Techniques for needles with microchannels

Abstract

A device for delivering a drug to a target recipient includes a planar substrate having a first surface and a second surface, a reservoir defined on the first surface of the planar substrate, and a plurality of microstructures protruding from the second surface of the planar substrate. Each of the plurality of microstructures includes a delivery channel extending from the reservoir to a channel opening defined on the outer surface of the microstructure. In some embodiments, a needle having a microchannel can be fabricated using a silicon wafer. A primary channel can be etched into the wafer, and then a second silicon wafer can be bonded onto the first wafer. The microchannel can be formed from the primary channel to the surface of the wafer using deep reactive ion etching. The diameter of the microchannel can be selected for drug delivery. An exemplary diameter of the microchannel is 4 micrometers.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Provisional Patent Application No. 62 / 877060, entitled "MICRONEEDLE WITH NANOCHANNEL AND ASSOCIATED METHOD OF FABRICATION," filed July 22, 2019, and Provisional Patent Application No. 62 / 903,298, entitled "TECHNOLOGIES FOR NEEDLES WITH MICROCHANNELS," filed September 20, 2019, both of which are incorporated herein by reference.

[0002]

[0002] This disclosure relates generally to nanotechnology, and more particularly to nanochannels and nanochannel-based delivery methods. [Background technology]

[0003]

[0003] The use of microneedle arrays has been proposed as a technique for delivering therapeutic agents across or into biological tissue. The microneedles are adapted to disrupt the barrier function of biological tissue and deliver therapeutic agents into cell layers below the barrier (e.g., the outermost cell layer of the tissue). However, the aspect ratio of the microneedles can significantly limit the ability to deliver therapeutic agents to deeper cell layers of the tissue. For example, longer microneedles may require larger diameters to aid in penetrating biological barriers (e.g., skin) and delivering therapeutic agents to deeper cell layers, but microneedles with diameters larger than a certain threshold may irreversibly disrupt the barrier function. Summary of the Invention [Means for solving the problem]

[0004]

[0004] This application discloses one or more of the features recited in the appended claims and / or the following features, which may, alone or in any combination, comprise patentable subject matter.

[0005] According to an aspect of the present disclosure, an apparatus for delivering a drug to a target recipient includes a planar substrate having a first surface and a second surface, a reservoir defined in the first surface of the planar substrate, and a plurality of microstructures protruding from the second surface of the planar substrate. Each of the plurality of microstructures includes a delivery channel extending from the reservoir to a channel opening defined in an outer surface of the microstructure. The reservoir is adapted to contain a drug to be delivered to the target recipient via the delivery channel. The delivery channel further includes a first channel having a first diameter and a second channel having a second diameter different from the first diameter.

[0006] According to another aspect of the present disclosure, a method for fabricating a microstructure array includes forming a generally planar substrate having a first surface and a second surface, forming a plurality of microstructures projecting obliquely from the second surface to a distal tip, forming a reservoir defined in the first surface, and forming a delivery channel in at least one of the microstructures extending from the reservoir to a channel opening defined outside the corresponding microstructure. In various embodiments, forming the microstructures may include semiconductor processing, 3D printing, embossing, injection molding, casting, photochemical etching, electrochemical machining, electrical discharge machining, precision stamping, high-speed computer numerical control milling, Swiss thread machining, soft lithography, directional chemically enhanced ion etching, or a combination thereof.

[0007] According to another aspect of the present disclosure, a method for delivering extracellular vesicles from one layer of cells to another layer of cells includes providing a microstructure array having a planar substrate having a first surface and a second surface, a reservoir defined in the first surface of the planar substrate, and a plurality of microstructures protruding from the second surface of the planar substrate. Each of the plurality of microstructures includes a delivery channel extending from the reservoir to a channel opening defined in an outer surface of the microstructure. The reservoir is adapted to contain a drug to be delivered to a target recipient via the delivery channel.

[0008]

[0008] According to another aspect of the present disclosure, a method for administering a drug to a subject using the device disclosed above includes inserting the microstructure of the device into the skin of the subject and causing the drug to be transported from the reservoir through the stratum corneum of the skin via delivery channels in the microstructure.

[0009]

[0009] According to one aspect of the present disclosure, the device comprises a mandrel extending from a proximal end to a distal end, the mandrel defining a primary channel within the mandrel extending from the proximal end toward the distal end, the primary channel being open at the proximal end and closed at the distal end, the mandrel further defining one or more microchannels, each of the one or more microchannels extending from the primary channel through a wall of the mandrel, each of the one or more microchannels having a diameter of less than 1,000 micrometers.

[0010] In some embodiments, the one or more microchannels comprise a plurality of microchannels, each of the plurality of microchannels extending from the primary channel through a sidewall of the mandrel.

[0011] In some embodiments, the mandrel is silicon.

[0012] In some embodiments, the mandrel is stainless steel.

[0013] In some embodiments, the mandrel is plastic.

[0012]

[0014] In some embodiments, each of the one or more microchannels has a diameter of between 1 and 1,000 micrometers.

[0015] In some embodiments, the primary channel has a diameter of between 10 and 1,000 micrometers.

[0013]

[0016] In some embodiments, the primary channel has a length of at least 1 millimeter.

[0017] In some embodiments, the one or more microchannels comprise a plurality of microchannels, each of the plurality of microchannels extending from the primary channel through a sidewall of the mandrel.

[0014]

[0018] In some embodiments, the mandrel comprises (i) a first silicon wafer that defines a bottom wall and two side walls of a primary channel, and (ii) a second silicon wafer bonded to the first silicon wafer, the second silicon wafer defining a top wall of the primary channel.

[0015]

[0019] In some embodiments, the mandrel is coated with titanium nitride.

[0020] In some embodiments, the device may further include a plurality of mandrels, each of the plurality of mandrels having an outer surface that is electrically conductive, each of the plurality of mandrels being electrically coupled to one another of the plurality of mandrels, each of the plurality of mandrels extending from a proximal end to a distal end, each of the plurality of mandrels defining a primary channel within the corresponding mandrel extending from the proximal end toward the distal end, the primary channel being open at the proximal end and closed at the distal end, each of the plurality of mandrels further defining one or more microchannels, each of the one or more microchannels extending from the primary channel through the wall of the corresponding mandrel, each of the one or more microchannels having a diameter of less than 1,000 micrometers.

[0016]

[0021] In some embodiments, the device may further include a plurality of electrodes, each of which is electrically coupled to one another, and which are positioned adjacent to the plurality of mandrels such that when a voltage is applied between the plurality of mandrels and the plurality of electrodes, an electric field is created perpendicular to the axis of each of the plurality of mandrels.

[0017]

[0022] In some embodiments, the device may further include an electrode electrically insulated from the mandrel, the electrode positioned adjacent to the mandrel such that when a voltage is applied between the mandrel and the electrode, an electric field is created perpendicular to the axis of the mandrel.

[0018]

[0023] In some embodiments, the device may further include a drug disposed in the primary channel.

[0024] In some embodiments, the apparatus may further include a syringe, the syringe being in fluid communication with the primary channel.

[0019]

[0025] In some embodiments, the device may further include a handpiece removably mechanically coupled to the mandrel.

[0020]

[0026] According to one aspect of the present disclosure, a method of manufacturing a device includes creating a primary channel in a first silicon wafer using photolithography, the primary channel having a depth of at least 10 micrometers and a length of at least 5 millimeters; after creating the primary channel, bonding a second silicon wafer to the first silicon wafer; and etching the second silicon wafer to create one or more microchannels, each of the one or more microchannels extending from the primary channel through the second silicon wafer, each of the one or more microchannels having a diameter of less than 1,000 micrometers.

[0021]

[0027] In some embodiments, the step of etching the second silicon wafer includes etching the second silicon wafer by deep reactive ion etching.

[0022]

[0028] In some embodiments, the method may further include depositing a coating of titanium nitride on at least one surface of the first silicon wafer or the second silicon wafer.

[0023]

[0029] According to one aspect of the present disclosure, a method of delivering a drug includes inserting a mandrel into a patient, the mandrel extending from a proximal end to a distal end, the mandrel defining a primary channel within the mandrel extending from the proximal end toward the distal end, the primary channel being open at the proximal end and closed at the distal end, the mandrel further defining one or more microchannels, each of the one or more microchannels extending from the primary channel through a wall of the mandrel, each of the one or more microchannels having a diameter of less than 1,000 micrometers; inserting an electrode into the patient adjacent to the mandrel; and applying a voltage across the electrode and the mandrel to create nanopores in at least some cells disposed between the mandrel and the electrode.

[0024]

[0030] In some embodiments, the mandrel has a length of at least 1 millimeter.

[0031] In some embodiments, the method may further include moving the plunger of the syringe to cause the drug to flow from the primary channel, through one or more microchannels, and out of the mandrel.

[0025]

[0032] In some embodiments, the step of applying a voltage across the electrode and the mandrel includes applying two or more pulses of voltage across the electrode and the mandrel, each of the two or more pulses being less than 2,000 milliseconds.

[0026]

[0033] In some embodiments, the mandrel is mechanically coupled to the handpiece, and the method further includes removing the mandrel from the patient and decoupling the handpiece from the mandrel.

[0034] The detailed description makes particular reference to the following drawings: [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 is a schematic diagram illustrating one embodiment of a microstructure array having a plurality of microstructures for drug delivery to a target cell layer. [Figure 2A] FIG. 1 is a schematic diagram illustrating one embodiment of a microstructure array having a plurality of microstructures with blunt tips. [Figure 2B] FIG. 1 is a schematic diagram illustrating one embodiment of a microstructure array having a plurality of microstructures with sharp tips. [Figure 3-1] 3A-3C are schematic diagrams illustrating how the microstructure array of FIG. 2A can be fabricated using semiconductor processes such as lithography and etching techniques. [Figure 3-2] 3D-3G are schematic diagrams illustrating how the microstructure array of FIG. 2A can be fabricated using semiconductor processes such as lithography and etching techniques. [Figure 4-1] 4A-4C are schematic diagrams illustrating how the microstructure array of FIG. 2B can be fabricated using semiconductor processes such as lithography and etching techniques. [Figure 4-2] 4D-4G are schematic diagrams illustrating how the microstructure array of FIG. 2B can be fabricated using semiconductor processes such as lithography and etching techniques. [Figure 4-3] 4H-4K are schematic diagrams illustrating a method for fabricating the microstructure array of FIG. 2B using semiconductor processes such as lithography and etching techniques. [Figure 5] FIG. 1 is a top view of one embodiment of a needle with microchannels. [Figure 6] FIG. 6 is a side view of the needle of FIG. 5. [Figure 7A] FIG. 3A is a cross-sectional view of one embodiment of the needle of FIG. [Figure 7B] FIG. 3B is a cross-sectional view of one embodiment of the needle of FIG. [Figure 7C] FIG. 3C is a cross-sectional view of one embodiment of the needle of FIG. [Figure 7D] FIG. 3D is a cross-sectional view of one embodiment of the needle of FIG. [Figure 7E] FIG. 3E is a cross-sectional view of one embodiment of the needle of FIG. [Figure 7F] FIG. 3F is a cross-sectional view of one embodiment of the needle of FIG. [Figure 7G] FIG. 3G is a cross-sectional view of one embodiment of the needle of FIG. [Figure 8] FIG. 6 is a cross-sectional view of the needle of FIG. 5. [Figure 9A] FIG. 9A is a cross-sectional view of one embodiment of the needle of FIG. [Figure 9B] FIG. 5B is a cross-sectional view of one embodiment of the needle of FIG. [Figure 10] FIG. 1 shows an embodiment of an array of needles with microchannels. [Figure 11A] FIG. 1 shows an embodiment of an array of needles with microchannels next to an array of electrodes. [Figure 11B] FIG. 1 shows an embodiment of an array of needles with microchannels next to an array of electrodes. [Figure 11C] FIG. 1 shows an embodiment of an array of needles with microchannels next to an array of electrodes. [Figure 12] FIG. 1 illustrates one embodiment of a wafer that can be used to create needles with microchannels. [Figure 13] FIG. 1 shows an embodiment of a wafer that can be used to create needles with microchannels, with the channels etched into the needles. [Figure 14] FIG. 14 illustrates one embodiment of a second wafer to be bonded to the wafer of FIG. 13. [Figure 15] FIG. 1 illustrates one embodiment of a wafer bonded onto another wafer, forming a channel. [Figure 16] FIG. 16 illustrates an embodiment of the wafer of FIG. 15 with microchannels formed in the wafer. [Figure 17] FIG. 17 illustrates an embodiment of the wafer of FIG. 16 with photoresist defining needles. [Figure 18] 18 shows an embodiment of a needle having microchannels formed from the wafer of FIG. 17. [Figure 19] FIG. 1 illustrates one embodiment of a roller system having one or more needles with microchannels. DETAILED DESCRIPTION OF THE INVENTION

[0028]

[0055] Terms used throughout this application are to be interpreted in the manner ordinary and typical to those skilled in the art. However, applicant wishes the following terms to be given particular definitions as defined below.

[0029]

[0056] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a cell" includes a plurality of cells, including mixtures thereof.

[0030]

[0057] The terms "about" and "approximately" are defined as "near" as understood by one of ordinary skill in the art. In one non-limiting embodiment, the term is defined to be within 10%. In another non-limiting embodiment, the term is defined to be within 5%. In yet another non-limiting embodiment, the term is defined to be within 1%.

[0031]

[0058] As used herein, the term "comprising" is intended to mean that the compositions and methods include the recited elements, but do not exclude others. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of elements as defined herein does not exclude trace contaminants from isolation and purification methods, as well as pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, and the like. "Consisting of" is intended to mean excluding trace elements of other components, and more than substantial method steps for administering the compositions of the invention. Embodiments defined by these transition terms are within the scope of the present invention.

[0032]

[0059] An "effective amount" is an amount sufficient to produce a beneficial or desired result. An effective amount can be administered in one or more administrations, applications, or doses. The term "carrier" or "pharmaceutically acceptable carrier" refers to a carrier or excipient that is generally safe and non-toxic and useful in preparing pharmaceutical or therapeutic compositions, including carriers that are acceptable for animal and / or human pharmaceutical or therapeutic use. As used herein, the term "carrier" or "pharmaceutically acceptable carrier" can include phosphate-buffered saline solution, water, emulsions (oil / water or water / oil emulsions), and / or various types of wetting agents. As used herein, the term "carrier" includes any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other substance well known in the art for use in pharmaceutical formulations, and as further described below.

[0033]

[0060] Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the antecedent "about," it is to be understood that the particular value forms another embodiment. It is to be further understood that the endpoints of each of the ranges are significant in relation to the other endpoint, and independently of the other endpoint. It is also to be understood that there are several values ​​disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed.

[0034]

[0061] The term "therapeutically effective amount" or "therapeutically effective dose" refers to the amount of a composition, such as glucose-modified insulin, that binds to a glucose-binding structure that elicits the biological or medical response in a tissue, system, animal, or human that is desired over a generalized time period by a researcher, veterinarian, physician, or other clinician. In some cases, the desired biological or medical response is achieved following administration of multiple doses of the composition to a subject over a period of days, weeks, or years.

[0035]

[0062] The term "subject" or "recipient" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In some embodiments, the subject is a human.

[0036]

[0063] The terms "treat," "treating," "treatment," and grammatical variations thereof, as used herein, include partially or completely slowing, alleviating, relieving, or reducing the intensity of one or more associated symptoms of a disease or condition, and / or alleviating, reducing, or preventing one or more causes of a disease or condition. Treatment in accordance with the present invention may be applied preventatively, prophylactically, palliatively, or therapeutically.

[0037]

[0064] While the concepts of the present disclosure are susceptible to various modifications and alternative forms, specific exemplary embodiments thereof have been shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that there is no intention to limit the concepts of the present disclosure to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.

[0038]

[0065] The microstructure arrays and methods of using the same disclosed herein are useful for transporting drugs into or across biological barriers (e.g., cell membranes). The microstructure arrays disclosed herein have the ability to deliver drugs to specific layers of cells within tissue. As described in detail below, the microstructure array includes multiple microstructures configured to penetrate a barrier (e.g., a biological barrier layer). Each microstructure includes one or more delivery channels adapted to deliver drugs through one or more channels to reach the environment surrounding the microstructure (e.g., a specific layer of cells within the tissue). In some embodiments, one or more microstructures of a microstructure array may include multiple delivery channels to enable simultaneous (or sequential) delivery of drugs to multiple layers of cells within the tissue. In such embodiments, one or more microstructures may have multiple delivery channels exiting the angled microstructure, allowing for different heights of the delivery channels within the microstructure. When the microstructure penetrates the tissue, the delivery channels may be positioned within different layers of cells, thus delivering drugs at different layers or levels within the tissue. It should be understood that the microstructure array can be used on the skin (or portions thereof), across the blood-brain barrier, mucosal tissue (e.g., oral, nasal, ocular, vaginal, urethral, ​​gastrointestinal, respiratory tract), blood vessels, lymphatic vessels, cell membranes (e.g., for the introduction of materials inside a cell(s)), or other biological barriers. The biological barrier can be in humans or other types of animals, as well as plants, insects, or other organisms, including bacteria, yeast, fungi, and embryos. Additionally, the microstructure array can be applied internally to tissue with the aid of a catheter or laparoscope. For certain applications, such as drug delivery to internal tissues, devices having the microstructure array can be surgically implanted.

[0039]

[0066] As shown in FIG. 1 , microstructure array 100 for delivering a drug to a subject includes a flat substrate 110 having a top surface 112 and a bottom surface 114 opposite top surface 112, and a plurality of microstructures 120 protruding outward from bottom surface 114 of flat substrate 110. During use, microstructure array 100 is positioned relative to a subject such that bottom surface 114 of flat substrate 110 faces the subject. The plurality of microstructures 120 on bottom surface 114 are then used to penetrate or puncture a barrier in the subject. To deliver a targeted agent to the subject, each microstructure 120 includes a body 126, a reservoir 122, and one or more delivery channels 124 defined within body 126. Specifically, as shown in FIGS. 2A and 2B , reservoir 122 extends inward from top surface 112 of flat substrate 102 and is configured to hold a targeted agent to be delivered to the subject. Delivery channel 124 is defined in an elongated body 126 that extends from the bottom surface 114 of planar substrate 102 to a tip 128. Delivery channel 124 is adapted to act as a conduit between reservoir 122 and channel opening 130 to allow a target agent disposed in reservoir 122 to be delivered to the environment surrounding microstructure 120 at channel opening 130.

[0040]

[0067] It should be understood that microstructure array 100 can include microstructures 120 having different tips 128. It should be understood that the method of fabricating microstructure array 100 will vary depending on the type of tips 128 that microstructures 120 have. Exemplary methods of fabricating microstructure array 100 are illustrated in Figures 3 and 4.

[0041]

[0068] For example, as shown in FIG. 2A , microstructure array 100 may include microstructures 120A with blunt tips 128A. In such embodiments, microstructure 120A has reservoir 122 and delivery channel 124A extending from the center of reservoir 122 to channel opening 130A positioned at the center of blunt tip 128A. A method of fabricating microstructure array 100 with microstructures 120A is further illustrated in FIG. 3 . However, it should be understood that in some embodiments, channel opening 130A may be positioned off-center of blunt tip 128A. Alternatively, as shown in FIG. 2B , microstructure array 100 may include microstructures 120B that may have sharp tips 128B. In such an embodiment, the microstructure 120B has a reservoir 122 and a delivery channel 124B that extends from an off-center portion of the reservoir 122 to a channel opening 130B positioned on the angled side of the pointed tip 128B.

[0042]

[0069] A method of fabricating microstructure array 100 having microstructures 120B is further illustrated in Figure 4. However, it should be understood that in some embodiments, channel opening 130B may be positioned at the center of pointed tip 128B. Alternatively, in other embodiments, microstructure array 100 may include both types of microstructures 120A, 120B.

[0043]

[0070] As described further below, each microstructure 120 may have a particular aspect ratio that enables the microstructure array 100 to transport targeted agents from reservoirs 122 through delivery channels 124 into or across a biological barrier to deeper cell layers without irreversibly disrupting barrier function. As used herein, aspect ratio is defined as the distance from base 114 to tips 128A, 128B divided by the width of body 126. In exemplary embodiments, microstructures 120 have a height greater than 150 μm and an aspect ratio greater than 3. In some embodiments, each microstructure 120 has a delivery channel 124 that is approximately 200-1000 μm in height and 50-5000 nm in diameter.

[0044]

[0071] Additionally, the delivery channel 124 has a diameter D1 that is smaller than the diameter D2 of the reservoir 122. For example, the diameter D1 of the delivery channel 124 is less than about 5000 nm, and the diameter D2 of the reservoir 122 is about 25 μm. In the exemplary embodiment, the microstructure 120 has a cylindrical body. However, it should be understood that in some embodiments, the elongated body 126 can be in any shape, such as a ridge, a herringbone pattern, a wave pattern, a cone, a pyramid, or a combination thereof. It should be understood that in some embodiments, the microstructure 120 can include multiple delivery channels 124. In such embodiments, the multiple delivery channels 124 can have the same height to enable simultaneous or sequential delivery of an agent to a target layer of cells within a tissue. Alternatively, in other embodiments, the multiple delivery channels 124 of the microstructure can have different heights that will position them within different layers of cells, thus delivering an agent to different layers or levels within the tissue.

[0045]

[0072] In some embodiments, the delivery channel 124 can be defined by a first channel and a second channel connected at a junction. Specifically, the first channel extends from the channel opening toward the junction, and the second channel extends from the junction toward the reservoir 122, such that the first and second channels are in fluid communication with the reservoir 122. As discussed further below, the first channel has an inner diameter that is smaller than the inner diameter of the second channel. For example, in an exemplary embodiment, the inner diameter of the first channel is less than about 5000 nm, and the inner diameter of the second channel is about 5-20 μm.

[0046]

[0073] In the exemplary embodiment, reservoir 122 is integrated with planar substrate 102 and sized to supply a single microstructure 120. However, in some embodiments, reservoir 122 may be sized to supply more than one microstructure 120. For example, in such an embodiment, microstructure array 100 may include a single large reservoir to supply multiple microstructures 120 of microstructure array 100. It should be understood that in some embodiments, reservoir 122 may be fabricated separately and interface with planar substrate 102. In one embodiment, reservoir 122 may include a porous material, and the agent to be administered is stored in the pores of the porous material. In another embodiment, the reservoir is sealed. In one variation of this embodiment, the microstructure array further includes at least one piercing barb extending from the first surface of the planar substrate, which may be used to pierce the sealed reservoir.

[0047]

[0074] Reservoirs 122 are adapted to contain any agent to be delivered to the target cell layer through delivery channels 124 of microstructure 120 by a release mechanism. The agent to be delivered across the barrier layer may be selected from the group including peptides, proteins, carbohydrates, nucleic acid molecules, lipids, organic molecules, biologically active inorganic molecules, and combinations thereof. For example, a wide variety of drugs may be formulated for delivery using microstructure array 100.

[0048]

[0075] As used herein, the terms "drug" or "formulation" are used broadly to refer to any prophylactic, therapeutic, diagnostic, or theranostic agent or other substance that may be suitable for introduction into biological tissue, including pharmaceutical excipients and materials for tattoos, cosmetics, and the like. A drug may be a biologically active agent. Formulations may include various forms, such as liquid solutions, gels, solid particles (e.g., microparticles, nanoparticles), or combinations thereof. A drug may include small molecules, large (i.e., macro) molecules, or combinations thereof. In representative, non-limiting embodiments, a drug may be selected from among amino acids, vaccines, antivirals, gene delivery vectors, interleukin inhibitors, immunomodulators, neurotrophic factors, neuroprotective agents, antitumor agents, chemotherapeutics, polysaccharides, anticoagulants, antibiotics, analgesics, anesthetics, antihistamines, anti-inflammatory agents, and viruses. A drug may be selected from suitable proteins, peptides, and fragments thereof, which may be naturally occurring, synthetic, or recombinantly produced. In one embodiment, the formulation comprises insulin. The formulation may further comprise one or more pharmaceutically acceptable excipients, including pH adjusters, viscosity adjusters, and diluents.

[0049]

[0076] In some embodiments, the drug may be an electrical stimulator. Pulsed electric fields have many applications, such as in regenerative medicine. In such embodiments, microstructure array 100 may be used to deliver pulsed electric fields at different levels across tissue thickness. In some embodiments, reservoir 122 may include a means for producing a drug to be transported to a target recipient. For example, reservoir 122 may contain cells capable of producing a drug to be administered or delivered to a recipient. The cells may be mammalian cells, such as human cells, or cells from any other source. For example, the cells may be pancreatic beta cells or stem cell-differentiated human pancreatic cells.

[0050]

[0077] The release mechanism may involve an electric field, a magnetic field, an electromagnetic field, a pressure field, ultrasonic energy, tension, diffusion, injection, osmosis, a concentration gradient, a vacuum, pressure, mechanical or shear force, heat, a chemical reaction, or a combination thereof. For example, during use, microstructure array 100 may be placed on a biological barrier layer, allowing tips 128 of microstructures 120 to penetrate the barrier layer and deliver agents contained within reservoirs 122 through delivery channels 124 to the environment surrounding channel openings 130 of microstructures 120 (e.g., intracellular spaces). To do so, a porating electric field may be applied across microstructure array 100 to disrupt or deform the biological barrier layer (e.g., cell membranes), thereby allowing the agents to be translocated intracellularly. The strength of the electric field required for translocation may depend on the target tissue or system. Alternatively, agents may be drawn from the environment outside channel openings 130 through delivery channels 124 and deposited in reservoirs 122 for return communication.

[0051]

[0078] In the exemplary embodiment, microstructure array 100 further includes first and second electrodes to create an electric field between electrodes positioned on either side of delivery channel 124 to facilitate delivery of the agent. Specifically, the first electrode is in contact with reservoir 122 and the second electrode is positioned at distal tip 128 of microstructure 120, such that an electric field is generated across the tissue between the two electrodes. The voltage, frequency, and other electric field parameters may be selected based on the distance between the electrodes.

[0052]

[0079] The electrode structure may be formed as concentric bands connected to conductive pads. Each band and banded segment may be wired to an electroporation power supply together or separately and energized in various geometric and temporal patterns and configurations. Furthermore, different bands and band segments may be maintained at different potentials (voltages) relative to the first electrode structure. A drug may be delivered through a channel opening 130 at the distal tip 128 so that it penetrates the tissue outward in a region. This region may coincide with the electric field generated between the first and second electrode structures. It should be understood that the electric field may promote cell permeability, thereby facilitating delivery of the desired drug to the cells.

[0053]

[0080] The electroporation-capable microstructure array may include an alternating current (AC) power source adapted to deliver electroporation current to the electrode structures at a desired voltage and frequency, typically selected to deliver the electroporation current to the electrodes at a voltage in the range of 0.1 V to 30 kV. In some cases, the voltage is less than about 50 to 500 V. The particular voltage depends at least in part on the spacing between the first and second electrode structures. The frequency is typically in the range of 10 Hz to 107 Hz, usually 104 Hz to 106 Hz. The current may be applied at pulse intervals such as every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 milliseconds or more, and any amount of pulses may be applied at a given interval, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more pulses, which may be repeated until the desired result is achieved.

[0054]

[0081] It should be understood that reservoir 122 may include a feedback component to alter the volume or amount of drug to be transported across the biological barrier based on a physiological signal. To do so, the feedback component may include a switch adapted to control a release mechanism to release the drug to the target recipient based on the detection or absence of a signal. For example, the drug may be contained in reservoir 122 (i.e., not released into delivery channel 124) until a signal is detected. Upon detection of the signal, the drug is released to the target recipient. For example, the feedback component may detect the presence of a pathogen in the subject, and when the pathogen is detected, the feedback component enables release of the drug from the reservoir. Alternatively, detection of a signal may have the opposite effect. In such an example, the reservoir will not fulfill delivery of the drug to the target recipient unless a signal is detected, causing reservoir 122 to not release the drug for delivery to the recipient.

[0055]

[0082] In some embodiments, the feedback component may detect a change in a physiological signal (e.g., pH or temperature). For example, the feedback component may determine whether to release a drug or change the volume or amount of drug to be released or administered to the target recipient in response to the physiological signal changing by a predetermined amount or reaching a predetermined value. Additionally or alternatively, the feedback component may also adjust the amount or volume of drug to be released based on the amount of signal detected. For example, a greater amount of signal detected may result in a greater amount of drug being released, or conversely, a greater amount of signal detected may result in a smaller amount of drug being released. The detected physiological signal may indicate the presence of a substance in the target recipient to which the microstructure array is applied. The physiological signal may occur naturally within the recipient or may be triggered by a non-endogenous or exogenous substance. For example, physiological signals may indicate the amount of substances present within the target recipient, such as, but not limited to, glucose, cholesterol, bilirubin, creatine, metabolic enzymes, hemoglobin, heparin, clotting factors, uric acid, carcinoembryonic antigen or other tumor antigens, reproductive hormones, oxygen, alcohol, tobacco metabolites, and illicit drugs.

[0056]

[0083] In some embodiments, reservoir 122 can be semi-permeable to allow fluid exchange with the target recipient, allowing the returning component to be in fluid communication with the target recipient and thereby detect changes in the recipient's physiological signals. For example, reservoir 122 can contain cells that are sensitive to changes in physiological signals from the recipient. Such physiological changes in the recipient can stimulate the cells to release or stop releasing a drug, as described above with respect to the returning component. In one example, the semi-permeable reservoir can be made of alginate microgel.

[0057]

[0084] In exemplary embodiments, the agents in the reservoirs to be delivered to the target recipient may be therapeutic, prophylactic, diagnostic, or therapeutic substances. Additionally, two or more agents may be delivered at once. Additionally or alternatively, different agents may be delivered at once through different channels, either sequentially or simultaneously. It should be understood that in embodiments in which multiple delivery channels 124 reach different layers of cells, different agents may be simultaneously administered to different layers of cells within a tissue using the microstructure arrays disclosed herein. Specifically, a first agent may be delivered to a first layer of cells via a first delivery pathway, and a second agent may be delivered to a second layer of cells via a second delivery pathway.

[0058]

[0085] 3, a method for creating a microstructure array 100 having a plurality of microstructures 120A with blunt tips 128A using semiconductor fabrication techniques, such as photolithographic and etching techniques, is shown. The method begins by creating reservoirs 122 on a wafer 140. In an exemplary embodiment, wafer 140 has a height D7 greater than 300 μm and is made of silicon, and oxide layer 150 is made of silicon dioxide or other oxides. However, it should be understood that in some embodiments, wafer 140 may be made of other materials, such as glass, silicon carbide, plastic, polymer, and metal.

[0059]

[0086] As illustrated in FIG. 3A, an oxide layer 150 is deposited on the first surface 142 of the wafer 140 using an oxidation process. The oxidation process may include chemical vapor deposition or wet oxidation at high temperatures. Chemical vapor deposition is the preferred method because it is cost-effective, can be performed at low temperatures, and has a high deposition rate, compared to wet oxidation, which requires high temperatures (over 1,000°C) and has a low growth rate. A photoresist material 152 is then deposited on the oxide layer 150 by spin coating, as illustrated in FIG. 3B, and exposed to UV light in an optical lithography tool using a photomask (not shown) to define a pattern (e.g., an array of holes) 154 in the photoresist material layer 152. In an exemplary embodiment, each hole 154 defined in the photoresist layer 152 has a diameter D3 of approximately 10-30 μm and is used as a mask to etch through the oxide layer 150. For example, plasma etching (e.g., using a fluorine containing plasma gas) can be performed to generate a mask that will be used to create the reservoirs 122 of the microstructure array 100. Once the mask is created, the remaining photoresist material 152 is removed. Subsequently, as illustrated in FIG. 3C, the wafer 140 is etched using an array of hole patterns 154 in the oxide layer 150 to create hollow channels (i.e., reservoirs 122) in the wafer 140, and the oxide layer 150 is removed. In an exemplary embodiment, each reservoir 122 has an initial diameter D3 of approximately 10-30 μm. However, as further described below in FIG. 3G, the diameter of the hollow reservoirs 122 can be further adjusted.

[0060]

[0087] Delivery channels 124 are then formed in wafer 140 to create microstructure array 100. To do so, as illustrated in FIG. 3D , an oxide layer 156 is deposited on second surface 144 of wafer 140 using an oxidation process (e.g., chemical vapor deposition or wet oxidation at high temperature). Photoresist material 158 is then deposited on oxide layer 156 by spin coating and exposed to UV light in an optical lithography tool using a photomask (not shown) to define disk shapes in photoresist layer 158 that align with each reservoir 122. In the exemplary embodiment, each disk-shaped photoresist layer (not shown) has a diameter D4 of approximately 50 μm and is used as a mask to etch through oxide layer 156 to produce disk-shaped oxide layers 160 having a diameter D4 of approximately 50 μm. 3E and 3F, a similar lithographic patterning and etching process is then repeated to create a narrow channel 162 in the center of each disk-shaped oxide layer 160. In an exemplary embodiment, a hole in the oxide layer 162 has a diameter D5 of approximately 0.05 μm to 5 μm and is used to define the delivery channel 124 of each microstructure 120.

[0061]

[0088] Each disk-shaped oxide layer 160 is then used to etch through the wafer 140 to form the outline of a blunt microneedle tip 128A having a delivery channel 138. The delivery channel 124 extends from the opening 130A in the blunt microneedle tip 128A through the center of the microstructure 120A to the reservoir 122, as illustrated in FIG. 3F. For example, the etching process is performed using highly anisotropic deep reactive ion etching (DRIE) to excavate the hollow channel 124 through the wafer 140. It should be understood that in some embodiments, the delivery channel 138 may be positioned off-center of the microstructure 120.

[0062]

[0089] The disk-shaped oxide layer 160 is then removed, and the wafer 140 is cleaned. In an exemplary embodiment, the resulting microstructure 120A has a delivery channel 130A with an initial diameter of approximately 2-10 μm and a length D6 greater than 150 μm. Etching narrow delivery channels with extremely high aspect ratios is difficult using conventional dry etching techniques. Instead, in some embodiments, the hollow channel is etched with a larger inner diameter, as illustrated in FIG. 3G, and the inner diameter is then reduced to a target size by depositing an oxide, silicon, or nitride film on the surface. These materials can be deposited by chemical vapor deposition or atomic layer deposition techniques that can conformally coat the structured surface, thereby reducing the diameter of the delivery channel but increasing the outer dimensions of the microneedle. In an exemplary embodiment, the target diameter of the delivery channel 138 is 0.05-5 μm. The reservoir diameter is approximately 10-30 μm.

[0063]

[0090] 4, a method for fabricating microstructure array 100 having microstructures 120B with sharp tips 128B using photolithographic and etching techniques is shown. The method begins by fabricating reservoirs 122 on wafer 140. In the exemplary embodiment, wafer 140 has a height D7 greater than 300 μm and is made of silicon, and oxide layer 150 is made of silicon dioxide or other oxides. However, it should be understood that in some embodiments, wafer 140 may be made of other materials, such as glass, silicon carbide, plastic, polymer, and metal.

[0064]

[0091] As illustrated in FIG. 4A, an oxide layer 150 is deposited on the first surface 142 of the wafer 140 using an oxidation process. The oxidation process may include chemical vapor deposition or wet oxidation at high temperatures. Chemical vapor deposition is a preferred method. Photoresist material 152 is then deposited on the oxide layer 150 by spin coating, as illustrated in FIG. 4B, and exposed to UV light in an optical lithography tool using a photomask (not shown) to define a pattern (i.e., an array of holes) 154 in the photoresist material layer 152. In an exemplary embodiment, each hole 154 defined in the photoresist layer 152 has a diameter D3 of approximately 10-30 μm and is used as a mask for etching through the oxide layer 150. For example, plasma etching (e.g., using fluorine containing plasma gases) may be performed to generate a mask that will be used to create the reservoirs 122 of the microstructure array 100. Once the mask is created, the remaining photoresist material 152 is removed. Subsequently, as illustrated in FIG. 4C, wafer 140 is etched using an array of hole patterns 154 in oxide layer 150 to create hollow channels (i.e., reservoirs 122) within wafer 140, and oxide layer 150 is removed. In an exemplary embodiment, each reservoir 122 has an initial diameter D3 of approximately 10-30 μm. However, as further described below in FIG. 4K, the diameter of hollow reservoirs 122 can be further adjusted.

[0065]

[0092] Delivery channels 124 are then formed in wafer 140 to create microstructure array 100. To do so, as illustrated in FIG. 4D , an oxide layer 170 is deposited on second surface 144 of wafer 140 using chemical vapor deposition (e.g., chemical vapor deposition or wet oxidation at high temperature). Photoresist material 172 is then deposited on oxide layer 170 by spin coating, as illustrated in FIG. 4E , and exposed to UV light in an optical lithography tool using a photomask (not shown) to define disk shapes in the photoresist layer that align with each reservoir 122. In an exemplary embodiment, each disk-shaped photoresist layer has a diameter of approximately 50 μm and is used as a mask to etch through oxide layer 170 to produce oxide disks 174 that are disk-shaped and have a diameter D8 of approximately 50 μm. A similar lithographic patterning and etching process is then repeated to create cavities 176 in each oxide disk 174, as illustrated in FIG. 4F . In the exemplary embodiment, the cavity 176 has a diameter D 9 of approximately 0.1 μm to 5 μm and is used to define the delivery channel 138 of each microstructure 120 .

[0066]

[0093] Each oxide disk 174 is then used to etch through the wafer 140 to form the sharpened microneedle tips 128B of the microstructures 120B by isotropic silicon etching, as illustrated in Figure 4G. Once the sharpened microneedle tips 128B are established, the cavities 176 in the oxide disks 174 are further etched until the cavities 176 protrude through the remainder of the oxide disk 174, as shown in Figure 4H. The wafer 140 is then further etched to form the contours of the microstructures 120B having delivery channels 124 extending from the microneedle tips 128 through the microstructures 120 to the reservoirs 122, as illustrated in Figure 4I.

[0067]

[0094] Subsequently, as shown in FIG. 4J, oxide disk 172 is removed and wafer 140 is cleaned. In an exemplary embodiment, the resulting microstructure 120B has delivery channels 124 with an initial diameter D11 of approximately 0.1-5 μm and a length D10 of greater than 150 μm. To further reduce the size of the diameter of delivery channels 124 to a target size of 0.05-5 μm, an oxide, silicon, or nitride layer can be deposited on microstructure array 100, as illustrated in FIG. 4K. As explained above, such a reduction process can also reduce the diameter of reservoirs 122 to a target size. In an exemplary embodiment, the target diameter of delivery channels 124 is 0.05-5 μm.

[0068]

[0095] Referring now to FIG. 5 , in an exemplary embodiment, a needle 500 is formed from silicon. In some embodiments, the needle 500 may be formed from a different material, such as stainless steel or plastic. The needle 500 has a mandrel 502 and a tip 504. The needle 500 has one or more primary channels 702 (see FIGS. 3-5 ) running along the inside of the mandrel. The needle 500 has several microchannels 506 extending from the one or more primary channels 702 to the surface of the needle 500. Each of the exemplary microchannels 506 has a diameter of approximately 4 micrometers. During use, the needle 500 may be inserted into a patient, such as through the skin or into an organ. Drugs may be administered by flowing from the primary channels 702 through the microchannels 506 into the patient. In embodiments having multiple primary channels 702, different drugs may be administered into different primary channels 702. In some embodiments, an electric field may be applied to cause electroporation of tissue cells and promote the flow of drugs to a desired location. In those embodiments, the needle 500 may be coated with a conductive coating, such as titanium nitride or other biocompatible material. Additionally or alternatively, in some embodiments, the electrodes may be in contact with a drug, and the drug itself may propagate with the electric field by electrophoresis. In some embodiments, instead of delivering a drug, one of the primary channels 702 and the corresponding microchannels 506 may be used to extract a sample from the patient, such as extracellular fluid, vesicles, or the needle 500 may integrate a device for monitoring the tissue environment, such as temperature, pH, etc.

[0069]

[0096] It should be understood that the width of the microchannel 506 can be varied so that a particular drug, such as a gene, DNA, or protein, can be administered at a desired rate. Additionally, drugs can be administered to a variety of different depths based on the positioning of the microchannel 506. In an exemplary embodiment, there is a single primary channel 702. Additionally or alternatively, in some embodiments, there can be two or more primary channels 702. It should be understood that different primary channels 702 can be used to deliver different drugs. In some embodiments, different microchannels 506 in the same needle 500 can have different diameters. For example, a microchannel 506 connected to one primary channel 702 can have a different diameter compared to a microchannel 506 connected to a second primary channel 702.

[0070]

[0097] The drug may be inserted into primary channel 702 in any suitable manner. For example, in an exemplary embodiment, primary channel 702 may be connected to a syringe by use of tubing that leads from the syringe to a block (such as polydimethylsiloxane) that is bonded to the opening of the primary channel. In some embodiments, the syringe may be embedded in or form part of the handpiece. The handpiece and syringe may be removably connected to needle 500 so that needle 500 can be discarded after a single use and the handpiece and syringe can be reused.

[0071]

[0098] With respect to the microstructure array described above, it should be understood that the needle 500 having microchannels 506 can be used on the skin (or portions thereof), across the blood-brain barrier, mucosal tissue (e.g., oral, nasal, ocular, vaginal, urethral, ​​gastrointestinal, respiratory tract), blood vessels, lymphatic vessels, cell membranes (e.g., for the introduction of materials inside a cell(s)), or other biological tissue or barrier. The biological barrier can be in humans or other types of animals, as well as plants, insects, or other organisms, including bacteria, yeast, fungi, and embryos. Additionally, the needle 500 having microchannels 506 can be applied to tissue internally with the aid of a catheter, endoscope, laparoscope, etc. For certain applications, such as drug delivery to internal tissue, a device having the needle 500 having microchannels 506 can be surgically implanted or incorporated into a surgical instrument.

[0072]

[0099] The exemplary needle 500 is approximately 10 millimeters long, with a width of approximately 1 millimeter and a height of 0.5 millimeters. In other embodiments, the needle 500 can be any suitable length, such as between 1 and 500 millimeters, and any suitable width and height, such as between 0.1 and 5 millimeters. The exemplary primary channel 702 has a width of approximately 100 micrometers and a height of approximately 100 micrometers. In some embodiments, the primary channel 702 can have different dimensions, such as a width and / or height of 10 to 5,000 micrometers. The microchannel 506 can have a diameter different from the exemplary diameter of 4 micrometers, such as a diameter of 0.1 to 500 micrometers.

[0073]

[0100] The exemplary needle 500 is formed from silicon using conventional semiconductor processes such as photolithography, wafer bonding, etching, etc., as discussed in more detail below with respect to Figures 8-14. Additionally or alternatively, the needle 500 may be formed from any suitable material (stainless steel, plastic, glass, etc.) that is compatible with manufacturing techniques for forming the needle 500 as described herein.

[0074]

[0101] 6, a side view of the needle 500 shows that the needle 500 can have a uniform thickness. In some embodiments, the tip 504 of the needle can have a variable thickness, such as a sharp taper at the end of the tip 504.

[0075]

[0102] 3A-3G, several cross-sectional views of a needle 500 are shown. In FIG. 7A, a single primary channel 702 is shown with microchannels 506 extending from the primary channel 702 to the surface of the needle 500. In FIGS. 3B-3D, different configurations of microchannels 506 are shown, such as microchannels 506 extending from the primary channel 702 to both the top and bottom surfaces of the needle 500 and / or microchannels 506 extending from the primary channel 702 to the sides of the needle 500. In some embodiments, the needle 500 can include two or more primary channels 702, as shown in FIG. 7E. Each of the primary channels 702 can be used to deliver a different drug.

[0076]

[0103] It should be understood that the microchannels 506 can be arranged in a variety of configurations as shown in Figures 3A-3E. For example, in one embodiment shown in Figure 7F, the needle 500 can have a circular shape with one primary channel 702 and several microchannels 506 extending radially from the central primary channel 702. In another embodiment shown in Figure 7G, the needle 500 can have a circular shape with several primary channels 702, each with one or more corresponding microchannels 506.

[0077]

[0104] 5A and 5B, a cross-sectional top view of a needle 500 having one primary channel 702 is shown in FIG. 9A, and a cross-sectional top view of a needle 500 having several primary channels 702 is shown in FIG. 9B. It should be understood that in some embodiments, the primary channel 702 may include one or more side channels 902 that extend perpendicular to the primary channel 702. Some or all of the microchannels 506 may extend from the side channels 902 to the surface of the needle 500.

[0078]

[0105] 10 , in some embodiments, two or more needles 500 may be joined together by anchors 1002 to form an array of needles 1000. Each of the needles 500 in the array of needles 1000 may have a primary channel 702 and one or more microchannels 506, as described in more detail above. In an exemplary embodiment, the needles may have a 3 millimeter gap between them. In some embodiments, the gap may be larger or smaller, such as 0.1 to 50 millimeters.

[0079]

[0106] 11A , in some embodiments, an array of needles 1000 may be positioned opposite an array of electrodes 1100. A voltage source 1102 (such as a battery) may be connected to the array of needles 1000 and the electrodes 1100, such as via a pair of wires 1104. The electrodes 1100 may be formed from any suitable material, such as metal or silicon needles coated with a biocompatible conductive material, such as titanium nitride, similar to the array of needles 1000. The array of needles 1000 and the array of electrodes 1100 may be separated by any suitable distance, such as between 0.5 and 100 millimeters. It should be understood that the smaller the spacing, the lower the voltage that can lead to a larger electric field.

[0080]

[0107] During use, the array of needles 1000 and the array of electrodes 1100 may be inserted into a patient. A voltage source 1102 may apply a voltage across the array of needles 1000 and the array of electrodes 1100, creating an electric field 1106. The applied voltage may be any suitable voltage, such as 0.1 to 30,000 volts, with a corresponding electric field of, for example, 1 to 1,000 volts per centimeter. In exemplary embodiments, the electric field 1106 may cause electroporation in some or all of the cells within the area of ​​the electric field, temporarily creating nanopores within the cells and allowing drugs to flow into the cells, for example, by electrophoresis or diffusion or hydrodynamic forces. In some embodiments, the electric field 1106 may be pulsed. For example, in an exemplary embodiment, the electric field 1106 may be applied in 10 pulses with 100 milliseconds between each pulse. In some embodiments, the pulses may have different amplitudes. For example, the amplitude of each pulse may be smaller than the previous pulse. The pulses may be applied for any suitable length of time, such as 10-1,000 milliseconds, may be repeated any suitable number of times, such as 1-30 times, and may have any suitable time between pulses, such as 10-1,000 milliseconds. It should be understood that in some embodiments, voltage source 1102 may apply a reverse voltage, reversing the direction of electric field 1106.

[0081]

[0108] 7B and 7C, it should be understood that the needles and electrodes may be configured differently than that shown in FIG. 11A. For example, in one embodiment, a system may include several arrays of needles 1000 and several arrays of electrodes 1100, as shown in FIG. 11B. Additionally or alternatively, in some embodiments, a single array 1108 may include needles 500 intermingled with electrodes 1110, as shown in FIG. 11C. In such embodiments, each needle 500 may be connected to one side of a voltage source 1102 and each electrode 1110 may be connected to the other side of the voltage source 1102, resulting in an electric field 1106 as shown. In such embodiments, the needles 500 and electrodes 1110 may be separated by insulating elements 1112.

[0082]

[0109] 8-14, there are shown various stages in the fabrication of needle 500. In Figure 12, the process begins with a silicon wafer 1202. The silicon wafer can be prepared using standard techniques, such as by cleaning it with a solvent and RCA cleaning.

[0083]

[0110] As shown in FIG. 13, wafer 1202 then has channels 1302 etched therein. Channels 1302 can be etched using standard semiconductor processing techniques. For example, in one embodiment, photoresist such as AZ1518 is spun onto the wafer. A mask is then used to expose the photoresist with a UV light source in the desired channel locations, and the photoresist covering the channels is removed. Channels 1302 are then etched, the remaining photoresist can be removed, and wafer 1202 can be cleaned again. It should be understood that because channels 1302 extend along the surface of wafer 1202, the length of channels 1302 is not limited by how deeply etching can penetrate below the surface of the wafer. It should be understood that in some embodiments, channels 1302 can have shapes other than simple straight channels that extend completely along wafer 1202. For example, channels 1302 may not extend to one edge of wafer 1202 and / or may have side channels, as shown in FIG. 9. The channel 1302 may have dimensions similar to the primary channel 702 described above.

[0084]

[0111] As shown in FIGS. 10 and 11 , a second wafer 1402 is then bonded onto wafer 1202 to form a single wafer 1502 having channels 1504 that are enclosed on all sides except for openings at one or both edges of wafer 1502. Wafer 1402 can be bonded to wafer 1202 using any suitable technique, such as using a bonding machine to bond wafers 1202 and 1402 together and then annealing wafer 1502 in nitrogen gas at 400-1,200°C for 2-8 hours to effectively bond the wafers. Wafer 1402 can be any suitable thickness, such as 10-1,000 micrometers. In some embodiments, wafer 1402 can be any suitable material, such as plastic, a polymer film, or a transparent material that can be suitably bonded to or coated on wafer 1202.

[0085]

[0112] 16, one or more microchannels 1602 are formed extending from the surface of wafer 1402 to channel 1504. The microchannels may be formed using photolithography and deep reactive ion etching (DRIE). Microchannel 1602 may have dimensions similar to microchannel 506 described above.

[0086]

[0113] A photoresist 1702, such as AZ9260, may be applied to wafer 1502 to define the final shape of the needle. After etching the remaining exposed portions of wafer 1502 and removing photoresist 1702, needles 1802 remain having channels 1504 and microchannels 1602. It should be understood that in some embodiments, the formed needles 1802 may have sharp tips, as shown in FIG.

[0087]

[0114] The techniques described above can be used to create needles of different shapes and sizes, as well as arrays of needles, such as an array of needles 1000. In some embodiments, a single wafer 1202 (combined with a second wafer 1402) can be used to create several individual needles. In some embodiments, needles 1802 may undergo additional fabrication steps. For example, in an exemplary embodiment, a coating of titanium nitride can be applied to needles 1802.

[0088]

[0115] 8-14 are not the only techniques that may be used to fabricate the needles disclosed herein, such as needle 500. For example, in some embodiments, needle 500 or an array of needles 1000 may be 3D printed or industrially manufactured.

[0089]

[0116] 19 , in one embodiment, a roller system 1900 for administering a drug includes a roller 1902 having one or more needles 1904 mounted thereon and a handpiece 1906 connected to the roller 1902. Each of the needles 1904 may be similar to the needles 500. In some embodiments, an electrode is positioned next to each needle 1904 so that a voltage can be applied across the needles 1904 and the electrodes to create an electric field, similar to the configuration shown in FIG. 11A . The drug may be administered by moving the plunger of a syringe fluidly coupled to the needles 1904, such as through tubing. It should be appreciated that the roller system 1900 may allow the drug to be delivered through the needles 1904 to a wide area by rotating the roller system 1900 along the area targeted for treatment.

[0090]

[0117] It should be understood that the techniques described herein may be suitable for additional embodiments not explicitly described. For example, in some embodiments, a structure having microchannels similar to the microchannels 506 described above may be placed within a patient using a catheter or incorporated into other surgical instruments, such as those used for endoscopy or labroscopy. Electrodes may be similarly placed, and drugs may be delivered through the microchannels 506 and into target cells using electroporation, as described in more detail above.

[0091]

[0118] There are multiple advantages of the present disclosure that arise from the various features of the methods, apparatus, and systems described herein. It should be noted that alternative embodiments of the methods, apparatus, and systems of the present disclosure may not include all of the described features, but may still benefit from at least some of the advantages of such features. Those skilled in the art may readily devise their own implementations of the methods, apparatus, and systems that incorporate one or more of the features of the present invention and fall within the spirit and scope of the present disclosure as defined in the appended claims.

Claims

1. a substrate having a first surface and a second surface; a reservoir defined in the first surface of the substrate; a microstructure protruding from the second surface of the substrate to a tip, the microstructure having an opening formed in the tip and a delivery channel extending from the reservoir to the opening; a plurality of electrodes, each of the plurality of electrodes being electrically coupled to each other of the plurality of electrodes, the plurality of electrodes being positioned adjacent to the plurality of microstructures such that when a voltage is applied between the plurality of microstructures and the plurality of electrodes, an electric field is created perpendicular to an axis of each of the plurality of microstructures; Equipped with The delivery channel has a first channel and a second channel that communicate at a junction, the first channel extending from the opening toward the junction, and the second channel extending from the junction toward the reservoir, the first channel having an inner diameter smaller than an inner diameter of the second channel. Device.

2. The device of claim 1 , wherein the reservoir is configured to hold a target agent.

3. The device of claim 1 , wherein the targeting agent comprises at least one of a peptide, a protein, a carbohydrate, a nucleic acid molecule, a lipid, an organic molecule, and a biologically active inorganic molecule.

4. The apparatus of claim 1 , wherein the microstructure is a plurality of microstructures.

5. The device of claim 1 , wherein the microstructure comprises a plurality of the delivery channels.

6. The device of claim 1 , wherein the tip is blunt.

7. The device of claim 6 , wherein the delivery channel is positioned off-center of the blunt tip.

8. The device of claim 1 , wherein the tip is sharp.

9. The device of claim 8 , wherein the delivery channel is positioned off-center of the pointed tip.

10. The device of claim 1 , wherein the microstructures have a height greater than 150 μm.

11. The apparatus of claim 10 , wherein the microstructure has an aspect ratio greater than 3.

12. The device of claim 1 , wherein the microstructures have a height of between 200 μm and 1000 μm.

13. The device of claim 12, wherein the delivery channel has a diameter of between 50 nm and 5000 nm.

14. The device of claim 1 , wherein the reservoir comprises a porous material.

15. The device of claim 1 , wherein the reservoir includes a return component.

16. The device of claim 1 , wherein the reservoir is semi-permeable.

17. The device of claim 1 , wherein the reservoir contains cells that are sensitive to changes in physiological signals from the recipient.

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