Technology for needles with microchannels

Abstract

A device for delivering a drug to a target recipient comprises a planar substrate having a first surface and a second surface, a storage portion formed 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 storage portion to a channel opening formed 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 initial 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

Technology Field

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 877,060, filed July 22, 2019, under the heading “Microneedle with microchannels and related manufacturing method,” and U.S. Provisional Application No. 62 / 903,298, filed September 20, 2019, under the heading “Technology for needles with microchannels,” which are incorporated herein by reference.

[0002] The present disclosure relates to nanotechnology in general, and more specifically, to nanochannels and nanochannel-based delivery methods. Background Technology

[0003] The use of microneedle arrays has been proposed as a technology for delivering therapeutic agents across or into biological tissues. Microneedles are designed to rupture the barrier function of biological tissues and deliver therapeutic agents to the cell layer beneath the barrier (e.g., the outermost cell layer of the tissue). However, the aspect ratio of microneedles can significantly limit the ability to deliver therapeutic agents to deeper cell layers of the tissue. For instance, longer microneedles may require a larger diameter to support penetration of biological barriers (e.g., skin) to deliver therapeutic agents to deeper cell layers, but microneedles with a diameter larger than a certain threshold may irreversibly rupture the barrier function. Prior art literature

[65535] U.S. Patent Publication 2015 / 0051582 (February 19, 2015) The problem to be solved

[0004] The present application discloses the following features that may comprise one or more features mentioned in the appended claims and / or alone or in any combination thereof, which may comprise patentable subject matter. means of solving the problem

[0005] According to an embodiment of the present disclosure, an apparatus for delivering an agent to a target recipient comprises a planar substrate having a first surface and a second surface, a reservoir formed 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 formed on the outer surface of the microstructure. The reservoir is configured to contain an agent delivered to the target recipient through the delivery channel. The delivery channel further comprises 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 comprises forming a substrate that is substantially planar having a first surface and a second surface, forming a plurality of microstructures that protrude at a predetermined angle from the second surface to a distal end, forming a storage portion formed on the first surface, and forming a transfer channel in at least one microstructure that extends from the storage portion to a channel opening formed outside the corresponding microstructure. In various embodiments, the step of forming the microstructure may include a semiconductor process, 3D printing, embossing, injection molding, casting, photochemical etching, electrochemical machining, electrical discharge machining, precision stamping, high-speed computer numerically controlled milling, Swiss screw machining, soft lithography, directional chemically assisted 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 a cell to another layer of a cell comprises providing a planar substrate having a first surface and a second surface, a storage portion formed on the first surface of the planar substrate, and a microstructure array having 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 storage portion to a channel opening formed on the outer surface of the microstructure. The storage portion is configured to contain a drug to be delivered to a target recipient through the delivery channel.

[0008] According to another aspect of the present disclosure, a method for administering a drug to a subject using the disclosed device comprises inserting a microstructure of the device into the skin of the subject and allowing the drug to be delivered from the storage portion through a delivery channel of the microstructure and through the stratum corneum of the skin.

[0009] According to one aspect of the present disclosure, the device comprises a shaft extending from a proximal end to a distal end, the shaft forming a primary channel within the shaft 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 shaft further forming one or more microchannels, each of the one or more microchannels extending from the primary channel through the wall of the shaft, and 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 include a plurality of microchannels, and each of the plurality of microchannels extends from the primary channel through the sidewall of the shaft.

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

[0012] In some embodiments, the shaft is made of stainless steel.

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

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

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

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

[0017] In some embodiments, the one or more microchannels include a plurality of microchannels, and each of the plurality of microchannels extends from the primary channel through the sidewall of the shaft.

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

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

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

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

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

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

[0024] In some embodiments, the device may further include a syringe, said syringe being fluidly connected to the primary channel.

[0025] In some embodiments, the device may further include a handpiece mechanically and removablely coupled to the shaft.

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

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

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

[0029] According to one aspect of the present disclosure, a drug delivery method comprises inserting a shaft extending from a proximal end to a distal end into a patient, wherein the shaft forms a primary channel within the shaft 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 shaft further forms one or more microchannels, each of the one or more microchannels extending from the primary channel through the wall of the shaft, and 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 shaft; and applying a voltage across the electrode and the shaft to create nanopores in at least some cells disposed between the shaft and the electrode.

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

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

[0032] In some embodiments, applying a voltage across the electrode and shaft comprises applying two or more voltage pulses across the electrode and shaft, and each of the two or more pulses is less than 2,000 milliseconds.

[0033] In some embodiments, the shaft is mechanically coupled to a handpiece, and the method further comprises removing the shaft from the patient and separating the handpiece from the shaft. One embodiment of the present disclosure is a device comprising a base having a first impermeable surface and a second surface on the opposite side; and a plurality of shafts, wherein each of the plurality of shafts extends from a second surface of the base to a tip, and each of the plurality of shafts defines one or more primary channels within the corresponding shaft, the primary channels extend from a proximal end to a distal end, the proximal end of each of the primary channels is in fluid communication with the first surface, and the distal end of each of the primary channels terminates within the shaft to define a primary channel bottom, and each of the plurality of shafts also defines one or more microchannels, and each of the one or more microchannels extends from the bottom of the primary channel to the tip of the shaft such that the primary channel is positioned in fluid communication with the outer surface of the shaft, the diameter of the microchannel is smaller than the diameter of the primary channel, the primary channel has a diameter selected from the range of 10 to 1000 micrometers, and each of the one or more microchannels is selected from the range of 1 to 1000 micrometers A device having a diameter can be provided.Another embodiment of the present disclosure is a method for manufacturing an apparatus, comprising the steps of: creating a primary channel having a depth of at least 10 micrometers and a length of at least 5 millimeters in a first silicon wafer using photolithography; and bonding a second silicon wafer to the first silicon wafer after the creation of the primary channel. A method for manufacturing an apparatus may be provided, comprising the step of etching the second silicon wafer to create one or more microchannels, wherein each of the one or more microchannels extends from the first channel through the second silicon wafer and each of the one or more microchannels has a diameter of less than 1,000 micrometers. In an apparatus according to one embodiment of the present disclosure, the shaft may be composed of silicon, stainless steel, plastic, or any combination thereof. Each shaft is provided with a single first channel and a single microchannel, and the major axis of the microchannel may be parallel to the major axis of the first channel. The tip may be pointed, and the microchannel may be positioned off-center from the tip. The shaft may also define one or more second sets of microchannels extending from the first channel through the wall of the shaft such that the first channel is fluidly in communication with the outer surface of the shaft, and the major axis of each of the second sets of microchannels may be at an angle to the major axis of the first channel.Another embodiment of the present disclosure may provide an apparatus comprising: a base having a first impermeable surface and a second surface on the opposite side; and one or more shafts protruding from the second surface of the base to a leading edge, wherein each shaft defines a primary channel extending from a proximal end to a distal end within each shaft, the proximal end of the primary channel fluidly communicating with the first surface, and the distal end terminates within the shaft to define the bottom of the primary channel, and each shaft also defines one or more microchannels, wherein each of the one or more microchannels extends from the primary channel through the wall of the shaft so as to be positioned so that the primary channel fluidly communicates with the outer surface of the shaft, and the major axis of each microchannel forms an angle with respect to the major axis of the primary channel. The device further comprises an electrode, and the device may be configured to perform maintaining a composition within a primary channel of the one or more shafts, inserting the one or more shafts into a tissue, inserting an electrode into the tissue adjacent to the one or more shafts, and applying a voltage across the electrode and the one or more shafts to create nanopores within at least a portion of the tissue disposed between the one or more shafts and the electrode. The device may also be configured to perform applying a force to move the composition from the primary channel of the one or more shafts and into the one or more microchannels. Applying a voltage across the electrode and the one or more shafts includes applying two or more voltage pulses across the electrode and the one or more shafts, and each of the two or more voltage pulses may be less than 2000 milliseconds.Each of the above shafts also defines one or more lateral channels extending perpendicularly to the major axis of the primary channel, and the lateral channels may be in fluid communication with both the primary channel and the microchannel. Each of the above shafts defines a plurality of primary channels extending from a proximal end to a distal end within each shaft, the major axis of each of the plurality of primary channels is parallel to each of the major axes of other primary channels, the proximal end of each of the primary channels is in fluid communication with the first surface, and the distal end of each of the primary channels is terminated within the shaft, and each of the primary channels may also be in fluid communication with one or more of the microchannels extending through the wall of the shaft such that each of the primary channels is positioned to be in fluid communication with the outer surface of the shaft. The diameter of the microchannel is smaller than the diameter of the primary channel, the primary channel has a diameter selected from the range of 10 to 1000 micrometers, and the microchannel may have a diameter selected from the range of 1 to 1000 micrometers. The shaft may be coated with an electrically conductive material. A plurality of electrodes may be further included, and the plurality of electrodes may be arranged adjacent to the plurality of shafts such that when a voltage is applied between the plurality of shafts and the plurality of electrodes, an electric field is generated perpendicular to the axis of each of the plurality of shafts. The major axis of one or more microchannels may independently form an angle with the major axis of the primary channel. A single primary channel may be provided in each shaft. Each of the shafts may have an aspect ratio greater than 3, defined by dividing the length of the microchannel by the diameter of the primary channel. The shaft may be composed of silicon, stainless steel, plastic, or any combination thereof.Another embodiment of the present disclosure may provide a system for inducing electroporation, comprising a device according to claim 7 and an electrode array configured to match the size and spacing of the shafts of the device, wherein when the device and the electrode array are inserted into the tissue of a patient, an electric field perpendicular to the long axis of each of the plurality of shafts is generated by applying a voltage across the shafts and the electrodes.

[0034] For a detailed description, refer specifically to the following drawings. Brief explanation of the drawing

[0035] FIG. 1 is a schematic diagram showing an example of a microstructure array having a plurality of microstructures for delivering a drug to a target cell layer. FIG. 2a is a schematic diagram showing an embodiment of a microstructure array having a plurality of microstructures having blunt tips. FIG. 2b is a schematic diagram showing an embodiment of a microstructure array having a plurality of microstructures having pointed tips. FIGS. 3a to 3g are schematic diagrams illustrating a method for fabricating the microstructure array of FIG. 2a using semiconductor processes such as lithography and etching techniques. FIGS. 4a to 4k are schematic diagrams illustrating a method for fabricating the microstructure array of FIG. 2b using semiconductor processes such as lithography and etching techniques. FIG. 5 is a plan view of an embodiment of a needle provided with a microchannel. Fig. 6 is a side view of the needle of Fig. 5. FIGS. 3a to 3g are cross-sectional views of various embodiments of the needle of FIG. 5. Fig. 8 is a cross-sectional view of the needle of Fig. 5. FIGS. 9a and FIGS. 5b are cross-sectional views of various embodiments of the needle of FIG. 6. FIG. 10 is an example of a needle array provided with a microchannel. FIGS. 7a to 7c are various embodiments of a needle array in which a microchannel is provided next to the electrode array. FIG. 12 is an example of a wafer that can be used to create a needle having a microchannel. FIG. 13 is an example of a wafer that can be used to create a microchannel needle with a channel etched inside. FIG. 14 is an example of a second wafer bonded to the wafer of FIG. 13. FIG. 15 is an example of a wafer bonded to the top of another wafer forming a channel. FIG. 16 is an example of the wafer of FIG. 15 having a microchannel formed inside. FIG. 17 is an example of a wafer of FIG. 16 having a photoresist that forms needles. FIG. 18 is an example of a needle having a microchannel formed from the wafer of FIG. 17. FIG. 19 is an example of a roller system having one or more needles with microchannels. Specific details for implementing the invention

[0036] Terms used throughout this application should be interpreted by those skilled in the art in their ordinary and typical sense. However, the applicant wishes that the following specific definitions be provided for the following terms.

[0037] The singular forms "a," "an," and "the" used in the specification and claims include plural references unless the context clearly indicates otherwise. For example, the term "cell" includes plural cells, including mixtures thereof.

[0038] The terms “about” and “approximately” are formed as “approximately” as understood by those skilled in the art. In one non-limiting embodiment, these terms are defined as being within 10%. In another non-limiting embodiment, these terms are defined as being within 5%. In yet another non-limiting embodiment, these terms are defined as being within 1%.

[0039] As used herein, the term “comprising” is intended to mean that the composition and method include the mentioned elements but do not exclude others. When used to define the composition and method, “essentially comprising” means excluding other elements that are essentially important to the combination. Thus, a composition essentially composed of the elements defined herein does not exclude trace amounts of contaminants in the isolation and purification method, and pharmaceutically acceptable carriers such as phosphate-buffered saline, preservatives, etc. “comprising” means excluding more than trace elements of other components and substantial method steps for administering the composition of the present invention. Examples defined by each of these transition terms are within the scope of the present invention.

[0040] "Effective amount" is an amount sufficient to achieve a beneficial or desired result. The effective amount may be administered in one or more doses, applications, or dosages. The term "carrier" or "pharmaceutically acceptable carrier" means a carrier or excipient useful for preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic, and includes carriers accepted for veterinary and / or human pharmaceutical or therapeutic use. As used herein, the term "carrier" or "pharmaceutically acceptable carrier" may include phosphate buffered saline solution, water, emulsions (e.g., 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 widely known in the art for use in pharmaceutical formulations and further described below.

[0041] A range may be expressed herein as “about” from one specific value and / or “about” another specific value. When such a range is expressed, other embodiments include one specific value and / or another specific value. Similarly, when a value is expressed as an approximation, it will be understood that by using the antecedent “about,” a specific value forms another embodiment. It will also be understood that each endpoint of a range is important in relation to and independently of other endpoints. Furthermore, multiple values ​​are disclosed in this specification, and each value is also understood to be disclosed in this specification as “about” that specific value in addition to the value itself. For example, if a value “10” is disclosed, “about 10” is also disclosed.

[0042] The terms “therapeutic effective dose” or “therapeutically effective dose” refer to the amount of a composition, such as glucose-modified insulin bound to a glucose-binding structure, that elicits a biological or medical response in tissues, systems, animals, or humans, which is being identified by researchers, veterinarians, physicians, or other clinicians over a wide period of time. In some examples, the desired biological or medical response is achieved after multiple administrations of the composition to a subject over a period of days, weeks, or years.

[0043] In this document, the terms “subject” or “recipient” are defined as animals such as mammals, including but not limited to primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0044] As used herein, the terms “treat,” “treating,” “treatment,” and their grammatical variations include partially or completely delaying, alleviating, mitigating, or reducing the intensity of one or more accompanying symptoms of a disorder or condition, and / or alleviating, mitigating, or delaying one or more causes of the disorder or condition. Treatment according to the present invention may be applied preventively, prophylactically, pallatively, or remedially.

[0045] While various modifications and alternative forms are possible for the concept of the present disclosure, specific exemplary embodiments are illustrated by way of example in the drawings and will be described in detail herein. However, it should be understood that there is no intention to limit the concept of the present disclosure to the specific forms disclosed, but on the contrary, the intention is to encompass all modifications, equivalents, and alternatives that fall within the spirit and scope of the invention as defined in the appended claims.

[0046] The microstructure array disclosed herein and the method using the same are useful for transporting drugs into or across biological barriers (e.g., cell membranes). The microstructure array disclosed herein has the ability to deliver drugs to specific layers of cells within a tissue. As described in detail below, the microstructure array comprises a plurality of microstructures configured to penetrate a barrier (e.g., a biological barrier layer). Each microstructure comprises one or more delivery channels configured 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 the microstructure array may comprise multiple delivery channels that allow drugs to be delivered to multiple layers of cells within the tissue simultaneously (or sequentially). In such embodiments, the one or more microstructures may have multiple delivery channels emerging from an angled microstructure that allows for different heights of the delivery channels within the microstructure. When the microstructure penetrates the tissue, the delivery channels are located within different layers of cells and thus can deliver drugs to different layers or levels within the tissue. It should be understood that the above-mentioned microstructure array may be used on the skin (or part thereof) across the blood-brain barrier, mucosal tissues (e.g., oral cavity, nasal cavity, eye, vagina, urethra, gastrointestinal, respiratory tract), blood vessels, lymphatic vessels, cell membranes (e.g., for the introduction of substances into cells or cells), or other biological barriers. The above-mentioned biological barriers may be present in plants, insects, or other organisms including bacteria, yeast, fungi, and embryos, as well as in humans or other types of animals. Additionally, the above-mentioned microstructure array may be applied inside tissues with the help of a catheter or a laparoscope.For specific applications such as drug delivery to internal tissues, a device equipped with the above-mentioned microstructure array can be surgically implanted.

[0047] As illustrated in FIG. 1, a microstructure array (100) for transporting a drug to a subject comprises a flat base (110) having a top surface (112) and a bottom surface (114) opposite to the top surface (112), and a plurality of microstructures (120) protruding outwardly from the bottom surface (114) of the flat base (110). When in use, the microstructure array (100) is positioned relative to the subject such that the bottom surface (114) of the flat base (110) faces the subject. Subsequently, the subject's barrier is penetrated or perforated using the plurality of microstructures (120) on the bottom surface (114). To deliver a target drug to the subject, each microstructure (120) comprises a main body (126), a storage unit (122), and one or more delivery channels (124) formed within the main body (126). Specifically, as illustrated in FIGS. 2a and 2b, the storage portion (122) extends inward from the top surface (112) of the planar base (102) and is configured to hold a target drug to be delivered to a subject. A delivery channel (124) is formed within an elongated body (126) extending from the bottom surface (114) of the planar base (102) to a tip (128). The delivery channel (124) is configured to act as a conduit between the storage portion (122) and the channel opening (130) so that the target drug placed in the storage portion (122) can be delivered to the environment surrounding the microstructure (120) at the channel opening (130).

[0048] It should be understood that the microstructure array (100) may include several microstructures (120) having several different tips (128). It should be understood that the method of fabricating the microstructure array (100) depends on the type of tip (128) that the microstructure (120) has. An exemplary method of fabricating the microstructure array (100) is illustrated in FIGS. 3 and FIGS. 4.

[0049] For example, as illustrated in FIG. 2a, the microstructure array (100) may include a microstructure (120A) having a blunt tip (128A). In this embodiment, the microstructure (120A) has a storage portion (122) and a transfer channel (124A) extending from the center of the storage portion (122) to a channel opening (130A) located at the center of the blunt tip (128A). A method for fabricating the microstructure array (100) having the microstructure (120A) is further described in FIG. 3. However, it should be understood that in some embodiments, the channel opening (130A) may be located away from the center of the blunt tip (128A). Alternatively, as illustrated in FIG. 2b, the microstructure array (100) may include a microstructure (120B) having a pointed tip (128B). In this embodiment, the microstructure (120B) comprises a storage portion (122) and a delivery channel (124B) extending from a position offset from the center of the storage portion (122) to a channel opening (130B) located on the inclined side of a pointed tip (128B).

[0050] A method for fabricating a microstructure array (100) having a microstructure (120B) is further described in FIG. 4. However, it should be understood that in some embodiments, the channel opening (130B) may be located at the center of the pointed tip (128B). Alternatively, in other embodiments, the microstructure array (100) may include two types of microstructures (120A, 120B).

[0051] As further described below, each microstructure (120) may have a specific aspect ratio that enables the microstructure array (100) to transport a target agent from a storage unit (122) through a delivery channel (124) into or across a biological barrier to a deeper cell layer without irreversibly destroying the barrier function. The aspect ratio used herein is defined as the distance from the bottom surface (114) to the tip (128A, 128B) divided by the width of the main body (126). In an exemplary embodiment, the microstructure (120) has a height greater than 150 μm and an aspect ratio greater than 3. In some embodiments, each microstructure (120) may have a height of approximately 200 to 1000 μm and a delivery channel (124) with a diameter of 50 to 5000 nm.

[0052] Additionally, the delivery channel (124) has a diameter (D1) smaller than the diameter (D2) of the storage portion (122). For example, the diameter (D1) of the delivery channel (124) is less than about 5000 nm, and the diameter (D2) of the storage portion (122) is about 25 μm. In an exemplary embodiment, the microstructure (120) has a cylindrical body. However, it should be understood that in some embodiments, the elongated body (126) may be 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) may include multiple delivery channels (124). In such embodiments, the multiple delivery channels (124) may have the same height so that the drug can be delivered to the target layer of cells within the tissue simultaneously or sequentially. As an alternative, in another embodiment, the microstructured multiple delivery channels (124) may have different heights that must be located within different layers of the cell, and thus can deliver the drug at different layers or levels within the tissue.

[0053] In some embodiments, the delivery channel (124) may be formed 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 storage unit (122), so that the first and second channels are in fluid communication with the storage unit (122). As will be discussed further below, the first channel has an inner diameter 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 to 20 μm.

[0054] In an exemplary embodiment, the storage unit (122) is integrated with the planar base (102) and is sized to administer to a single microstructure (120). However, in some embodiments, the storage unit (122) may be sized to administer to two or more microstructures (120). For example, in such an embodiment, the microstructure array (100) may include a single large storage unit for administering to a plurality of microstructures (120) of the microstructure array (100). It should be understood that in some embodiments, the storage unit (122) may be manufactured separately and interfaced with the planar base (102). In one embodiment, the storage unit (122) may include a porous material, and the drug to be administered is stored in the pores of the porous material. In another embodiment, the storage unit is sealed. In one variation of this embodiment, the microstructure array may further include at least one puncturing barb extending from a first surface of a planar substrate, and the puncturing barb may be used to puncture the sealed storage portion.

[0055] The storage unit (122) is configured to contain any drug to be delivered to a targeted cell layer through a delivery channel (124) of the microstructure (120) via a release mechanism. The drug to be delivered across the barrier layer may be selected from the group comprising peptides, proteins, carbohydrates, nucleic acid molecules, lipids, organic molecules, biologically active inorganic molecules, and combinations thereof. For example, a wide range of drugs may be formulated for delivery by the microstructure array (100).

[0056] As used herein, the terms “drug” or “drug formulation” are used to broadly refer to prophylactic drugs, therapeutic drugs, diagnostic drugs or theranostic agents, or other substances including pharmaceutical excipients and substances for tattoos, cosmetics, etc. that may be suitable for introduction into biological tissues. A drug may be a biologically active agent. A drug formulation 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 a non-limiting representative embodiment, the drug may be selected from amino acids, vaccines, antiviral agents, gene delivery vectors, interleukin inhibitors, immunomodulators, neurotropic factors, neuroprotective agents, antineoplastic agents, chemotherapeutic agents, polysaccharides, anticoagulants, antibiotics, analgesic agents, anesthetics, antihistamines, anti-inflammatory agents, and viruses. The drug may be selected from suitable proteins, peptides, and fragments thereof that may be naturally occurring, synthetically produced, or recombinantly produced. In one embodiment, the drug formulation comprises insulin. The drug formulation may further comprise one or more pharmaceutically acceptable excipients, including pH adjusters, viscosity adjusters, and diluents.

[0057] In some embodiments, the agent may be an electrical stimulant. Pulsed electric fields have many applications, such as regenerative medicine. In these embodiments, the microstructure array (100) may be used to deliver pulsed electric fields at different levels across tissue thickness. In some embodiments, the storage unit (122) may include means for generating the agent to be delivered to a target recipient. For example, the storage unit (122) may include cells capable of generating the agent 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 β cells or human pancreatic cells differentiated into stem cells.

[0058] The release mechanism may include 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, when in use, the microstructure array (100) may be placed on a biological barrier layer, which allows the leading edge (128) of the microstructure (120) to penetrate the barrier layer and deliver the agent contained in the storage unit (122) through the delivery channel (124) to the environment (e.g., intracellular space) surrounding the channel opening (130) of the microstructure (120). To do so, a porating electric field may be applied across the microstructure array (100) to rupture or deform the biological barrier layer (e.g., cell membrane) so that the agent can be translocated into the cell. The strength of the electric field required for translocation may vary depending on the target tissue or system. Conversely, the drug can be drawn from the environment outside the channel opening (130) through the delivery channel (124) and stored in the storage unit (122) for feedback communication.

[0059] In an exemplary embodiment, the microstructure array (100) further includes first and second electrodes for generating an electric field between electrodes located on both sides of a delivery channel (124) to enhance the delivery of a drug. Specifically, the first electrode is in contact with the storage portion (122) and the second electrode is located at the distal end (128) of the microstructure (120), so that the electric field is generated across the tissue between the two electrodes. Voltage, frequency, and other electric field parameters may be selected based on the distance between the electrodes.

[0060] The electrode structure may be formed as concentric bands connected to a conductive pad. Each band and band segment may be wired together to an electroporation power source or wired separately to an electroporation power source and may be supplied with energy in various geometric and timed patterns and arrangements. Furthermore, different bands and band segments may be maintained at different potentials (voltages) relative to the first electrode structure. The drug may be delivered through a channel opening (130) at the distal end (128) to penetrate the tissue to the outside in a certain area. This area may coincide with the electric field generated between the first electrode structure and the second electrode structure. It should be understood that the electric field can enhance cell permeability, thereby improving the delivery of the desired drug to the cells.

[0061] The above-described microstructure array capable of electroporation may include an alternating current (AC) power source configured to deliver an electroporation current to an electrode structure at a desired voltage and frequency, selected to deliver an electroporation current to the electrode at a voltage generally in the range of 0.1 V to 30 kV. In some cases, the voltage is about 50 to less than 500 V. The specific voltage will depend at least partially on the spacing between the first electrode structure and the second electrode structure. The frequency will typically be 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, or more milliseconds, and any amount of pulses may be applied within the 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. The interval may be repeated until a desired result is obtained.

[0062] It should be understood that the storage unit (122) may include a feedback component to change the volume or amount of drug to be transported across a biological barrier based on a physiological signal. To do so, the feedback component may include a switch configured to control a release mechanism to release the drug to a target recipient based on the detection or absence of a signal. For example, the drug may be contained within the storage unit (122) until the signal is detected (i.e., not released into the delivery channel (124)). When the signal is detected, 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 causes the drug to be released from the storage unit. Alternatively, the detection of the signal may have the opposite effect. In this example, the storage unit essentially delivers the drug to the target recipient unless a signal is detected that prevents the storage unit (122) from releasing the drug to be delivered to the recipient.

[0063] In some embodiments, the feedback component may detect changes in physiological signals (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 a judgment that the physiological signal has changed by a predefined amount or has reached a predefined value. Additionally, or alternatively, the feedback component may adjust the amount or volume of drug to be released based on the amount of the detected signal. For example, if a larger amount of signal is detected, a larger amount of drug may be released, or conversely, if a larger amount of signal is detected, a smaller amount of drug may be released. It should be understood that the detected physiological signal may indicate the presence of a substance within the target recipient to whom the microstructure array is administered. The physiological signal may be naturally generated within the recipient or may be induced by non-endogenous or foreign substances. For example, physiological signals may indicate the amount of substances present in a target recipient, such as but not limited to glucose, cholesterol, bilirubin, creatinine, metabolic enzymes, hemoglobin, heparin, clotting factors, uric acid, carcinoembryonic antigen, or other tumor antigens, reproductive hormones, oxygen, alcohol, tobacco metabolites, and illicit drugs.

[0064] In some embodiments, the reservoir (122) may be semipermeable to allow fluid exchange with the target recipient. This, in turn, enables the feedback component to fluidly connect with the target recipient to detect changes in the recipient's physiological signals. For example, the reservoir (122) may include cells sensitive to changes in physiological signals from the recipient. Such physiological changes in the recipient may stimulate the cells to release a drug or stop drug release, as described above in relation to the feedback component. In one example, the semipermeable reservoir may be made of alginate microgel.

[0065] In an exemplary embodiment, the agent in the storage unit to be delivered to the target recipient may be a therapeutic, preventive, diagnostic, or therapeutic diagnostic substance. Additionally, two or more agents may be delivered at once. Additionally, or alternatively, different agents may be delivered sequentially or simultaneously through different channels. In an embodiment where multiple delivery channels (124) reach different layers of cells, it should be understood that different agents may be administered to different cell layers within the tissue using the microstructure array disclosed herein simultaneously. Specifically, a first agent may be delivered to a first layer of cells through a first delivery pathway, and a second agent may be delivered to a second layer of cells through a second delivery pathway.

[0066] Referring to FIG. 3, a method for creating a microstructure array (100) having a plurality of microstructures (120A) having blunt tips (128A) is illustrated using semiconductor manufacturing techniques such as photolithography and etching techniques. The method begins by creating a storage area (122) on a wafer (140). In an exemplary embodiment, the wafer (140) has a height (D7) greater than 300 μm and is made of silicon, and the oxide layer (150) is made of silicon dioxide or other oxides. However, it should be understood that in some embodiments, the wafer (140) may be made of other substrates such as glass, silicon carbide, plastic, polymer, and metal.

[0067] As illustrated in FIG. 3a, an oxide layer (150) is deposited on a first surface (142) of a wafer (140) using an oxidation process. The oxidation process may include chemical vapor deposition or wet oxidation at a high temperature. Chemical vapor deposition is a preferred method because it is cost-effective compared to wet oxidation, which requires a high temperature (1,000°C or higher) and has a slow growth rate, can be performed at a low temperature, and has a fast deposition rate. Next, a photoresist material (152) is deposited on top of the oxide layer (150) by spin coating, and exposed to UV light in an optical lithography tool equipped with a photomask (not shown) to form a pattern (e.g., a hole array) (154) on the photoresist material layer (152) as illustrated in FIG. 3b. In an exemplary embodiment, each hole (154) formed in the photoresist layer (152) has a diameter (D3) of about 10 to 30 μm and is used as a mask for etching the oxide layer (150). For example, plasma etching (e.g., using a fluorine-containing plasma gas) may be performed to create a mask to be used to create a storage portion (122) of the microstructure array (100). Once the mask is created, the remaining photoresist material (152) is removed. Subsequently, the wafer (140) is etched using an array of hole patterns (154) of the oxide layer (150) to create a hollow channel (i.e., storage portion (122)) in the wafer (140), and the oxide layer (150) is removed as shown in FIG. 3C. In an exemplary embodiment, each storage portion (122) has an initial diameter (D3) of about 10 to 30 μm. However, as further explained in FIG. 3g below, the diameter of the hollow storage portion (122) can be further adjusted.

[0068] Next, a transfer channel (124) is formed on the wafer (140) to create a microstructure array (100). To do this, as illustrated in FIG. 3d, an oxide layer (156) is deposited on the second surface (144) of the wafer (140) using an oxidation process (e.g., chemical vapor deposition at high temperature or wet oxidation). Next, a photoresist material (158) is deposited on the oxide layer (156) by spin coating, and exposed to UV light in an optical lithography tool equipped with a photomask (not shown) to form a disc shape on the photoresist layer (152) that is aligned with each storage unit (122). In an exemplary embodiment, each disc-shaped photoresist layer (not shown) has a diameter (D4) of about 50 μm and is used as a mask to etch the oxide layer (156) to create a disc-shaped oxide layer (160) having a diameter (D4) of about 50 μm. Next, as illustrated in FIGS. 3e and 3f, similar lithographic patterning and etching processes are repeated to create a narrow channel (162) in the center of each disc-shaped oxide layer (160). In an exemplary embodiment, the hole in the oxide layer (162) has a diameter (D5) of about 0.05 μm to 5 μm and is used to form a transfer channel (124) of each microstructure (120).

[0069] Next, each disk-shaped oxide layer (160) is used to etch the wafer (140) to form the contour of a blunt microneedle tip (128A) having a delivery channel (138). The delivery channel (124) extends from the opening (130A) of the blunt microneedle tip (128A) through the center of the microstructure (120A) to the storage portion (122), as shown in FIG. 3f. For example, the etching process is performed using highly anisotropic deep reactive ion etching (DRIE) to perforate the hollow channel (124) through the wafer (140). It should be understood that in some embodiments, the delivery channel (138) may be located off-center in the microstructure (120).

[0070] Next, the disc-shaped oxide film (160) is removed and the wafer (140) is cleaned. In an exemplary embodiment, the resulting microstructure (120A) has a transfer channel (130A) with an initial diameter of about 2 to 10 μm and a length (D6) greater than 150 μm. It is difficult to etch a narrow transfer channel with a very high aspect ratio using conventional dry etching techniques. Instead, in some embodiments, a hollow channel with a larger inner diameter is etched, and then an oxide, silicon, or nitride film is deposited on the surface as shown in FIG. 3g to reduce the inner diameter to a target size. These materials can be deposited by chemical vapor deposition or atomic layer deposition techniques capable of conformally coating the structured surface, thereby reducing the diameter of the transfer channel but increasing the outer size of the microneedle. In an exemplary embodiment, the target diameter of the transfer channel (138) is 0.05 to 5 μm. The diameter of the storage portion is about 10 to 30 μm.

[0071] Now, referring to FIG. 4, a method for creating a microstructure array (100) having a microstructure (120B) having a pointed tip (128B) using photolithography and etching techniques is illustrated. The method begins by creating a storage area (122) on a wafer (140). In an exemplary embodiment, the wafer (140) has a height (D7) greater than 300 μm and is made of silicon, and the oxide layer (150) is made of silicon dioxide or other oxides. However, it should be understood that in some embodiments, the wafer (140) may be made of other substrates such as glass, silicon carbide, plastic, polymer, and metal.

[0072] As illustrated in FIG. 4a, an oxide layer (150) is deposited on a first surface (142) of a wafer (140) using an oxidation process. The oxidation process may include chemical vapor deposition or wet oxidation at a high temperature. Chemical vapor deposition is a preferred method. Next, a photoresist material (152) is deposited on top of the oxide layer (150) by spin coating, and exposed to UV light in an optical lithography tool equipped with a photomask (not shown) to form a pattern (e.g., a hole array) (154) on the photoresist material layer (152) as illustrated in FIG. 4b. In an exemplary embodiment, each hole (154) formed in the photoresist layer (152) has a diameter (D3) of about 10 to 30 μm and is used as a mask for etching the oxide layer (150). For example, plasma etching (e.g., using a fluorine-containing plasma gas) may be performed to create a mask to be used to create a storage portion (122) of a microstructure array (100). Once the mask is created, the remaining photoresist material (152) is removed. Subsequently, as illustrated in FIG. 4c, the wafer (140) is etched using an array of hole patterns (154) of the oxide layer (150) to create a hollow channel (i.e., storage portion (122)) in the wafer (140), and the oxide layer (150) is removed. In an exemplary embodiment, each storage portion (122) has an initial diameter (D3) of about 10 to 30 μm. However, as further described in FIG. 4k below, the diameter of the hollow storage portion (122) may be further adjusted.

[0073] Next, a transfer channel (124) is formed on the wafer (140) to create a microstructure array (100). To do this, as shown in FIG. 4d, an oxide layer (170) is deposited on the second surface (144) of the wafer (140) using chemical deposition (e.g., chemical deposition at high temperature or wet oxidation). Next, a photoresist material (172) is deposited on the oxide layer (170) by spin coating, and exposed to UV light in an optical lithography tool equipped with a photomask (not shown) to form a disk shape aligned with each storage unit (122) on the photoresist layer as shown in FIG. 4e. In an exemplary embodiment, each disk-shaped photoresist layer has a diameter of about 50 μm and is used as a mask to etch the oxide layer (170) to create an oxide disk (174) having a disk shape and a diameter (D8) of about 50 μm. Next, as illustrated in FIG. 4f, a similar lithography patterning and etching process is repeated to create a hollow cavity (176) in each oxide disk (174). In an exemplary embodiment, the hollow cavity (176) has a diameter (D9) of about 0.1 μm to 5 μm and is used to form a delivery channel (138) of each microstructure (120).

[0074] Next, each oxide disk (174) is used to etch the wafer (140) to form a pointed microneedle tip (128B) of the microstructure (120B) through isotropic silicon etching, as shown in FIG. 4g. Once the pointed microneedle tip (128B) is established, the hollow cavity (176) of the oxide disk (174) is further etched until the hollow cavity (176) penetrates the rest of the oxide disk (174), as shown in FIG. 4h. Subsequently, the wafer (140) is further etched to form the contour of the microstructure (120B) having a transfer channel (124) extending from the microneedle tip (128) through the microstructure (120) to the storage portion (122), as shown in FIG. 4i.

[0075] Next, as illustrated in FIG. 4j, the oxide disk (172) is removed and the wafer (140) is cleaned. In an exemplary embodiment, the resulting microstructure (120A) has a transfer channel (124) having an initial diameter (D11) of about 0.1 to 5 μm and a length (D10) greater than 150 μm. To further reduce the diameter of the transfer channel (124) to a target size of 0.05 to 5 μm, an oxide, silicon, or nitride layer may be laminated on the microstructure array (100), as illustrated in FIG. 4k. As described above, this shrinkage process can also reduce the diameter of the storage portion (122) to a target size. In an exemplary embodiment, the target diameter of the transfer channel (124) is 0.05 to 5 μm.

[0076] Referring now to FIG. 5, in an exemplary embodiment, a needle (500) is formed from silicone. In some embodiments, the needle (500) may be formed from other materials such as stainless steel or plastic. The needle (500) has a shaft (502) and a tip (504). The needle (500) has one or more primary channels (702) that extend along the interior of the shaft (see FIG. 3 through FIG. 5). The needle (500) has several microchannels (506) that extend from one or more primary channels (702) to the surface of the needle (500). Each exemplary microchannel (506) has a diameter of approximately 4 micrometers. In use, the needle (500) may be inserted into a patient, such as through the skin or into an organ. A drug may be administered by allowing it to flow from the primary channel (702) through the microchannels (506) into the patient. In an embodiment where multiple primary channels (702) are provided, different drugs may be administered to different primary channels (702). In some embodiments, an electric field may be applied to induce electroporation of tissue cells and facilitate the flow of the drug to a desired location. In such embodiments, the needle (500) may be coated with an electrically conductive coating, such as titanium nitride or other biocompatible materials. Additionally, or alternatively, in some embodiments, an electrode may come into contact with the drug, and the drug itself may propagate along with the electric field by electrophoresis. In some embodiments, instead of delivering the drug, one of the primary channels (702) and the corresponding microchannel (506) may be used to extract samples such as extracellular fluid, vesicles, etc. from the patient, or a device for monitoring the tissue environment, such as temperature, pH, etc., may be integrated into the needle (500).

[0077] It should be understood that the width of the microchannel (506) can be varied to allow a specific drug, such as a gene, DNA, or protein, to be administered at a desired rate. Additionally, the drug can be administered at various different depths depending on the location of the microchannel (506). In an exemplary embodiment, there is a single primary channel (702). Additionally, or alternatively, in some embodiments, there may 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) on the same needle (500) may have different diameters. For example, a microchannel (506) connected to one primary channel (702) may have a different diameter compared to a microchannel (506) connected to a second primary channel (702).

[0078] The drug may be inserted into the primary channel (702) in any suitable manner. For example, in an exemplary embodiment, the primary channel (702) may be connected to the syringe using a tube extending from the syringe to a block (e.g., polydimethylsiloxane) coupled to the opening of the primary channel. In some embodiments, the syringe may be embedded in the handpiece or form part of the handpiece. The handpiece and syringe may be removablely connected to the needle (500) so that the needle (500) can be discarded after a single use and the handpiece and syringe can be reused.

[0079] In relation to the above microstructure array, it should be understood that the needle (500) having microchannels (506) can be used on the skin (or part thereof) across the blood-brain barrier, mucosal tissues (e.g., oral cavity, nasal cavity, eyeball, vagina, urethra, gastrointestinal tract, respiratory tract), blood vessels, lymphatic vessels, cell membranes (e.g., for introducing substances into cells or cells), or other biological tissues or barriers. The biological barrier may be present in plants, insects, or other organisms including bacteria, yeast, fungi, and embryos, as well as in humans or other types of animals. Additionally, the needle (500) having microchannels (506) can be applied inside tissues with the help of a catheter, endoscope, laparoscope, etc. In certain applications, such as drug delivery to internal tissues, a device equipped with the needle (500) having microchannels (506) may be surgically implanted or integrated into a surgical instrument.

[0080] An exemplary needle (500) has a length of approximately 10 millimeters, a width of approximately 1 millimeter, and a height of 0.5 millimeters. In other embodiments, the needle (500) may have any suitable length, such as 1 to 500 millimeters, and any suitable width and height, such as 0.1 to 5 millimeters. An 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) may have different dimensions, such as a width and / or height of 10 to 5,000 micrometers. The microchannel (506) may have a diameter different from the exemplary diameter of 4 micrometers, such as a diameter of 0.1 to 500 micrometers.

[0081] An exemplary needle (500) is formed from silicon using conventional semiconductor processes such as photolithography, wafer bonding, etching, etc., as described in more detail below in relation to FIGS. 8 through 14. Additionally, or alternatively, the needle (500) may be formed from any suitable material (stainless steel, plastic, glass, etc.) compatible with the manufacturing technology for forming the needle (500) as described herein.

[0082] Now, referring to FIG. 6, the side view of the needle (500) indicates that the needle (500) may have a uniform thickness. In some embodiments, the tip (504) of the needle may have a variable thickness, such as reaching a point at the end of the tip (504).

[0083] Now, referring to FIGS. 3a through 3g, various cross-sectional views of the needle (500) are shown. In FIG. 7a, a single primary channel (702) is shown, along with a microchannel (506) extending from the primary channel (702) to the surface of the needle (500). Referring to FIGS. 3b through 3d, different configurations of the microchannel (506) are shown, such as a microchannel (506) extending from the primary channel (702) to the top and bottom surfaces of the needle (500) and / or a microchannel (506) extending from the primary channel (702) to the side of the needle (500). In some embodiments, the needle (500) may include two or more primary channels (702), as shown in FIG. 7e. Each primary channel (702) may be used to deliver a different drug.

[0084] It should be understood that the microchannels (506) may be arranged in a configuration different from that shown in FIG. 3a through 3e. For example, in one embodiment shown in FIG. 7f, the needle (500) may have a circular shape having one primary channel (702) and several microchannels (506) extending radially from the central primary channel (702). In another embodiment shown in FIG. 7g, the needle (500) may have a circular shape having several primary channels (702), each primary channel having one or more corresponding microchannels (506).

[0085] Now, referring to FIGS. 5a and 5b, a planar cross-sectional view of a needle (500) having one primary channel (702) is shown in FIG. 9a, and a planar cross-sectional view of a needle (500) having multiple primary channels (702) is shown in FIG. 9b. In some embodiments, it should be understood that the primary channel (702) may include one or more lateral channels (902) extending perpendicularly to the primary channel (702). Part or all of the microchannel (506) may extend from the lateral channel (902) to the surface of the needle (500).

[0086] Now, referring to FIG. 10, in some embodiments, two or more needles (500) may be joined together by an anchor (1002) to form a needle array (1000). Each needle (500) of the needle array (1000) may have a primary channel (702) and one or more microchannels (506) as described in detail. In an exemplary embodiment, the needles may have a gap of 3 millimeters between them. In some embodiments, the gap may be larger or smaller, such as 0.1 to 50 millimeters.

[0087] Now, referring to FIG. 11a, in some embodiments, the needle array (1000) may be positioned opposite the electrode array (1100). A voltage source (1102) (such as a battery) may be connected to the needle (1000) array and the electrode (1100), for example, through a pair of wires (1104). The electrode (1100) may be formed of any suitable material, such as metal, silicon needles coated with a biocompatible conductive material such as titanium nitride similar to the needle array (1000). The needle array (1000) and the electrode array (1100) may be spaced apart by a suitable distance, such as 0.5 to 100 mm. It should be understood that at smaller intervals, a relatively low voltage can induce a relatively large electric field.

[0088] When in use, the needle array (1000) and the electrode array (1100) may be inserted into a patient. A voltage source (1102) may generate an electric field (1106) by applying voltage across the needle (1000) array and the electrode (1100) array. The applied voltage may be any suitable voltage, such as 0.1 to 30,000 volts, and the corresponding electric field may be, for example, 1 to 1,000 volts per centimeter. In an exemplary embodiment, the electric field (1106) may cause electroporation in some or all of the cells in the region of the electric field, thereby creating temporary nanopores in the cells and allowing drugs to flow into the cells, for example, by electrophoresis, diffusion, or fluidic force. 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 of 100 milliseconds for each pulse. In some embodiments, the pulses may have different amplitudes. For example, the amplitude of each pulse may be lower than the amplitude of the previous pulse. The pulses may be applied for any suitable time length, such as 0.001 to 1,000 milliseconds, and may be repeated for any suitable number of times, such as 1 to 1,000 times, and may have any suitable time between pulses, such as 10 to 1,000 milliseconds. In some embodiments, it should be understood that the voltage source (1102) may apply a reverse voltage to reverse the direction of the electric field (1106).

[0089] Now, referring to FIGS. 7b and 7c, it should be understood that the needles and electrodes may be configured differently from the configuration shown in FIG. 11a. For example, in one embodiment, the system may include multiple needle arrays (1000) and multiple electrode arrays (1100) as shown in FIG. 11b. Additionally, or alternatively, in some embodiments, as shown in FIG. 11, a single array (1108) may include needles (500) with electrodes (1110) interspersed therein. In such an embodiment, 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) to produce an electric field (1106) as shown. In such an embodiment, the needles (500) and electrodes (1110) may be separated by an insulating element (1112).

[0090] Now, referring to FIGS. 8 through 14, various manufacturing steps of the needle (500) are illustrated. In FIG. 12, the process begins with a silicon wafer (1202). The silicon wafer can be prepared using standard techniques such as solvent cleaning and RCA cleaning.

[0091] Next, the wafer (1202) has an internally etched channel (1302) as illustrated in FIG. 13. The channel (1302) can be etched using standard semiconductor processing techniques. For example, in one embodiment, a photoresist such as AZ1518 is spun over the wafer. Next, the photoresist is exposed to a UV light source over a desired channel location using a mask, and the photoresist covering the channel is removed. Next, the channel (1302) can be etched, the remaining photoresist can be removed, and the wafer (1202) can be cleaned again. It should be understood that because the channel (1302) extends along the surface of the wafer (1202), the length of the channel (1302) is not limited by how deeply the etching can penetrate below the surface of the wafer. It should be understood that in some embodiments, the channel (1302) may have a shape different from a simple straight channel that extends completely along the wafer (1202). For example, the channel (1302) may not extend to one end of the wafer (1202), and / or the channel may have a side channel as shown in FIG. 9. The channel (1302) may have dimensions similar to the primary channel (702) described above.

[0092] As illustrated in FIGS. 10 and 11, a second wafer (1402) is bonded to the top of the wafer (1202) to form a single wafer (1502) having a channel (1504) enclosed on all sides except for an opening at one or both ends of the wafer (1502). The wafer (1402) may be bonded to the wafer (1202) using any suitable technique, such as bonding the wafers (1202, 1402) using a bonding machine and then annealing the wafer (1502) at 400 to 1,200°C for 2 to 8 hours in nitrogen gas. The wafer (1402) may have any suitable thickness, such as 10 to 1,000 micrometers. In some embodiments, the wafer (1402) may be any suitable material, such as plastic, polymer film, or transparent material, which can be properly bonded to the wafer (1202) or coated on the wafer (1202).

[0093] Now, referring to FIG. 16, one or more microchannels (1602) are formed extending from the surface of the wafer (1402) to the channel (1504). The microchannels can be formed using photolithography and deep reactive ion etching (DRIE). The microchannels (1602) may have dimensions similar to the microchannels (506) described above.

[0094] A photoresist (1702), such as AZ9260, can be applied to a wafer (1502) to form the final shape of the needle. After etching the remaining exposed portion of the wafer (1502) and cleaning the photoresist (1702), a needle (1802) having a channel (1504) and a microchannel (1602) remains. It should be understood that in some embodiments, the formed needle (1802) may have a pointed tip as shown in FIG. 5.

[0095] It should be understood that the above-described technology can be used to produce needle arrays such as the needle array (1000) as well as needles of various shapes and sizes. In some embodiments, a single wafer (1202) (combined with the second wafer (1402)) may be used to produce multiple individual needles. In some embodiments, the needle (1802) may undergo additional fabrication steps. For example, in an exemplary embodiment, a titanium nitride coating may be applied to the needle (1802).

[0096] Additionally, it should be understood that the technology disclosed in connection with FIGS. 8 through 14 is not the only technology that can be used to produce the needles disclosed herein, such as the needle (500). For example, in some embodiments, the needle (500) or the needle array (1000) may be 3D printed or industrially manufactured.

[0097] Now, referring to FIG. 19, in one embodiment, a roller system (1900) for administering a drug comprises a roller (1902) to which one or more needles (1904) are attached, and a handpiece (1906) connected to the roller (1902). Each needle (1904) may be similar to a needle (500). In some embodiments, an electrode may be positioned next to each needle (1904), and, similar to the configuration of FIG. 11a, a voltage may be applied across the needle (1904) and the electrode to generate an electric field. The drug may be administered by moving the plunger of a syringe fluidly coupled to the needle (1904), such as through a tube. It should be understood that the roller system (1900) may allow the drug to be delivered over a wide area through the needle (1904) simply by rolling the roller system (1900) along the area targeted for treatment.

[0098] It should be understood that the technology described herein may be suitable for additional embodiments not explicitly described. For example, in some embodiments, a structure having a microchannel similar to the microchannel (506) described above may be placed in a patient using a catheter or incorporated into other surgical tools, such as those used for endoscopy or labroscopy. Electrodes may be similarly placed, and drugs may be delivered to target cells through the microchannel (506) using electroporation as described in detail above.

[0099] There are multiple advantages of the present disclosure arising from various features of the methods, apparatuses, and systems described herein. It should be noted that alternative embodiments of the methods, apparatuses, and systems of the present disclosure may not include all the features described but may still benefit from at least some of the advantages of such features. Those skilled in the art can readily devise their own implementations of methods, apparatuses, 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 by the appended claims.

Claims

Claim 1 As a device, a base having a first impermeable surface and a second surface on the opposite side; and a plurality of shafts, wherein each of the plurality of shafts extends from a second surface of the base to a tip, and each of the plurality of shafts defines one or more primary channels within the corresponding shaft, the primary channels extend from a proximal end to a distal end, the proximal end of each of the primary channels is in fluid communication with the first surface, and the distal end of each of the primary channels terminates within the shaft to define a primary channel bottom, and each of the plurality of shafts also defines one or more microchannels, and each of the one or more microchannels extends from the bottom of the primary channel to the tip of the shaft such that the primary channel is positioned in fluid communication with the outer surface of the shaft, the diameter of the microchannel is smaller than the diameter of the primary channel, the primary channel has a diameter selected from the range of 10 to 1000 micrometers, and each of the one or more microchannels is from the range of 1 to 1000 micrometers A device having a selected diameter. Claim 2 A method for manufacturing a device, comprising: a step of creating a primary channel having a depth of at least 10 micrometers and a length of at least 5 millimeters within a first silicon wafer using photolithography; a step of bonding a second silicon wafer to the first silicon wafer after the creation of the primary channel; and a step of etching the second silicon wafer to create one or more microchannels, wherein each of the one or more microchannels extends through the second silicon wafer from the primary channel and each of the one or more microchannels has a diameter of less than 1,000 micrometers. Claim 3 A device according to claim 1, wherein the shaft is composed of silicon, stainless steel, plastic, or any combination thereof. Claim 4 A device according to claim 1, wherein each shaft is provided with a single primary channel and a single microchannel, and the long axis of the microchannel is parallel to the long axis of the primary channel. Claim 5 A device according to claim 1, wherein the tip is pointed and the microchannel is positioned away from the center of the tip. Claim 6 A device according to claim 1, wherein the shaft also defines one or more second sets of microchannels extending through the wall of the shaft from the first channel so as to be fluidly connected to the outer surface of the shaft, and the major axis of each of the second sets of microchannels forms an angle with respect to the major axis of the first channel. Claim 7 A device comprising: a base having a first impermeable surface and a second surface on the opposite side; and one or more shafts protruding from the second surface of the base to a tip, wherein each of the shafts defines a primary channel extending from a proximal end to a distal end within each shaft, the proximal end of the primary channel fluidly communicating with the first surface, and the distal end terminates within the shaft to define the bottom of the primary channel, and each of the shafts also defines one or more microchannels, wherein each of the one or more microchannels extends through the wall of the shaft from the primary channel so as to be positioned so that the primary channel fluidly communicates with the outer surface of the shaft, and the major axis of each of the microchannels forms an angle with respect to the major axis of the primary channel. Claim 8 The apparatus of claim 7 further comprises an electrode, wherein the apparatus is configured to perform the following: maintaining a composition within a primary channel of the one or more shafts; inserting the one or more shafts into a tissue; inserting an electrode into the tissue adjacent to the one or more shafts; and applying a voltage across the electrode and the one or more shafts to create nanopores in at least a portion of the tissue disposed between the one or more shafts and the electrode. Claim 9 In claim 8, the device is configured to also perform the action of applying a force to move the composition from the primary channel of the one or more shafts and into the one or more microchannels. Claim 10 A device according to claim 8, wherein applying a voltage across the electrode and one or more shafts comprises applying two or more voltage pulses across the electrode and one or more shafts, and each of the two or more voltage pulses is less than 2000 milliseconds. Claim 11 A device according to claim 7, wherein each of the shafts also defines one or more lateral channels extending perpendicularly to the major axis of the primary channel, and said lateral channels are fluidly connected to both the primary channel and the microchannel. Claim 12 An apparatus according to claim 7, wherein each of the shafts defines a plurality of primary channels extending from a proximal end to a distal end within each shaft, the major axis of each of the plurality of primary channels is parallel to each of the major axes of other primary channels, the proximal end of each of the primary channels is in fluid communication with the first surface, the distal end of each of the primary channels is terminated within the shaft, and each of the primary channels is in fluid communication with one or more of the microchannels extending through the wall of the shaft such that each of the primary channels is positioned in fluid communication with the outer surface of the shaft. Claim 13 An apparatus according to claim 7, wherein the diameter of the microchannel is smaller than the diameter of the primary channel, the primary channel has a diameter selected from the range of 10 to 1000 micrometers, and the microchannel has a diameter selected from the range of 1 to 1000 micrometers. Claim 14 In paragraph 13, the device wherein the shaft is coated with an electrically conductive material. Claim 15 A device according to claim 7, further comprising a plurality of electrodes, wherein the plurality of electrodes are arranged adjacent to the plurality of shafts such that an electric field is generated perpendicular to the axis of each of the plurality of shafts when a voltage is applied between the plurality of shafts and the plurality of electrodes. Claim 16 A device according to claim 7, wherein the major axis of one or more microchannels independently forms an angle with the major axis of the primary channel. Claim 17 A device according to Clause 13, wherein each shaft is provided with a single primary channel. Claim 18 In claim 7, each of the above shafts is a device having an aspect ratio greater than 3, defined by dividing the length of the microchannel by the diameter of the primary channel. Claim 19 In claim 7, the device wherein the shaft is composed of silicon, stainless steel, plastic, or any combination thereof. Claim 20 A system for inducing electroporation, comprising a device according to claim 7 and an electrode array configured to match the size and spacing of the shafts of the device, wherein when the device and the electrode array are inserted into the tissue of a patient, an electric field perpendicular to the major axis of each of the plurality of shafts is generated by applying a voltage across the shafts and the electrodes. Claim 21 A device comprising: a base having a first surface and a second surface; a storage portion defined on the first surface of the base; a microstructure protruding from the second surface of the base to a tip, wherein the microstructure has an opening formed at the tip and a transmission channel extending from the storage portion to the opening; and a plurality of electrodes, wherein each of the plurality of electrodes is electrically coupled to each other and the plurality of electrodes are arranged 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 generated perpendicular to each axis of the plurality of microstructures, and the transmission channel comprises a first channel and a second channel communicating at a junction, wherein the first channel extends from the opening toward the junction and the second channel extends from the junction toward the storage portion, and the first channel has an inner diameter smaller than the inner diameter of the second channel. Claim 22 In paragraph 21, the device wherein the storage unit is configured to hold a target drug. Claim 23 A device in which, in paragraph 22, the target 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. Claim 24 In paragraph 21, the device wherein the microstructure is a plurality of microstructures. Claim 25 In claim 21, the device wherein the microstructure comprises a plurality of delivery channels. Claim 26 In paragraph 21, the device having a blunt tip. Claim 27 In paragraph 26, the device wherein the transmission channel is positioned away from the center of the blunt tip. Claim 28 In paragraph 21, the device having a pointed tip. Claim 29 In claim 28, the device wherein the transmission channel is located away from the center of the pointed tip. Claim 30 In claim 21, the device wherein the microstructure has a height exceeding 150 μm. Claim 31 In paragraph 30, the device wherein the microstructure has an aspect ratio greater than 3. Claim 32 In claim 21, the device wherein the microstructure has a height of 200 μm to 1000 μm. Claim 33 In claim 32, the device wherein the delivery channel has a diameter of 50 nm to 5000 nm. Claim 34 In paragraph 21, the device wherein the storage portion comprises a porous material. Claim 35 In paragraph 21, the device wherein the storage unit includes a feedback component. Claim 36 In paragraph 21, the above storage portion is semipermeable, the device. Claim 37 In paragraph 21, the device wherein the storage unit comprises cells sensitive to changes in physiological signals from a recipient. Claim 38 A device comprising: a base having a first impermeable surface and a second surface on the opposite side; and a plurality of shafts formed from a non-conductive material and protruding to a leading edge from the second surface of the base, wherein each of the shafts defines a primary channel extending from a proximal end to a distal end within each shaft, the proximal end of the primary channel fluidly communicating with the first surface, and the distal end of the primary channel terminates within the shaft to define the bottom of the primary channel, each of the shafts also defines one or more microchannels, each of the one or more microchannels extending through the wall of the shaft from the primary channel such that the primary channel is fluidly communicating with the outer surface of the shaft, the outer surface being non-conductive, and the major axis of each of the microchannels being at an angle to the major axis of the primary channel, and the primary channel and the microchannels being formed to receive a liquid solution containing a drug; An apparatus comprising a plurality of electrodes, wherein each of the plurality of electrodes is electrically coupled to one another, and the plurality of electrodes are arranged adjacent to the plurality of shafts but are electrically separated from the shafts by an insulating element, and when a first wire connected to one side of a voltage source is arranged to contact a liquid solution introduced into the microchannel and primary channel of each shaft and a second wire connected to the other side of the voltage source is electrically connected to the plurality of electrodes, the one side of the voltage source and each electrode are connected to the other side of the voltage source, and when a voltage is applied between the plurality of shafts and the plurality of electrodes, an electric field is generated in the microchannel formed in each of the plurality of shafts. Claim 39 delete Claim 40 delete Claim 41 delete Claim 42 delete

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