
65. The 3D MEA according to claim 64.
ことを特徴とする請求項３４～５２、６４又は６５のいずれかに記載の３Ｄ ＭＥＡ。 The 3D MEA is configured to measure compound action potentials to estimate conduction velocity, amplitude, integral, excitability after compound administration, threshold, sensitivity, CAP duration, CAP waveform shape, or a combination thereof. Ru,
66. The 3D MEA according to any one of claims 34 to 52, 64, or 65.
ことを特徴とする請求項１０～１２及び３０～３２のいずれかに記載の方法。 The plurality of cells include one or more nerve cells,
The method according to any one of claims 10 to 12 and 30 to 32, characterized in that:
ことを特徴とする請求項６７記載の方法。 The one or more neural cells include peripheral nervous system neurons, central nervous system neurons, Schwann cells, oligodendrocytes, microglial cells, glial cells, other peripheral or central nervous support cells, or combinations thereof.
68. The method of claim 67.
ことを特徴とする請求項３９、４０、４７、４８のいずれかに記載の３Ｄ ＭＥＡ。 The cells include one or more nerve cells,
49. The 3D MEA according to any one of claims 39, 40, 47, and 48.
ことを特徴とする請求項６９記載の３Ｄ ＭＥＡ。 The one or more neural cells include peripheral nervous system neurons, central nervous system neurons, Schwann cells, oligodendrocytes, microglial cells, glial cells, other peripheral or central nervous system supporting cells, or combinations thereof.
70. The 3D MEA according to claim 69 .
ことを特徴とする請求項３９～５２、５５～６１、６４～６６、６９又は７０のいずれかに記載の３Ｄ ＭＥＡ。 At least one of the plurality of microneedles has a maximum height of about 1000 μm.
71. The 3D MEA according to any one of claims 39 to 52, 55 to 61, 64 to 66, 69 , or 70 .
ことを特徴とする請求項７１記載のマイクロ電極アレイ。 the at least one three-dimensional electrode has a height between about 300 μm and about 1000 μm;
72. The microelectrode array according to claim 71 .
ことを特徴とする請求項７１記載のマイクロ電極アレイ。 the at least one three-dimensional electrode has a height of up to about 150 μm;
72. The microelectrode array according to claim 71 .
ことを特徴とする請求項７１記載のマイクロ電極アレイ。 the at least one three-dimensional electrode has a height between about 50 μm and about 150 μm;
72. The microelectrode array according to claim 71 .
ことを特徴とする請求項５５又は６４記載の３Ｄ ＭＥＡ。 The 3D MEA provides real-time and reliable sensing of one or more bioelectrical signals in a microengineered physiological system.
65. The 3D MEA according to claim 55 or 64.
ことを特徴とする請求項７５記載の３Ｄ ＭＥＡ。 The microengineered physiological system comprises a tissue graft, a cell suspension, or a combination thereof.
76. The 3D MEA according to claim 75 .
ことを特徴とする請求項７５記載の３Ｄ ＭＥＡ。 The microengineered physiological system comprises neural cells cultured on a micropatterned platform or tissue grafts seeded on a micropatterned platform, and the micropatterned platform facilitates the formation of neural constructs. the neural structure comprises an axonal growth region, a ganglion region, a dendritic region, a synaptic region, a spheroid region, or a combination thereof;
76. The 3D MEA according to claim 75 .
ことを特徴とする請求項７７記載の３Ｄ ＭＥＡ。 The second part is arranged in the ganglion region or the spheroid region, and the first part comprises a plurality of microneedles arranged at defined intervals below the axon growth region.
78. The 3D MEA according to claim 77 .
ことを特徴とする請求項７８記載の３Ｄ ＭＥＡ。 the first set of 3D microneedles, the second set of 3D microneedles, or both comprise recording electrodes, stimulation electrodes, or a combination thereof;
79. The 3D MEA according to claim 78 .
ことを特徴とする請求項７８記載の３Ｄ ＭＥＡ。 the defined spacing includes a spacing of up to about 50 μm;
79. The 3D MEA according to claim 78 .
ことを特徴とする請求項７５記載の３Ｄ ＭＥＡ。 the microelectrode array provides sensing of one or more bioelectrical signals in the microengineered physiological system for up to one year;
76. The 3D MEA according to claim 75 .
ことを特徴とする請求項８１記載の３Ｄ ＭＥＡ。 the microelectrode array provides sensing of one or more bioelectrical signals in the microengineered physiological system for up to about 8 weeks;
82. The 3D MEA according to claim 81 .
ことを特徴とする請求項８１又は８２記載の３Ｄ ＭＥＡ。 The 3D MEA is configured to allow simultaneous electrophysiological and optical tracking of the microengineered physiological system while the microengineered physiological system is maturing.
83. The 3D MEA according to claim 81 or 82 .
前記マイクロエンジニアリング生理学的システムにおける一又は複数の生体電気信号の検知をリアルタイムで行うこと、
を更に備える、
ことを特徴とする請求項６２又は６３記載の方法。 placing neuronal cells on at least a portion of the second portion or seeding a tissue graft on at least a portion of the second portion; forming a microengineered physiological system by growing it on;
sensing one or more bioelectrical signals in the microengineered physiological system in real time;
further comprising;
64. A method according to claim 62 or 63, characterized in that.
ことを特徴とする請求項８４記載の方法。 the first plurality of electrodes, the second plurality of electrodes, or both comprise recording electrodes, stimulation electrodes, or a combination thereof;
85. The method of claim 84 .
を更に備える、
ことを特徴とする請求項８４記載の方法。 sensing a bioelectrical signal within the microengineered physiological system during formation and optically tracking the microengineered physiological system; and sensing a bioelectrical signal within the microengineering physiological system; and optically tracking said microengineered physiological system for up to one year;
further comprising;
85. The method of claim 84 .
ことを特徴とするシステム。 76. A system for reproducibly sensing compound action potentials in a microengineered physiological system, the system comprising the 3D MEA of claim 75 , wherein the microengineered physiological system comprises one or more neuronal cells. Equipped with
A system characterized by:
ことを特徴とする請求項１～１６又は２１～３１のいずれかに記載の方法。 further comprising conductively separating the plurality of 3D microneedles;
The method according to any one of claims 1 to 16 or 21 to 31, characterized in that:
平面導電性シートに複数の切り欠きを形成することと、
複数のマイクロニードルが前記平面導電性シートに対して直角に延びるように、前記複数の切り欠きで材料を移行させることと、
前記平面導体シートを切断し、前期複数のマイクロニードルを前期平面シートから切り離し、切り離された複数のマイクロニードルを製造することと、
前記切り離された複数のマイクロニードルを上面、下面、及び前記上面と下面の間にある縁面を備える透明な平面基板体に固定することと、
を備える方法。 A method of manufacturing a three-dimensional microelectrode array (3D MEA), the method comprising:
Forming a plurality of notches in a planar conductive sheet;
transferring material in the plurality of cutouts such that the plurality of microneedles extend perpendicularly to the planar conductive sheet;
Cutting the planar conductor sheet and separating the plurality of microneedles from the planar sheet to produce a plurality of separated microneedles;
fixing the plurality of separated microneedles to a transparent flat substrate body having an upper surface, a lower surface, and an edge surface between the upper surface and the lower surface;
How to prepare.
ことを特徴とする請求項８９記載の方法。 one or more conductive traces are deposited on the edge surface and/or on the bottom or top surface;
90. The method of claim 89 .
導電性材料を前記少なくとも一つのチャネルに蒸着し、前記導電性材料が前記少なくとも一つのトレースと導電的に接続するようにすることと、
を更に備える、
ことを特徴とする請求項８９記載の方法。 attaching to the transparent planar substrate body at least one frame member having at least one groove into which the edge surface is inserted and at least one channel defined therein extending from the upper surface to the lower surface;
depositing a conductive material in the at least one channel such that the conductive material is in conductive connection with the at least one trace;
further comprising;
90. The method of claim 89 .
ことを特徴とする請求項８９記載の方法。 The plurality of detached microneedles comprises a first set of 3D microneedles, a first portion having a first width dimension and a first length dimension, and a second set of 3D microneedles. , a second portion having a second width dimension and a second length dimension, the second width dimension being greater than the first width dimension, and the first length dimension being larger than the second length dimension. greater than a length dimension, and optionally further comprising conductively separating the plurality of 3D microneedles.
90. The method of claim 89 .
ことを特徴とする請求項５記載の方法。 The angle is about 60° to 90°, about 70° to 90°, or about 80° to 90°,
6. The method according to claim 5, characterized in that:
ことを特徴とする請求項１５又は１８～２０のいずれかに記載の方法。 The angle of the substrate body is about 25° to 85° with respect to the direction of the vapor deposition.
The method according to claim 15 or any one of claims 18 to 20.
ことを特徴とする請求項９４記載の方法。 the angle of the substrate is about 40° to 50° with respect to the angle of deposition;
95. The method of claim 94.
ことを特徴とする請求項９４又は９５記載の方法。 said vapor deposition is performed using an electron beam;
96. The method according to claim 94 or 95 .
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| US63/083,976 | 2020-09-27 | ||
| PCT/US2020/060779 WO2021097447A1 (en) | 2019-11-15 | 2020-11-16 | 3d microelectrode array (mea) for optical and electrical probing of electrogenic cells |
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