WO2020214802A1 - Micro-aiguille ultra-pointue - Google Patents

Micro-aiguille ultra-pointue Download PDF

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Publication number
WO2020214802A1
WO2020214802A1 PCT/US2020/028497 US2020028497W WO2020214802A1 WO 2020214802 A1 WO2020214802 A1 WO 2020214802A1 US 2020028497 W US2020028497 W US 2020028497W WO 2020214802 A1 WO2020214802 A1 WO 2020214802A1
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WO
WIPO (PCT)
Prior art keywords
microneedle
membrane
lumen
base
tip
Prior art date
Application number
PCT/US2020/028497
Other languages
English (en)
Inventor
Aykut AKSIT
Jeffrey W. KYSAR
Anil K. LALWANI
Original Assignee
The Trustees Of Columbia University In The City Of New York
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Trustees Of Columbia University In The City Of New York filed Critical The Trustees Of Columbia University In The City Of New York
Publication of WO2020214802A1 publication Critical patent/WO2020214802A1/fr
Priority to US17/503,304 priority Critical patent/US20220032023A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/84—Drainage tubes; Aspiration tips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/329—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles characterised by features of the needle shaft
    • A61M5/3291—Shafts with additional lateral openings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/003—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0612—Eyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2210/00—Anatomical parts of the body
    • A61M2210/06—Head
    • A61M2210/0662—Ears

Definitions

  • the disclosed subject matter describes an apparatus for controlled precision of perforating a thin membrane and delivery or aspiration of fluid. More particularly, the subject matter described is an ultra-sharp microneedle configured to produce a controlled and precisely shaped and sized perforation in a thin membrane, for example, of the inner ear. Further, the needle apparatus may be configured for safe, controlled, local injection delivery to or aspiration of fluid across the thin membrane.
  • Symptoms such as hearing loss, tinnitus, and vertigo - which can have
  • volumes of this size are quite significant with regards to the total size of the cochlea, and can create problems if not replaced, especially with volumes over 3 pL. This can be crucial for some potential diagnostic tests which require large amounts of biofluids to be processed. Artificial perilymph is known to be a good substitute for perilymph, and can be created easily. It would be useful to be able to withdraw a sample of perilymph from a subject’s inner ear while simultaneously replacing it with an equal volume of artificial perilymph.
  • An ultra-sharp microneedle is provided.
  • the microneedle is sized for use in the eye, ear and central nervous system.
  • the microneedle has multi-lumen for simultaneous delivery and sampling into a fixed volume of biological tissue.
  • the microneedle generally includes a base disposed at a proximal end of the microneedle body and a tip disposed at the distal end of the microneedle body.
  • a cylindrical shaft having a longitudinal body is disposed between the base and the tip.
  • the base, shaft and tip may be integral.
  • the base can have a cylindrical shape configured to mount onto a medical instrument, such as a syringe.
  • the microneedle may be mounted on a 30 gauge syringe.
  • the base has a width greater than the width of the tip, and in some embodiments is also greater than the shaft. In other words, for a cylindrical base and shaft, the diameter of the base is greater than the diameter of the shaft.
  • the base is sized to mount and securely engage an instrument such as a driver or syringe.
  • an instrument such as a driver or syringe.
  • mounting on a hollow or solid material of any cross-sectional shape may be achieved.
  • the mount may also consist of one or more lumen that would allow the delivery or aspiration of varying amounts of material through each lumen.
  • the at least one lumen defines a channel that provides fluid communication and passage through at least the shaft of the needle.
  • the lumen is disposed within at least the shaft cylindrical body of the microneedle.
  • An opening is defined at the distal end of the lumen body and also at a loci of the shaft body to communicate to the exterior of the microneedle.
  • the opening is offset from a central longitudinal axis of the tip.
  • the central longitudinal axis of the tip may also be the central longitudinal axis of the shaft. In this regard, the opening would also be offset from the shaft central axis.
  • the at least one lumen has a body may extend through the base to the shaft of the microneedle. Thus, the lumen may terminate prior to or proximate the tip of the microneedle.
  • the tip includes a sharp, pointed apex.
  • the tip may have 500-nm curvature of radius.
  • the shaft may have a total length of about 350 micrometers.
  • the maximum tip diameter may be about 10-20 microns.
  • the shaft in some embodiments has a tapered longitudinal, cylindrical body configured with a taper along a portion of its length.
  • the a microneedle comprising a base, a shaft, a sharp tip and two or more lumens wherein a first lumen provides fluid communication and passage from a first portion of the base of the microneedle to a first locus proximate to the tip of the microneedle and a second lumen provides fluid communication and passage from a second portion of the base of the microneedle to a second locus on the shaft of the microneedle.
  • the first locus and the second locus are diametrically opposed on the microneedle, e.g., shaft.
  • the microneedle may have a maximum tip diameter of about 10-20 microns.
  • the microneedle shaft is configured with a taper along a portion of its length.
  • the taper comprises a gradual taper having a gradual decrease in diameter along the length of the microneedle.
  • the taper may comprise a stepped taper with abrupt changes in diameter that serve as reinforcing ribs or ledges.
  • the microneedle distal portion comprises a narrow sharp tip, the proximal end may comprise a wide base and a shaft between the tip and the base.
  • the base of the distal portion may comprise one or more projections or barbs that engage the distal side of the membrane after penetration through the membrane and is held in place thereby.
  • the base may be configured to physically engage a driver device capable of creating temporary perforations in an anatomic membrane.
  • The may be configured to penetrate an anatomic membrane and simultaneously inject a first liquid into the distal side of the membrane and withdraw a second liquid from the distal side of the membrane.
  • the anatomic membrane may be a membrane of the inner ear.
  • one lumen is an aspirating lumen which is connected to a suction device, such as a vacuum source, to suction a fluid from the distal side of the membrane.
  • a suction device such as a vacuum source
  • the same or a second lumen may an injection lumen which is connected to an injection device, such as a syringe, to inject a fluid into the distal side of the membrane.
  • a medical device comprises the microneedle described in any of the embodiments above, wherein the base the microneedle is physically engaged with a driver device capable of creating temporary perforations in an anatomic membrane and simultaneously inject a first liquid into the distal side of the membrane and withdraw a second liquid from the distal side of the membrane.
  • the membrane may be the round window membrane of an inner ear.
  • the microneedle and the driver comprise separate components that are engaged to each other to define a modular system.
  • the medical device may further comprise an indicator to indicate when the membrane is fully penetrated by the microneedle.
  • a method of delivering a therapeutic agent through an anatomic membrane includes positioning a microneedle proximate the membrane wherein the microneedle is configured to penetrate the membrane. Perforating the anterior side of the membrane, dispensing a therapeutic agent at the perforation from a first lumen and withdrawing an amount of fluid from the posterior side of the membrane, wherein the amount of fluid withdrawn is substantially equivalent to the amount of the therapeutic agent injected. The withdrawal and aspiration steps can occur simultaneously.
  • the method delivers a therapeutic agent into the cochlea and comprises positioning at least one microneedle proximate the round window membrane.
  • the microneedle is configured to penetrate the round window membrane, and the method includes perforating the round window membrane, dispensing a therapeutic agent at said perfbration(s), and withdrawing perilymph from the inner ear.
  • the microneedle can sample microliter amounts of perilymph fluid, such as aspirating 1 microliter of perilymph fluid.
  • the sampling does not cause lasting damage to hearing and heals within hours, such as 72 hours after perforation. Perforations with the microneedle described herein may also result in no hearing loss.
  • the method comprises positioning a microneedle proximate the membrane wherein the microneedle is configured to penetrate the membrane, perforating the membrane, sampling the bodily fluid at said perforation via a first lumen by withdrawing an amount of fluid from the posterior side of the membrane, and dispensing a second fluid into the posterior side of the membrane that is substantially equivalent or equivalent to the amount of bodily fluid withdrawn via a second lumen.
  • the method is for sampling a subject’s perilymph from the cochlea and comprises positioning at least one microneedle proximate the round window membrane wherein the microneedle is configured to penetrate the round window membrane; perforating the round window membrane; withdrawing perilymph from the inner ear via a first lumen; and dispensing artificial perilymph into the distal side of the membrane that is substantially equivalent or equivalent to the amount of the subject’s perilymph withdrawn via a second lumen.
  • FIGURE l is a schematic illustration of a microneedle in accordance with the disclosed subject matter.
  • FIGURE 2 is another schematic illustration of the microneedle of FIGURE 1.
  • FIGURE 3 is another schematic illustration of an offset lumen within the shaft of the microneedle of FIGURE 1
  • FIGURE 4 shows perspective views of another embodiment of a microneedle in accordance with the disclosed subject matter.
  • FIGURES 5 A - 5D show schematic views of a microneedle in accordance with the disclosed subject matter.
  • FIGURES 6 A and 6B shows top and cross-section schematic views of a microneedle according to an embodiment of this disclosure.
  • FIGURE 7A-7D show schematic views of a mold for fabricating a microneedle by two- photon templated electrodeposition according to an embodiment of this disclosure.
  • FIGURE 8 shows top and cross-section schematic views of a microneedle mold according to an embodiment of this disclosure, similar to the embodiment shown in FIGURES
  • FIGURE 9 shows a view of an array of microneedles on a unitary base according to an embodiment of this disclosure.
  • a microneedle for controlled precision of perforating a thin membrane and delivery or aspiration of fluid.
  • the microneedle may be configured to produce a controlled and precisely shaped and sized perforation in a thin membrane, for example, of the inner ear.
  • the microneedle may achieve a safe, reliable method for intracochlear delivery.
  • the microneedle 10 generally comprises a base 101, shaft 102 and ultra-sharp, pointed tip 103.
  • a lumen 104 having a longitudinal body is disposed within the shaft 102.
  • the lumen 104 defines a channel for fluid communication and passageway from a first portion of the microneedle to a first opening 105 defined at the distal end of the lumen and a locus of the shaft 102, said opening 105 proximate to the end of tip 103.
  • first opening 105 is offset from a center longitudinal axis 110 of the shaft 102 and tip 103.
  • first opening 105 may have a diameter of about 30 micrometers, and first opening 105 is offset from the center longitudinal axis 110 of the shaft and/or tip apex by about 25 micrometers.
  • the base includes a first section defined by a cylindrical body 112 and skirt 114. Skirt 114 may function as a stop in certain applications.
  • base 101 further includes leg members 116, as shown in FIGURE 3.
  • the shaft 102 has a length extending from the base 101 to the tip 103.
  • the first section is defined by a cylindrical, hollow body having a substantially uniform diameter.
  • the second section is defined by a conical, shaped body defined by a taper along a portion of its length terminating at a sharp or pointed tip.
  • the tip is closed, i.e., does not have a port or opening. In some embodiments depending on the
  • the microneedle may a maximum tip diameter of about 10-20 microns.
  • Lumen 104 extends from shaft 102 through to or through at least a portion of base 101, and has a second opening (not shown) disposed in base 101.
  • Base 101 is configured to mount to a commercially available standard blunt syringe.
  • second opening of lumen is in fluid communication with syringe and provides a channel for passage of therapeutic agent from syringe through lumen 102 to opening 105 and exterior of microneedle 10.
  • Introduction of the lumen 104 through substantially the entire the microneedle body enables direct injection of fluids, such as therapeutics agents, from inside the syringe, and/or allows sampling of fluids from body, such as the inner ear, into the syringe structure.
  • the outer diameter of shaft 102 is 100 micrometers and the inner diameter is 35 micrometers, the height of the microneedle from proximal end of base 101 to distal end of tip 103, or alternatively, from proximal end of shaft 102 to distal end of tip 103 is not greater than 350 micrometers.
  • the microneedle may be configured to penetrate a thin membrane with tip 103 and is suitably sized to fit within small spaces of the anatomy, such as the cochlear, or other sites, for local delivery of therapeutic agent or aspirate fluid, such as perilymph fluid from the inner ear.
  • the ultra-sharp microneedle has a 500-nm tip radius of curvature.
  • a dual-lumen microneedle is provided.
  • the multi-lumen structure enables, for example, a sample of perilymph from a subject’s inner ear to be withdrawn, while simultaneously replacing it with an equal volume of artificial perilymph.
  • this application which should not be construed to limit the microneedle to this application, permits acquisition of samples from the cochlea for diagnostic purposes, for example in volumes of greater than I pL, for example 3 pL or more, while simultaneously replacing the withdrawn biofluid with an equal or substantially equal volume of fluid, such as artificial biofluid.
  • I pL for example 3 pL or more
  • a multi-lumen microneedle 10’ having a first lumen 104a’ and a second lumen 104b’ disposed within shaft 102’ of the microneedle is provided.
  • the first lumen 104a’ has a first opening 105a’ and second opening 106a’ and defines a first channel therebetween.
  • the first channel defined by first lumen provides fluid
  • the shaft may be hollow as depicted in FIGURE 1 -3 or only partially hollow, for example, hollow portions created by the one or more lumen, as depicted in FIGURE 4.
  • the one or more lumen may extend through the shaft or the entire microneedle including base 101. Each individual lumen could run to near the tip of the microneedle, or it could run only a portion of the way up the shaft as described.
  • Opening 105a’ is offset from the center longitudinal axis 110’ of the shaft 102’ and tip 103’.
  • the second lumen 104b’ defines a second channel for fluid communication and passageway from a second portion of the microneedle to opening 105b’ defined at the distal end of the lumen 104b’ and at a second locus of shaft 102’ proximate tip 103.
  • first opening 105a’ associated with lumen 104a’ is disposed at a first locus that is diametrically opposed to the disposition of the second opening 105b’ of second lumen 104b’ at the second locus.
  • Lumen 104b’ further includes opening 106b’ extending through base 10G, for example, through the skirt 114’ to the exterior of the microneedle 10’. In this regard, lumen 104b’ may withdraw fluid from a subject after penetration with microneedle 10’ and dispel said withdrawn fluid to the exterior of the subject and microneedle 10’.
  • FIGURE 5A-5D show schematic views of a microneedle according to an embodiment of this disclosure, similar to the embodiment shown in FIGURE 4, wherein solid lines denote visible aspects of the microneedle and dashed lines denote invisible aspects of the microneedle, for example portions of the microneedle on the interior of the microneedle.
  • a first lumen 104a’ provides fluid communication and passage from a first portion of the base of the microneedle to a first locus proximate to the tip of the microneedle and a second lumen provides fluid communication from a second portion of the base of the microneedle to a second locus on the shaft of the microneedle.
  • FIGURE 2B shows a top schematic view of the microneedle.
  • FIGURE 5C shows a side schematic view of the
  • FIGURE 5D shows a side schematic view of the microneedle, viewed along line 5D shown in FIGURE 5B.
  • FIGURE 6 shows top and cross-section schematic views of a microneedle according to an embodiment of this disclosure, similar to the embodiment shown in FIGURE 1.
  • the upper image shows a top schematic view of the microneedle, wherein solid lines denote visible aspects of the microneedle and dashed lines denote invisible aspects of the microneedle, for example portions of the microneedle on the interior of the microneedle.
  • the bottom image shows a cross-section view of the microneedle wherein the structure of the microneedle has been cut away along line A-A shown in the upper image. Solid (i.e. polymerized) portions of the microneedle are shown as hashed areas. The lumens are shown as non-hashed.
  • Microneedles according to embodiments of this disclosure may have the following dimensions.
  • a method of delivering a therapeutic agent through an anatomic membrane comprises positioning the microneedle, described herein, proximate the membrane wherein the microneedle is configured to penetrate the membrane; perforating the membrane; dispensing a therapeutic agent at said perforation from a first lumen; and withdrawing an amount of fluid from the distal side of the membrane that is equivalent to the amount of the therapeutic agent injected.
  • the method may deliver a therapeutic agent into the cochlea and comprises positioning at least one microneedle proximate the round window membrane wherein the microneedle is configured to penetrate the round window membrane; perforating the round window membrane; dispensing a therapeutic agent at said perforation(s); and withdrawing perilymph from the inner ear.
  • a method of sampling a bodily fluid through an anatomic membrane comprises positioning a microneedle proximate the membrane wherein the microneedle is configured to penetrate the membrane; perforating the membrane; sampling the bodily fluid at said perforation via a first lumen by withdrawing an amount of fluid from the distal side of the membrane; and dispensing a second fluid into the distal side of the membrane that is equivalent to the amount of bodily fluid withdrawn via a second lumen.
  • the method is for sampling a subject’s perilymph from the cochlea and comprises positioning at least one microneedle proximate the round window membrane wherein the microneedle is configured to penetrate the round window membrane; perforating the round window membrane; withdrawing perilymph from the inner ear via a first lumen; and dispensing artificial perilymph into the distal side of the membrane that is equivalent to the amount of the subject’s perilymph withdrawn via a second lumen.
  • fluid could be aspirated from the lumen exiting near the base of the microneedle at the same time a therapeutic is injected out of the lumen exiting near the tip.
  • aspiration could occur from one of the lumina while artificial perilymph (or another “inert” substance) is injected through the other.
  • This method could maintain the same volume of fluid within the cochlea thus minimizing pressure changes within the cochlea during such interventions.
  • the aspiration and injection flow rates and tidal volumes could be prescribed not to be the same to introduce purposely a change in pressure in the closed volume. Of course these same principles would apply if more than two lumina are in the microneedle.
  • the microneedles decribed herein may be fabricated using Two Photon
  • Two-Photon Polymerization (2PP) is a new technology suited for the fabrication of nearly arbitrary 3D micro- and macro-structures. Many items can be produced by either subtracting materials, such as machining or carving, or by adding materials, for example 3D printing.
  • two-photon polymerization a photosensitive material is provided and very short pulses of laser light are used to build structures within that material. Once the structure is done, the non- polymerized material is removed, by for example washing the workpiece with a suitable solvent. Using this method, complex shapes can be created that would be impossible with routine 3D printing.
  • 2PP In contrast to conventional 3D printing, 2PP is not limited to a layer-wise fabrication of the desired structure. In fact, it is an inherently 3D process technology. 2PP technology is based on a process where light triggers a chemical reaction, leading to
  • Polymerization is a process in which monomers or weakly cross-linked polymers (liquid or solid) interconnect and form three-dimensional network of highly cross-linked polymer (solid).
  • Photoinitiators molecules which have low photo dissociation energy, are often added in order to increase the material photosensitivity. Absorption of a photon in the photoreactive material leads to a bond cleavage (photo dissociation) and formation of highly reactive radicals. Absorption of a UV photon breaks C-C bond and results in the formation of two radicals, which react with the monomer, e.g. methyl methacrylate, and initiate radical polymerization. The reaction is terminated when two radicals react with each other.
  • 2PP is made possible by tightly focusing femto-second laser pulses into a transparent photopolymer.
  • the femtosecond laser radiation induces a highly localized chemical reaction leading to polymerization of the photosensitive material.
  • the photon-polymerization triggered by the laser pulses is strongly confined to the focal volume as the underlying process.
  • Two- Photon Absorption (TP A) can only occur if the intensity is sufficiently large. As a consequence, the site of the reaction i.e. the solidification of the material is located in the tiny focal volume.
  • the focal volume is scanned in 3D space followed by a solvent wash to separate the rest of the (nonpolymerized) photopolymer from the solidified 3D structure.
  • 2PP is not limited to the optical diffraction limit as the photon-polymerization is a threshold process. By adjusting the photon dose only slightly beyond the polymerization threshold, feature sizes in the order of 100 nm can be achieved.
  • Freeform microlenses and microoptics used in 2PP allow for the fabrication of more complex topographies, particularly non-spherical or free-form designs.
  • the photosensitive material is typically supported on a substrate such as silicon, borosilicate glass or fused silica, and the substrate may be transparent or opaque.
  • the microneedle(s) can be separated from the substrate.
  • the microneedle can be separated from the substrate by leaving a portion of the photopolymer adjacent to the substrate nonpolymerized, which is then removed by the solvent wash.
  • portions of the microneedle, such as a portion of the base may comprise a substrate that the polymerized microneedle remains adhered to after
  • microneedles may also be possible to create similar microneedles using two-photon templated electrodeposition, which means the microneedles will then be fully metallic.
  • This fabrication process directly links three-dimensional (3D) modeling and simulation with microscale printing and replication.
  • the process involves micromolds fabricated by 3D stereolithography directly from CAD drawings, which are then used to provide shaped metal microneedles using eletrodeposition techniques.
  • the mods may be prepared by 2PP.
  • FIGURE 7A shows a perspective schematic view of mold 700 for manufacturing a plurality of microneedles.
  • the mold comprises multiple cavities 701 -709 arranged in a 3 by 3 array (for example but not limitation) for preparing microneedles according to this disclosure.
  • the microneedles in this embodiment are similar in design to the microneedles shown in FIGURES 1 through 6.
  • the microneedles manufactured in mold 700 are metallic.
  • a first lumen provides fluid communication from a first portion of the base of the microneedle to a first locus proximate to the tip of the microneedle and a second lumen provides fluid communication from a second portion of the base of the microneedle to a second locus on the shaft of the microneedle.
  • FIGURE 7B shows a top schematic view of the microneedle mold.
  • FIGURE 7C shows a side schematic view of the microneedle mold, viewed along line 7C shown in FIGURE 7B.
  • FIGURE 7D shows a side schematic view of the microneedle, viewed along line 7D shown in FIGURE 7B.
  • FIGURE 8 shows top and cross-section schematic views of a microneedle mold according to an embodiment of this disclosure, similar to the embodiment shown in FIGURE 8A-8D.
  • the upper image shows a top schematic view of the microneedle mold, wherein solid lines denote visible aspects of the microneedle mold and dashed lines denote invisible aspects of the microneedle, for example portions of the microneedle cavities on the interior of the microneedle mold.
  • the bottom image shows a cross-section view of the microneedle mold wherein the structure of the microneedle mold has been cut away along line B-B shown in the upper image.
  • the manufacturing process can be summarized as described below.
  • High precision 3D molds can be manufactured via two-photon lithography or two-photon polymerization.
  • the fabrication method starts with manufacturing of the molds on a conductive substrate. We have shown that microneedles with 0.5 micrometer radius of curvature tips can be manufactured. Using the same order of magnitude feature sizes, the molds are made in the negative image of the desired needles by curing photoresist using two-photon lithography. The uncured photoresist is then stripped away by means of chemical treatment to leave cavities or voids in the mold. The substrate would then be left bare only at locations where the tips of the microneedles will be.
  • the substrate needs to have a conductive surface to enable electrodeposition of metal. Every part of the conductive surface, except for the bare parts inside the patterned molds will need to be masked before being submerged into the electrolyte for electrodeposition. The mold- substrate assembly would then be submerged into an electrolyte and electrochemical deposition of metal would occur, filling the cavities or voids inside the molds, taking the shape prescribed by the voids.
  • Electrochemical deposition of metal into the mold can be accomplished using a rotating disk electrode.
  • the bulk of the microneedle can be made by electodeposition of a metal such as copper.
  • the molds After the molds are filled with metal, the molds can be stripped away by means of heat treatment or chemical treatment.
  • the metal needles may be released as a final step by electropolishing or etching the underlying layer of material. Because copper is not
  • the microneedles are treated to put conformal layers of 1.5 microns of nickel and lOOnm of immersion gold to ensure biocompatibility. Conformal coating can be verified via energy-dispersive X-ray spectroscopy.
  • the microneedle(s) may be prepared in an array comprising a plurality of microneedles on a conductive substrate.
  • the microneedles of this disclosure may be used singly or as part of an array of a plurality microneedles 900 on a unitary base such as shown in FIGURE 9.
  • a unitary base such as shown in FIGURE 9.
  • the unitary base may include a portion in fluid communication with the injection lumens of the plurality of the microneedles and a reservoir holding a therapeutic agent or replacement fluid, such as artificial perilymph for inner ear applications, depending on whether the microneedles are used for delivery of a therapeutic agent or for sampling a subject’s bodily fluid.
  • a second portion of the unitary base may be in fluid communication with the aspiration lumens of the plurality of the microneedles and a vacuum source and a receptacle for collecting fluids aspirated from the distal side of the membrane.
  • the microneedles are composed of only metallic material.
  • the microneedle may be fabricated from copper and may have a coating, such as but not limited to metals, ceramics, polymers, organics, etc.
  • the coating is gold.
  • the coatings could consist of multiple layers and multiple materials and material classes.
  • microneedle is described for the use the thin membrane of the inner ear, this application should not be construed as limiting.
  • the microneedles described and embodied herein may be used for other applications.
  • the microneedle may be modified to suit a plethora of needs, for sampling or delivering across different physiological structures.
  • One of ordinary skill in the art would also appreciate that the selection of materials to fabricate the microneedle may be modified to create more rigid structures to penetrate other membrane and anatomies.

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  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Engineering & Computer Science (AREA)
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  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Vascular Medicine (AREA)
  • Medical Informatics (AREA)
  • Dermatology (AREA)
  • Surgery (AREA)
  • Media Introduction/Drainage Providing Device (AREA)

Abstract

Une micro-aiguille ayant un corps comprenant une base, un arbre et une extrémité pointue, et au moins une lumière disposée à l'intérieur de l'arbre. La lumière présente une ouverture décalée par rapport à l'extrémité et ouvre sur l'extérieur de la micro-aiguille.
PCT/US2020/028497 2019-04-16 2020-04-16 Micro-aiguille ultra-pointue WO2020214802A1 (fr)

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US201962834807P 2019-04-16 2019-04-16
US62/834,807 2019-04-16
US202062965701P 2020-01-24 2020-01-24
US62/965,701 2020-01-24

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Cited By (3)

* Cited by examiner, † Cited by third party
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CN114939229A (zh) * 2021-02-17 2022-08-26 株式会社Ｇｌ 微针组件
WO2023150564A3 (fr) * 2022-02-01 2023-09-28 The Trustees Of Columbia University In The City Of New York Micro-aiguille à lumières multiples pour injection et aspiration intracochléaires simultanées
WO2023172907A3 (fr) * 2022-03-07 2023-12-07 The Trustees Of Columbia University In The City Of New York Distribution intracochléaire à médiation par microaiguilles

Citations (3)

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Publication number Priority date Publication date Assignee Title
US20090093776A1 (en) * 2006-04-10 2009-04-09 Ruifeng Yue 3d solid or hollow silicon microneedle and microknife with "-" shape structure
US20120172820A1 (en) * 2009-07-15 2012-07-05 Debiotech S.A. Multichannel micro-needles
WO2017143149A1 (fr) * 2016-02-17 2017-08-24 Polymer Technology Systems, Inc. Systèmes et procédés pour dispositif de collecte de sang à volume amélioré à l'aide de techniques capillaires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093776A1 (en) * 2006-04-10 2009-04-09 Ruifeng Yue 3d solid or hollow silicon microneedle and microknife with "-" shape structure
US20120172820A1 (en) * 2009-07-15 2012-07-05 Debiotech S.A. Multichannel micro-needles
WO2017143149A1 (fr) * 2016-02-17 2017-08-24 Polymer Technology Systems, Inc. Systèmes et procédés pour dispositif de collecte de sang à volume amélioré à l'aide de techniques capillaires

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114939229A (zh) * 2021-02-17 2022-08-26 株式会社Ｇｌ 微针组件
CN114939229B (zh) * 2021-02-17 2024-02-02 株式会社Ｇｌ 微针组件
WO2023150564A3 (fr) * 2022-02-01 2023-09-28 The Trustees Of Columbia University In The City Of New York Micro-aiguille à lumières multiples pour injection et aspiration intracochléaires simultanées
WO2023172907A3 (fr) * 2022-03-07 2023-12-07 The Trustees Of Columbia University In The City Of New York Distribution intracochléaire à médiation par microaiguilles

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