Injector and injection method thereof

Abstract

A syringe for injecting an injectable substance into at least one of epidermal tissue and dermal tissue of a subject is disclosed. The syringe includes a housing and a control member disposed within the housing. A needle head configured to support a plurality of needles is operably coupled to the control member. A first means is provided in communication with the control member and configured to be driven by the control member to translate movement of the control member into movement of the needle along the injection direction and towards the injection position of the needle. The second device is configured to move the needle in a direction having a component perpendicular to the injection direction and without movement of the housing relative to the subject's skin.

Description

Technical Field

[0001] The present invention relates to devices and methods for administering injections to mammalian subjects, and more particularly to syringes and injection methods for injecting substances into the epidermal / dermal tissue of mammalian subjects. Background Art

[0002] Vaccines are a key defense against the spread of infectious diseases in populations. Vaccines also provide protection at the individual level by either fully preventing infection or by reducing the severity of the disease. Due to past successful vaccination campaigns, diseases such as smallpox and polio, to name just a few, have been largely or completely eradicated. More recently, mass immunization has played a key role in limiting the impact of the COVID-19 pandemic, despite widespread resistance due to concerns about the immediate side effects and potential long-term effects of the vaccines. It is more or less obvious that vaccines that are considered safe and effective can bring benefits to society as a whole and can reduce the demand on the healthcare system, even if not 100% uptake in the population.

[0003] Vaccines are typically administered intramuscularly or subcutaneously, but other routes of administration are known, including oral, intradermal, and transdermal administration. Subcutaneous administration of vaccines is performed using a needle long enough to reach the subcutaneous fat layer (subcutaneous tissue), and as the name implies, intramuscular administration of vaccines is performed using a needle long enough to reach the muscle beneath the fat layer. Conventional syringes for subcutaneous or intramuscular vaccination can inject a large volume of vaccine solution, which is typically more than 1 ml and includes a suitable adjuvant to enhance the body's immune response to the antigen in the vaccine solution. These types of injections can cause local discomfort and swelling at the injection site, as well as more severe side effects, including fever, chills, and body aches.

[0004] Subcutaneous and intramuscular vaccination techniques also have other known drawbacks or limitations. A typical device for subcutaneous and intramuscular injection is a hypodermic syringe, which poses a risk of needle stick injury, has a dead volume that results in vaccine waste, may require a relatively large amount of vaccine to trigger a suitable immune response, causes patient anxiety due to fear of needles, and must be administered by trained nurses, pharmacists, doctors, etc., thus limiting the number of people who can be vaccinated in a short period of time. Further, muscle tissue has a low density of immune cells and thus is not the optimal site for immunity.

[0005] In contrast, skin tissue contains a wide range of antigen-presenting cells (APCs), which may affect the strength, duration, and orientation of antigen-specific immune memory and represent a potentially excellent vaccine delivery route. Human skin has approximately 2m 2The surface area, and the average thickness is about 2.5 mm, making it the largest organ of the human body. The skin has two broad tissue types: the epidermis and the dermis. The epidermis is a continuously keratinized stratified epithelium. The outermost layer of the skin is the stratum corneum and serves as the main barrier. The stratum corneum is a layer of 15 - 30 cell - thick non - viable but biochemically active keratinocytes. The other three layers of the epidermis (stratum granulosum, stratum spinosum, stratum basale) all contain keratinocytes at different stages of differentiation, melanocytes that produce melanin to protect the skin from ultraviolet damage, and immune Langerhans cells and dermal dendritic cells. The term epidermal vaccination refers to a vaccination method that targets the epidermis after passing through the stratum corneum with microneedles. These semi - invasive techniques can target Langerhans cells and sometimes dermal dendritic cells, depending on the depth achieved.

[0006] The dermis is a dense, fibrous elastic tissue that serves as the firm support of the skin. The dermis promotes the recruitment of immune cells (Langerhans cells, neutrophils, monocytes, monocyte - derived DCs, memory T cells, etc.) through the rich vascularization of blood vessels and lymphatic vessels, and is recycled and activated by the activity of a variety of locally produced inflammatory chemokines and cytokines. Intradermal vaccination refers to the direct delivery of an antigen into the dermis using a syringe and needle or microneedles or a pressure injector. The intradermal route mainly targets dermal dendritic cells and macrophages.

[0007] Performing epidermal or intradermal injection requires a fairly high level of skill if a traditional syringe is used to deliver the vaccine to the target depth. Depending on the device used to perform the injection, applying too much or too little force, or the angle of the device relative to the skin being too steep or too shallow, the vaccine may flow back out onto the outer surface of the skin or be delivered to lower tissues beneath the dermis. These types of injections lack reproducibility and can be a problem especially among subjects of different ages.

[0008] A variety of injection devices capable of delivering a vaccine or other medicament from a container to a target injection site are known in the art. Selecting the appropriate injection device for a particular vaccine depends on many factors, including the target injection site of the vaccine, the age of the vaccine recipient, the skill level of the individual administering the vaccine, etc. That is, known injection devices can belong to one of two very broad categories (manual devices and autoinjectors). In manual devices, the user must provide the mechanical energy required to drive the fluid through the needle. This is typically done via some form of button or plunger that must be continuously pressed by the user during the injection. This method has many drawbacks. If the user stops pressing the button or plunger, the injection will also stop. This means that if the device is not used properly (i.e., the plunger is not fully pressed to its end position), the user may deliver an insufficient dose. Additionally, the required force that must be applied to the button or plunger may be too high for the user, especially when the user is elderly or has dexterity issues. Further, the protrusion of the button or plunger may be too large, so that when fully extended, it may be inconvenient for the user to reach. The combination of injection force and button or plunger protrusion may cause shaking or tremors of the hand, which in turn increases the discomfort of the subject receiving the injection when the inserted needle moves within the target tissue. Additionally, manual devices (such as injection needles) typically must be filled with the vaccine or other medicament manually from a vial. This adds an additional step, which can be significant in the case of large-scale vaccination. Manual filling also poses a risk of contaminating the syringe.

[0009] Autoinjector devices are designed to make self-administration of injection therapies feasible for patients. Treatments currently administered by self-administered injections include diabetes medications (insulin and newer GLP-1 class drugs), migraine medications, hormone therapy medications, anticoagulant medications, etc. An autoinjector is a device that fully or partially replaces the manual activities involved in performing an injection using a standard syringe. These activities include removing the protective syringe cap, inserting the needle into the subject's skin, injecting the vaccine or other medicament, removing the needle, shielding the needle, and preventing reuse of the device. Each of these activities is associated with related, but often unrecognized, costs when performed using a manual injection device. The triggering of an autoinjector can be performed by many means, such as a trigger button or the action of the needle reaching its injection depth. In some devices, the energy to deliver the fluid is provided by a spring.

[0010] It will be apparent that the task of selecting the best injection site and the best type of injection device for administering a particular vaccine is quite complex. This task becomes even more complex if additional techniques need to be incorporated to facilitate the delivery and / or absorption of the injected substance. One such additional technique is electroporation, which involves applying brief electrical pulses that cause the formation of aqueous pathways within the lipid bilayer membranes of mammalian cells. This allows even large molecules, including DNA plasmids, to cross the cell membrane, which would otherwise have low permeability. Injection devices capable of performing electroporation are also known in the art.

[0011] Although various auto-injection devices are known, there is currently no device that provides an optimized method for delivering a vaccine or other medicament to the dermal / epidermal layer. Most known devices are simple in design and do not incorporate all of the functions necessary to allow for safe and reproducible injection by an untrained user or a user with limited training. More specifically, known devices are not capable of advancing a needle or needle array in a timed sequence starting from the activation of the injection device, injecting the full dose of the vaccine or other medicament per injection, performing electroporation, optionally performing other additional techniques, and retracting the needle or needle array. They also do not have a robust method of activating the latent potential that is always present in response to repeated mechanical stimulation, puncture / trauma by Langerhans and other immune cells to attack antigens, which can be activated by complex and not fully understood cytokine release. Accordingly, it would be beneficial to provide an improved auto-injector that overcomes at least some of the limitations of the prior art. SUMMARY OF THE INVENTION

[0012] According to one aspect of at least one embodiment, there is provided an auto-injector for injecting an injectable substance into at least one of the epidermal tissue and dermal tissue of a subject, the auto-injector comprising: a housing; a control member disposed within the housing; a needle array including a plurality of needles, the needle array being movable between a retracted position, in which the needles are fully disposed within the housing, and an extended position, in which the needles are at least partially disposed outside the housing; a first means configured to be driven by the control member during injection of the injectable substance, wherein movement of the control member is converted into translational movement of the needle array between the retracted position and the extended position; and a second means configured to generate an oscillatory translational movement of the needle array when the needle array is in the extended position.

[0013] In one embodiment, the control member is a rotatable control member that includes a control cylinder having a first control groove formed along its inner surface, and the first device includes a follower plate coupled to the needle array, the follower plate including a protrusion seated within the first control groove, wherein rotation of the rotatable control member guides the protrusion along the first control groove, the first control groove including a portion having a component along the length direction of the autoinjector to produce translational movement of the needle array between a retracted position and a deployed position.

[0014] In one embodiment, an energy source is provided that is in communication with the rotatable control member and in communication with the second device to provide energy to rotate the rotatable control member and to produce oscillatory translational movement of the needle array, respectively.

[0015] In one embodiment, the energy source includes a torsion spring configured to store mechanical potential energy and a flywheel for converting the mechanical potential energy released from the torsion spring into stored rotational kinetic energy.

[0016] In one embodiment, the energy source includes an electric motor and a DC power source or an AC power source in electrical communication with the electric motor.

[0017] In one embodiment, the second device includes a rotatable plate disposed in a stacked arrangement with a fixed plate, the fixed plate having a grooved surface facing the rotatable plate and defining a series of depressions and ridges, and the second device further includes a pair of spherical spacer elements retained within openings formed in the rotatable plate, and wherein, when the rotatable plate rotates, each of the pair of spherical spacer elements is guided along a ridge between corresponding adjacent pairs of depressions such that the separation distance between the rotatable plate and the fixed plate varies in an oscillatory manner over time.

[0018] In one embodiment, a plunger assembly is provided that includes a plunger and a cylinder that contains a known volume of gas prior to injection of the injectable substance.

[0019] In one embodiment, an interface is provided for receiving a container that houses the injectable substance, the interface being fluidly coupled to the cylinder via a first conduit and fluidly coupled to the needle array via a second conduit.

[0020] In one embodiment, the known volume of gas is equal to the combined volume of the first conduit, the second conduit, the container received within the interface, and the dead volume of the needle array.

[0021] In one embodiment, the interface includes a housing that is keyed or shaped to receive only a correspondingly keyed or shaped container, and wherein the keying or shaping is dedicated to a known injectable substance or a known group of injectable substances.

[0022] In one embodiment, a current source is provided that is in electrical communication with at least some of the needles of the needle array via a conductor to provide an electroporation current to at least one of the epidermal and dermal tissues of a subject during injection of an injectable substance, wherein the at least some needles are hollow or solid needles made of a conductive material.

[0023] In one embodiment, the control cylinder further includes a second control groove and a third control groove formed along the inner surface of the control cylinder, respectively, wherein the second control groove controls the movement of the plunger, the third control groove controls the actuation of the current source, and wherein the shapes of the first control groove, the second control groove, and the third control groove are configured to control the translational movement of the needle array, the movement of the plunger, and the actuation of the current source in a predetermined timing to inject the injectable substance.

[0024] In one embodiment, a sealing skirt or gasket is disposed at the injection end of the housing to form a seal against the skin of the subject during injection of the injectable substance, wherein the seal is substantially airtight such that a partial vacuum is formed above the skin of the subject when the needle array moves from the extended position to the retracted position, whereby the partial vacuum creates a suction effect.

[0025] According to one aspect of at least one embodiment, an autoinjector for injecting an injectable substance into at least one of the epidermal and dermal tissues of a subject includes: a rotatable control cylinder having a plurality of control grooves formed along its inner surface and having a plurality of alignment protrusions protruding outwardly from its outer surface; a housing disposed in a spaced concentric arrangement with the rotatable control cylinder and extending along at least a portion of the length of the rotatable control cylinder, the housing including a plurality of alignment grooves formed along its inner surface to receive the alignment protrusions of the rotatable control cylinder when the autoinjector is in an assembled state; a needle array including a plurality of needles; a first means configured to rotate the rotatable control cylinder relative to the housing during injection of the injectable substance, wherein the rotational movement of the rotatable member is converted into a translational movement of the needle array between a retracted position and an extended position; and a second means configured to generate an oscillatory translational movement of the needle array when the needle array is in the extended position, wherein, during use, the needles of the needle array extend beyond the skin contact end of the autoinjector and penetrate the skin of the subject to a predetermined target depth when the needle array is in the extended position.

[0026] According to one aspect of at least one embodiment, there is provided a syringe for injecting an injectable substance into at least one of the epidermal tissue and the dermal tissue of the skin of a subject, the syringe comprising: a housing; a control member disposed within the housing; a needle configured to support a plurality of needles; a first device in communication with the control member and configured to be driven by the control member to convert the movement of the control member into movement of the needle along an injection direction and towards an injection position of the needle; and a second device configured to move the needle in a direction having a component perpendicular to the injection direction and without movement of the housing relative to the skin of the subject.

[0027] According to one aspect of at least one embodiment, there is provided an autoinjector for injecting an injectable substance into at least one of the epidermal tissue and the dermal tissue of a subject, comprising: a housing; a needle array including a plurality of needles and movable between a retracted position, in which the needles are entirely disposed within the housing, and an extended position, in which the needles are at least partially disposed outside the housing; a plunger member in fluid communication with a source of the injectable substance; a control cylinder having a plurality of grooves formed along its inner surface and including at least: a plunger control groove; and a needle array control groove; and means for rotating the control cylinder relative to the housing, the plunger member, and the needle array; wherein the control cylinder is in mechanical communication with the needle array via the needle array groove and with the plunger member via the plunger control groove, and wherein the plunger control groove and the needle array control groove are shaped separately in the circumferential and longitudinal directions of the control cylinder to convert the rotational movement of the control cylinder into a predetermined translational movement of the plunger member and the needle array, respectively, and wherein the shapes of the plunger control groove and the needle array control groove cooperate to define the timing of the predetermined translational movement of the plunger member and the needle array during an injection event.

[0028] According to one aspect of at least one embodiment, there is provided an autoinjector for injecting an injectable substance into at least one of the epidermal tissue and dermal tissue of a subject, comprising: a housing; a needle array including a plurality of needles, the needle array being movable between a retracted position and a deployed position, in the retracted position, the needles are fully disposed within the housing, and in the deployed position, the needles are at least partially disposed outside the housing; a flywheel disposed within the housing for storing rotational kinetic energy; an oscillating element rotatably coupled to the flywheel for converting a first portion of the stored rotational kinetic energy into an oscillatory translational movement of the needle array; a gear system coupled to the flywheel; a control cylinder including: a circumferential annular gear formed on its inner surface, the annular gear engaging with the gear of the gear system for converting a second portion of the stored rotational kinetic energy into a rotational movement of the control cylinder; and a plurality of control slots formed on its inner surface; and a plate member fixedly coupled to the needle array, the plate member having a protrusion extending therefrom, the protrusion being received in a first control slot of the plurality of control slots, wherein rotation of a rotatable control member guides the protrusion along the first control slot, the first control slot including a portion having a component along the length direction of the autoinjector to produce a translational movement of the needle array between the retracted position and the deployed position.

[0029] According to one aspect of at least one embodiment, there is provided a method for injecting an injectable substance into at least one of the epidermal tissue and dermal tissue of a subject using a syringe, the method comprising: placing an injection end of the syringe in contact with a region of the skin of the subject, the syringe containing a single dose of the injectable substance having a dose volume; triggering an auto-injection sequence of the syringe, wherein the auto-injection sequence includes: moving a needle array including a plurality of needles along an injection direction and piercing the skin of the subject at a first plurality of positions; injecting a first portion of the dose volume into the skin of the subject at the first plurality of positions; at least partially withdrawing the plurality of needles from the skin of the subject; moving the needle array including the plurality of needles along a direction having a component perpendicular to the injection direction; moving the needle array including the plurality of needles along the injection direction and piercing the skin of the subject at a second plurality of positions, at least some of the second plurality of positions being different from at least some of the first plurality of positions; and injecting a second portion of the dose volume into the skin of the subject at the second plurality of positions, wherein the autoinjector remains in contact with the same region of the skin of the subject during execution of the entire auto-injection sequence such that the entire dose volume of the injectable substance is injected without moving the autoinjector along the skin of the subject.

[0030] According to one aspect of at least one embodiment, there is provided a method for injecting an injectable substance into at least one of the epidermal and dermal tissues of a subject using an autoinjector, the method comprising: placing the injection end of the autoinjector in contact with a region of the subject's skin, the autoinjector containing a single dose of the injectable substance having a dose volume; triggering an auto-injection sequence of the autoinjector, wherein the auto-injection sequence includes; extending the needle array of the autoinjector from a retracted position to an extended position along the length of the autoinjector, at the extended position, the needles of the needle array penetrate the subject's skin to a target depth; controllably depressing a plunger member to transfer the injectable substance from a storage container to the needle array; continuing to depress the plunger member to inject the entire dose volume of the injectable substance into the subject's skin via the needle array; during the step of continuing to depress the plunger, moving the needle array in an oscillating translational motion along the length of the autoinjector; and retracting the needle array of the autoinjector from the extended position to the retracted position along the length of the autoinjector, wherein the autoinjector remains in contact with the same region of the subject's skin during execution of the entire auto-injection sequence, such that the entire dose volume of the injectable substance is injected without moving the autoinjector along the subject's skin.

[0031] According to one aspect of at least one embodiment, there is provided an autoinjector for injecting an injectable substance into at least one of the epidermal and dermal tissues of a subject, the autoinjector comprising: a housing containing: an interface for receiving a container having an internal volume that houses the injectable substance; a needle array including a plurality of needles and in fluid communication with the interface via a conduit; means for extending the needle array between a retracted position and an extended position, at the extended position, the plurality of needles being at least partially outside the housing; an oscillating element for moving the needle array in an oscillating manner and in a direction generally perpendicular to the subject's skin when the needle array is in the extended position; a current source in electrical communication with the needle array via a conductor to provide an electroporation current to at least one of the epidermal and dermal tissues of the subject during injection of the injectable substance; and a plunger assembly in fluid communication with the interface to pressurize the volume of the container when moved from an initial position to a depressed position to move the injectable substance out of the container and via the conduit to the needle array, wherein the injection end of the housing includes a substantially airtight sealing element for forming a seal against the subject's skin, and wherein, after injection of the injectable substance, the plunger assembly is configured to return to its initial position to draw gas through the conduit from the injection end of the housing, thereby creating a decompression region above the subject's skin and thereby creating a suction effect.

[0032] According to one aspect of at least one embodiment, there is provided an autoinjector for injecting an injectable substance into at least one of the epidermal and dermal tissues of a subject, the autoinjector comprising: a housing having a sealing element disposed at its skin contact end to form a substantially airtight seal when the sealing element is placed in contact with the subject's skin; a needle array including a plurality of needles; means for moving the needle array between a retracted position within the housing and an extended position where at least a portion of the plurality of needles are outside the housing; means for moving the needle array in an oscillating manner when the needle array is in the extended position; means for applying an electroporation current via at least some of the needles in the needle array when the needle array is in the extended position; a plunger assembly for providing the injectable substance under pressure to the needle assembly when the needle assembly is in the extended position and for forming a decompression zone within the skin contact end of the housing when the needle assembly moves from the extended position to the retracted position.

[0033] According to one aspect of at least one embodiment, there is provided a method for injecting an injectable substance into at least one of the epidermal and dermal tissues of a subject using an autoinjector, the method comprising: placing the injection end of the autoinjector in contact with a skin area of the subject, the autoinjector containing a single dose of the injectable substance having a dose volume; triggering an auto-injection sequence of the autoinjector, wherein the auto-injection sequence comprises: piercing the subject's skin with the needles of the needle array of the autoinjector to a target depth; injecting the entire dose volume of the injectable substance into the subject's skin via the needle array without moving the autoinjector along the subject's skin; during injection, moving the needle array in an oscillating translational motion in a direction substantially perpendicular to the subject's skin; during injection, applying an electroporation current via at least some of the needles of the needle array; forming a decompression zone at the injection end of the autoinjector to apply suction to the subject's skin before moving the injection end of the autoinjector out of contact with the area of the subject's skin; and moving the needle array of the autoinjector to a retracted position where the needles of the needle array are not in contact with the subject's skin. Description of the Drawings

[0034] Exemplary embodiments will be described with reference to the drawings, which are not drawn to scale, and in which:

[0035] Figure 1 is a simplified perspective view showing the main features of a syringe according to one embodiment.

[0036] Figure 2 is a simplified perspective view showing the external and internal features of a housing according to one embodiment.

[0037] Figure 3is a simplified perspective view showing the external and internal features of a control cylinder according to one embodiment.

[0038] Figure 4 is a simplified side view showing the external and internal features of the control cylinder Figure 3 as viewed from different points around the circumference of the control cylinder.

[0039] Figure 5 is a simplified side view showing a plunger and vial interface sub - assembly according to one embodiment.

[0040] Figure 6 is Figure 5 a simplified bottom view of the sub - assembly.

[0041] Figure 7 is a simplified perspective view showing the Figure 5 sub - assembly before syringe actuation.

[0042] Figure 8 is a simplified perspective view showing the Figure 5 sub - assembly after syringe actuation.

[0043] Figure 9 is a simplified exploded view showing a needle control sub - assembly according to one embodiment.

[0044] Figure 10 is a simplified perspective view showing the Figure 9 needle control sub - assembly in an assembled state.

[0045] Figure 11 is an enlarged perspective view showing a possible configuration of the needles of a needle array.

[0046] Figure 11A is a simplified end view of a cap for use with a needle head, the cap having a needle array including twelve needles arranged in two rows and optionally including individual needles that are hollow and solid and / or conductive and non - conductive.

[0047] Figure 11B is Figure 11A a perspective view of the cap.

[0048] Figure 11C is Figure 11A a side view of the cap.

[0049] Figure 11D is a simplified exploded view showing a needle control sub - assembly according to one embodiment, wherein the needle head is configured to receive a replaceable cap carrying a needle array.

[0050] Figure 12 is a simplified side view of the lower part of the needle control sub - assembly Figure 9 during the first part of the oscillatory translational movement of the needle array.

[0051] Figure 13 Is a simplified side view of the lower part of the needle control sub - assembly during the second part of the oscillatory translational movement of the needle array. Figure 9 of the needle control sub - assembly.

[0052] Figure 14A Is a simplified side view of the Figure 3 control cylinder and Figure 2 within the housing of Figure 9 the needle control sub - assembly in the fully retracted position.

[0053] Figure 14B Is a simplified partial bottom perspective view of the Figure 9 needle control sub - assembly in the fully retracted position.

[0054] Figure 15A Is a simplified side view of the Figure 3 control cylinder and Figure 2 within the housing of Figure 9 the needle control sub - assembly in the first intermediate position during the movement of the needle array towards the subject's skin.

[0055] Figure 15B Is a simplified side view of the Figure 9 needle control sub - assembly in the first intermediate position.

[0056] Figure 16A Is a simplified side view of the Figure 3 control cylinder and Figure 2 within the housing of Figure 9 the needle control sub - assembly in the fully extended position.

[0057] Figure 16B Is a simplified side view of the Figure 9 needle control sub - assembly in the fully extended position.

[0058] Figure 17A Is a simplified side view of the Figure 3 control cylinder and Figure 2 within the housing of Figure 9 the needle control sub - assembly in the second intermediate position during the movement of the needle array away from the subject's skin.

[0059] Figure 17B Is a simplified side view of the Figure 9 needle control sub - assembly in the second intermediate position.

[0060] Figure 18 Shows details of the trigger mechanism components.

[0061] Figure 19Is a simplified perspective view of a trigger and guide leg.

[0062] Figure 20 Shows details of the trigger mechanism in an unaligned and untriggered state.

[0063] Figure 20A Shows details of a washer or skirt at the injection end of an autoinjector.

[0064] Figure 21 Is a simplified perspective view showing the arrangement of a torsion spring and a flywheel disposed within a respective housing.

[0065] Figure 22A Is a simplified top view showing the flywheel and torsion spring arrangement before triggering the syringe.

[0066] Figure 22B Is a simplified top view showing the flywheel and torsion spring arrangement after triggering the syringe.

[0067] Figure 23 Is a simplified perspective view showing the underside of a flywheel housing having a planetary gear and a sun gear of a planetary gear system.

[0068] Figure 24 Is a simplified enlarged perspective view of a portion of a control cylinder having internal gear teeth formed thereon.

[0069] Figure 25 Is a simplified perspective view showing Figure 23 and Figure 24 of the components when the auto-injection device is in an assembled state.

[0070] Figure 26 Is a simplified perspective view showing details of an electro-piercing subassembly.

[0071] Figure 27 Is a simplified view showing details of the electro-piercing subassembly connection to a needle array.

[0072] Figure 28 Is a simplified perspective view showing details of a fluid tube and electro-piercing subassembly electrical conductors.

[0073] Figure 29 Is a simplified perspective view showing a piezoelectric assembly before electro-piercing activation.

[0074] Figure 30 Is a simplified front view showing a piezoelectric assembly before electro-piercing activation.

[0075] Figure 31 Is a simplified perspective view showing a piezoelectric assembly after electro-piercing activation.

[0076] Figure 32 Is a simplified front view showing a piezoelectric assembly after electro-piercing activation.

[0077] Figure 33 is a simplified side view showing a first exemplary auto-injector device in a fully assembled state.

[0078] Figure 34 Shown separately is Figure 33 the components of a first exemplary auto-injector within the A-B portion of , where the housing, control cylinder, and various other housings are omitted for clarity.

[0079] Figure 35 Shown separately is Figure 33 the components of a first exemplary auto-injector within the B-C portion of , where the housing, control cylinder, and various other housings are omitted for clarity.

[0080] Figure 36 is a simplified diagram showing the layers of human skin.

[0081] Figures 37A to 37E is a series of schematic diagrams corresponding to different times during the injection of an injectable substance into a subject's tissue, where: Figure 37A shows the needle protruding into the epidermis before the injection of the injectable substance; Figure 37B shows the injectable substance within the dermis and near the injection tip of the needle; Figure 37C shows the injectable substance after it has diffused within the dermis; Figure 37D shows the injectable substance after it has diffused to a target depth within the dermis; and Figure 37E shows the response of Langerhans cells to the injection of the injectable substance into the dermis.

[0082] Figure 38 is a simplified exploded view showing a needle control subassembly and a needle configured to produce movement of the needle in a direction perpendicular to the injection direction of the syringe according to another embodiment.

[0083] Figure 39 is showing Figure 38 the arrangement of bearing elements between the needle control subassembly and the needle of .

[0084] Figure 40 is a simplified perspective view showing the position of the bearing element relative to the lower plate of the oscillating element of the Figure 38 needle control subassembly when the syringe is in an assembled state.

[0085] Figure 41 is a simplified perspective view showing the position of the bearing element relative to the Figure 38 needle when the syringe is in an assembled state.

[0086] Figure 42 is showing the in an assembled state.Figure 38 Simplified perspective view of the needle control subassembly.

[0087] Figure 43A and Figure 43B is an illustration Figure 38 of the oscillatory translational motion of the needle, with the rotary drive housing omitted for increased clarity.

[0088] Figure 44A Perspective view showing the needle separated from the rotary drive housing.

[0089] Figure 44B Cross-sectional view through the side wall of the rotary drive housing.

[0090] Figure 44C Cross-sectional view through the side wall of the rotary housing with the needle mounted.

[0091] Figures 45A to 45E Series of illustrations showing the interaction between the external protrusions of the needle and two sets of internal protrusions of the rotary drive housing during the oscillatory motion of the needle, where: Figure 45A shows the interaction before the start of the oscillatory motion; Figure 45B shows the interaction at the first time after the start of the oscillatory motion; Figure 45C shows the interaction at the second time after the start of the oscillatory motion; Figure 45D shows the interaction at the third time after the start of the oscillatory motion; and Figure 45E shows the interaction at the fourth time after the start of the oscillatory motion.

[0092] Figure 45F Simplified diagram showing a series of five different puncture patterns in the skin of a subject's arm caused by the curvilinear translational movement of the needle array during injection.

[0093] Figure 45G Top view showing the independent linear drive housing.

[0094] Figure 45H Top view showing the needle used with the linear drive housing.

[0095] Figure 45I is shown mounted on Figure 45G inside the linear drive housing of Figure 45H longitudinal cross-sectional view of the needle.

[0096] Figure 45J Simplified diagram showing a series of three different puncture patterns in the skin of a subject's arm caused by the linear translational movement of the needle array during injection.

[0097] Figure 46Is a simplified side view showing a second exemplary auto-injector device in a fully assembled state.

[0098] Figure 47 Shown separately Figure 46 Components of a second exemplary auto-injector within the A-B portion of, where the housing, control cylinder, and various other housings are omitted for clarity.

[0099] Figure 48 Shown separately Figure 46 Components of a second exemplary auto-injector within the B-C portion of, where the housing, control cylinder, and various other housings are omitted for clarity.

[0100] Figure 49 Is a simplified flow chart of a method according to one embodiment. Detailed Description

[0101] Although the present teachings are described in connection with various embodiments and examples, the present teachings are not intended to be limited to these embodiments. Instead, the present teachings cover various alternatives and equivalents, as will be understood by those skilled in the art. All statements herein reciting principles, aspects, and embodiments of the invention and specific examples thereof are intended to cover their structural and functional equivalents. Additionally, these equivalents are intended to include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function regardless of structure.

[0102] 1. Definitions

[0103] As used herein, the term "electroporation" refers to the use of transmembrane electric field pulses to induce microscopic pathways (pores) in biological membranes. The pores allow biomolecules (such as plasmids, oligonucleotides, siRNAs, drugs, ions, and water) to transiently pass from one side of the cell membrane to the other.

[0104] The term "minimally invasive" refers to a limited penetration into the skin layer of a subject. Preferably, the needle penetrates the stratum corneum and enters the epidermal layer, and depending on the design of the needle and the pressure used, it may be optimal for the needle to remain within the epidermis or protrude into the dermis but not into the subcutaneous layer. The maximum penetration depth of the needle is preferably no more than 2.58 mm (according to IONAID). In some embodiments, the auto-injector is equipped with a set of needles of different lengths, and the penetration depth is preferably in the range of about 0.2 mm to about 2.5 mm.

[0105] The term "injectable substance" refers to a liquid containing an active agent (such as a vaccine or another medicament) that will be delivered to a subject by injection into one or more layers of the subject's skin tissue. The injectable substance may include suspended solid particles, or it may be a homogeneous liquid. The injectable substance may include other components in addition to the active agent, such as an adjuvant. Alternatively, the injectable substance does not include an adjuvant. The vaccine type may be selected from the following types: DNA vaccine; messenger RNA (mRNA) vaccine; virus-like particle (VLP) vaccine; inactivated vaccine; live attenuated vaccine; subunit, recombinant, polysaccharide or conjugate vaccine; toxoid vaccine; viral vector vaccine; cancer vaccine or any other vaccine therapy and / or disease prevention or immunomodulation (such as allergy alleviation) technology that generates antigen specificity.

[0106] The term "subject" refers to a living mammalian organism that receives an injection using an autoinjector. The subject may be a human or another type of mammal. In the case of self-injection, the subject is a human and is also the user or operator of the syringe.

[0107] As used herein, the terms "top" and "upper" and similar equivalents are intended to denote a specific orientation of the syringe as described in the drawings. Similarly, the terms "bottom" and "lower" and similar equivalents are also intended to denote a specific orientation of the syringe as described in the drawings. These terms and their similar equivalents are merely for convenience of labeling, which is used to help better understand the disclosed embodiments, and they are not intended to imply any specific orientation of the syringe during actual injection.

[0108] The term "outer housing" as used herein refers to a housing disposed outside a rotatable control member (control cylinder). In some embodiments, the "outer housing" may be the outermost housing. In other embodiments, additional housings may be disposed outside the "outer housing". The "outer housing" may be a housing that is continuous along the length of the syringe, or the "outer housing" may be two or more discontinuous housing portions that together form the "outer housing".

[0109] As used herein, the term "oscillatory translational motion" refers to a component or assembly moving a first distance along a first direction, and subsequently the component or assembly moving a second distance along a second direction. In some embodiments, "oscillatory translational motion" consists of a single movement along the first direction and a subsequent single movement along the second direction (i.e., a single oscillation). In some embodiments, "oscillatory translational motion" includes at least two such single oscillations. In some embodiments, "oscillatory translational motion" includes from 2 to 100 such single oscillations. In some embodiments, the second direction is opposite to the first direction. In some embodiments, the second distance is substantially the same as the first distance such that there is a net zero movement of the component or assembly after the "oscillatory translational motion". In some embodiments, the second distance is greater than or less than the first distance.

[0110] As used herein, the term "auto-injector" refers to an injection device that, once triggered, performs a predetermined series of steps for injecting an injectable substance into a subject. In some embodiments, a subject can trigger the "auto-injector" to perform self-injection. In some embodiments, a user can trigger the "auto-injector" to perform an injection into another person.

[0111] 2. Syringe

[0112] The present invention relates to an injection device which, in some embodiments, can be an auto-injector and has a needle array that is extendable and retractable relative to a housing. In various embodiments, the syringe performs one or more of the following:

[0113] Extend the needle array from a storage (retracted) position to an injection (extended) position.

[0114] Oscillate the needle array along the length of the syringe (i.e., substantially perpendicular to the skin of the subject) when the needle array is in the injection position.

[0115] Transfer the injectable substance from a storage container to the needle array.

[0116] Inject the injectable substance into the epidermal and / or dermal tissue of the subject via the needle array.

[0117] Apply a current for inducing electroporation during and / or after injecting the injectable substance into the epidermal and / or dermal tissue of the subject.

[0118] Form a decompression (mild or partial vacuum) region above the injection site during retracting the needle array back to the storage position.

[0119] In various embodiments, the syringe is an auto-injector that may take from 0.5 - 5 seconds to perform an injection, preferably from 1 - 3 seconds to perform an injection, and more preferably no more than about 2 seconds to perform an injection. In various embodiments, oscillating the needle array along the length of the auto-injector includes translating the needle array a distance of 0.1 mm to 3.0 mm, preferably about 0.5 mm, between reversals during each oscillation. In various embodiments, the injectable substance is displaced from the auto-injector and into the subject's skin under pressure provided by a plunger assembly and using a precisely calibrated amount of gas to transfer and inject all of the injectable substance. A control assembly (e.g., a rotating grooved cylinder) controls the various sub-assemblies of the auto-injector to ensure that the injection of the injectable substance matches the deepest needle penetration into the skin. In various embodiments, the current used to induce electroporation (i.e., the electroporation current) is applied as a single pulse or as a train of pulses that includes multiple pulses having the same or different durations and / or intensities. In various embodiments, at least some of the needles of the needle array are made of a conductive material and are used to apply the electroporation current. In various embodiments, the needles of the needle array are made of a non-conductive material and separate electrodes, also referred to as solid needles, are disposed within the needle array to apply the electroporation current. In various embodiments, a mild or partial vacuum is sufficient to apply suction (i.e., cupping) to the subject's skin.

[0120] Now referring to Figure 1 , a simplified perspective view is shown that depicts various elements, sub-assemblies, and / or components of a syringe in the form of an auto-injector 100 according to one embodiment. Figure 1 The auto-injector 100 shown is a specific non-limiting example that is adapted to, for example, perform an auto-injection of an injectable substance (e.g., a vaccine solution or another medicament). The auto-injector 100 is configured to inject the injectable substance into the skin tissue of a subject and, more specifically, into the epidermal tissue below the stratum corneum. Of course, the auto-injector 100 can be modified and adapted for other purposes, such as withdrawing fluid from a subject's tissue, injecting a vaccine solution or other medicament at different depths (including depths suitable for subcutaneous and intramuscular injections), and even measuring a voltage or current for interrogating a subject's tissue. As will be apparent, a modified version of the auto-injector 100 may not need to perform all of the functions listed in the foregoing paragraphs, or alternatively, such a modified version of the auto-injector may need to perform functions in addition to those listed in the foregoing paragraphs.

[0121] The auto-injector 100 includes a housing 102, which is not shown in Figure 1 for purposes of clarity, but is shown in Figure 2is shown. In the specific non-limiting examples described herein, the housing 102 is generally cylindrical in shape and has an outer surface 104 for being grasped by a user when administering an injection to a subject. The housing 102 can be made of a suitable rigid plastic material or another suitable material such as a metal or ceramic material, and can include various ergonomic features including curved surfaces and / or textured surfaces, rubber grip inserts, etc. to facilitate user grasping. In Figure 2 the specific example shown, the housing 102 has a length of approximately 13 cm, a diameter of approximately 2.5 cm, and can be easily grasped by most users. The autoinjector 100 can envision other form factors, including a device in the shape of a computer mouse that is grasped in the user's palm and pressed against the subject's skin.

[0122] Still referring to Figure 2 , the inner surface 106 of the housing 102 has a plurality of circumferential grooves formed therein. In Figure 2 the specific example shown, there are three circumferential grooves 108a - 108c that are spaced along the length L of the housing 102. The circumferential grooves 108a - 108c are configured to receive mating protrusions disposed along the outer surface of a rotatable control cylinder 120 (which is shown in Figure 1 but not shown in Figure 2 ), as discussed in more detail below. One end of the housing 102 (i.e., its injection end) has an end face 110 that extends radially inwardly and has a central opening 112. Additionally, a radially inwardly extending flange 114 having a central opening 116 is positioned adjacent the injection end of the housing 102 and is spaced from the radially inwardly extending end face 110 along the length L of the housing 102. During injection, when the needle array ( Figure 2 not shown) moves between its retracted and extended positions, the needle array passes through the central openings 112 and 116. The end face 110 and the flange 114 also have a plurality of smaller openings 113 defined therethrough. The smaller openings 113 in the end face 110 are aligned with the smaller openings 113 in the flange 114 to receive the actuating legs or shafts of a trigger mechanism (not illustrated) therein. The actuating legs or shafts perform a stabilizing function in addition to their function of triggering the autoinjector 100. In particular, the actuating legs or shafts prevent relative rotational movement of the various components through which they extend.

[0123] Figures 3 to 4 The above-described control cylinder 120 is shown, which is in Figure 1Also shown as a transparent cylinder. When the auto-injector 100 is in an assembled state, the control cylinder 120, which can be made of a suitable rigid plastic, metal, ceramic material, etc., is nested within the housing 102. When the auto-injector 100 is in an assembled state, multiple sets of protrusions 122a - 122c extend radially outwardly away from the outer surface 124 of the control cylinder 120 and are received in corresponding circumferential grooves 108a - 108c of the housing 102. For example, the housing 102 includes two halves that are secured together around the control cylinder 120 (e.g., via welding, adhesives, and / or mechanical fasteners, etc.), where the protrusions 122a - 122c are seated within the circumferential grooves 108a - 108c.

[0124] In Figures 3 to 4 the specific example shown, each set of protrusions 122a - 122c includes 4 individual protrusions that are circumferentially spaced apart around the control cylinder 120 (i.e., at 90° intervals). Alternatively, at least some sets of protrusions 122a - 122c may include more than 4 protrusions or less than 4 protrusions, and / or the individual protrusions in at least some sets of protrusions 122a - 122c may be replaced by continuous or semi - continuous ridges that are shaped to be received in the corresponding circumferential grooves 108a - 108c of the housing 102. After the auto - injector 100 has been triggered, the control cylinder 120 can rotate relative to the housing 102, but is prevented from moving relative to the housing 102 in the longitudinal direction by seating the multiple sets of protrusions 122a - 122c within the circumferential grooves 108a - 108c.

[0125] Still referring Figures 3 to 4 , features formed along the inner surface 126 of the control cylinder 120 are shown using dashed lines. In particular, multiple control grooves are formed along the inner surface 126 of the control cylinder, including i) a plunger control groove 128, ii) a piezoelectric element control groove 130, and iii) a needle array control groove 132. An inner annular gear 134 and a trigger mechanism control slot 136 are also formed along the inner surface 126 of the control cylinder 120. Multiple notches 138 lead to the trigger mechanism control slot 136. The functions of the inner annular gear 134, the trigger mechanism control slot 136, and the multiple notches 138 are described in more detail below.

[0126] Now referring to all Figures 1 to 4 , various elements, sub - assemblies, and / or components are shown arranged within the control cylinder 120, which itself is nested within the housing 102 of the auto - injector 100. The various elements, sub - assemblies, and / or components have been divided as shown in Figure 1The upper set 150 and the lower set 152 shown. This division is somewhat arbitrary, but provides a convenient basis for describing the structure and function of the auto-injector 100. It should be understood that the various elements, sub-assemblies, and / or components may be arranged differently in the auto-injector 100, especially when the form factor of the auto-injector is different from the form factor described in this specific non-limiting example.

[0127] Referring again to Figure 1 , in this example, the upper set 150 includes a plunger sub-assembly 154, a vial interface 156, and a piezoelectric element 158. In this example, the lower set 152 includes an energy source and storage sub-assembly 159, a needle 162, and a needle control sub-assembly generally designated 164.

[0128] Now referring to Figures 5 to 8 , different views of the plunger sub-assembly 154 and the vial interface 156 are shown. The plunger sub-assembly 154 includes a housing 160, which is omitted in Figure 1 for clarity. A compression spring 161 is disposed within the housing 160 between one end 164 of the plunger member 166 and the end face (not shown) of the housing 160. The second end 168 of the plunger member 166 is disposed within a cylinder 170. A substantially airtight seal is formed between the second end 168 of the plunger member 166 and the inner surface 172 of the cylinder 170. The cylinder 170 has an internal volume 174 for containing a suitable gas (such as air). Alternatively, another suitable gas may be provided in the internal volume 174. Suitable gases include gases that are non-irritating to human skin, non-toxic, non-flammable, etc.

[0129] A vial 176 having an internal volume 178 is inserted and held within a vial housing 180 of the vial interface 156. The vial 176 is, for example, a vial with a capacity of up to 5 ml or another suitable capacity depending on the injectable substance to be injected (containing a known amount of the prepared injectable substance, such as a vaccine solution). During injection, after the auto-injector 100 has been triggered, the compression spring 161 applies a force on one end 164 of the plunger member 166, which displaces the second end 168 of the plunger member 166 into the cylinder 170. The contents of the cylinder 170 (such as a precisely known amount of gas, such as air) are expelled through a first conduit 182 that fluidly connects the cylinder 170 to the internal volume 178 of the vial 176. The gas flowing into the internal volume 178 of the vial 176 forces the injectable substance to leave the vial 176 via a second conduit 184. The second conduit 184 is directed through an opening 186 in a support base or plate 188 to an unillustrated needle array for injection into the tissue of a subject. In Figure 6 's top view, the arrangement of the first conduit 182 and the second conduit 184 relative to the plunger sub-assembly 154 and the vial interface 156 is most clearly shown.

[0130] The projection 190 extends outwardly from the plunger member 166 near one end 164 thereof. As Figure 7 and Figure 8 most clearly shown, the projection 190 is held within a slot 192 formed in the housing 160. The projection 190 extends outwardly through the slot 192 and is received within a plunger control slot 128 formed along the inner surface 126 of the control cylinder 120 ( Figures 5 to 8 not shown). Although not shown in Figures 5 to 8 , the housing 160 is rigidly fixed to the outer housing 102 to prevent relative rotation therebetween. Thus, during operation, the control cylinder 120 rotates within the space (i.e., substantially an annular space) between the inner surface 106 of the outer housing 102 and the housing 160 of the plunger subassembly 154. When the control cylinder 120 rotates about a longitudinal axis parallel to the length L of the autoinjector 100, the projection 190 follows within the plunger control slot 128, and when the shape of the plunger control slot 128 permits translational movement along the length direction L, the compression spring 161 provides sufficient force to advance the plunger member 166 into the cylinder 170. Thus, the projection 190 follows a path controlled by the plunger control slot 128 and the slot 192 formed in the housing 160, thereby controlling the translational movement of the plunger 166 during injection.

[0131] The shape of the plunger control slot 128, in combination with the direction and speed of rotation of the control cylinder 120, controls the timing or the rate of advancement and retraction of the movement of the plunger member 166. Only the portion of the plunger control slot 128 that extends circumferentially of the control cylinder 120 does not result in translational movement of the plunger member 166. The portion of the plunger control slot 128 that extends circumferentially and longitudinally of the control cylinder 120 results in translational movement of the plunger member 166. The greater the amount of extension of the plunger control slot 128 in the longitudinal direction, the greater the translational movement of the resulting plunger member 166.

[0132] Now referring specifically to Figure 7 and Figure 8 , there are shown the plunger subassembly 154 and the vial interface 156 before ( Figure 7 ) and after ( Figure 8 ) the injectable substance contained in the vial 176 has been completely injected. Comparing Figure 7 and Figure 8, the compression spring 161 has extended to advance the plunger member 166 into the cylinder 170, and the second end 168 of the plunger 166 is located at the bottom of the cylinder 170. As described above, the plunger 166 forces the gas initially contained in the cylinder 170 to enter the vial 176 via the first conduit 182, which in turn pressurizes the vial 176 and forces the injectable substance to leave the vial 176 via the second conduit 184. The amount of gas (such as air) initially contained in the cylinder 170 is precisely calibrated so that the entire volume of the injectable substance is displaced out of the vial 176 and also out of the second conduit 184 to reach a needle assembly (not shown), such that substantially no injectable substance remains in the vial 176 or the second conduit 184 after injection. By precisely calibrating the amount of gas initially present in the cylinder 170 to match the internal volume 178 of the vial 176 plus the volume of the second conduit 184, it becomes possible to ensure that the autoinjector 100 has a zero dead volume, thereby avoiding waste of the injectable substance.

[0133] After the injectable substance has been fully injected into the skin tissue of the subject, the control cylinder 120 continues to rotate, and the protrusion 190 extending from the plunger member 166 continues to follow the plunger control groove 128. As Figure 3 and Figure 4 shown, the plunger control groove 128 is shaped such that the plunger member 166 returns to Figure 7 the initial state shown, where the compression spring 161 is compressed and the end 164 of the plunger member 166 is close to the end face of the housing 160. The action of returning the plunger member 166 to Figure 7 the initial state shown has the effect of drawing air back into the cylinder 170 from the area above the injection site. As discussed in more detail below, when the end of the autoinjector 100 forms a seal against the subject's skin, the action of withdrawing the plunger member 166 from the cylinder 170 creates a suction force that causes "cupping" at the injection site. The "cupping" effect causes mechanical shear within the skin tissue, which helps to distribute the injectable substance and also helps to trigger the subject's immune response.

[0134] Although the exemplary autoinjector 100 described herein is configured to use, for example, a standard 2 ml vial (or up to 5 ml, or less than 2 ml, depending on the type of injectable substance being administered) to contain the injectable substance, other alternative containers can alternatively be used. For example, since injecting into the skin can trigger a more robust immune response than injecting into muscle tissue, and since injecting into the skin does not require adjuvants and other components required for intramuscular injection, the amount of vaccine or antigen present in the injectable substance and the overall volume of injectable substance required can be much less than 2 ml, and thus smaller vials (e.g., 0.25 ml) can be used. Alternatively, a cartridge system can be used in place of a traditional vial. The cartridge system can have a specially designed loading system. It should also be noted that, to avoid accidental administration of the wrong vaccine or other agent, the autoinjector can include safety features such as the housing 180 being keyed or shaped to receive only a corresponding keyed or shaped vial / cartridge, etc. that contains the intended vaccine or other agent, a barcode reading or blockchain technology system, etc. Thus, it is not possible to accidentally inject the wrong vaccine or other agent because a vial containing the wrong vaccine or other agent cannot be properly inserted into the housing 180.

[0135] It should also be noted that the plunger subassembly 154 and the vial interface 156 as described herein are provided only by way of non-limiting example. Various modifications within the capabilities of a person of ordinary skill in the art can be envisioned. For example, the compression spring 161 of the plunger subassembly 154 can be omitted, and the energy required to extend the plunger 166 can be provided by another suitable element such as a small electric motor.

[0136] Now referring Figures 9 to 19 , different views of the needle 162 and the needle control subassembly 164 of a first exemplary autoinjector are shown, and together with the energy source and storage subassembly 159, they form Figure 1 a lower group 152 of the various elements, subassemblies, and / or components generally shown in Figure 9 is an exploded view that shows the various components in the order in which they are assembled but in an unassembled state. The sun gear 200, which is part of the planetary gear system of the autoinjector 100, is disposed at one end of the shaft 202. The sun gear 200 and the shaft 202 can be integrally formed, for example, by a molding process, or the sun gear 200 and the shaft 202 can be separate parts that are assembled together. The sun gear 200 does not rotate relative to the shaft 202. Figure 9Shows a possible configuration of the lower portion of shaft 202, which in this example is generally hexagonal in a cross-section taken in a plane perpendicular to the longitudinal direction of shaft 202. Alternatively, the shaft may have a cross-section shaped generally triangular, square, rectangular, pentagonal, etc. Shaft 202 passes through a central opening 204 in follower plate 206. The lower end of shaft 202 is received within a complementary-shaped opening 208 formed in the upper side 210 of upper plate 212 of oscillating element 214. Oscillating element 214 also includes a lower plate 216 having an upper grooved surface 218, two spherical spacer elements 220, and a plurality of tension springs 222. When in the assembled state, the two spherical spacer elements 220 sit within unillustrated openings formed in the bottom side of upper plate 212. The unillustrated openings are arranged 180° apart such that the two spherical spacer elements 220 are symmetrically positioned on the upper grooved surface 218 of lower plate 216. The two spherical spacer elements 220 are, for example, metal balls or plastic balls.

[0137] Now also referring to Figure 10 , shows the Figure 9 components in the assembled state. Figure 10 Also shown are a plurality of actuating legs 230. In the illustrated example, there are four actuating legs 230, but the number of actuating legs 230 can be more or less than four. Each actuating leg 230 has a shaft portion 232 which is configured to extend through a set of aligned openings 113 that pass through follower plate 206, lower plate 216 of oscillating element 214, needle 162, end face 110 of housing 102, and flange 114 of the housing. Shaft portion 232 prevents relative rotational movement between any of the above elements. Also as most clearly shown in Figure 10 , shaft 232 passes through tension springs 222 which are arranged between the bottom side of follower plate 206 and the upper grooved surface 218 of lower plate 216. The diameter of upper plate 212 is less than the diameters of follower plate 206 and lower plate 216. Thus, upper plate 212 fits within the space between shaft 232s and is not visible in the view shown in Figure 10 . Since upper plate 212 is rigidly coupled to shaft 202 and since upper plate 212 is too small to be rotationally constrained by shaft 230, any rotational movement of shaft 202 causes a corresponding rotational movement of upper plate 212 relative to lower plate 216 of oscillating element 214.

[0138] Now referring to Figure 11, shows a bottom perspective view of the end of the needle 162 from which four actuation legs 230 extend. For clarity, the housing 102 and the control cylinder 120 are not shown. The needle 162 includes a needle array that includes a plurality of needles 300. In this particular non-limiting example, the needles 300 are arranged in a square array and are distributed substantially symmetrically with respect to a central axis of rotation passing through the center of the needle 162. However, other arrangements may be employed without departing from the scope of the present invention.

[0139] The needles 300 may have a uniform length as shown Figure 11 . Preferably, some of the needles have a different length than other needles. Providing a needle array that includes needles of different lengths advantageously facilitates penetration of the subject's skin (avoiding the "pin cushion" effect), can compensate for slight misalignment of the auto-injector relative to the subject's skin, and allows the injectable substance to be injected at slightly different depths within a larger volume of the subject's skin tissue. Further, the needles 300 may be of only one type (e.g., only hollow plastic needles or hollow metal needles) or of different types (e.g., some hollow plastic needles, some hollow metal needles, and / or some solid metal needles). Including at least some hollow and / or solid metal needles facilitates the application of electrical pulses to the subject's skin during electroporation.

[0140] In some embodiments, Figure 9 the needle 162 shown may be differently configured to receive a replaceable cap, such as Figures 11A to 11D the cap 1100 shown. As shown Figure 11A , the cap 100 may have an end face 1102 from which an array of needles 1104 (e.g., an array of twelve needles arranged in two rows) extends. Of course, other arrangements of needles may be provided. As most clearly shown in Figures 11B to 11D , the cap 1100 may be generally cup-shaped and have a side wall 1106 sized to fit over the Figure 11D reduced-diameter distal end 1108 of the needle 162A. Optionally, one or more sealing elements (e.g., O-rings) are disposed between the outer surface of the distal end 1108 and the inner surface of the side wall 1106. In Figure 11DIn an exemplary embodiment, the needle 162A has a central opening 1110. With the aid of pressurized gas, the injectable substance is provided via the central opening 1110 to the array of needles 1104 and out into the target layer of the subject's skin. Advantageously, after injecting a predetermined number of subjects, the cap 1110 can be replaced by a new cap 1110. For human subjects, after injecting a single subject, the cap 1110 can be replaced by a new cap 1110. For veterinary applications, the cap 1110 can be replaced after injecting several animals or an entire herd of animals. Further advantageously, a plurality of different caps 1110 can be provided, each cap having a different needle array configuration that is adapted to inject different injectable substances and / or is adapted to inject subjects of different ages, etc.

[0141] Now referring to Figure 12 and Figure 13 , during use, the upper plate 212 is rotated relative to the lower plate 216 in the direction indicated by the arrow in the figure (i.e., clockwise in this example). When the upper plate 212 rotates relative to the lower plate 216, two spherical spacer elements 220 (shown in dashed lines in Figure 12 ) located in openings (not shown) in the bottom side of the upper plate 212 are guided along a circular path around the grooved upper surface 218 of the lower plate 216 as they follow the upper plate 212. As the two spherical spacer elements 220 move along the circular path, they move from one groove to the next along the grooved upper surface 218 of the lower plate 216. This movement of the spherical spacer elements 220 can be seen as the spherical spacer elements 220 initially occupying the depression of one groove, such that the upper plate 212 and the lower plate 216 are very closely spaced together as shown in Figure 12 , then rolling upward along the side of the groove to the apex and forcing the upper plate 212 and the lower plate 216 to move apart from each other as shown in Figure 13 , and then rolling downward along the side of the next groove to occupy the depression of the next groove, such that the upper plate 212 and the lower plate 216 are again very closely spaced together as shown in Figure 12 . A tension spring 222 is used to pull the upper plate 212 and the lower plate 216 back together after the upper plate 212 and the lower plate 216 have been forced apart by the spherical spacer elements 220 passing over the apex between adjacent depressions of the upper grooved surface 218.

[0142] The structural configuration of the oscillating element 214 converts the rotational movement of the shaft 202 into an oscillating translational movement of the lower plate 216 relative to the upper plate 214 along the length direction of the autoinjector 100 (as shown in Figure 13The double-headed arrow "A" therein indicates). Since the upper plate 212 is fixed relative to the outer housing 100, as a result, the needle 162 attached to the lower plate 216 oscillates in the longitudinal direction (relative to its fully extended position) during injection. The oscillation rate depends at least on the number of vertices and depressions formed along the upper grooved surface 218 of the lower plate 216 and the rotation rate of the upper plate 212.

[0143] The mechanism described above for generating the longitudinal oscillatory movement of the needle 162 is merely a specific example, which is applicable to, for example, a mechanical version of the syringe 100. Other mechanisms for generating a similar longitudinal oscillatory movement can be envisioned, and in some electromechanical embodiments, a motor or the like can be used to drive the needle 162 in this manner.

[0144] Referring again to Figure 9 and Figure 10 , the follower plate 206 has a single protrusion 240 that extends radially outward from its side edge and is used to control the extension and retraction of the needle 162. When the auto-injector 100 is in the assembled state, the protrusion 240 is received within the needle array control slot 132. During use, the control cylinder 120 rotates relative to the follower plate 206, and the protrusion 240 moves relative within the needle array control slot 132. Some portions of the needle array control slot 132 extend only circumferentially around the control cylinder 120 (see the slot portions 132a and 132c in FIGS. 14 to 17), which causes the needle 162 to remain in a predetermined extended position relative to the outer housing 102. Other portions of the needle array control slot 132 extend both circumferentially around the control cylinder 120 and longitudinally along the length of the control cylinder 120 (see the slot portions 132b and 132d), which causes the needle array of the needle 162 to extend from or retract into the outer housing 102.

[0145] The extension and retraction movements of the needle array 162 controlled by the needle array control slot 132 will be described in more detail below with specific reference to FIGS. 14 to 17.

[0146] Figure 14A is a simplified side view showing a portion of the auto-injector 100 proximate the needle array control slot 132. Figure 14B is a bottom perspective view showing Figure 14A the position of the needle 300 of the needle array in Figure 14AIn this case, the protrusion 240 on the follower plate 206 is within the first groove portion 132a of the needle array control groove 132. The first groove portion 132a only extends circumferentially around the control cylinder 120 (i.e., there is no component along the length direction of the auto-injector). When the control cylinder 120 rotates in the indicated direction, the protrusion 240 remains at the same position along the length of the control cylinder 120. Therefore, after the auto-injector 100 is triggered, the needle 162 remains in its initial retracted position for a predetermined length of time, which is based on the length of the first groove portion 132a and the rotation rate of the control cylinder 120. The needle 300 of the needle 162 is initially shielded within the housing 102 and retracts a safe distance from the central opening 112 at the injection end of the housing. By way of a specific non-limiting example, the needle 300 can retract approximately 2.5 cm from the central opening 112. This configuration reduces the risk of accidental needle stick before the auto-injector 100 is placed in contact with the subject's skin.

[0147] Figure 15A is a simplified side view showing a part of the auto-injector 100 adjacent to the needle array control groove 132. Figure 15B is a view showing Figure 15A the position of the needles of the needle array in Figure 15A relative to the central opening 112 at the injection end of the housing 102 in a bottom perspective view. In Figure 15A this case, the protrusion 240 on the follower plate 206 is within the second groove portion 132b of the needle array control groove 132. The second groove portion 132b extends circumferentially around the control cylinder 120 and longitudinally along the length L of the control cylinder 120 (i.e., there is a component along the length direction of the auto-injector). When the control cylinder 120 rotates in Figure 15A the indicated direction, the needle array control groove 132 moves relative to the protrusion 240 on the follower plate 206. This relative movement causes the protrusion 240 to be displaced longitudinally, i.e., towards the injection end of the housing 102. The follower plate 206 moves together with the protrusion 240, which causes the follower plate 206, the oscillation element 214, and the needle 162 to slide in the direction of the injection end of the housing 102 along the shaft portion 232 of the actuating leg 230. This movement causes the needle 300 of the needle 162 to extend towards the central opening 112 at the injection end of the housing and come into contact with the subject's skin (not shown).

[0148] Figure 16A is a simplified side view showing a part of the auto-injector 100 adjacent to the needle array control groove 132. Figure 16B is a view showing Figure 16A the position of the needles of the needle array in Figure 16AIn [description], the protrusion 240 on the follower plate 206 is within the third groove portion 132c of the needle array control groove 132. The third groove portion 132a only extends circumferentially around the control cylinder 120 (i.e., there is no component along the length direction of the auto-injector). Therefore, the needle 162 remains in the extended position for a predetermined length of time, which is based on the length of the third groove portion 132c and the rotation rate of the control cylinder 120. The needles 300 of the needle array penetrate into the skin (not shown) of the subject during this time, and perform the oscillating translational movement caused by the oscillating element 214. Moreover, during this time, the injectable substance is injected into the skin tissue of the subject via at least some of the needles 300 of the needle array. When there is an oscillating translational movement, it can cause the needles 300 of the needle array to repeatedly penetrate into and withdraw from the skin tissue of the subject. During this oscillating translational movement, the needles 300 can also move in a direction substantially parallel to the surface of the subject's skin, for example, via linear or curvilinear translational movement of the needles 300, so that at least some of the needles 300 penetrate into previously unpenetrated portions of the subject's skin, and this results in the injectable substance being injected into a larger volume of the subject's skin tissue.

[0149] Figure 17A is a simplified side view showing a part of the auto-injector 100 close to the needle array control groove 132. Figure 17B is a view showing Figure 17A the position of the needles of the needle array in [description] relative to the central opening 112 at the injection end of the housing 102 in a bottom perspective view. In Figure 17A In [description], the protrusion 240 on the follower plate 206 is within the fourth groove portion 132d of the needle array control groove 132. The fourth groove portion 132d extends circumferentially around the control cylinder 120 and longitudinally along the length L of the control cylinder 120 (i.e., there is a component along the length direction of the auto-injector). When the control cylinder 120 rotates in the Figure 17A indicated direction, the needle array control groove 132 moves relative to the protrusion 240 on the follower plate 206. This relative movement causes the protrusion 240 to be displaced longitudinally, i.e., displaced away from the injection end of the housing 102. The follower plate 206 moves together with the protrusion, which causes the follower plate 206, the oscillating element 214, and the needle 162 to slide along the shaft portion 232 of the actuating leg 230 in a direction away from the injection end of the housing 102. This movement retracts the needles 300 of the needle 162 through the central opening 112 at the injection end of the housing and disengages them from contact with the skin (not shown) of the subject. When the rotation of the control cylinder 120 stops, the needles 300 of the needle 162 substantially return to their initial retracted position. By way of a specific non-limiting example, the needles 300 can retract approximately 2.5 cm from the central opening 112. This configuration reduces the risk of accidental needlestick injuries after the auto-injector 100 has been used to perform an injection.

[0150] The relative shapes of the plunger control groove 128 and the needle array control groove 132 cooperate to define the timing of the individual steps of the injection. The shape of the grooves is designed such that the needles of the needle 162 protrude properly from the housing 102 before the vaccine is transferred from the vial 176 to the needles 300 of the needle 162 via the second conduit 184, and the needles of the needle are at the correct depth within the skin of the subject. The shape of the grooves must also take into account the delay between depressing the plunger and the vaccine reaching the needles 300 of the needle 162. In some embodiments, the plunger control groove 128 includes an intermediate portion that extends only circumferentially around the control cylinder 120. In such embodiments, the first portion of the plunger control groove 128 causes the plunger element 166 to be partially depressed to move the injectable substance out of the vial 176 and through the second conduit 184 to the needles of the needle 162. The intermediate portion of the plunger control groove 128 then pauses the movement of the plunger until the needle 162 is properly positioned and the needles 300 have penetrated the skin of the subject to the desired depth. Finally, the second portion of the plunger control groove 128 causes the plunger element 166 to be fully depressed, thereby injecting the entire volume of the injectable substance initially in the vial 176 into the tissue of the subject. As will be apparent, modifying the shape and / or number of the grooves formed along the inner surface 126 of the control cylinder 120 allows different timings of different operations to be programmed to suit different applications.

[0151] In some embodiments, the initial retracted position of the needle 300 can be more than Figure 14A and Figure 14BThe central opening 112 closer to the injection end of the housing 102 in the illustrated example. For example, the needle 300 may retract from the central opening 112 by about 0 mm to about 10 mm, and in some embodiments, the needle 300 may retract from the central opening 112 by about 0 mm to about 5 mm. When the needle retracts a smaller distance from the central opening 112 (e.g., 0 mm to 10 mm or 0 mm to 5 mm), the shape of the needle array control slot 132 is configured to produce a suitable smaller protrusion of the needle 300 of the needle tip. Similarly, the shape of the plunger control slot 128 is configured to cooperate to define the timing of the various steps of the injection, as described above. In some embodiments where the initial retracted position of the needle 300 is near or in the plane of the central opening 112, a cap or other removable protective element may be provided to prevent stabbing. In at least some of these embodiments, the oscillating element 214 may be omitted, and the needle array control slot may be configured to extend the needle 300 into the subject's skin and then retract it from the subject's skin one or more times, such as two, three, four, etc. The movement of the needle 300 may also occur generally in the plane of the central opening after retracting the needle from the subject's skin or even while the needle is within the subject's skin. This movement of the needle 300 results in injecting the injectable substance into a larger volume of skin tissue and causes more damage in order to enhance the body's natural immune response at the injection site. Optionally, after the injection has been completed, the needle 300 is further withdrawn rearward from the central opening 112, thereby reducing the risk of stabbing without the need for the user to replace the protective cap.

[0152] Now referring again to Figure 10 And also referring to Figure 18 and Figure 19 , each of the plurality of actuating legs 230 further includes a protrusion 234 that is oriented to extend generally radially outward from the longitudinal axis of the autoinjector 100 in the assembled state. Each protrusion 234 is shaped to be received in a notch 138 that leads to the trigger mechanism control slot 136 along the inner surface 126 of the control cylinder 120. When the protrusion 234 is held in a respective notch 138, rotation of the control cylinder 120 relative to the housing 102 or relative to the various internal components, sub-assemblies, and / or assemblies housed within the control cylinder 120 is prevented. In this state, the autoinjector 100 is locked in its initial state and is ready to be triggered to inject the injectable substance.

[0153] For the sake of clarity, Figure 19A single actuating leg 230 is shown separately. As described above, the actuating leg 230 has a shaft 234 along which the follower plate 206, the oscillating element 214, and the needle 162 slide during the extending movement and the retracting movement. The shaft 234 also passes through an opening 113 in the end face 110 and the flange 114 of the housing 102, which prevents relative rotational movement between the follower plate 206, the oscillating element 214, the needle 162, and the housing 102. In this specific non-limiting example, triggering of the auto-injector 100 is achieved by placing the "foot" 236 at the bottom end of the actuating leg 230 in contact with the skin surface of the subject and pressing down on the auto-injector 100. This causes the actuating leg to move upward, such that the protrusion 234 moves out of the notch 138 and into the trigger mechanism control slot 136 along the inner surface 126 of the control cylinder 120. The control cylinder 120 then becomes "unlocked" and can begin to rotate relative to the housing 102 and relative to the various components, sub-assemblies, and / or assemblies housed within the control cylinder 120.

[0154] Figure 20 The injection end of the auto-injector 100 is shown when the auto-injector is not properly positioned against the skin of the patient. Since one foot 236* does not properly contact the skin of the subject, the shaft 234* does not move upward into the auto-injector 100, and thus the protrusion 234* remains seated within the notch 138* and does not enter the trigger mechanism control slot 136. When the auto-injector 100 is not properly positioned against the skin of the subject, the protrusion 234* prevents the rotatable control cylinder 120 from rotating, thereby ensuring that injection occurs only when the auto-injector 100 is properly positioned to deliver the injectable substance to the target depth within the skin of the subject.

[0155] Although the feet 236 are shown as separate elements at the ends of the respective shafts 234 of the actuating legs 230, in some embodiments, the feet 236 are joined to form a continuous contact surface surrounding the central opening 112. The material forming the contact surface is preferably flexible enough to allow the shafts 234 to move independently of each other, which is necessary to prevent triggering when the auto-injector 100 is not properly positioned. If a rigid material were used to form the contact surface in this alternative implementation, the shafts could move only as a unit, and the auto-injector could be triggered even when not properly positioned against the skin of the subject.

[0156] In at least some embodiments, a device is provided for sealing the injection end of the auto-injector against the skin of the subject. Figure 20AA possible implementation of the device for sealing is shown. In this example, a skirt or gasket 404 is disposed at the injection end of the housing 102. The skirt or gasket 404 is made of, for example, silicone or another suitable deformable material. The skirt or gasket 404 extends from the injection end of the housing 102 and forms a substantially airtight seal against the subject's skin, while still allowing the foot 236 of the actuating leg 230 to engage the subject's skin to trigger the autoinjector 100. Optionally, a one-way valve 402 is provided, for example, through the housing 102, to allow air in the area above the injection site to escape during the extension of the needle of the needle 162 through the central opening 112.

[0157] Now referring to Figure 21 , an example energy source and storage subassembly 159 for providing and storing the energy required for the upper plate 220 that houses the rotary control cylinder 120 and the rotary oscillating element 214 is shown, and the control cylinder controls the movement of the plunger member 166 and the needle 162. In this specific non-limiting example, the torsion spring 300 stores mechanical potential energy, which is used to spin up the flywheel 302 when released, and the flywheel in turn stores rotational kinetic energy for use in rotating the control cylinder 120 and the upper plate 220 during the injection operation. However, in an alternative (electromechanical) embodiment, the energy source and storage subassembly 159 may include an electric motor and a DC power source or an AC power source. The torsion spring 300 is housed within a torsion spring housing 304, and the flywheel 302 is housed within a flywheel housing 306. Optionally, the torsion spring housing 304 and the flywheel housing 306 are replaced with a single housing that houses both the torsion spring 300 and the flywheel 306. The torsion spring housing 304 is mounted below the support base or plate 188 described in Figures 5 to 8 . Optionally, the support base or plate 188 performs a dual function and also serves as the torsion spring housing 304.

[0158] Still referring to Figure 21 , the torsion spring 300 has a fixed end 308 that is rigidly coupled to, for example, an unillustrated top surface of the torsion spring housing 304. The torsion spring 300 also has a free end 310. Before the autoinjector 100 is triggered, the free end 310 of the torsion spring 300 is held by a ridge or protrusion 312 along the top of the flywheel 302. As described in more detail below, the flywheel 302 is coupled to the control cylinder 120 via a planetary gear system (shown in Figures 23 to 25 ). Since the control cylinder 120 is initially "locked" by sitting with a protrusion 234 of the actuating leg 230 within a notch 138 of the trigger mechanism control slot 136, the flywheel 302 is also initially "locked" and thus prevented from rotating. When the autoinjector 100 is triggered, the protrusion 234 of the actuating leg 230 moves out of the notch 138, and the control cylinder 120 is free to rotate. The flywheel 302 is no longer prevented from rotating, and the free end 310 of the torsion spring 300 begins to move in a circular direction ( Figure 21Push a ridge or projection 312 extending from the top of the flywheel 302 in the counterclockwise direction (as shown in the figure).

[0159] Now also referring to Figure 22A and Figure 22B which show top views of the torsion spring 300 and the flywheel 302 before and after triggering the auto-injector 100 respectively. As Figure 21 shown, the center 314 of the torsion spring 300 is offset from the center 316 of the flywheel 302. Thus, the torsion spring 300 contacts the flywheel only when transferring energy to the flywheel 302, and once completed, as Figure 22A shown, the free end 310 of the torsion spring 300 moves out of the path of the ridge or projection 312 and does not interfere with the rotation of the flywheel 302. Figure 22B Figure 22A Figure 22B and also more clearly show a central opening 318 in the flywheel housing 306 that houses pipes and electrical conductors, as described in more detail below.

[0160] Figures 23 to 25 Figure 23 shows details of the planetary gear system briefly mentioned above, which is used to transfer the stored rotational kinetic energy from the flywheel 302 to the control cylinder 120. As Figure 23 shown, a pair of planetary gears 320 are mounted on an axis 322 extending from the lower surface 324 of the flywheel housing 306. The flywheel housing 306 is fixed relative to the outer housing 102, and the control cylinder 120 rotates within the annular space formed therebetween. The sun gear 200 is coupled to the flywheel 302 via a cylindrical connector 319 extending through the opening 318 and rotates at the same speed as the flywheel 302. When the sun gear 200 starts to rotate (e.g., in the counterclockwise direction), the two planetary gears 320 also start to rotate about their respective axes 322 but in opposite directions (e.g., in the clockwise direction). Since the flywheel housing 306 is fixed and the planetary gears 320 are mounted to the lower surface 324 of the flywheel housing 306, the rotational movement of the planetary gears 320 causes an internal annular gear 134 formed on the inner surface 126 of the control cylinder 120 (see Figure 24) also rotates in the same direction (e.g., clockwise). Since the rotational speed of the flywheel 302 is substantially constant over the injection time scale, the control cylinder 120 is rotated at a substantially constant speed and can control various movements in a predictable and reproducible manner. Optionally, the torsion spring 300 is replaced by another suitable mechanism for providing energy to spin the flywheel. Further optionally, manual assistance or fully manual operation can be envisioned. For example, the user can tap a button or another suitable mechanism to provide supplementary energy for initiating the rotational movement of the flywheel 302 before releasing the torsion spring 300. In this case, the torsion spring 300 is not required to overcome the inertia of the flywheel, and a torsion spring providing a smaller force can be used. Alternatively, the user can tap a button or another suitable mechanism to provide all the energy required to spin the flywheel 302. In this case, the torsion spring 300 can be completely eliminated.

[0161] Now referring to Figure 25 , details of the arrangement of the sun gear 200, the planetary gears 320, and the internal ring gear 134 are shown when the auto-injector 100 is in the assembled state. As will be apparent, a different number of planetary gears 320 can be used, and / or planetary gears 320 of different sizes relative to the size of the sun gear 200 can be used, and / or the planetary gears 320 can be mounted to a rotating carriage rather than the fixed lower surface 324 of the flywheel housing 306, thereby enabling different relative rotational movements between the flywheel 302 and the control cylinder 120. In Figure 25 the example shown, the control cylinder 120 is caused to rotate at a lower speed and in a direction opposite to that of the flywheel 302. On the other hand, both the sun gear 200 and the shaft 202 rotate at the same rate and in the same direction as the flywheel 302. Since the rotational movement of the shaft 202 is directly transmitted to the upper plate 212 of the oscillating element 214, and since there are a plurality of ridges (e.g., 15 - 30 ridges) between adjacent depressions defined along the grooved surface 218, an oscillatory translational movement in the range of 10 - 100 Hz can be achieved. Thus, the needle 300 of the needle 162 can be moved up and down against the skin of the subject 10 - 100 times per second.

[0162] Optionally, a "stop" is provided within the above-described planetary gear system or within one or more control slots of the control cylinder 120, etc., to prevent the rotational movement of the control cylinder 120 after the injection has been completed and the needle array has been fully retracted into the housing 102. Regardless of its nature, this stop is a safety feature designed to prevent the residual rotational kinetic energy stored in the flywheel 302 from causing the control cylinder body 102 to continue rotating, thereby causing the needle array to protrude through the injection end of the housing 102 a second time.

[0163] Of course, the flywheel 302, torsion spring 300, planetary gear system, etc. are described in the context of a specific non-limiting embodiment of the autoinjector 100. As will be apparent, there are alternative mechanisms for converting the stored potential energy into a regulated rotation of the shaft and these can be used alternatively in different embodiments. Of course, those skilled in the art can envision various modifications to the disclosed embodiments. For example, as noted above, an electromechanical autoinjector can include a motor powered by a DC power source or an AC power source (such as a battery). The output shaft of the motor can be coupled to, for example Figure 23 the sun gear 200 shown and provide the power needed to drive the various components of the autoinjector in a manner similar to that described above. A suitable electronic controller can be employed to control the movement of the various components and sub-assemblies during injection. As will be further apparent, the flywheel 306 and / or various other components can be omitted or replaced in an electromechanical autoinjector. Although the cost of such an electromechanical version of the autoinjector 100 may be higher than that of a purely mechanical version, such a device is still well-suited for certain applications, including for example veterinary applications, where a single device can be used to inject an entire herd of animals without changing the needle array, etc.

[0164] In addition to injecting an injectable substance into the skin tissue of a subject, the autoinjector 100 can also employ various supplementary techniques to promote a robust immune response in the subject. One such supplementary technique has been discussed above and involves an oscillatory up-and-down translational movement of the needle 162. The oscillatory translational movement of the needle 162 causes the needle 300 to move rapidly up and down at a rate between 10 and 100 times per second during injection, which causes a minimal amount of local damage to the subject's skin tissue around the injection site. This damage has several functions. First, it promotes the distribution of the injectable substance into the subject's skin tissue. Second, the damage triggers a response through various antigen-presenting cells (APCs) in the subject's skin tissue, which respond to this damage by initiating an immune response.

[0165] Another supplementary technique that can be used during injection is electroporation. As described in the introduction section, electroporation involves the application of brief electrical pulses that cause the formation of aqueous pathways within the lipid bilayer membranes of mammalian cells. This allows even large molecules (including DNA) to cross the cell membrane, which would otherwise have a lower permeability. Although the exact mechanism by which electroporation achieves cell transformation has not been elucidated, the proposed theoretical model involves pore formation events due to membrane destabilization, followed by electrophoretic movement of charged molecules into the cell. For electroporation to occur, the formation of pores requires a threshold energy to be reached, and the movement generated by the electrophoretic effect depends on the electric field and pulse length. In the case of DNA vaccines, electroporation has been shown to quantitatively enhance the immune response, increase the breadth of these immune responses, and improve dose efficiency.

[0166] Figures 26 to 33Shows various details of an electro - perforation subsystem suitable for incorporation into an auto - injector 100. Figure 26 Is highly simplified and shows only Figure 1 The piezoelectric element 158, the needle array 162, and the electrical connector extending therebetween. During use, a hammer (not illustrated) presses on a piezoelectric crystal (not illustrated) in the piezoelectric element 158, which generates a current that flows via conductor 400 to the needles 300 of the needle head 162. At least some of the needles 300 within a portion 402 of the needle head 162 are conductive (e.g., metallic) and conduct the current into the skin of the subject. Alternatively, instead of the hollow needles 300, the conductive elements of the needle head 162 can be micro - electrodes (i.e., “solid needles”) that do not carry the injectable substance into the skin of the subject. Figure 27 Shows a side view of the conductor 400 connected to the portion 402 of the needle head 162. In this example, all of the needles 300 are the same, i.e., hollow metal needles for injecting the injectable substance and for applying the current.

[0167] Figure 28 Shows the conductor 400 extending from the piezoelectric element 158 through an opening 186 in a support base or plate 188 (which is shown as transparent in Figure 28 for better understanding). Figure 28 Also shown in dashed lines in

[0168] Figure 29 and Figure 30 Illustrates the characteristics of the piezoelectric element 158 at a first point during rotation of the control cylinder 120, Figure 31 and Figure 32 Illustrates the characteristics of the piezoelectric element 158 at a second point during rotation of the control cylinder 120. First, referring to Figure 30 and Figure 32 , the piezoelectric element 158 has a housing 450 that can be fixed to the support base or plate 188. The housing 450 has a longitudinal slot 452 defined through one of its sides. A hammer 454 is mounted on one end of a shaft 456 within the housing 450. A protrusion 458 extends outwardly from the shaft 456 through the slot 452 and is received within a piezoelectric - element control slot 130 on the inner surface 126 of the control cylinder 120. A compression spring 460 is accommodated at the upper end of the housing 450.

[0169] Now referring toFigure 29 During injection, after the auto-injector 100 has been triggered, the control cylinder 120 rotates relative to the piezoelectric element 158, and the protrusion 458 initially follows the first groove portion 130a of the piezoelectric element control groove 130. The first groove portion 130a only extends circumferentially around the control cylinder 120. As the control cylinder 120 continues to rotate, the protrusion 458 eventually enters the second groove portion 130b of the piezoelectric element control groove 130, which only extends longitudinally of the control cylinder. This allows the protrusion 458 to move within the slot 452 of the housing 450, which in turn allows the compression spring 460 to expand and press down on the hammer 454 and contact the piezoelectric crystal 462 housed at the lower end of the housing 450. The pressure applied to the piezoelectric crystal 462 by the compression spring 460 via the hammer 454 generates an electric current, which flows through the conductor 400 to the needle 162. During the time when the protrusion follows the third groove portion 130c of the piezoelectric element control groove 130, the hammer 454 continues to be applied to the piezoelectric crystal, and this third groove portion only extends circumferentially around the control cylinder 120. When the rotation of the control cylinder 120 causes the protrusion to enter the fourth groove portion 130d of the piezoelectric element control groove 130, the pressure is removed from the piezoelectric crystal 462 and the hammer 454. The fourth groove portion 130d extends circumferentially and longitudinally within the inner surface of the control cylinder 120, such that the protrusion 458 is guided back to its initial position within the slot 452 against the force of the compression spring 460.

[0170] The timing of the electrical pulses generated by the piezoelectric element 158 is determined by the shape of the piezoelectric element control groove 130 and the rotational rate of the control cylinder 120. In this specific non-limiting example, there is a single relatively long third groove portion 130c, during which the hammer 454 applies pressure to the piezoelectric crystal, thereby generating an electric current. However, the shape of the piezoelectric element control groove 130 can be modified, for example, by providing multiple third groove portions 130c having similar lengths or different lengths, to produce a pulse sequence, in which during injection the electric current is applied to the subject's skin multiple times, with periods during which no current is applied between the applications of the current.

[0171] In some embodiments, the electroporation pulses are associated with an electric field that prevents damage to the cells of the epidermal tissue. In additional embodiments, the electroporation pulses are associated with a nearly painless electric potential. For example, the electroporation pulses are associated with an electric potential of about 1 volt to about 30 volts, or preferably about 15 volts to about 20 volts, a current of about 1 mA to about 50 mA, or preferably about 10 mA to about 15 mA, and a duration ranging from about 80 ms to about 150 ms, or preferably 100 ms, or a combination thereof. These pulses can be delivered in the form of a series of pulses (preferably 1 - 10 pulses, more preferably 1 - 3 pulses).

[0172] Alternatively, a system utilizing a battery can be used to generate an electric current. Further alternatively, the rotational movement of the flywheel 302 can be used to generate an electric current using appropriately placed magnets and conductors.

[0173] The main features of the first exemplary autoinjector 100 have been described above with reference to Figures 1 to 32 been described. Figure 33 is presented as showing the autoinjector 100 in a fully assembled state. Since the autoinjector 100 includes a nested arrangement of individual elements, there is a significant amount of overlap in Figure 33 which obscures the arrangement of the various elements. For better understanding, in Figure 33 regions denoted as A - B and B - C are indicated. Figure 34 shows the individual elements in the region A - B separated from each other, thus avoiding overlap so that the individual elements can be seen more clearly. Similarly, Figure 35 shows the individual elements in the region B - C separated from each other, thus avoiding overlap so that the individual elements can be seen more clearly.

[0174] The autoinjector 100 described herein and the various modified versions explicitly or implicitly discussed above can achieve at least some of the following advantageous results.

[0175] Dose savings of up to ten - fold relative to subcutaneous and intramuscular routes without compromising immunogenicity.

[0176] Zero dead - volume and injection under pressure eliminate waste of the injectable substance, thus ensuring that the full amount of the injectable substance is injected.

[0177] A combination of injections performed using one or more supplementary techniques selected from electroporation, oscillating needle arrays to cause local skin damage, and suction (e.g., cupping) above the injection site after the injectable substance has been injected enhances the immune response of the subject.

[0178] A fool - proof design ensures proper orientation of the autoinjector on the subject's skin before triggering the injection.

[0179] Is easily graspable by the subject receiving the injection or by another user administering the injection to the user without the need to clumsily manipulate a physical plunger, etc.

[0180] As described above, the autoinjector 100 can be modified and adapted for purposes such as withdrawing a fluid sample from a subject's tissue. In such an embodiment, the needle 162 can include needles that pierce the subject's skin to reach a desired target layer, such as the dermis layer, and can include needles that do not pierce all the way to the target layer but instead serve as stabilizing elements during the process of withdrawing the fluid sample. The autoinjector can be modified to include a sampling chip that includes a large number (e.g., 5000) of sample locations or another suitable sample holding element. Some of the sampling locations may be redundant. Diagnostic tests can be performed on the withdrawn fluid sample.

[0181] 3. Target injection site

[0182] Now referring to Figure 36 , a representation of the anatomical structure of human skin is shown, which is constructed in a layered form and includes the epidermis, dermis, subcutaneous tissue, and muscle tissue. The epidermis is approximately 0.1 to 2 mm thick and can be differentiated or classified into the stratum corneum and the stratum germinativum. Among the layers of the skin structure, the tissues and the main cells used to construct the tissues have different characteristics.

[0183] Specifically, the stratum corneum in the epidermis is mainly composed of keratinocytes and is located on the outermost surface side of the skin. Generally, the stratum corneum is approximately 0.01 to 0.015 mm thick and serves as a so-called barrier layer. A relatively high strength is required to physically isolate the interior of the human body from the external environment to some extent. Other cells in the epidermis are Langerhans cells and pigment cells (melanocytes). The pigment cells in the epidermis are used to avoid the effects of ultraviolet light radiated from the external environment. On the other hand, the dermis includes dendritic cells. The dendritic cells in the dermis are cells involved in the antigen-antibody reaction. They can be linked by Langerhans cells, which can be triggered by the disruption of the epidermis and can jointly participate in the immune process. More specifically, dendritic cells recognize the presence of an antigen by incorporating the antigen and induce an antigen-antibody reaction, in which lymphocytes are activated to play a role in attaching to foreign substances.

[0184] The dermis contains a network of blood vessels and capillaries and also includes sweat glands for regulating body temperature, hair roots of body hair (including hair on the head), and sebaceous glands associated therewith. The dermis is the skin layer that communicates between the epidermis and the interior of the human body (subcutaneous tissue and muscle tissue). The dermis also includes fibroblasts and collagen cells.

[0185] Now referring to Figures 37A to 37D , a series of schematic diagrams corresponding to different times during the injection of an injectable substance into a subject's tissue are shown. Figure 37AThe needle 300 of the head 162 of the auto-injector 100 in contact with the skin 3600 of the subject is shown, the skin including an epidermal layer 3602, a dermal layer 3604, and a subcutaneous fat layer 3606. In the presently preferred embodiment, the plurality of needles 300 includes needles of at least two lengths, including relatively long needles 300A and relatively short needles 300B. Langerhans cells 3608 are shown within the epidermal layer 3602.

[0186] The auto-injector 100 is configured such that the needles 300 of the needle head 162 move into contact with the skin 3600 of the subject at a sufficient speed and pressure to allow the needles 300A and 300B to pierce the dry protective stratum corneum. The different lengths of the needles 300A and 300B avoid the "pin cushion" problem that occurs when all the needles have the same length. Another advantage of performing the injection using needles 300A and 300B of different lengths is that the delivery of the injectable substance is better targeted to the desired layer of the skin 3600 and can be more evenly spread over a larger area.

[0187] Still referring Figure 37A , some of the needles 300A penetrate the skin 3600 of the subject to the depth of the dermal layer 3604, while other needles 300B penetrate the skin 3600 of the subject only to the epidermal layer 3602. During one or more oscillatory movement cycles of the needle head 162, the injectable substance is extruded through the needles 300A and 300B under pressure. Figure 37B The injectable substance after injection into the skin 3600 of the subject is shown. The dashed rectangle 3610 indicates the distribution of the injectable substance. As will be apparent, the individual needles 300A and 300B inject "clouds" of the injectable substance separately, which are distributed throughout the epidermal layer 3602 (when injected via the needle 300B) and throughout the dermal layer 3604 (when injected via the needle 300A). The inner bores and / or other characteristics of the different types of needles 300A and 300B can be selected so as to inject the injectable substance in a controlled manner targeting the dermal layer 3604. For example, the characteristics of the needles can be customized such that the pressure at which the injection is performed is sufficient to deliver the injectable substance to the target dermal layer 3604 without "blowing through" to the underlying subcutaneous fat layer 3606. The pressure can be customized at least in part taking into account the characteristics of the skin tissue layer into which each of the different types of needles is injecting. Injecting the injectable substance within the dermal layer 3604 via a first subset of the needles may require a different pressure than that required to inject the injectable substance within the epidermal layer 3602 via a second subset of the needles.

[0188] Initially, the individual clouds of the injectable substance are slightly separated from each other and are positioned and generally aligned with the ends of the respective needles, and the clouds are injected into the skin tissue of the subject through the respective needles. The clouds of the injectable substance diffuse and spread within the skin 3600 of the subject, as Figure 37C andFigure 37D is illustrated by using a larger dashed - line rectangle 3610 than that shown Figure 37B As a result, the injectable substance is highly uniformly distributed within the target dermal layer 3604.

[0189] It is also worth noting that, in at least some embodiments, the auto - injector 100 causes translational oscillatory movement of the needle 162 during injection, and thus the needles 300A and 300B are not stationary as Figures 37A to 37D suggested. Instead, the needles 300A and 300B repeatedly extend to their respective maximum penetration depths and are at least partially withdrawn from the subject's skin tissue. The injection of the injectable substance is preferably controlled to occur when the needles 300A and 300B extend to their respective maximum penetration depths. Preferably, the injectable substance is injected during multiple oscillations of the needle array, where each portion of the injection occurs when the needles 300A and 300B extend to their respective maximum penetration depths, so as to be injected into the corresponding target layer of the subject's skin.

[0190] According to another embodiment, an auto - injector is provided, in which a rotational movement of the needle is performed during the oscillatory translational movement. For example, each time the needle is at least partially withdrawn from the subject's skin tissue, the needle array undergoes a small rotational movement such that new perforations are formed when the needles subsequently extend again to their respective maximum penetration depths. Depending on the nature of the injectable substance, the optimal required number of piercing events (i.e., the oscillation and rotation of the needle array) can vary. For example, from 10 oscillations per second of the needle array to 100 oscillations per second of the needle array can be suitable for different injectable substances. The multiple piercing events create additional trauma at the injection site to maximize the amount of stimulation of Langerhans cells 3608, which have the ability to move from the epidermal layer 3602 to the dermal layer 3604 and initiate an immune - response cascade. Advantageously, stimulating the Langerhans cells 3608 by mechanically damaging the subject's skin tissue obviates the need to include adjuvants in the injectable substance, which reduces the occurrence and / or severity of undesirable side effects.

[0191] Now referring to Figures 38 to 48 , different views of the main components of an alternative needle 3900 and an alternative needle control sub - assembly 3902 of a second exemplary auto - injector are shown. A bearing element 3940 supports the rotational movement of the needle 3900 relative to the needle control sub - assembly 3902 during operation. In this embodiment, the needle 3900 and the needle control sub - assembly 3902 respectively replace the reference Figures 9 to 19The described needle 162 and needle control subassembly 164. In some embodiments, the remainder of the autoinjector 100 remains substantially the same or requires only minor modifications. For example, the second exemplary autoinjector may include a plunger subassembly 154, a vial interface 156, a piezoelectric element 158, and the energy source and storage subassembly 159 described above. When referring to an autoinjector device that includes a needle 3900 and a needle control subassembly 3902, the term "autoinjector 100" will continue to be used.

[0192] Figure 38 is an exploded view showing the arrangement of the main components of the needle control subassembly 3902 and the needle 3900. A sun gear 3904, which is part of the planetary gear system of the autoinjector 100, is disposed at one end of a shaft 3906. The sun gear 3904 and the shaft 3906 may be integrally formed using a molding process, or the sun gear 3904 and the shaft 3906 may be separate parts assembled together. The sun gear 3904 does not rotate relative to the shaft 3906. In this example, the shaft 3906 has a generally hexagonal cross-section in a plane taken perpendicular to its length. Alternatively, the shaft 3906 may have a cross-section shaped generally like a triangle, square, rectangle, or pentagon, etc. The shaft 3906 passes through a central opening 3908 in a follower plate 3910, which has a projection 3911 that performs the same function as the projection 240 described above. The lower end of the shaft 3906 is received within a complementary-shaped opening 3912 formed in an upper side 3914 of an upper plate 3916 of an oscillating element 3918. The oscillating element 3918 also includes a lower plate 3920, which has an upper grooved surface 3922, two spherical spacer elements 3924, and a plurality of tension springs 3926. When in the assembled state, the two spherical spacer elements 3924 are seated within unillustrated openings formed in the bottom side of the upper plate 3916. The unillustrated openings are arranged 180° apart such that the two spherical spacer elements 3924 are symmetrically positioned on the upper grooved surface 3922 of the lower plate 3920. The two spherical spacer elements 3924 are, for example, metal balls or plastic balls.

[0193] Now also referring to Figure 42 , there is shown Figure 38 in an assembled state. Figure 42 Also shown are a plurality of actuating legs 4300, which are part of the trigger mechanism of the autoinjector 100. Each actuating leg 4300 has a shaft portion 4302, which is configured to extend through one of a plurality of sets of aligned openings. Each set of aligned openings includes a first opening 3928 formed through the follower plate 3910, a second opening 3930 formed through the lower plate 3920 of the oscillating element 3918, a third opening 4304 formed through a lower portion of the sidewall of a rotary drive housing 4306, and the aforementioned opening 113 formed through an end face 110 and a flange 114 of the outer shell 102. Also asFigure 42 As most clearly shown, each shaft portion 4302 passes through a tension spring 3926, which is disposed between the bottom side of the upper plate 3916 and the grooved upper surface 3922 of the lower plate 3920.

[0194] The shaft portions 4302 prevent relative rotational movement between any of the above-mentioned elements. However, the diameter of the upper plate 3916 is smaller than the corresponding diameters of the follower plate 3910 and the lower plate 3920. Therefore, the upper plate 3916 is received within the space between the shaft portions 4302. Since the upper plate 3916 is rigidly coupled to the shaft 3906 and since the upper plate 3916 is too small to be rotationally constrained by the shaft portions 4302 of the actuating legs 4300, any rotational movement of the shaft 3906 will cause a corresponding rotational movement of the upper plate 3916 relative to the lower plate 3920 of the oscillating element 3918.

[0195] Now referring to Figure 38 and Figure 42 , the diameter of the lower plate 3920 is also smaller than the diameter of the follower plate 3910, such that a second opening 3930 formed through the lower plate 3920 extends through the outer sidewall of the lower plate 3920, thereby forming a plurality of circumferentially spaced gaps in its outer sidewall. The diameter of the lower plate 3920 is configured to allow the lower plate 3920 to be received within the rotary drive housing 4306. As Figure 42 shown, the upper portion of the sidewall of the rotary drive housing 4306 has a plurality of openings 4308 formed therethrough, which receive the shaft portions 4302 of the actuating legs 4300 and the tension spring 3926.

[0196] Referring again to Figure 38 , the needle 3900 includes a first sidewall portion 3932 and a second sidewall portion 3934 having a diameter smaller than the first sidewall portion 3932. An internal shoulder feature 3936 is formed between the first sidewall portion 3932 and the second sidewall portion 3934. A bearing element 3940 is disposed between the needle 3900 and the lower plate 3920. In particular, the bearing element 3940 has an outer ring 3942 sized to be inserted within the first sidewall portion 3932 of the needle 3900 and to abut the internal shoulder feature 3936. The bearing element 3940 also has an inner ring 3944 sized to receive a flanged projection extending from the lower plate 3920 (i.e., Figure 39 the flanged projection 4000 shown). A rolling element assembly 3946 including a plurality of rolling elements (e.g., balls) and a retainer (e.g., a ball separator) completes the bearing element 3940. The bearing element 3940 supports the rotational movement of the needle 3900 relative to the lower plate 3920 and other elements rotationally constrained by the shaft portions 4302 of the actuating legs 4300.

[0197] Figure 39is an exploded perspective view showing the lower plate 3920, the bearing element 3940, and the needle 3900, where the needle 4002 is in an unassembled but aligned state. Figure 40 shows the relationship between the bearing element 3900 and the circular flange 4000 in the assembled state. Figure 41 shows the relationship between the bearing element 3940 and the needle 3900 in the assembled state. The bearing element 3940 can be fixed to the circular flange 4000 and the needle 3900 by any suitable means, including by friction fit, adhesive, snap fit, etc.

[0198] Figure 43A and Figure 43B illustrates the oscillatory translational movement of the needle 3900. During use, the upper plate 3916 is rotated relative to the lower plate 3920 in the direction indicated by the arrow in the figure (i.e., clockwise in this example). When the upper plate 3916 rotates relative to the lower plate 3920, two spherical spacer elements 3924 located in unillustrated openings in the bottom side of the upper plate 3916 are guided along a circular path around the grooved upper surface 3922 of the lower plate 3920 as they follow the upper plate 3916. As the two spherical spacer elements 3924 move along the circular path, they move from one groove to the next along the upper grooved surface 3922 of the lower plate 3920. This movement can be seen as the spherical spacer elements 3924 initially occupying the depression of one groove, such that the upper plate 3916 and the lower plate 3920 are Figure 43A shown very closely spaced together, and then rolling up along the side of the groove to the apex and forcing the upper plate 3916 and the lower plate 3920 to be Figure 43B shown moving away from each other, and then rolling back down along the side of the next groove to occupy the depression of the next groove, such that the upper plate 3916 and the lower plate 3920 are again Figure 43A shown very closely spaced together. A tension spring 3926 is used to pull the upper plate 212 and the lower plate 216 back together after the upper plate 3916 and the lower plate 3920 have been forced apart by the spherical spacer elements 3924 passing over the apex between pairs of adjacent depressions.

[0199] The structural configuration of the oscillating element 3918 converts the rotational movement of the shaft 3906 into an oscillatory translational movement of the lower plate 3920 relative to the upper plate 3916 along the length direction of the autoinjector 100 (as indicated by the double-headed arrow "A" in Figure 43B ). Since the upper plate 3916 is fixed relative to the housing 102, the result is that the needle array 3900 attached to the lower plate 3920 oscillates in the length direction (relative to its fully extended position) during injection. The oscillation rate depends at least on the number of apexes and depressions formed along the upper grooved surface 3922 of the lower plate 3920 and the rotational rate of the upper plate 3916.

[0200] Figure 44A is a perspective view showing the features of the needle array 3900 and the features of the rotary drive housing 4306, which cooperate to cause rotational movement of the needle array 3900 during oscillatory translational movement. Figure 44B is a cross-sectional view taken along Figure 44A line A-A in Figure 44A through the sidewall of the rotary drive housing 4306. As most clearly shown in

[0201] Figure 44B[[ is a cross-sectional view showing the material ring 4310 and the inwardly extending protrusions 4312 arranged along a portion III of the inner surface of the rotary drive housing 4306. As will be apparent, the sidewall thickness of the rotary drive housing 4306 varies along the longitudinal direction. A third opening 4304 for receiving the shaft portion 4302 of the actuating leg 4300 is formed within portion III. The sidewall is thinnest within portion II, which provides sufficient space to accommodate the lower plate 3920 of the oscillating element 3918. Portion I of the sidewall has a thickness intermediate between those of portions II and III, which provides sufficient space to accommodate the upper plate 3916 of the oscillating element. As will be apparent from ​ it is apparent that the outer diameter of the rotary drive housing 4306 is substantially the same as the diameter of the follower plate 3910, which in the assembled state is arranged adjacent to the top edge of the rotary drive housing 4306.

[0202] Now also referring to ​ , when in the assembled state, the protrusions 3948 formed around the circumference of the first sidewall portion 3932 of the needle head 3900 are arranged within the circumferential space 4316 between the material ring 4310 and the inwardly extending protrusions 4312. As more clearly shown in ​ , during the oscillatory movement of the needle head 3900, the protrusions 3948 move along the longitudinal direction "L". The rotational movement of the needle head 3900 is caused by the interaction between the inclined upper and lower surfaces of the protrusions 3948, the inclined asymmetric lower surface of the material ring 4310, the inclined upper surface of the protrusions 4312, and the offset between the inclined surfaces in the material ring 4310 and the protrusions 4312.

[0203] ​shows the inclined upper surface of a projection 3948 that abuts the corresponding inclined front surface of the material ring 4310. This is the configuration that occurs when the upper plate 3916 and the lower plate 3920 of the oscillating element 3918 are spaced very closely together as ​ shown. When the upper plate 3916 and the lower plate 3920 of the oscillating element 3918 start to move away from each other towards the maximum extension of the oscillating element "A" as ​ shown, the lower inclined surface of the projection 3948 moves longitudinally towards the upper inclined surface of the projection 4312 and starts to slide along the upper inclined surface, causing the projection 3948 to move to the ​ right side in. The movement of the projection 3948 causes the needle 3900 to rotate as a whole. Now referring to ​ , when the oscillating element continues to force the upper plate 3916 and the lower plate 3920 of the oscillating element 3918 to separate, the needle array 3900 continues to move in the longitudinal direction, and the lower inclined surface of the projection 3948 continues to slide along the upper inclined surface of the projection 4312, resulting in the needle 3900 continuing to rotate until the projection 3948 moves past the end of the upper inclined surface of the projection 4312. At this time, as ​ shown, the projection 3948 only moves in the longitudinal space between two adjacent projections 4312. When the oscillating movement of the needle 3900 reverses and the upper plate 3916 and the lower plate 3920 of the oscillating element 3918 move back towards each other, the upper inclined surface of the projection 3948 moves longitudinally towards the lower inclined surface of the material ring 4310*, and starts to slide along the lower inclined surface, causing the projection 3948 to move to the ​ right side in. The movement of the projection 3948 causes the needle 3900 to rotate as a whole.

[0204] During each oscillatory translational movement of the needle 3900 in the injection direction, one step of the rotational movement of the needle 3900 as described above occurs. The rotational movement of the needle 3900 causes the needles 300 extending therefrom to perform a curvilinear translational movement during the oscillatory translational movement. The needles can include hollow and / or solid needles, needles all having the same length or needles having different lengths, conductive and / or non-conductive needles, and the conductive and / or non-conductive needles can be arranged in any desired pattern to meet the requirements of a specific type of injection, etc. The curvilinear translational movement is in a direction having a component perpendicular to the injection direction.

[0205] ​ Illustratively shows, on an enlarged scale, the effect of the curvilinear translational movement of the needles 300 caused by the rotation of the needle 3900 in the direction indicated by the dashed arrow during injection. In ​In the specific example shown, the needles 300 are arranged in an array of two rows of six needles. A sequence of five oscillatory translational movements of the needle tips 3900 in the direction of injection creates five different puncture patterns (numbered 1, 2, 3, 4, 5 in the indicated direction of rotation of the needle tips 3900) in the skin of the subject's arm 4500. Each puncture pattern occurs within a different part of the subject's skin. In fact, the number of different puncture patterns and / or the number of needles 300 in the needle array can be different from ​ as illustrated therein. The different puncture patterns can be more closely spaced and can even partially overlap.

[0206] Alternatively, a syringe including a suitably constructed mechanism can be used to cause the needles 300 to perform a linear translational movement. A possible example of such a suitably constructed mechanism is shown in the relevant part in ​ Therein. This alternative construction is based on a modified version of the needle tip 3900 and the rotary drive housing 4306, but other suitable constructions can be envisioned. ​ is a top view of the linear drive housing 4502, which has features 4504 and 4506 that are respectively similar to the material ring 4310 and the inwardly extending protrusion 4312 of the rotary drive housing 4306. These features are shown more clearly in the ​ cross-sectional side view, but for simplicity, the inclined surfaces of these features are not shown explicitly. It should be understood that the surfaces of the features 4504 and 4506 are similar to the Figures 45A to 45F surfaces of the material ring 4310 and the inwardly extending protrusion 4312 shown therein. Now referring to Figure 45H , a top view of the needle tip 4508 with an outwardly extending protrusion 4410 is shown, and the outwardly extending protrusion is functionally and structurally similar to the outwardly extending protrusion 3948 of the needle tip 3900.

[0207] is a partial cross-sectional view of Figure 45I which shows how the needle tip 4508 is mounted within the linear drive housing 4502. The outwardly extending protrusions 4410 formed along opposite sides of the needle tip 4508 are disposed within the corresponding spaces between the features 4504 and 4506 along the sides of the linear drive housing 4502.

[0208] Figures 45G to 45I The mechanism shown therein is essentially a straight version of the mechanism described above with reference to Figures 38 to 45E During injection, the needle tip 4508 performs an oscillatory translational movement along the injection direction of the injection device. As referred to Figures 45A to 45FAs described, but by using a mechanism with a straight configuration instead of a cylindrical configuration, as a result of the interaction between the inclined upper and lower surfaces of the protrusion 4410 (not illustrated), the inclined asymmetric lower surface of the feature 4504 (not illustrated), the inclined upper surface of the feature 4506 (not illustrated), and the offset between the loop of the feature 4504 and the inclined surface in the protrusion 4506 (not illustrated), the needle moves along a direction having a component perpendicular to the injection direction.

[0209] Figure 45J The effect of the linear translational movement of the needle 300 due to the movement of the needle 4508 in the direction indicated by the dashed arrow during injection is illustrated diagrammatically at an enlarged scale. In Figure 45J the specific example shown, the needles 300 are arranged in an array of two rows of six needles. A sequence of three oscillatory translational movements of the needle 4508 along the injection direction creates three different puncture patterns (numbered 1, 2, 3 along the indicated direction of movement of the needle 4508) in the skin of the subject's arm 4500. Each puncture pattern occurs within a different part of the subject's skin. In fact, the number of different puncture patterns and / or the number of needles 300 in the needle array can be different from those Figure 45J illustrated. The different puncture patterns can be more closely spaced and can even partially overlap.

[0210] It should be understood that the movement indicated by the dashed arrow in Figure 45F and Figure 45J occurs while the syringe remains fixed relative to the subject's skin 4500. Only the needle moves relative to the subject's skin 4500, resulting in, for example, a curvilinear translational movement of the needle 300 as shown in Figure 45F or a linear translational movement of the needle 300 as shown in Figure 45J .

[0211] Causing the needle 300 to undergo a certain type of translational movement during the oscillatory translational movement provides several advantages, including injecting the entire dose of injectable substance in a series of rapid injections of partial doses, where at least a portion of each partial dose is injected into a fresh area of the skin tissue rather than multiple injections into the same set of perforations. Since a larger area of the subject's skin is mechanically damaged when the needle undergoes translational movement during injection, it is expected that the body will mount a more robust immune response, thereby increasing the effectiveness of the injection.

[0212] Figure 46 is presented as showing a second exemplary autoinjector in a fully assembled state. Since the autoinjector includes a nested arrangement of individual elements, there is a significant amount of overlap in Figure 33 , which obscures the arrangement of the various elements. For better understanding, in Figure 33The regions denoted as A - B and B - C are indicated therein. Figure 34 Each of the components in the region A - B that are separated from each other is shown, thus avoiding overlap, such that each component can be seen more clearly. Similarly, Figure 35 Each of the components in the region B - C that are separated from each other is shown, thus avoiding overlap, such that each component can be seen more clearly.

[0213] 4. Injection Method

[0214] The above - mentioned auto - injector 100 is adapted to perform the injection of an injectable substance into the skin tissue of a mammalian subject. In particular, the injection can occur into a suitable injection site, such as the epidermal tissue and / or dermal tissue of the subject's skin, as discussed in more detail in section 3 above.

[0215] A method of providing an injection of an injectable substance to a mammalian subject can include all or only some of the following.

[0216] Extend the needle array from the housing 102 and penetrate the subject's skin to a known depth.

[0217] Oscillate the needle array along the length direction of the device.

[0218] Inject the injectable substance under pressure.

[0219] Send an electric current to the skin to trigger electroporation.

[0220] Move the needle array in a direction perpendicular to the length of the device between oscillations.

[0221] Retract the needle array into the housing 102 and cause a suction effect.

[0222] The auto - injector 100 can be fully prepared for administering an injection before being transported to the user who will perform the injection. In particular, the auto - injector 100 can be provided in a ready - to - trigger state, wherein the vial 176 contains the desired injectable substance pre - loaded within the housing 180 of the vial interface 156. Optionally, a protective end - cap or end - seal can be provided at the injectable end of the auto - injector 100.

[0223] As described above, the auto - injector 100 can be used to apply transmembrane electric - field pulses, which induce microscopic pathways (pores) in biological membranes, thus allowing the delivery of one or more antigens from one side of the cell membrane to the other side (electroporation). The method can include the steps of administering an antigen to the cells of the epidermal tissue, bringing the epidermal tissue into contact with the electrodes within the needle array (i.e., hollow and / or solid metal needles), and delivering an electroporation pulse to generate an immune response. The method can also include using the same needles of the needle array or a separate set of needles to simultaneously deliver the antigen to the cells and deliver an electroporation pulse to generate an immune response.

[0224] Now referring to Figure 49 , a simplified flowchart of a method of injecting an injectable substance into the skin tissue of a mammalian subject is shown. At step 3700, the injection end of a syringe (i.e., autoinjector 100) is placed in contact with an area of the subject's skin. The syringe houses a single dose of injectable substance having a dose volume. Optionally, a protective cap or seal (if present) is removed from the injection end of autoinjector 100 before being placed in contact with the subject's skin. In some embodiments, the protective cap may be saved and replaced before disposing of autoinjector 100 after injection. Optionally, the skin surface of the injection site is prepared, such as by wiping with an alcohol swab, before placing the injection end of the autoinjector in contact with the subject's skin. At step 3702, the autoinjection sequence of autoinjector 100 is triggered. In the specific non-limiting example described herein, triggering is performed by placing the foot 236 of the actuating leg 230 in contact with the subject's skin around the injection site and pressing downward so as to move the shaft 232 of the actuating leg 230 upward into the housing 100 and move the protrusion 234 out of its initial position within the corresponding notch 138 and into the trigger mechanism control slot 136. Once the autoinjector is triggered, injection occurs automatically in a timing controlled by the control cylinder 120. The injection sequence includes the following steps. At step 3704, the needle array of autoinjector 100 including a plurality of needles is moved along the injection direction and the subject's skin is pierced at a first plurality of positions. At step 3706, a first portion of the dose volume is injected into the subject's skin at the first plurality of positions. Optionally, an electric current is applied to the subject's skin during injection of the first portion of the dose to trigger electroporation. At step 3708, the plurality of needles are at least partially withdrawn from the subject's skin. At step 3710, the needle array including a plurality of needles is moved in a direction having a component perpendicular to the injection direction. At step 3712, the needle array is moved along the injection direction and the subject's skin is pierced at a second plurality of positions. At step 3714, a second portion of the dose volume is injected into the subject's skin at the second plurality of positions. Because the needle array moves in a direction having a component perpendicular to the injection direction between piercing the subject's skin at the first plurality of positions and the second plurality of positions, at least some of the second plurality of positions are different from at least some of the first plurality of positions. Accordingly, the first portion of the dose and the second portion of the dose are injected into different areas of the subject's skin. After the injection sequence is completed, the user optionally replaces the protective cap (if present) according to a prescribed procedure and discards autoinjector 100, such as by placing the autoinjector in a medical waste container.

[0225] 4. Antigen

[0226] The present invention also relates to a method of delivering at least one antigen using the MIDs 100, 200 having a plurality of electrode arrays 106, 108 as described above. The method may involve delivering two or more antigens or combinations thereof using heterogeneous delivery by the MIDs 100, 200. In certain embodiments, the MIDs 100, 200 described herein may be used to enhance antigen delivery. As used herein, "antigen" refers to any substance or organism that elicits an immune response.

[0227] Throughout the description and claims of this specification, the words "comprise", "comprising", "have" and "having" and variations of these words mean "including but not limited to", and are not intended to and do not exclude other components.

[0228] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in the specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0229] For the recitation of numerical ranges herein, all intermediate numbers therebetween having the same degree of precision are expressly contemplated. For example, for the range of 6-9, in addition to 6 and 9, the numbers 7 and 8 are also contemplated, and for the range of 6.0-7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are expressly contemplated.

[0230] It should be understood that variations may be made to the foregoing embodiments of the invention while still falling within the scope of the invention. Unless otherwise stated, each of the features disclosed in this specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless otherwise stated, each of the features disclosed is only one example of a series of general equivalent or similar features.

[0231] All features disclosed in this specification may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. In particular, the preferred features of the invention apply to all aspects of the invention and may be used in any combination. Similarly, features described in non-essential combinations may be used alone (not in combination).

Claims

1. A syringe for injecting an injectable substance into at least one of the epidermal tissue and dermal tissue of a subject's skin, the syringe comprising: A housing; A control member disposed within the housing; A needle configured to support a plurality of needles; A first device in communication with the control member and configured to be driven by the control member to convert the movement of the control member into movement of the needle along an injection direction and towards an injection position of the needle; And A second device configured to move the needle in a direction having a component perpendicular to the injection direction and without movement of the housing relative to the subject's skin.

2. The syringe according to claim 1, comprising a third device configured to produce an oscillatory movement of the needle along the injection direction.

3. The syringe according to claim 2, wherein The second device and the third device cooperate to cause the needle to move a movement increment in the direction having a component perpendicular to the injection direction during each oscillatory movement of the needle along the injection direction.

4. The syringe according to claim 3, further comprising a plurality of needles supported by the needle and forming a needle array having a predetermined arrangement, wherein, The movement in the direction having a component perpendicular to the injection direction causes one of a linear translational movement of the needles of the needle array and a curvilinear translational movement of the needles of the needle array.

5. The syringe according to claim 2, wherein, The third device includes a rotatable plate disposed in a stacked arrangement with a fixed plate, the fixed plate having a grooved surface facing the rotatable plate and defining a series of depressions and ridges, and the third device further includes a pair of spherical spacer elements held within openings formed in the rotatable plate, and wherein, when the rotatable plate rotates, each of the pair of spherical spacer elements is guided along the ridge between corresponding adjacent pairs of depressions such that the separation distance between the rotatable plate and the fixed plate varies in an oscillatory manner over time to produce the oscillatory movement of the needle along the injection direction.

6. The syringe according to claim 1, wherein, The second device includes: A plurality of first surfaces, each inclined relative to the injection direction and disposed at respective positions fixed relative to the housing; and A plurality of second surfaces, each inclined relative to the injection direction and facing a respective one of the plurality of first surfaces, the second surfaces being disposed at respective positions fixed relative to the needle array, Wherein, when the needle array moves along the injection direction, the second surfaces slide on the first surfaces, thereby causing the needle to rotate about a rotation axis and producing a movement of one increment of the needle in the direction having a component perpendicular to the injection direction.

7. The syringe according to claim 1, wherein, The control member is a rotatable control member including a control cylinder having a first control groove formed along its inner surface, and wherein the first device includes a follower plate including a protrusion seated within the first control groove, and wherein, during a rotational movement of the rotatable control member, the protrusion is guided along the first control groove, the first control groove including a portion having a component along the injection direction to convert the rotational movement of the rotatable control member into the movement of the needle array along the injection direction.

8. The syringe according to claim 7, comprising an energy source in communication with the first device to provide energy to rotate the rotatable control member.

9. The syringe according to claim 8, wherein, The energy source comprises: a torsion spring configured to store mechanical potential energy; and a flywheel for converting the mechanical potential energy released from the torsion spring into stored rotational kinetic energy.

10. The syringe according to claim 8, wherein, The energy source comprises: an electric motor; and a DC power source or an AC power source in electrical communication with the electric motor.

11. The syringe according to claim 1, comprising: a plurality of needles supported by the needle head and forming a needle array having a predetermined arrangement; a plunger assembly including a plunger and a cylinder, the cylinder containing a known volume of gas before injecting the injectable substance; and an interface for receiving a container containing the injectable substance, the interface being fluidly coupled to the cylinder via a first conduit, and the interface being fluidly coupled to the needle array via a second conduit, wherein the known volume of the gas is equal to the combined volume of the first conduit, the second conduit, the container received within the interface, and the dead volume of the needle array.

12. The syringe according to claim 11, wherein, The interface includes a housing bonded or shaped to receive only a correspondingly bonded or shaped container, and wherein the bonding or shaping is dedicated to a known injectable substance or a known group of injectable substances.

13. The syringe according to claim 1, comprising a plurality of needles supported by the needle and forming a needle array having a predetermined arrangement, wherein, The plurality of needles includes at least one hollow needle and at least one solid needle.

14. The syringe according to claim 13, wherein, The lengths of some of the needles in the needle array are different from the lengths of other needles in the needle array.

15. The syringe according to claim 13, comprising a current source that is in electrical communication with at least some of the needles of the needle array via a conductor so as to provide an electroporation current to at least one of the epidermal tissue and the dermal tissue of the subject during injection of the injectable substance, wherein, At least some of the needles are hollow needles or solid needles made of a conductive material.

16. The syringe according to claim 1, comprising a plurality of needles supported by the needle and forming a needle array having a predetermined arrangement, wherein, The plurality of needles includes at least one hollow needle and at least one solid needle, and the syringe further includes a current source in electrical communication with at least some of the plurality of needles via a conductor to provide an electroporation current to at least one of the epidermal tissue and the dermal tissue of the subject during injection of the injectable substance, wherein at least some of the needles are hollow needles or solid needles made of a conductive material.

17. The syringe according to claim 6, comprising: a plurality of needles supported by the needle head and forming a needle array having a predetermined arrangement; a plunger assembly including a plunger and a cylinder, the cylinder containing a known volume of gas before injecting the injectable substance; an interface for receiving a container containing the injectable substance, the interface being fluidly coupled to the cylinder via a first conduit, and the interface being fluidly coupled to the needles of the needle array via a second conduit, wherein the known volume of the gas is equal to the combined volume of the first conduit, the second conduit, the container received within the interface, and the dead volume of the needle array, wherein the plurality of needles includes at least one hollow needle and at least one solid needle, and the syringe further includes: a current source in electrical communication with at least some of the needles of the needle array via a conductor to provide an electroporation current to at least one of the epidermal tissue and the dermal tissue of the subject during injection of the injectable substance, wherein at least some of the needles are hollow needles or solid needles made of a conductive material, and Wherein, the control cylinder further includes a second control groove and a third control groove, which are respectively formed along the inner surface of the control cylinder, wherein the second control groove is connected to the plunger to control the movement of the plunger, and the third control groove is connected to the current source to control the actuation of the current source. Wherein, the shapes of the first control groove, the second control groove and the third control groove are configured to control the translational movement of the needle, the movement of the plunger and the actuation of the current source in a predetermined time sequence, so as to inject the injectable substance.

18. The syringe according to claim 1, wherein, The needle has a central cavity for receiving the injectable substance from a source of the injectable substance, and includes a removable cap configured to be sealingly mounted to the mounting head, the removable cap having a through hole formed in its end face, and each through hole is in fluid communication with a hollow needle among a plurality of hollow needles forming a needle array. Wherein, during use, the injectable substance is provided into the central cavity, and is extruded through the through hole and into the needle by fluid pressure to be injected into at least one of the epidermal tissue and the dermal tissue of the subject.

19. The syringe according to claim 18, wherein, The needle array further includes at least one solid needle made of a conductive material.

20. A method for injecting an injectable substance into at least one of the epidermal tissue and the dermal tissue of a subject using a syringe, the method comprising: Placing the injection end of the syringe in contact with a region of the skin of the subject, the syringe containing a single dose of the injectable substance having a dose volume; Triggering an automatic injection sequence of the syringe, wherein the automatic injection sequence includes: Moving a needle array including a plurality of needles along an injection direction and piercing the skin of the subject at a first plurality of positions; Injecting a first portion of the dose volume into the skin of the subject at the first plurality of positions; At least partially withdrawing the plurality of needles from the skin of the subject; Moving the needle array including the plurality of needles along a direction having a component perpendicular to the injection direction; Moving the needle array including the plurality of needles along the injection direction and piercing the skin of the subject at a second plurality of positions, at least some of the second plurality of positions being different from at least some of the first plurality of positions; and Injecting a second portion of the dose volume into the skin of the subject at the second plurality of positions, Wherein, the auto-injector is in contact with the same region of the skin of the subject during the execution of the entire automatic injection sequence, so that the entire dose volume of the injectable substance is injected without moving the auto-injector along the skin of the subject.

21. The method according to claim 20, comprising applying an electroporation current to at least one of the epidermal tissue and the dermal tissue of the subject during at least one of the injection of the first portion of the dose and the injection of the second portion of the dose. Use of a syringe according to any one of claims 1 to 19 for injecting an injectable substance into at least one of the epidermal tissue and dermal tissue of a subject.

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