Injection System and Usage Method

Abstract

The infusion system comprises an infusion barrel; a first sealing element and a second sealing element movably disposed in the infusion barrel; an infusion chamber between them; and a puncture element extending from the first sealing element to deliver an infusion agent from the infusion chamber to a biological space, wherein one or more of the infusion barrel, the first or second sealing element are configured to prevent proximal movement of the first sealing element past a predetermined position and, while the second sealing element comes into contact with the first sealing element, the system is configured to respond to the first sealing element when a force is applied distally to the second sealing element. When an opposing force is applied, the puncture element advances, and in response to the second opposing force, the puncture element remains stationary and the infusion agent is delivered through the puncture element.

Description

Technology Field

[0001] This application claims the benefit and priority of U.S. provisional application 63 / 052,518 filed July 16, 2020 and U.S. provisional application 62 / 903,406 filed September 20, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to a system and method for enabling injection into a cavity or into a cavity, particularly through tissue, into a cavity or cavity of the human body, such as the supracorbital space of ocular tissue. Background Technology

[0003] Posterior ocular diseases are a leading cause of permanent visual impairment affecting millions of people and can lead to blindness if left untreated. These include several diseases such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema (DME), choroidal (CHM), retinal vein occlusion (RVO), uveitis, and endophthalmitis. In many cases, medication can be used to prevent disease progression, but systemic delivery cannot achieve therapeutic concentrations in the posterior part due to the blood-ocular barrier. The problem to be solved

[0004] While local delivery via local, transscleral, and intravitreal routes can be effective, higher concentrations at the delivery site are required to maintain therapeutic levels in diseased retinal areas following vitreous diffusion. Although there are reports of intravitreal implants for continuous delivery, they can be significantly more invasive than intravitreal injection. Subretinal injection has also been performed to increase concentration in diseased retinal areas. However, subretinal injection requires a demanding and inconsistent technique that must be performed in a surgical setting, resulting in the risk of retinal detachment due to the occurrence of detachment and spotting. Furthermore, repeated administration via subretinal injection may not be feasible or desirable, as additional injections could cause further damage to the infected, fragile retina. Additional strategies to accelerate the movement of drug molecules into the retina, such as iontophoresis and magnetic fields, have been reported, adding another level of complexity to the overall drug delivery problem.

[0005] Recently, the supracranial space (SCS) has been explored as a potential drug delivery route to the posterior part of the eye. The supracranial space is the potential space between the sclera and the choroid. Drugs delivered through this space can travel to the posterior part of the eye by rotating around the eyeball. This route for drug delivery has been shown to be more effective for treating the posterior segment than intravitreal injection. However, the simplicity of intravitreal injection is more important than the surgical procedures previously required for supracranial delivery. Historically, supracranial delivery was achieved by making a small incision with a scalpel and then delivering the drug using a puncture element or cannula. More recently, predefined short-length micropuncture elements capable of penetrating only to a specific depth have been used to target the supracranial space. Since thickness varies significantly within patient populations, prior mapping of ocular geometry or trial and error is required when injecting hollow micropuncture elements. If the puncture element is too long, it can easily penetrate the thin supracranial space and deliver the drug into the vitreous humor. If it is too short, delivery occurs to the sclera. The sclera is 10 times harder than the choroid and 200 times harder than the retina, making it much more difficult to penetrate the sclera without injecting into the vitreous humor. In some cases, a small amount (about 100 microliters) of therapeutic agent must be injected into the supracorbital space, and it must be injected with sufficient force to displace the positive resistance of intraocular pressure compressing the choroid against the sclera. It can cover an extensive portion of the back of the eye.

[0006] Therefore, there is a need for improved systems and methods for supracorbital drug delivery that accurately, consistently, and safely target the supracorbital space and extensively cover the posterior portion of the eye. means of solving the problem

[0007] In some embodiments, the present invention comprises an injector barrel forming a lumen between a proximal end and a distal end; a first sealing element movably disposed within the lumen; a second sealing element movably disposed within the lumen adjacent to the first sealing element, the first sealing element and the second sealing element forming a seal with the lumen and forming an injection chamber between them; and a puncture element extending from the distal end of the first sealing element, and

[0008] The above-mentioned puncture element is in fluid communication with the infusion chamber to deliver the injectable agent from the infusion chamber into a space within the patient's tissue, and

[0009] One or more of the injector barrel, the first sealing element, and the second sealing element are configured to prevent proximal movement of the first sealing element passing through a predetermined position while allowing the second sealing element to contact the first sealing element, and

[0010] The system moves distally to advance the puncture element distally without delivering the injector through the puncture element when a force is applied to the second sealing element distally in response to the first opposing force, and

[0011] In response to the second opposing force, the first sealing element remains stationary and the injection agent is delivered from the injection chamber through the puncture element.

[0012] In some embodiments, the first counter-force is due to back pressure applied to the puncture element as the puncture element advances through the tissue; and the second counter-force is due to back pressure applied to the puncture element when the puncture element opens into the space of the tissue. In some embodiments, the force applied to the second sealing element is sufficient to advance the first sealing element but insufficient to deliver the injector through the puncture element in response to the first counter-force; and the force applied to the second sealing element is insufficient to advance the first sealing element but sufficient to deliver the injector through the puncture element in response to the second counter-force.

[0013] In some embodiments, a unidirectional stop is disposed in the injector barrel between the first sealing element and the second sealing element, and the unidirectional stop is configured to prevent proximal movement of the first sealing element passing through the unidirectional stop while allowing the second sealing element to pass through the mechanical stop and come into contact with the first sealing element. The unidirectional stop may include a section of the injector barrel having a reduced diameter, and the first sealing element has a diameter sufficiently larger than the reduced diameter so that the first sealing element cannot pass through the section, while the second sealing element is configured to pass through the section to come into contact with the first sealing element. In some embodiments, the unidirectional stop includes a portion of the inner surface of the injector barrel having a coefficient of friction sufficient to prevent proximal movement of the first sealing element. In some embodiments, the unidirectional stop includes a mechanical stop. In some embodiments, the unidirectional stop comprises a foldable stop positioned between a first sealing element and a second sealing element, said foldable stop is configured to prevent proximal movement of the first sealing element passing through the foldable stop and is configured to fold when a distal force is applied on the foldable stop to cause the second sealing element to pass through the foldable stop to contact the first sealing element. In some embodiments, the first sealing element has a frictional or sliding force on the first sealing element in the proximal direction that is greater than the frictional or sliding force on the first sealing element in the distal direction and inserts the puncture element into the tissue.

[0014] In some embodiments, in the relaxed state, the first sealing element has a size 1.01 to 2 times larger than the lumen size of the injector barrel. In some embodiments, in the relaxed state, the first sealing element has a size 1.01 to 1.10 times larger than the lumen size of the injector barrel. In some embodiments, in the relaxed state, the first sealing element has a size 1.01 to 1.4 times larger than the lumen size of the injector barrel. The inner surface of the injector barrel may be modified to increase friction between the inner surface of the injector barrel and the first sealing element. In some embodiments, a locking device is positioned on the circumference of the first sealing element and configured to optionally lock the first sealing element in place. The locking device may include a sealed compartment defined in the lumen of an injector barrel distal to a first sealing element, an incompressible material inside the compartment, and a valve for releasing the incompressible material from the compartment, such that when the valve is closed, distal movement of the first sealing element is prevented, and when the valve is opened, distal movement of the first sealing element is allowed.

[0015] In some embodiments, a touch trigger mechanism is positioned between a first sealing element and a second sealing element, and the touch trigger mechanism is configured to deploy when the first sealing element contacts the second sealing element to prevent distal movement of the first sealing element. In some embodiments, a filling port is positioned on the surface of an injector barrel and fluidly communicates with an injection chamber. In some embodiments, such a filling port comprises a receptacle positioned on the outer surface of an injector barrel and configured to receive a vial; a channel connecting the receptacle and the injection chamber; a self-sealing member configured to seal the channel; and a puncture element positioned in the receptacle, wherein the puncture element is configured to penetrate the self-sealing member to fluidly connect the vial received in the receptacle with the injection chamber. In some embodiments, the puncture element is movable relative to the receptacle, so that when a vial is received in the receptacle, the puncture element moves toward the injection chamber to penetrate the self-sealing member and fluidly connect the vial with the injection fluid. In the chamber, when the drug container is removed from the receptacle, the puncture element moves away from the injection chamber, thereby allowing the self-sealing member to seal the flow path.

[0016] In some embodiments, a support element is positioned around a distal portion of a puncture element, and the support element may move in relation to the puncture element and the injector barrel. The injection chamber may include a first chamber and a second chamber, wherein the chamber seal portion of the second sealing element fluidly isolates the first chamber from the second chamber, so that movement of the chamber seal portion fluidly connects the first and second chambers. In some embodiments, the injection chamber includes a first chamber and a second chamber, wherein the first chamber and the second chamber are fluidly isolated from each other when the second sealing element is in an initial position, and movement of the second sealing element fluidly connects the first and second chambers. In some embodiments, the second sealing element is coupled with the first sealing element and configured to pull the first sealing element and the puncture element into the injector barrel.

[0017] In some embodiments, the present invention provides a method for treating an ophthalmic disease, the method comprising: a step of pre-inserting a puncture element of an injection system into the sclera of a patient, wherein the injection system comprises:

[0018] Injector barrel forming a lumen between the proximal end and the distal end;

[0019] A first sealing element movably disposed within the lumen;

[0020] A second sealing element movably disposed within a lumen adjacent to the first sealing element, the first sealing element and the second sealing element form a seal with the lumen and form an injection chamber between them;

[0021] A puncture element extending from the distal end of a first sealing element, said puncture element fluidly communicating with an infusion chamber to deliver an infusion agent from the infusion chamber into a space within the patient's tissue; and comprising an infusion barrel,

[0022] The first sealing element and the second sealing element are configured to allow contact with the first sealing element while preventing proximal movement of the first sealing element passing through a predetermined position, while the second sealing element is configured to come into contact with the injector barrel;

[0023] A step of applying force to a second sealing element to advance a puncture element through the sclera, wherein the force is sufficient to move a first sealing element distally to advance the puncture element distally without delivering an injector through the puncture element; and

[0024] The step includes maintaining force on the second sliding element when the puncture element passes through the sclera and opens into the supraclavicular space (SCS) so that the injector is delivered from the injection chamber through the puncture element to the SCS without further distal movement of the first sealing element.

[0025] In some embodiments, the ophthalmic disease is age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, retinal vein occlusion (RVO), uveitis, endophthalmitis, Stargardt disease, Leber congenital amaurosis (LCA), retinitis pigmentosa, or choroidemia. In some embodiments, the infusion fluid comprises one or more infusion formulations comprising a viral delivery vector containing a gene of interest and a promoter selected to promote the gene of interest. The gene may be an anti-VEGFR2 gene, the delivery vector may be an AAV vector, and the promoter for the anti-VEGFR2 gene may be a CAG promoter. In some embodiments, the infusion fluid comprises one or more infusion formulations comprising an anti-VEGFR2 compound selected from the group consisting of bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandin, tryptophanyl-tRNA synthetase-derived polypeptide, IMPDH (inosine monophosphate dehydrogenase) inhibitor, and anti-PDGF for treating AMD; and a corticosteroid for treating uveitis, chorioretinitis, or other inflammatory eye diseases; a botulinum toxin for various ocular applications; and a tyrosine kinase inhibitor.

[0026] In some aspects, the present invention:

[0027] Injector barrel forming a lumen between the proximal end and the distal end;

[0028] A first sealing element movably disposed within the lumen;

[0029] A second sealing element movably disposed within a lumen adjacent to a first sealing element, the first sealing element and the second sealing element form a seal with the lumen and form an injection chamber between them;

[0030] A puncture element extending from the distal end of a first sealing element, said puncture element fluidly communicating with an infusion chamber to deliver an injectable agent from the infusion chamber to a space within the patient's tissue; and

[0031] A kit for injecting an injector into tissue, comprising an injector barrel, wherein one or more of the first sealing element and the second sealing element are configured to prevent proximal movement of the first sealing element passing through a predetermined position, while allowing the second sealing element to come into contact with the first sealing element, and

[0032] The above system is:

[0033] When a force is applied to the second sealing element in the distal direction in response to the first opposing force, the first sealing element moves distally to advance the puncture element distally without delivering the injector through the puncture element, and,

[0034] In response to a second opposing force, the first sealing element is configured to remain in a stationary state and the injection agent is transferred from the injection chamber through the puncture element; and

[0035] It includes the volume of an infusion solution containing one or more infusion preparations.

[0036] In some embodiments, the ophthalmic disease is age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, retinal vein occlusion (RVO), uveitis, endophthalmitis, Stargardt disease, Leber congenital amaurosis (LCA), retinitis pigmentosa, or choroidemia. In some embodiments, the infusion fluid comprises one or more infusion formulations comprising a viral delivery vector containing the gene of interest and a promoter selected to promote the gene of interest.

[0037] The gene of interest may be the anti-VEGFR2 gene, the delivery vector may be an AAV vector, and the promoter for the anti-VEGFR2 gene may be a CAG promoter.

[0038] In some embodiments,

[0039] The infusion fluid comprises one or more infusion formulations comprising an anti-VEGFR2 compound selected from the group consisting of bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandin, tryptophanyl-tRNA synthetase-derived polypeptide, inosine monophosphate dehydrogenase (IMPDH) inhibitor, and anti-PDGF for treating AMD, and a corticosteroid for treating uveitis, chorioretinitis, or other inflammatory eye diseases; botulinum toxin for various ocular applications; and a tyrosine kinase inhibitor. Effects of the invention

[0040] The present invention is further described in the following detailed description with reference to a plurality of drawings mentioned as non-limiting examples of exemplary embodiments, wherein similar reference numbers indicate similar parts across several drawings. Brief explanation of the drawing

[0041] FIG. 1a is an embodiment of the injection system of the present invention; FIG. 1b is various embodiments of a puncture element suitable for use in connection with the injection system of the present invention; FIG. 2 is an exemplary method of use of an embodiment of the injection system of the present invention; FIG. 3 is an embodiment of the injection system of the present invention having a unidirectional stop; FIG. 4 is an exemplary method of use of an embodiment of the injection system of the present invention having a unidirectional stop; FIG. 5a and FIG. 5b are embodiments of the injection system of the present invention in which the diameter of the injector barrel is reduced; FIG. 6a and FIG. 6b are embodiments of the injection system of the present invention in which a sealing element is molded to have asymmetric frictional force; FIG. 7a to FIG. 7c are embodiments of the injection system of the present invention having a foldable unidirectional stop; FIG. 7d and FIG. 7e are various embodiments of a foldable unidirectional stop suitable for use in the injection system of the present invention; FIG. 8a to FIG. 8d are exemplary processes for manufacturing an injection system having a foldable unidirectional stop; FIG. 9a and FIG. 9b are various embodiments of the distal end of the injection system of the present invention having a needle support; FIG. 10a and FIG. 10b are needle supports Various embodiments of the distal end of the injection system of the present invention having; FIGS. 11a to 11c are various embodiments of a safety cap suitable for use with the injection system of the present invention; FIGS. 12a to 12e are embodiments of the injection system of the present invention pre-filled with a multi-component injection agent; FIG. 13 is a graph of the injection fluid viscosity as a function of the inner diameter of the puncture element in the injection system of the present invention; FIG. 14 is an embodiment of the injection system of the present invention having an extra-large sealing element; FIGS. 15a to 15e are embodiments of the injection system of the present invention having a locking device for the sealing element; FIG. 16 is an embodiment of the injection system of the present invention having an access port at the distal end; FIGS. 17a and 17b are embodiments of the injection system of the present invention having a touch trigger mechanism between the sealing elements; FIG. 18 is an embodiment of the injection system of the present invention having a rapid charging port; FIGS. 19a to 19d are exemplary processes for charging the injection system of the present invention through the rapid charging port.FIGS. 20a to 20c are exemplary processes for reverse charging the injection system of the present invention; FIGS. 21a and 21b are exemplary processes for charging the injection system of the present invention through a port at the proximal end; FIGS. 22a to 22c are exemplary processes for charging the injection system of the present invention through a port sealed with a self-sealing polymer; FIGS. 23a to 23d are embodiments of the injection system of the present invention having a port at the distal end; and FIGS. 24a to 24e are embodiments of the injection system of the present invention configured for safe disposal. Specific details for implementing the invention

[0042] The drawings described above illustrate the embodiments currently disclosed, but other embodiments are also considered as mentioned in the discussion. The present invention presents exemplary embodiments in a manner of expression rather than limitation. A multitude of other modifications and embodiments may be devised by those skilled in the art within the scope and spirit of the principles of the embodiments currently disclosed.

[0043] Therefore, there is a need for improved systems and methods for injecting agents into biological spaces, existing or potential (e.g., supracorbital spaces), that accurately, consistently, and safely target such spaces and provide extensive coverage of adjacent structures or organs. For example, the injection system of the present invention can be used for drug delivery into the supracorbital space to provide extensive coverage of the posterior portion of the eye. The injection system currently disclosed is configured such that the puncture element automatically stops at the boundary of the target space, thereby limiting the depth to which the needle penetrates the cavity. Accordingly, the injection system of the present invention can be configured to self-regulate the penetration depth of the puncture element into the target space. The injection system of the present invention can be used to penetrate tissue (e.g., sclera) and deliver an injector into a biological space (e.g., supracorbital space), while self-regulating the penetration depth into the biological space and the injection site based on the resistance the system encounters at various stages of the delivery cycle. In some embodiments, the precision and miniaturization of the injection system of the present invention enable the puncture element to accurately target and stop thin potential cavities, such as the supracorbital space, and allow for the accurate delivery of an accurate volume of injector with extensive coverage. In some embodiments, the volume may be sub-milliliter. In some embodiments, the infusion system of the present invention is configured to deliver a therapeutic agent to a target space with microliter accuracy.

[0044] The following description of the injection system of the present invention and methods of using them is merely illustrative and is not intended to limit the scope, applicability, or configuration of the present invention. Rather, the following description of illustrative embodiments will provide those skilled in the art with possible descriptions for implementing one or more illustrative embodiments. It will be understood that various changes may be made to the function and arrangement of elements without departing from the spirit and scope of the embodiments currently disclosed.

[0045] The subject matter will now be more fully explained with reference to the accompanying drawings, which form part of the present invention and illustrate specific exemplary aspects and embodiments of the invention as examples. However, the subject matter may be embodied in various different forms, and thus the subject matter covered or claimed is not intended to be interpreted as being limited to any exemplary embodiments described herein. Exemplary embodiments are provided merely for illustrative purposes. Accordingly, the following detailed description is not intended to be taken in a limiting sense.

[0046] Referring to FIG. 1, the infusion system of the present invention may include an infusion barrel (102) having a proximal end (104) and a distal end (106) and forming a lumen (108) between the proximal end (104) and the distal end (106). The infusion system further includes a first sealing element (110) and a second sealing element (112) slidably disposed within the lumen (108) of the infusion barrel (102). As illustrated in FIG. 1, in an initial state, the first sealing element (110) and the second sealing element (112) are spaced apart from each other, and the space between the sealing elements within the infusion barrel defines an infusion chamber (114) for holding an appropriate volume of infusion agent within. As used herein, the term “infusion agent” refers to a composition comprising a single substance or a combination of substances that can be injected into a space or potential space of tissue. The infusion agent may be provided as a fluid, liquid, gas, suspension, solution, emulsion, or other fluid composition. In some embodiments, the infusion agent may comprise one or more therapeutic substances or preparations, including but not limited to small molecule compounds, antibodies, nucleic acid molecules, polypeptides, as well as compounds that assist in the delivery of the aforementioned substances to a patient, such as viruses or vectors for nucleic acid delivery. In some embodiments, a standard infusion barrel having a volume of 10 µl to 50 ml may be used. In some embodiments, the infusion chamber may have a volume of about 0.025 ml to 20 ml, but larger or smaller infusion barrels may also be used. In some embodiments, the infusion chamber may have a volume of approximately 0.025 ml, 0.05 ml, 0.1 ml, 0.5 ml, 1 ml, 3 ml, 5 ml, or 10 ml before the displacement of the infusion agent.

[0047] The sealing elements (110, 112) can be tightly fitted into the injector barrel (102) and form a seal with the wall of the injector barrel (102) to prevent the injection material from leaking out of the injection chamber (114). In some embodiments, the second sealing element may slide or move relative to the injector barrel by being screwed in. Thus, in some embodiments, the device disclosed herein does not require feedback (e.g., tactile) by an operator. In some embodiments, the sealing element frictionally interacts with the wall of the injector barrel as the sealing element slides along the lumen of the injector barrel. In some embodiments, the size and shape of the sealing element may be modified to change the frictional force between the sealing element and the injector barrel. In some embodiments, the sealing element may be made of a natural or synthetic polymer, such as, for example, natural or synthetic rubber or an elastomer material.

[0048] In some embodiments, the puncture element (116) extends from the distal end of the first seal element, and the lumen of the puncture element is in fluid communication with the injection chamber to deliver the injection agent from the injection chamber to the target injection space. The puncture element may be protected by a safety cap (118) during storage, transport, and handling of the injection system. During operation, as described in more detail below, a force may be applied to the second seal element in a distal or forward direction using a push rod (120). This force causes the second seal element to move forward, pressurizes the injection agent, and applies a forward force to the first seal element. Depending on the proximal force (back pressure or counter-force) on the puncture element, the first seal element may move distally to advance the puncture element distally without delivering the injection agent through the puncture element, or the first seal element may remain fixed and the injection agent delivered from the injection chamber through the puncture element. Thus, for ease of understanding, the first seal element may be referred to as a floating seal element and the second seal element as a pushing seal element.

[0049] The term "puncture element" refers to a device that can be used to penetrate tissue and deliver an injector to a space or potential space within the tissue. In some embodiments, the puncture element may be a generally extended device having a pointed distal end that can be used to puncture and penetrate tissue. The puncture element may have any number of suitable dimensions and / or geometric shapes. For example, the puncture element may have a circular or non-circular cross-section. In some embodiments, the puncture element may have one or more lumens for delivering an injector to a target space or potential space within the tissue, and each of the one or more lumens has one or more openings distal to or along the side of the lumen.

[0050] FIG. 1b illustrates various embodiments of puncture elements that can be used in connection with the injection system of the present invention. In some embodiments, the puncture element has a variable diameter to improve the delivery of viscous agents while maintaining a portion of the puncture element inserted into the eye with a small diameter (e.g., 30G, 27G). In some embodiments, the puncture element tip bevel geometry is designed to minimize insertion force and bevel by modifying the cutting edge bevel, the number of bevels, the angle of bevel, and the insertion force. Puncture element tip shapes include, but are not limited to, bevel tips, lancet points, back bevel tips, and curved tips. Puncture elements with low insertion force are generally easier to guide and have less deflection.

[0051] In some embodiments, the puncture element includes a standard needle between 34G and 25G. In some embodiments, the puncture element may be a standard 30G needle. In some embodiments, the puncture element may be 25 gauge or larger, 27 gauge or larger, or 30 gauge or larger. In some embodiments, the needle has a secondary slope to reduce cutting force. However, various puncture element sizes and shapes may be used in connection with the injection system of the present invention. In some embodiments, a puncture element having a larger lumen may be used, particularly for higher viscosity formulations. Various sizes, shapes, and geometries may be used depending on the desired results and operating parameters (e.g., viscosity of the injection agent, density of the tissue into which the puncture element is inserted, desired flow rate of the injection agent, and desired parameters).

[0052] The puncture element can be connected to the floating seal element using various techniques. In some embodiments, the puncture element is inserted into the floating seal element and secured with a waterproof adhesive. In some embodiments, the floating seal element can be molded around the puncture element. In some embodiments, a puncture element having threads on its outer surface can be screwed into the floating seal element.

[0053] Referring to FIG. 2, the injection system of the present invention may be used to advance a puncture element through a first region (211) and to inject an injector into a second region (212) that generates a smaller opposing force against the injection than the first region. In some embodiments, less force may be required to inject the injector into the second region than into the first region. In some embodiments, the density of the first region may be higher than the density of the second region, so that it may be easier to inject the injector into the second region than into the first region. In some embodiments, the first region applies a higher back pressure to the puncture element than the second region, so that the opposing force or resistance to the flow of the injector into the first region is greater than that of the second region.

[0054] Referring to FIG. 2, an embodiment of the injection system is shown in an initial position at step 201. The injection system contains an injection agent in an injection chamber (114), and a puncture element is exposed and extends slightly beyond the distal tip (106) of the injector barrel. At step 202, the puncture element is pre-inserted into a first region (tissue, e.g., the sclera of the eye). During pre-insertion, the tip of the puncture element is inserted into the first region of tissue (e.g., the sclera) such that at least the lumen of the puncture element is buried or blocked by contact. In some embodiments, this step may be achieved manually by penetrating the sclera with the exposed length of the puncture element. In some embodiments, the need to be able to pre-insert the puncture element into the first region may set limits on the range of lumen diameter and slope size of the puncture element that can be effectively used to target the SCS. For example, the density of the first region may be a factor when selecting a suitable puncture element. In some embodiments, the puncture element may be inserted tangentially into the sclera with a puncture element tip pointing toward the posterior part of the eye. When the puncture element is inserted into a first region beforehand, the lumen of the puncture element is blocked so that the injector can be delivered through the puncture element.

[0055] In some embodiments, with minimum human sclera thickness in mind, when the puncture element is inserted perpendicularly to the sclera surface, optimal results can be obtained by limiting the pre-insertion depth to about 0.5 mm or less (e.g., about 0.05 mm to 0.5 mm). When the puncture element is pre-inserted at an angle other than perpendicular, the puncture element can be sufficiently inserted with a longer bevel without penetrating the sclera. In some embodiments, the puncture element may have a bevel length of less than 2 mm, less than 1 mm, or less than 0.5 mm. The bevel angle may be 15 degrees or more, 30 degrees or more, or 45 degrees or more. For example, a 30-gauge hole element with a standard bevel (angle: 12 degrees, length: 1.45 mm) inserted at an angle of about 20º or less relative to the surface according to geometric correlation reaches a depth of less than 0.5 mm when measured normally from the surface. Similarly, larger puncture elements with longer bevel lengths may also be used. A shorter bevel allows for a wider range of pre-insertion angles for a given puncture element size. Roughly speaking, a puncture element with an outer diameter smaller than a scleral thickness of about 0.5 mm can easily access the SCS, and the insertion angle of the puncture element is determined based on the beveled tip length.

[0056] In step 203, a force is applied distally to the pushing seal element, causing the pushing seal element to advance distally. In some embodiments, the pushing seal element advances by sliding motion or rotational motion (e.g., screw). The movement of the pushing seal element applies force to the injection element and the floating seal element, which pressurize the injection element distally. In the first region, the frictional force between the floating seal element and the injector barrel is less than the force required to inject the injection element into the first region. Thus, in the first region, the force applied to the pushing seal element is sufficient to overcome the frictional force between the floating seal elements, but insufficient to inject the injection element into the first region. Therefore, in step 203, the force applied to the pushing seal element causes the flow seal element and the consequent puncture element to advance further distally into the first region without transporting the injection element from the injection chamber.

[0057] In step 204, the puncture element reaches the interface between the first region and the second region, causing the lumen of the puncture element to partially or completely open to the second region, thereby fluidically connecting the second region to the injection chamber. The force opposing the flow of the injection agent into the second region is smaller than the force in the first region. Therefore, the force required to inject the injection agent into the second region is smaller than the frictional force between the floating seal element and the injector barrel. In this way, when the lumen of the puncture element approaches the second region, the floating seal element automatically stops, limiting the depth to which the puncture element penetrates the cavity.

[0058] In step 205, because the force required to inject the injector into the second region is less than the frictional force against the floating seal element, the force against the pushing seal element causes the injector to be injected into the second region, and the floating seal element remains in a fixed state. The puncture element no longer penetrates into the second region but essentially maintains its position at the interface between the first and second regions. In some embodiments, the vector of the fluid flow is parallel to the supracranial space to provide a wide coverage of the posterior part of the eye instead of the fluid force used to radially displace the choroidal and retinal tissues.

[0059] As a non-limiting example, the back pressure or counter-force experienced by the pushing seal element is a function of the pushing seal element speed and the puncture element size. In some embodiments, such force may range from 2 to 100 N. In some embodiments, such force may range from 2 to 50 N. As a non-limiting example, for a 30 G puncture element, 1 ml injector, if the pushing seal element is pushed at 0.5 mm / s, the force experienced by the pushing seal element to inject into the sclera is approximately 5-20 N. Injection in the SCS is closer to field injection between 0 and 2 N for the same set of parameters.

[0060] In some embodiments, the force applied to the first sealing element may be greater than 2N in the first region (depending on the injector barrel ID / puncture element ID ratio) and less than 1N in the second region. Thus, the maximum force that can be applied to move the puncture element distally without releasing the injection fluid is greater than 2N in the first region (e.g., sclera) and less than 1N in the second region (e.g., SCS). It should be noted that in the first region, the force applied to the second sealing element is less than the force required to inject the injection fluid into the first region. In some embodiments, as the injection agent exits the puncture element, force is applied to the puncture element and the first sealing element, which increases to a higher flow rate. When the flow rate increases above a critical value, the puncture element is pushed forward. To prevent movement of the puncture element, the maximum critical flow rate may be increased by increasing friction against the first sealing element. As described below, the present invention also provides other means for preventing distally moving the first sealing element and the puncture element once the second region is reached. Additional non-limiting examples of permissible forces and flow rates are disclosed in Nat Biomed Eng. August 3, 2019 (8): 621-631, the full contents of which are incorporated herein by reference.

[0061] Referring again to FIG. 2, once the puncture element reaches the boundary between the first and second regions, the opposing force against the injector decreases, so that as the operator continues to push the pushing seal element, the injector in the injection chamber is delivered to the next region. In the second region, the puncture element maintains its position at the boundary between the first and second regions. The floating seal element can travel the entire length of the injector (i.e., a millimeter distance), but can stop with micron-level precision when the puncture element reaches the boundary between regions. This allows the therapeutic agent to be targeted and delivered primarily, and in some cases, only to thin "cavity" sections of the anatomical structure, rather than to "tissue" sections of the anatomical structure as illustrated in FIG. 2. In some embodiments, the injection system of the present invention is configured such that when the lumen of the puncture element opens into the second region, the floating seal element and the puncture element can stop within a length of 250 microns, 200 microns, 150 microns, 100 microns, 50 microns, and 25 microns when entering the second region.

[0062] In some embodiments, the puncture element may be moved in a first region at a constant speed so that quasi-static equilibrium can be assumed, indicating that forward and backward forces are balanced. When the needle enters the second region (cavity / space), the backward force is immediately reduced. Therefore, the stopping distance can be directly related to the deceleration of the puncture element and its original moving speed. Generally, the moving speed is low (0.1 mm / s to 10 mm / s depending on the diameter of the puncture element). The deceleration is a function of the forward force (driving force or pushing force) applied to the sealing element and the puncture element, and the backward force applied by friction between the seal and the barrel. Assuming that friction remains relatively constant for a given design, the deceleration depends on the driving force related to the shape of the puncture element and the fluid viscosity. When injection is complete, the pushing sealing element comes into direct contact with the floating sealing element. This can cause the puncture element to move forward, which is a safety issue. The present invention provides various safety features that ensure the pushing sealing element maintains its position even when in contact with the floating sealing element once the puncture element has stopped as described above.

[0063] In some embodiments, the first region may correspond to the patient's tissue, and the second region may correspond to a space or potential space within or adjacent to the tissue. In other words, the infusion system (100) of the present invention may be used to advance a puncture element (116) through the patient's tissue (e.g., the sclera of the eye) and inject an infusion agent into an adjacent space or potential space of tissue (e.g., supracorbital space or anterior intra-tissue space). The term "space" includes actual space or cavity or potential space of tissue. A potential space refers to a space that collapses under normal physiological conditions (e.g., a state where multiple tissues are in contact with each other) but is likely to expand when forced open (e.g., in response to fluid infusion). For example, the supracorbital space (SCS) is a potential space between the choroid and the sclera that spans the posterior periphery of the eye. In some embodiments, the infusion system of the present invention may deliver drugs and gene therapies that benefit from localization into the SCS, including treating diseases and disorders of the choroid and retina. Various embodiments are disclosed herein to enhance the ability of an infusion system to target the SCS and deliver an agent of interest to posterior ocular tissues (e.g., retina, retinal pigment epithelium, Bruch's membrane, choroid). Successful infusion penetrating the sclera to accurately and consistently target the SCS can deliver various types of therapeutic agents to the choroid. Between the SCS and the retinal pigment epithelium lies the Bruch's membrane, which acts as a diffusion barrier for agents reaching the retina through the SCS. Moore et al. (2001) reported that the permeability of Bruch's membranes isolated from human donated eyes in vitro decreased with age. Bruch's membranes from young donors showed permeability to proteins greater than 200 kDa, whereas those from older donors showed reduced permeability. Bruch's membranes from older donors continued to show permeability to proteins greater than 100 kDa.However, while the present invention describes an infusion system in relation to drug delivery into the SCS cavity, the currently disclosed system and method may be used to deliver the infusion agent to other cavities or chambers of the human body or to other application sites outside the human body. For example, the infusion system of the present invention may be used to inject into the pericardium, the pleural cavity (the potential space between the two pleura of the lungs (visceral parietal cavity)), the synovial cavity between joints, the space between scar tissue and implants (e.g., scar tissue around a breast implant to treat capsular contracture), airway access, vascular access, and similar biological or potential spaces.

[0064] In some embodiments, it may be desirable to prevent proximal movement of the floating seal element during the initial insertion of the puncture element into the tissue. In particular, the injector barrel, the pushing seal element, and the floating seal element of the infusion system may be configured individually or in combination to prevent posterior (proximal) movement of the floating seal element over a predetermined position. In some embodiments, the infusion system of the present invention may be used to deliver an infusion agent that is expensive and needs to be administered in an accurate dose. In some embodiments, such a dose may be within 10% of the labeled volume. Accordingly, in some embodiments, the infusion system may include one or more features to ensure that the entire or substantially entire volume of the infusion agent is administered to the patient. In some embodiments, these two features are combined. In some embodiments, the injector barrel, the pushing seal element, and the floating seal element of the infusion system may be configured individually or in combination to avoid posterior (proximal) movement of the floating seal element over a predetermined position while the pushing seal element contacts the floating seal element to minimize or eliminate the volume between the seal elements. In some embodiments, this design can ensure that all or substantially all of the therapeutic payload is delivered to the patient.

[0065] Referring to FIG. 3, in some embodiments, the infusion system of the present invention may include a one-way stop (210) configured to prevent backward movement of a floating seal element, for example, while pre-inserting a puncture element into tissue. In some embodiments, the one-way stop (210) is positioned and configured so that pre-insertion of the puncture element is achieved without the floating seal element moving backward and causing a loss of more than 10% of the therapeutic agent infusion volume.

[0066] In some embodiments, a unidirectional stop may prevent the pushing seal element from moving past the stop. In some embodiments, the unidirectional stop may also be configured to allow the pushing seal element to pass through unimpeded. In this way, at the end of the injection, the gap between the pushing seal element and the floating seal element is reduced or eliminated so that the entire therapeutic fluid payload can be injected into the cavity and the dead volume can be reduced or eliminated. In some embodiments, the distal side of the pushing seal element is allowed to substantially contact or come into contact with the proximal side of the floating seal element so that a minimum dead volume exists between the seal elements. In some embodiments, another unidirectional stop may also be provided proximal to the pushing seal element to prevent proximal movement of the pushing seal past a desired point.

[0067] In some embodiments, a unidirectional stop (210) may be provided directly (i.e., behind) the floating seal element. In this way, after initial setup, the floating seal element is prevented from moving proximally past the unidirectional stop. In some embodiments, at initial setup, the tip of the puncture element is exposed sufficiently to allow blockage of the lumen when the puncture element is pre-inserted into the tissue, depending on the bevel angle. This length may vary depending on the size and angle of inclination of the puncture element. In some embodiments, at initial setup, the tip of the puncture element is exposed by 0.2 mm to 2 mm. In some embodiments, about 0.5 mm of the puncture element is exposed when the floating seal element is at initial setup. In some embodiments, the tip of the puncture element may be exposed more than the length of the sclera, so that the puncture element can be inserted into the sclera at an angle rather than perpendicular to the surface.

[0068] The operation of an injection system with a unidirectional stop is illustrated in FIG. 1. The injection system of the present invention having a unidirectional stop (210) operates essentially the same as described in relation to FIG. 4. The unidirectional stop (210) can ensure that the floating seal element (110) is not pushed back when the puncture element is first inserted into the tissue. On the other hand, the unidirectional stop (210) is designed so that the pushing seal element (112) can pass through the unidirectional stop to contact the floating seal element at the end of the injection. In this way, all or substantially all of the injection agent can be delivered into the target space.

[0069] Referring to FIGS. 5a and 5b, in some embodiments, the infusion system (100) of the present invention includes a diameter reduction section (310) of the infusion barrel at one or more locations. In some embodiments, the reduction section (310) may be provided near the floating seal element (110) as a one-way stop. In some embodiments, the inner diameter of the infusion barrel may be reduced to create a one-way stop at a predetermined location between the pushing seal element and the floating seal element. In some embodiments, the reduction in diameter provides sufficient resistance to back pressure while pre-inserting the puncture element in question to prevent backward movement by the floating seal element. However, the reduced inner diameter is sufficiently large and / or the pushing seal element is configured so that the pushing seal element can pass through the area relatively easily to meet the floating seal element, thereby allowing the user to fully dispense the treatment fluid, which reduces both dead volume and infusion volume variability. For example, the pushing seal element may be made of a softer material than the floating seal element so that the pushing seal element can be compressed by the reduction in the diameter of the injector barrel. In some embodiments, additionally or optionally, the diameter of the injector barrel proximal to the pushing seal element may be reduced.

[0070] In some embodiments, the diameter of the injector barrel may be reduced, for example, by crimping or pinching the injector barrel at a desired location close to the floating seal element. In some embodiments, the injector may be formed to include a mechanical stop inside the lumen of the injector barrel, thereby reducing the diameter at that location. In some embodiments, the inner diameter of the injector barrel may be reduced by modifying the inner surface of the injector barrel, for example, by including one or more protrusions, ridges, or flanges on the inner surface of the injector barrel. In some embodiments, the injector barrel may have a variable diameter along its length, a larger diameter to accommodate the floating seal element in the distal section, and a smaller diameter close to the floating seal element to prevent the floating seal element from moving too far backward.

[0071] Referring to FIGS. 6a and 6b, in some embodiments of the injection system of the present invention, a unidirectional stop may be provided by modifying the floating seal element (110) to have a shape that causes asymmetric sliding movement acting on the floating seal element (110) while the floating seal element (110) is operating. For example, due to such a shape modification, the floating seal element may experience much higher friction when moving in the proximal direction than when moving in the distal direction. In this way, the floating seal element can easily move in the distal direction from its initial position, but movement in the proximal position can be prevented. On the other hand, the pushing seal element can move freely toward and over the floating seal element without any obstacles or impediments. In some embodiments, the design of the floating seal element is unique in that it allows only unidirectional movement compared to the bidirectional movement of a conventional injector plunger. In some embodiments, as shown in FIG. 6a, the floating seal element includes a series of special ridges having a steeper angle toward the rear of the floating seal element than the angle toward the front part of the pushing seal element. For example, the floating seal element may include one or more cone truncates or barbs oriented in the distal direction. Such a design may facilitate forward movement of the floating seal element relative to backward movement. In some embodiments, the interior of the injector barrel includes barbs inclined toward the proximal direction. In some embodiments, the interior of the injector barrel may include ribs, ridges, toroidal shapes, or similar shapes that are angled toward the proximal direction or are flat. In some embodiments, similar modifications may be made in the injector barrel adjacent to the propulsion seal element and / or the propulsion floating element.

[0072] In some embodiments, the frictional force between the floating seal element and the inner surface of the injector barrel can be adjusted (increased or decreased) by the choice of material (e.g., polytetrafluoroethylene, polyethylene, polypropylene, thermoplastic elastomer, fluoroelastomer—all can be siliconeized or non-silicified), the number of angled ribs to handle the viscosity of the formulation, or the thickness of the ribs. In some embodiments, the frictional force on the floating seal element can be reduced by using a polytetrafluoroethylene surface.

[0073] Referring to FIGS. 7a, 7b, and 7c, in some embodiments, the unidirectional stop may include a foldable unidirectional stop (410) positioned within an injector barrel (102). The injector barrel creates a unidirectional stop that allows the foldable stop to be folded downward during injection dispensing, thereby allowing the pushing seal element to advance past the foldable stop, while preventing the floating seal element from moving backward during pre-insertion. In some embodiments, the foldable unidirectional stop may be provided as an insert for the injector barrel. Referring to FIGS. 7d ​​and 7e, such a foldable stop (410) may include a body (412) having one or more foldable gates (414) that can be folded only by the application of a force in the distal direction. In some embodiments, the floating seal element may be positioned relative to the foldable stop. During the insertion of the puncture element, the floating seal element may be pushed backward in the proximal direction but is held in place by the foldable stop device. In some embodiments, the floating seal element is rigidly connected to the folding stop, so that minimal compliance exists when the floating seal element is pushed backward by the insertion force. However, during the administration of the injector, when the pushing seal element reaches the folding stop, the releasing seal element applies force to the gate distally to cause the gate to fold and allow the pushing seal element to pass through the folding stop toward the floating seal element. In some embodiments, the insert with the folding stop can be demonstrated in the injector barrel.

[0074] FIGS. 8a through 8d provide an exemplary process for manufacturing an injector including a unidirectional folding stop. For example, FIG. 8a shows a hollow tube of a size that fits snugly inside a selected injector. A strategic non-peripheral cut is made to create a folding gate as illustrated in FIG. 8b. This flap is then formed into a desired shape as illustrated in FIG. 8c. The structure can be inserted into the injector barrel as illustrated in FIG. 8d. The structure can be bonded, welded, or mechanically fixed to the injector barrel if necessary.

[0075] In addition to or optionally regarding the unidirectional stop and / or change in frictional force between the floating seal element and the injector barrel, in some embodiments, the contents of the injector barrel (e.g., the injector in the injection chamber) apply pressure before the puncture element is pre-inserted into the tissue to prevent proximal movement of the floating seal element during the pre-insertion phase. In some embodiments, the user may apply pressure to the pushing seal element, but preferably not to a pressure sufficient to move the floating seal element. In some embodiments, the pushing rod may be temporarily locked in place (e.g., using a linear actuator) to fix the position of the pushing seal element so as not to move the floating seal element during the pre-insertion phase. In some embodiments, the puncture element may be provided with a plug to prevent leakage when the injector barrel is pressurized. Such a plug may allow the puncture element to move when the pushing seal element is pressed until the plug contacts the tissue. In some embodiments, the plug may be configured so that the puncture element penetrates through the plug for pre-insertion into the tissue, while the plug contacts the tissue with sufficient force to form a fluid-tight seal with the tissue. In some embodiments, the plug is made of a material that can be punctured by a puncture element and creates a seal with the tissue surrounding the pre-insertion site.

[0076] In some embodiments, the injection system of the present invention is designed such that the frictional resistance / force between the injector barrel and the pushing seal element, the floating seal element, or both may be greater than the insertion force required to penetrate into the sclera. In some embodiments, the frictional resistance may be increased by modifying the inner surface of the injector barrel, modifying the size or shape of the seal element, or by using a material having higher friction, as described elsewhere in this application in relation to the embodiment for the high-viscosity injection agent illustrated in FIG. 14, for example. In this way, the puncture element may be pre-inserted into the tissue (sclera) without a floating seal element moving backward. In some embodiments, the frictional resistance of the floating seal element may be higher than the force required to inject the cavity for a specific formulation viscosity, injector barrel inner diameter, and puncture element inner diameter, so that the floating seal element may automatically stop at 100°C. In the cavity, the puncture element does not advance further even when the pushing seal element is pressed to express the injection agent from the injector tip. In other words, the frictional resistance of the floating seal element can also be higher than the force applied to the pushing seal element for joint injection with respect to a specific formulation viscosity, the injector barrel inner diameter, and the puncture element inner diameter. In this way, the floating seal element can stop automatically in the joint, and pressing the pushing seal element to express the injection agent at the injector tip will not cause the puncture element to advance further.

[0077] In such a design, the user may have haptic feedback when the floating seal element automatically stops and the injector is at the tip of the puncture element in the cavity. In some embodiments, the haptic feedback is based on the sensation of resistance loss when pushing the seal element. In some embodiments, the haptic feedback may be used in combination with visual feedback of the stopping floating seal element to determine when delivery of the therapeutic fluid begins. In some embodiments, in relation to the visual feedback, for example, if the pushing seal element continues to move while the floating seal element does not move and no visible leakage is observed on the tissue surface, this indicates that the puncture element is delivering the injector to the desired location.

[0078] It is miniaturized to deliver a volume of about 100 to 250 microliters with 10% precision using a long, thin gauge puncture element that penetrates stiff scleral tissue. In some embodiments, precision can be increased to 5%. The size of the injector can be 10 µl to 50 ml.

[0079] FIGS. 9a and 9b illustrate embodiments of the distal end (106) of the injection system. In some embodiments, a puncture element support (500) may be provided at the distal end of the injector barrel to support the puncture element. This sliding support may be fixed or sliding relative to the injector barrel. In some embodiments, the sliding support (500) may include support flanges (510, 512) that may be positioned near the distal end of the injector barrel. The support flanges (510, 512) are spaced apart from each other to provide an orifice (514) that allows the puncture element (116) to slide between the support flanges. At the same time, the support flanges (510, 512) may provide support for the puncture element near the tip to reduce movement of the puncture element due to bending of the puncture element while penetrating the sclera and changing the force on the floating seal element. In some embodiments, the flange (510, 512) may be integrated with the injector barrel.

[0080] In some embodiments, the puncture element support contacts the sclera. In some embodiments, the puncture element support may be inclined to allow oblique injection into the surface of the sclera. In some embodiments, the pre-insertion angle is greater than 45 degrees from the vertical plane. In some embodiments, the surface of the puncture element support in contact with the sclera may be serrated to partially penetrate the sclera. In this way, the puncture element support can firmly grip the sclera to prevent unwanted sclera movement. The orifice of the sliding puncture element may be sized to accommodate the size and shape of the puncture element used.

[0081] In some embodiments of the injection system, the puncture element is exposed only for a short distance (100 µm to 5 mm) so that the puncture element does not completely penetrate the sclera, but can be further extended while performing SCS delivery while the floating seal element is activated. In some embodiments, the puncture element support can be in contact with the sclera surface before the puncture element, the puncture element, and slightly after the puncture element.

[0082] Referring to FIGS. 10a and 10b, the puncture element support is slidably positioned in the injector barrel so that the exposed length of the puncture element can be adjusted before performing SCS delivery. In some embodiments, the distal surface of the puncture element support may be orthogonal or oblique to the central axis of the injector barrel. In some embodiments, the pre-exposed length of the puncture element may be adjusted prior to pre-insertion, which may be independent of the floating seal element. For example, FIG. 10b illustrates that the puncture support may be moved proximally to increase the exposed length of the puncture element compared to when the puncture support is set further distally in the injector barrel as shown in FIG. 10a. However, since the puncture element is pre-inserted into the patient's eye, the penetration length of the puncture element can still be controlled by the movement of the floating seal element. The operator may feel the difference in the force required to be applied to the pushing seal element when the pushing seal element is manually pushed. The puncture element stops without the user / doctor needing to change their action (e.g., continuing to push the sealing element) and immediately begins the delivery of the injectable payload.

[0083] Referring to FIGS. 11a through 11c, various embodiments of the safety cap (118) are illustrated. The safety cap can protect the puncture element from mechanical damage before use. In some embodiments, the safety cap can also seal the puncture element to prevent leakage of the injection agent or injection from the injection chamber during storage. The cap can be secured to the injector using friction, an interlock, or threads.

[0084] Referring to FIGS. 12a through 12e, in some embodiments, the injector may be provided as a multi-component that can be stored separately within the infusion chamber and mixed immediately before use in the infusion system for delivering the injector to a target. In some embodiments, the injector may be separated from its diluent and stored separately within the infusion chamber. When pressure is applied, the diluent mixes with the therapeutic agent to produce a solution or suspension, which can then be injected into the SCS. In some embodiments, the therapeutic agent may be a lyophilized therapeutic agent.

[0085] In some embodiments, the infusion system may have multiple chambers so that the chambers are isolated from each other. In some embodiments, the infusion agent may include a dry component stored in one chamber and a diluent stored in another chamber. When in use, the diluent may be forced from the chamber containing the dry component into the chamber, thereby achieving in-situ reconstitution of the two components of the infusion agent.

[0086] As illustrated in FIG. 12a, in some embodiments, two chambers (610, 612) are initially separated by a rubber (or other material) seal (614) mounted on a floating sealing element. Chamber (610) may be defined by the seal (614) and the floating sealing element (110), while chamber (612) may be defined by the seal (614) and the rear seal (616) of the pushing sealing element (112). In some embodiments, there may be a groove in the inner wall of the injector barrel connecting the two chambers when the seal moves in one direction. In some embodiments, chamber (610) contains a lyophilized active substance of the therapeutic agent, while chamber (612) contains a carrier injector that can be used to reconstitute the active substance. A one-way stopper (618) may be positioned close to the rear seal (616) of the pushing sealing element so that the rear seal (616) can move forward but not backward. As the seal (614) moves backward, the fluid inside the chamber (612) is pressurized. At the same time, the movement of the seal (614) connects the two chambers as shown in FIG. 12b. The pressurized fluid from the chamber (612) now enters the chamber (610) and mixes with the contents inside the chamber (610). The seal (614) can move back and forth to enable efficient mixing of the two components. As the seal is fully extended backward, the seal engages with the rear seal of the pushing seal element so that the two seals now move together, as shown in FIG. 12c. In some embodiments, the seal may be provided with a corresponding anchor and anchoring port. Force can now be applied to the pushing seal element to operate the injection system. The injection system can now be primed as shown in FIG. 12d and thus ready for use as shown in FIG. 12e.

[0087] The mechanism for joining the seal portion (614) and the rear seal portion (616) may be mechanical, adhesive, or magnetic. In some embodiments, this is indicated by a mechanical anchor. In some embodiments, the therapeutic solution or suspension is pre-filled and stored in the infusion system. In some embodiments, the therapeutic agent is stored as a ready-to-use solution in one or more vials containing a kit, or as a lyophilized powder requiring reconstitution. In these embodiments, the ready-to-use or reconstituted therapeutic agent is loaded into the system for delivery and then injected into the SCS.

[0088] In some embodiments, as mentioned above, the infusion system of the present invention may be used to deliver infusion agents having a high viscosity greater than 10 centipoise (cP). In some embodiments, the ability to deliver high-viscosity therapeutic agents may depend on multiple parameters, such as, for example, the length of the puncture element, the lumen diameter and cross-sectional area of ​​the puncture element, fluid density, syringe size, friction and sliding force between the floating seal element and the syringe barrel, and the minimum flow rate. For example, referring to FIG. 13, for a standard plastic 1 ml injector / seal element combination with a minimum flow rate of 100 µl / min, the maximum viscosity as a function of the puncture element gauge is plotted in Plot 1. In some embodiments, by increasing the friction force, the maximum viscosity that can be injected for a puncture element of a given size between the floating seal element and the injector barrel may be increased as shown in Plot 2. For example, to generate data for Plot 1, the friction element between the floating seal and the injector barrel were doubled. In some embodiments, a viscosity modifier is added to a carrier fluid for a therapeutic solution or suspension, so that haptic feedback to the pushing seal element can be increased to the user to improve control over the injection.

[0089] Referring to FIG. 14, the injection system of the present invention includes an injector barrel having an inner diameter smaller than the diameter of the floating seal element to increase the frictional force against the floating seal element. Generally, the frictional force is a function of both the relative size of the floating seal element (e.g., diameter and / or length) and the inner surface and material properties (elasticity and bending modulus) of the injector barrel. Both the floating seal element and the injector barrel. As a non-limiting example, the frictional force for a 1 ml injector was measured to be ~1 N. The allowable viscosity and the frictional force are directly proportional. Therefore, to increase the allowable viscosity limit tenfold, the frictional force must be increased tenfold. Even a small change in the relative size of the floating seal element and the injector barrel can change the vertical force against the floating seal element, which enables the administration of high-viscosity injectors. In some embodiments, when no external force is applied to the floating seal element, i.e., in a relaxed state, the first seal element may have a size 1.01 to 2 times larger than the lumen size of the injector barrel. In some embodiments, in the relaxed state, the first sealing element has a size 1.01 to 1.10 times larger than the lumen size of the injector barrel. In some embodiments, in the relaxed state, the first sealing element may have a size 1.01 to 1.4 times larger than the lumen size of the injector barrel. In some embodiments, the diameter of the lumen of the injector barrel may be reduced to increase the frictional force between the floating sealing element and the injector barrel.

[0090] In some embodiments, this frictional force on the floating seal element may be sufficient to prevent proximal movement of the floating seal element during the pre-insertion step of the puncture element. That is, an increase in the frictional force on the floating seal element may have the following two advantages: 1) to keep the floating seal element in place during pre-insertion, and 2) to allow the user to deliver the therapy at a higher viscosity. In some embodiments, the frictional or sliding force between the floating seal element and the injector barrel may be increased higher than the pre-insertion force to keep the floating seal element in place during pre-insertion. The pre-insertion force may vary depending on the shape of the puncture element. In some embodiments, a viscosity modifier is added to the injector to enable increased frictional or sliding force on the floating seal element, while the automatic stop function is retained. In some embodiments, an increase or decrease in the surface roughness of the injector barrel may allow an increase or decrease in the frictional force between the floating seal element and the injector barrel to adjust the viscosity of the injector.

[0091] In some embodiments, the relationship between the size of the floating seal element and the injector barrel can be adjusted by increasing the diameter of the floating seal element while keeping the inner diameter of the injector barrel constant, or by decreasing the inner diameter of the injector barrel. The diameter of the floating seal element can be kept constant, or a combination of these two options can be used. In both cases, in some embodiments, the pushing seal element is configured to pass through the injector barrel to contact the floating seal element to eliminate dead mass between the seal elements as discussed above. In some embodiments, the pushing seal element may be made of a softer material and / or a material capable of reducing friction between the pushing seal element and the injector barrel. Additionally or optionally, the rigid portion of the pushing seal element may be smaller in size compared to the elastic portion relative to the floating seal element to allow the pushing seal element to advance easily toward the floating seal element. In some embodiments, additionally or optionally, the diameter or shape of the puncture element may be modified to enable the delivery of high-viscosity injection agents using the injection system of the present invention.

[0092] In some embodiments, the infusion system of the present invention is equipped with one or more safety features for limiting or controlling the depth to which the puncture element may extend to the patient's eye. In some embodiments, since these features may limit the distance the floating seal element may travel distally, the puncture element cannot extend outside the SCS. In some embodiments, because the distance the puncture element must travel to reach the cavity boundary varies from patient to patient, these safety features must be sufficiently flexible or adjustable so that the maximum puncture element insertion distance can be set according to each procedure.

[0093] Referring to FIG. 15a, in some embodiments, this safety feature portion may include a locking device for selectively locking and unlocking the floating seal element (110) in place. In some embodiments, the locking device (700) includes a compartment sealed in the distal region of the injector barrel at the distal end of the floating seal element. The compartment (700) may be equipped with a valve (712) (e.g., a ball valve, a butterfly valve, a pinch valve, a control valve, a gate valve, a globe valve, or a puncture element valve) so that incompressible material, such as a sterile fluid, a liquid (e.g., sterile saline), or a gas, may flow into or out of the compartment (710). Because the material within the compartment is incompressible, the floating seal element cannot move distally when the valve is closed. The valve may be a binary valve or an adjustable valve. When the valve is opened, the incompressible material is released from the compartment, allowing the floating seal element to move distally. The valve closes to re-lock the floating seal element.

[0094] The operation of the distal safety lock is illustrated in FIGS. 15b through 15e. Before using the injection system, the floating seal element is placed in a desired initial position, the sealed compartment (710) may be filled with an incompressible material, and the valve (712) is closed to lock the floating seal element in the initial position as shown in FIG. 15b. The valve is kept closed during the injector filling and puncture element pre-insertion steps, where applicable, to keep the floating seal element in place. As shown in FIG. 15c, once the puncture element is pre-inserted into the tissue, the valve (712) is opened to release a portion of the incompressible material from the sealed compartment, allowing the floating seal element to move distally to advance the puncture element into the SCS. In some embodiments, a collection reservoir may be provided to collect the fluid released from the compartment. As illustrated in FIG. 15d, when the puncture element is positioned as desired for the injection of the injection agent into the SCS (e.g., at the interface between the sclera and the SCS), the valve closes to lock the floating seal element in place, which also ensures that the puncture element remains in the desired position. Since the fluid remaining in the compartment is incompressible, the floating seal element cannot move distally when the valve closes. The fluid lock can also close the valve after the puncture element reaches the SCS to prevent overshoot by the puncture element. For example, as illustrated in FIG. 15e, the fluid lock design keeps the floating seal element in a fixed state even when the pushing seal element comes into contact with the floating seal element, which can fix the floating seal element forward or prevent the user from accidentally continuing to push the pushing seal element.

[0095] In some embodiments, the viscosity of the incompressible material used in the sealed compartment may be selected to balance the viscosity of the injection agent. Increasing the viscosity of the fluid within the compartment increases the amount of force required to discharge the viscous fluid through the valve. This increases the sliding force of the floating seal element by applying additional resistance to the proximal movement of the floating seal element.

[0096] Referring to FIG. 16, in some embodiments, an opening or valve (712) in the distal region of the injector may also be used to sterilize the section of the injector between the floating seal element and the distal end of the injector. In particular, creating an access port in front of the floating seal element in a part of the injector barrel, such as a valve or hole, allows sterilizing gas or vapor to easily enter that part of the injector. In some embodiments, such an access port may be provided even when a locking device is not used.

[0097] Referring to FIGS. 17a and 17b, in some embodiments, the safety feature for locking the floating seal element includes a touch trigger lock (800) positioned between the floating seal element (110) and the pushing seal element (112). Similar to the lock (700) discussed above, the touch trigger lock (800) may be configured to prevent movement of the floating seal element when the injector is delivered, particularly when the pushing seal element comes into direct contact with the floating seal element at the end of the delivery cycle, which may cause the floating seal element to be struck forward. In some embodiments, the touch trigger lock is a spring-mounted device that springs outward into the inner part of the injector barrel when the pushing seal element comes into contact with the floating seal element, thereby increasing friction between one or both seal elements and the injector barrel. In this way, the touch trigger lock acts as an anchor for the floating seal element, the pushing seal element, or both, so that when the touch trigger lock is released, further movement of them can be prevented. In some embodiments, the touch trigger locking device (800) includes a resistance member (810) and a trigger (812) that releases the resistance member (810). The touch trigger mechanism may be placed on a floating seal element or a pushing seal element, or both. When operated, the resistance member is initially hidden within the touch trigger mechanism, allowing the seal element to move freely within the injector barrel. When the seal elements come into contact with each other, the trigger (812) is activated to release the resistance member (810) from the touch trigger mechanism, which significantly increases the frictional force between the injector barrel and the seal element containing the touch trigger mechanism, thereby stopping the seal element. This prevents the seal element from advancing in a distal direction. Essentially, the resistance member acts as a brake that locks the seal element in place. In some embodiments, the resistance mechanism may include a circular spring. In an initial configuration, the spring may be compressed within the touch trigger mechanism.When the trigger is activated, the circular spring is released from the touch trigger mechanism. The spring expands to come into contact with the injector barrel, significantly increasing the friction between the injector barrel and one or both of the sealing elements, thereby locking them in place.

[0098] In some embodiments, additionally or optionally, separate mechanical structure(s) that prevent the advancement of the puncture element (e.g., another mechanical stop that prevents the push seal element from moving beyond a predetermined point) may be provided. During operation, if the advancement of the push seal element is blocked, the floating seal element cannot be pressurized and therefore cannot advance further.

[0099] In some embodiments, the infusion system of the present invention may be pre-filled with the infusion agent during manufacturing as described above. In some embodiments, the infusion system of the present invention may be filled with the infusion agent immediately before administering the infusion agent to a patient. In some embodiments, the infusion agent may be provided in a vial for storage and may be transferred to the SCS system by the user only when the infusion agent is ready to be administered to a patient.

[0100] Referring to FIG. 18, in some embodiments, the infusion system of the present invention is provided with a rapid filling port (900) that enables loading of an infusion agent from a vial (902) into an infusion chamber. In some embodiments, the rapid filling port (900) includes a receptacle. The receptacle (904) is configured to receive the vial (902) to fluidly connect the vial to the infusion chamber. In some embodiments, a hole or passage is created through the wall of the infusion barrel adjacent to the floating seal element (110) (e.g., by molding, machining, etc.), and the receptacle (904) is placed over this hole or passage. In some embodiments, when the floating seal element is set in an initial position and the pushing seal element comes into contact with the floating seal element, the rapid filling port is fluidly connected to the infusion barrel at a portion between the seal elements. Connected to the passage partially or completely placed therein is a side port filling needle (906) (preferably larger than an infusion puncture element, such as an 18-gauge puncture element). These filling needles may be angled to penetrate the elastomer cap (903) of the therapeutic agent-containing vial (902). In some embodiments, the filling puncture element of the rapid filling port may have an opening on the side of the filling puncture element rather than at the tip. This side port may be covered by a casing or a self-sealing perforating membrane (908) that blocks fluid flow when in a closed position. The casing (908) may be placed within a receptacle and deflected by a spring (910) to close the port of the filling needle when the vial is not present in the receptacle. In some embodiments, a safety cap (118) may be configured to provide a hermetic seal when attached to the infusion system.

[0101] When in operation. As illustrated in FIG. 19a, the vial (902) is snapped into the receptacle (904) of the rapid charging port (900), which pushes the sliding charging puncture element casing out of the side port of the charging puncture element. The charging puncture element of the rapid charging port then penetrates the stopper of the vial and fluidly connects the internal volume of the vial to the injector barrel through the side port of the charging puncture element. Referring to FIG. 19b, the injection flows from the vial (902) into the injection chamber as the pushing seal element (112) is withdrawn. In some embodiments, a safety cap is provided on the puncture element of the injection system to fluidly seal the puncture element so that air bubbles are not drawn into the injector barrel when the pushing seal element is withdrawn.

[0102] Referring to FIG. 19c, when the desired amount of infusion agent is loaded into the infusion system, the vial can be removed from the receptacle of the rapid filling port, allowing the sliding filling puncture element casing to seal the side port of the filling. The puncture element seals the infusion barrel. The safety cap can be removed to allow fluid to flow through the infusion puncture element. As shown in FIG. 19d, the pushing seal element can be pressed until the infusion fluid appears at the tip of the infusion puncture element, indicating that air has been removed from the infusion puncture element. In some embodiments, the infusion system can be tilted upward to help remove air from the puncture element. The infusion system is then ready for use. Other infusion port designs allow the infusion system to be filled with the infusion agent at the treatment point while maintaining sterility outside the sterilization facility.

[0103] In some embodiments, the infusion system of the present invention may be refilled with an infusion agent. This may occur in a hospital during the initial manufacture of the infusion device or immediately before use.

[0104] In some embodiments, as shown in FIG. 20a, the pushing seal element can be removed so that the injection agent can be added to the injection barrel through the rear of the injection barrel as shown in FIG. 20b. Next, as shown in FIG. 20c, the pushing seal element can be inserted and pushed toward the floating seal element to remove any air within the injection puncture element and prime the injection system for use.

[0105] In some embodiments, as shown in FIG. 21a, a filling port (930) may be provided in a proximal region of the injector barrel (102) distal to the pushing seal element (112). The injector (114) may be added to the injection system through this filling port (930). Then, the pushing seal element (112) may be pushed past the filling port (930), so that the pushing seal element seals the injection fluid from the filling port as shown in FIG. 21b. In particular, another sterile injector / puncture element may be used to add to the injection system through the filling port, such that the puncture element is directed downward (the tip of the puncture element is blocked). In some embodiments, the total volume of the injector may be about 80% of the volume between the seal elements. Then, the pushing seal element may be advanced toward the floating seal element to remove air through the filling port. Once the pushing seal element has passed through the filling port and blocked the filling port, the injector may be flipped so that the hole element face upward. Next, the pushing sealing element advances further distally to release the remaining air from the injector barrel and the injection puncture element.

[0106] In some embodiments, as illustrated in FIGS. 22a through 22c, the filling port (930) (as illustrated in FIGS. 21a and 21b) may be sealed using a self-sealing seal (932) (e.g., silicone rubber or polytetrafluoroethylene or a similar polymer). In this way, while the injector barrel of the injection system can remain sealed throughout the process, the filling port can be filled with a separate, larger bore loading needle (934) of a standard injector. When the filling hole element is removed from the filling port, the filling port is sufficiently self-sealed to prevent leakage due to pressure applied by the pushing seal element during use.

[0107] In some embodiments, as illustrated in FIGS. 23a through 23d, a filling port (950) may be provided in the distal portion of the injector barrel (102) distal to the floating seal element (110). This allows the user to set the floating seal element at a desired position in the distal portion of the injector barrel using a pushing tool (952) (e.g., a long, thin, rigid object long enough to fit into a hole and reach the outside). For example, when using the rapid filling port (900), the injector element may be extended outward so that it can be pushed through an elastomer vial stopper, and then the injection material may be introduced into the injector by pulling out the pushing seal element. Afterward, the pushing seal element may be further withdrawn proximally so that the floating seal element can be pushed back to a pre-insertion position within the injector barrel.

[0108] In some embodiments, the volume of the infusion chamber is 20 to 200 microliters. For improved haptics, in some embodiments, the stroke length of the pushing seal element for delivering the therapeutic fluid or suspension is at least 1 cm. In some embodiments, the infusion flow rate is targeted to be an average of 0.2 to 20 microliters per second. In some embodiments, the infusion barrel is lined with silicone rubber, glass, polytetrafluoroethylene, or polypropylene to minimize adsorption of the therapeutic agent onto the inner surface of the infusion barrel.

[0109] In some embodiments, referring to FIGS. 24a through 24e, the injection system of the present invention is configured for safe disposal. In some embodiments, at the end of an injection cycle, as shown in FIGS. 24a and 24b, the pushing seal element (112) may come into contact with the floating seal element (110) as shown in FIG. 24c. In some embodiments, the injection system is configured so that the pushing plunger may be coupled directly or indirectly to the floating seal element as shown in FIG. 24d. When the seal element is coupled, the pushing seal element may be withdrawn, thereby causing the floating seal element and the puncture element to also be withdrawn into the injector barrel as shown in FIG. 24d. In some embodiments, the puncture element is configured to be deflected within the injector barrel so that it cannot extend further outside the injector barrel as shown in FIG. 24e.

[0110] In some embodiments, the injection system of the present invention is used to deliver viral gene delivery vectors or vectors comprising, but not limited to, adeno-associated viruses (AAVs), AAV serotypes 1-11, particularly variants or serotypes thereof including but not limited to AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAV11, and recombinant serotypes such as Rec2 and Rec3 for treating genetic disorders of retinal or choroidal disease. AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9 are all incorporated herein by reference in their entirety.

[0111] It may exhibit affinity for retinal tissues, including retinal pigment epithelium and photoreceptors, as described in https: / / www.retinalphysician.com / issues / 2020 / special-edition-2020 / vector-considerations-for-ocular-gene-therapy. Exemplary diseases may include, but are not limited to, wet age-related macular degeneration, dry age-related macular degeneration (AMD), glaucoma, choriorethromycin, and other hereditary visual diseases and disorders. In some embodiments, the injection system is used to deliver a viral delivery vector or vectors comprising, but not limited to, AAV or a variant thereof, to transfect retinal and / or choroidal cells, such as photoreceptors, pigment cells, bipolar cells, ganglion cells, horizontal cells and amacrine cells, vascular endothelial cells, vascular smooth muscle cells, non-vascular smooth muscle cells, melanocytes, fibroblasts, resident immune cells, anti-vascular endothelial growth factor (anti-VEGF), and anti-vascular endothelial growth factor receptor (anti-VEGFR) genes that, when transcribed, produce anti-VEGF proteins or proteins for treating wet AMD, but not limited to. In some embodiments, the gene therapy composition may also include a promoter for the gene of interest.

[0112] In some embodiments, the delivery system is used to deliver gene therapies including, but not limited to, small interfering ribonucleic acid (siRNA), short hairpin ribonucleic acid (shRNA), micro-ribonucleic acid (microRNA), closed-terminal deoxyribonucleic acid (ceDNA), polymer-DNA conjugates or clustered regularly spaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) systems and variants thereof, transcription activator-like effector nucleases (TALEN) and variants thereof, zinc finger nucleases (ZFN) and variants thereof, transposon-based gene delivery such as Sleeping Beauty (SB), piggyBac (PB), Tol2 or variants thereof. These gene therapies may be packaged in viral vectors, non-viral vectors, or nanoparticles.

[0113] In some embodiments, the injection system is used to deliver a viral gene delivery vector or vectors, and a non-viral gene delivery system or other gene therapy achieves a transfection efficiency of less than 0.001%, 0.01%, 0.1%, 1%, 3%, 5%, 10%, 25%, 50%, 75%, or 90% of retinal and / or choroidal cells.

[0114] In some embodiments, the infusion system is used to deliver small molecule or large molecule therapies targeting VEGF or VEGFR, including but not limited to Ziv-Aflibercept, pazopanib, bevacizumab, cabozantinib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, and bevacizumab.

[0115] 일부 실시예에서, 주입 시스템은 MTP, HGD, SLC16A2, POLG, ALMS1, FGFR2, PRPS1, APTX, ATM, DNMT1, TGFBI, ACTB, FGFR2, BEST1, CYP4V2, NOD2, FOXL2, ABCC9, ERCC6, CYP27A1, CHS1, HDAC SH3BP2, OPN1MW, OPN1LW, OPN1SW, KERA, IGBP1, OPA3, UGT1A1, FGFR2, FGFR3, ATP6V0A2, CTNS, EFEMP1, SALL4, ADAMTSL4, FBN1, ADAMTSL4, NR2E3, TGFBI, GLA, IKB, PORCN, TGFBI, 귀리, ENG, CBS, MBTPS2, IKBKG, CNNM4, ATRX, GALC, TGFBI, HADHA, OCRL1, PLP1, B3GALTL, PAH, ARX, LOXL1, TGFBI, PQBP1, RB1, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, GLB1, ARSB, GUSB, FGFR3, LMX1B, NHS, STAC3, NF1, NF2, NF1, MT-ATP6, NDP, RP1L1, GPR143, PABN1, HEXB, UBIAD1, AGK, TIRAIL H ATP2B3, ABCA4, ELOVL4, PROM1, GNAQ, SUOX, NAA10, BCOR, SOX2, OTX2, BMP4, HCCS, STRA6, VAX1, RARB, HMGB3, MAB21L2, RBM10, HEXA, TGFBI, SHOX, TAT, PTEN, VHL, VCAN, NF1, ZC4H2, ATP7B, CNGA3, CNGB3, JAG1, NOTCH2, PAX6, ELP4, PAX6, ELP4, GPITX2, FOXC1, CHD7, SEMA3E, ERCC6, ERCC8, CYP1B1, MYOC, MYOC, CYP1B1, FGFR1, FGFR2, FGFR1, FGFR2, NDN, SNRPN, PHYH, PEX7, CREBBP, EP1,TWOP1, EFGFR2,GPC3, OFD1, TSC1, TSC2, PRPH2, BEST1, WFS1, CISD2, COL4A5, COL4A4, COL4A3, UBE3A, CDKLS, MECP2, PTCH1, PTCH2, SUFU, NSD1, H19, CD1KNQ1OT1, SIX1, SIX5, KIF21A, PHOX2A, ARIX, TUBB3, SMC1A, HDAC8, COL5A1, COL5A2, COL3A1, TNXB, OPTN, ASB10, WDR36, MTND1, MTND4, MTNDS, MTND6, PAX6, PKCP CABP, NPC1, NPC2, SMPD1, TYR, OCA2, TYRP1, or SLC45A2, MC1R, COL1A1, COL1A2, CRTAP, It is used to deliver gene therapy that targets, replaces, inhibits, or promotes one or more of the following genes to confer a therapeutic effect on hereditary eye diseases or disorders, including but not limited to LEPRE1, NPHP1, NPHP4, SDCCAG8, WDR19, CEP290, IQCB1, HESX1, OTX1, IQCB1, HESX1, OTX1, COL9A1, COL9A2, MYO7A, USH2A, EDN3, EDNRB, MITF, PAX3, SNAI2, SOX10, ADAMTS10, FBN1, LTBP2, XPA, XPC, ERCC2, ERCC3, and POLH.

[0116] In some embodiments, the delivery system of the present invention may be used to deliver gene therapy for treating age-related macular degeneration (AMD) or diabetic macular edema (DME). In some embodiments, the delivery system of the present invention is used for the choroidal (SCS) delivery of a composition comprising an AAV vector containing one or more genes that block VEGFR-2, optionally with a CAG promoter. In some embodiments, other suitable promoters include, but are not limited to, human bestropin (hVMD2), cytomegalovirus (CMV), SV40, mGluR6, CB7, UbiC, RZ, RedO, Rho, and Best1. In some embodiments, the system may include a polypropylene or glass injector and 25-34 gauge puncture elements made of fluoropolymer, silicone, or rubber for a pushing seal element stopper and a floating seal element stopper. In some embodiments, about 80 to 120 (e.g., 100) microliters of this gene therapy composition may be delivered over 5 to 60 seconds. In some embodiments, the puncture element may have a bevel length of less than 2 mm, less than 1 mm, or less than 0.5 mm. The bevel angle may be 15 degrees or more, 30 degrees or more, or 45 degrees or more. In some embodiments, the puncture element may be 25 gauge or more, 27 gauge or more, or 30 gauge or more. In some embodiments, the needle has a secondary bevel to reduce cutting force.

[0117] In some embodiments, the delivery system is used to deliver small molecule or large molecule infusions such as bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandin, tryptofanyl-tRNA synthetase-derived polypeptide, inosine monophosphate dehydrogenase (IMPDH) inhibitors and anti-PDGF for treating AMD; corticosteroids for treating uveitis, chorioretinitis, or other inflammatory eye diseases; botulinum toxins for various ocular applications; tyrosine kinase inhibitors for treating pterygium, dry eye, or AMD (e.g., vandetanib, axitinib, pazopanib, sunitinib, sorafenib); levo-betaxolol, or other beta-adrenergic receptor antagonists and 5-HT1A agonists for treating retinal pathology, including but not limited to anti-VEGF drugs.

[0118] In some embodiments, the infusion system is used to deliver a small molecule Wnt inhibitor to reduce angiogenesis. These small molecule Wnt inhibitors include indazole-3-carboxamide compounds or analogs thereof (W02013040215A1), y-diketones or salts or analogs thereof (W02014130869A1), azaindazole compounds or analogs thereof (e.g., 3-(1h-benzo[d]imidazole-2-yl)-1h-pyrazolo[3,4-c]pyridine) (W02016040180A1), N-(5-(3-(7-(3-fluorophenyl)-3H-imidazole[4,5-c]pyridine-2-yl)-1H-indazole-5-yl)pyridine-3-yl)-3 - methylbutanamide including its amorphous and polymorphic forms (W02017210407A1), isoquinoline-3-γ1 Carboxamide or salt or analogues and their amorphous and polymorphic forms (W02017189823A2), diazanaphthalene-3-yl carboxamide or salt or analogues and their amorphous and polymorphic forms (US20190127370A1), 6-(5-one-heteroaryl)isoquinoline-3-yl-(5-one-heteroaryl)carboxamide or salt or analogues and their amorphous and polymorphic forms (W02019084496A1), 6-(6-one-heteroaryl and aryl)isoquinoline-3-yl carboxamide or salt or analogues and their amorphous and polymorphic forms (US20190125740A1), 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridin (US20190119303A1), Wnt inhibitor containing an indazole core or salt or analog and comprising amorphous and polymorphic forms (W02013151708A1), lh-pyrazolo[3,4-b]pyridin or salt or analog and comprising amorphous and polymorphic forms (W02013166396A2), 2-(1h-indazole-3-y1)-3h-imidazo[4,5-b]pyridin or salt or analog and comprising amorphous and polymorphic forms (US20190055238A1), f3-diketone, y-diketone or y-hydroxyketone or salt thereof or Analogue (W02012024404A1),3-(benzimidazole-2-yl)-indazole inhibitors or salts or analogs and amorphous and polymorphs including (US10183929B2), 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-b]pyridin or salts or analogs and amorphous and polymorphs including (US20180325910A1), 1h-pyrazolo[3,4-b]pyridin or salts or analogs and amorphous and polymorphs including (CY-1119844-T1), 3-(1h-imidazo[4,5-c]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridin or salts or analogs and amorphous and polymorphs including (US-2018250269-A1), N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazole-5-yl)pyridin-3-yl)-3-methylbutanamide or salt or analog and amorphous and polymorphic forms (US20180133199A1), indazole-3-carboxamide or salt or analog and amorphous and polymorphic forms (US-2018185343-A1), 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[3,4-c]pyridin or salt or analog and amorphous and polymorphic forms (US-2018201624-A1), 2-(1h-indazole-3-y1)-1h-imidazo[4,5-c]pyridine or salt or analog and amorphous and polymorphs including (US-2018215753-A1), 3-(3H-imidazo[4,5-C]pyridine-2-yl)-1H-pyrazolo[3,4-C]pyridine or salt or analog and amorphous and polymorphs including (US-10052331-B2), 5-substituted indazole-3-carboxamide or salt or analog and amorphous and polymorphic forms including (US-2018127377-A1), 3-(3H-imidazo[4,5-C]pyridine-2-yl)-1H-pyrazolo[4,3-B]pyridine or salt or analog and amorphous and polymorphs Includes (US-10188634-B2), 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridin or salt or analogue and amorphous and polymorphic forms (US-10195185-B2),3-(1h-pyrrolo[2,3-b]pyridin-2-y1)-1h-indazole or salt or analog (including amorphous and polymorphs) (W0-2017024021-A1), 3-(1h-pyrrolo[2,3-c]pyridin-2-y1)-1h-pyrazolo[3,4-c]pyridin or salt or analog and including amorphous and polymorphs (W0-2017023975-A1), 3-(1h-indo1-2-y1)-1h-pyrazolo[3,4-b]pyridin or salt or analog and including amorphous and polymorphic forms (US-2018214428-A1), 3-(1h-pyrrolo[3,2-c]pyridin-2-yl)-1h-indazole or salt or analog and including amorphous and polymorphic forms (US-2018221350-A1), 3-(1h-indo1-2-y1)-1h-indazole or salt or analogue and including amorphous and polymorphic forms (W0-2017023986-A1), 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridin or salt or analogue and including amorphous and polymorphic forms (US-10206909-B2), 3-(1h-pyrrolo[3,2-c]pyridin-2-y1)-1h-pyrazolo[4,3-b]pyridin or salt or analogue and including amorphous and polymorphic forms (WO-2017024003-A1), 3-(1h-pyrrolo[3,2-c]pyridin-2-y1)-1h-pyrazolo[3,4-b]pyridin or salt or analog and amorphous and polymorphs including (US-2018221341-A1), 3-(3h-imidazo[4,5-b]pyridin-2-yl)-1h-pyrazolo[4,3-b]pyridin or salt or analog and amorphous and polymorphs including (W0-2017024015-A1), 3-(1h-pyrrolo[2,3-c]pyridin-2-y1)-1h-pyrazolo[3,4-b]pyridin or salt or analog and amorphous and polymorphs including (US-2018221352-A1), It may include 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridin or salts or analogs and amorphous and polymorphs (US-10206908-B2). Each reference referenced herein is incorporated by reference in its entirety.

[0119] In some embodiments, the infusion system is used to deliver a suspension of an infusion agent comprising a microencapsulated formulation, a nanoencapsulated formulation, pure protein nanoparticles, and a water-insoluble or water-insoluble formulation.

[0120] In some embodiments, an injectable or encapsulated injectable is delivered together with a retention time extension matrix. The matrix may consist of a reverse heat-reactive hydrogel, a self-assembling hydrogel, a bioadhesive polymer network, a hydrogel, a fibronectin-containing hydrogel, an enzyme-reactive hydrogel, an ultrasound-sensitive hydrogel, a pH-sensitive hydrogel, a carbohydrate, a hydrogel with two or more components, and a multi-component dual-network hydrogel.

[0121] In some embodiments, the injector is dimethyl sulfoxide (DMSO), collagenase, elastase, protease, papain, bromelain, peptidase, lipase, alcohol, polyol, short-chain glyceride, amine, amide, cyclodextrin, fatty acid, pyrrolidone, cyclopentadecalactone, sodium N-[8-(2-hydroxylbenzoyl)amino]caprylate (SNAC), 8-(N-2-hydroxy-5-chloro-benzoyl1)-amino-caprylic acid (5-CNAC), sodium caprate, sodium caprylate, omega-3 fatty acid, protease inhibitor, alkyl glycoside, chitosan, dodecyl-2-N,N-dimethylaminopropionate (DDAIP), N-methyl-2-pyrrolidone (NMP), argon, sulfoxide, surfactant, benzyl alcoholconium chloride, saponin, It is delivered via an injection system together with a permeability enhancer including, but not limited to, bile salts, bile acids, cell permeable peptides, polyarginine, low molecular weight protamine, polyserine, capric acid, gellucir, hemifluorinated alkanes, terpenes, phospholipids, chelating acids (EDTA), citrates, crown ethers, and combinations thereof.

[0122] In some embodiments, an infusion agent having one or more therapeutic formulations is delivered via an infusion system with or after the administration of one or more vasoconstrictors to reduce the outflow of the infusion agent through the choroidal vessels, including but not limited to 25I-NBOMe, amphetamine, AMT, antihistamine, caffeine, cocaine, dopamine, dobutamine, DOM, LSA, LSD, methylphenidate, mephedrone, norepinephrine, oxymetazoline, phenylephrine, propylhexerine, hydrochlordagon-hydroxyhydrochlorochloride, cerdoephedrine, tripidene, and stimulants. In some embodiments, these agents may be administered via an SCS using the infusion system of the present invention or via intravitreal injection using a standard infusion device. Vasoconstrictors may be delivered before, simultaneously with, or after the administration of one or more therapeutic formulations.

[0123] In some embodiments, the injection delivered through the injection system achieves an SCS coverage exceeding 20%, 40%, 60%, or 80%.

[0124] In some embodiments, the infusion delivered through the infusion system with or without one or more vasoconstrictors to reduce the outflow of the infusion agent through the choroidal vessels achieves SCS coverage of less than 180, 120, 60, 30, or 15 minutes.

[0125] In some embodiments, the injector delivered through the infusion system has a residence time in the SCS of 180, 120, 60, 30, 15, 10, or less than 5 minutes.

[0126] In some embodiments, the injector is delivered through an injection system in amounts of less than 500, 400, 300, 200, or 100 microliters.

[0127] In some embodiments, the injector is delivered through an infusion system at a concentration of 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or less than 1%.

[0128] In some embodiments, the percentage dose of the injector delivered through an infusion system delivered into the subretinal space is 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or less than 1%.

[0129] In some embodiments, the infusion agent delivered through the infusion system is administered at least once every 10 years, once every 5 years, once every 2 years, once every 1 year, once every 6 months, once every 3 months, once a month, or once a week.

[0130] In some embodiments, the infusion system is for A-beta-lipoproteinemia (Basen-Konzweig syndrome), alkaptonuria, Allan-Herrndon-Dudley syndrome, Alpers syndrome, Alstrom syndrome, Apert syndrome, Esther syndrome (mental retardation, X-linked, syndrome 18), ataxia syndrome, ataxia telangiectasia-Barr syndrome), autosomal dominant cerebellar ataxia hearing loss and narcolepsy (ADCADN), Avellino corneal dystrophy (compound granular-lattice corneal dystrophy), Baraitser-Winter syndrome 1, Baer-Stevensson syndrome, supramacytic macular dystrophy, Vietti crystalline corneal dystrophy, Blau, ptosis, ptosis and retrograde blepharoscopy (BPES), Cantu syndrome, cranial neuromyofascial syndrome, dry xanthomatosis, Chediak-Higashi syndrome, cherubism Syndrome, Chondrodysplasia with CK syndrome, Chondrodysplasia with migraine, Phenophoresis, Microcephaly, Microcephaly, Hydrocephalus, Deutan, Color blindness, Protan, Color blindness, Tritanopic, Corneal plane, Corpus Callosum, Ocular colonoma and micrognathia with intellectual disability, Costeff syndrome, Crigler-Najjar, Crouzon syndrome, Crouzon syndrome with acanthosis nigricans (Crouzonodermoskeletal syndrome), Cutis Laxa, Debre type, Cystinosis, Doyne Honeycomb Dystrophy (Malattia Leventine), Duane-Radial Ray Syndrome, Ectopia Lentis et Pupillae, Ectopia Lentis, Familial, Ectopia Lentis, Isolation, Reinforced S-Cone syndrome, Epithelial basement membrane cornea, Dystrophy (Map-dot-fingerprint corneal dystrophy), Fabry disease (hereditary, dystrophic), steatosis), familial autonomic dysfunction, fisheye disease, galactokinase deficiency, galactosemia, Gaucher disease, GM1-gangliosidosis, Type I, GM1-gangliosidosis, Type II, GM1-gangliosidosis, Type III, Goltz syndrome, granular, corneal DI), swivel atrophy,Hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), homocystinuria, IFAP syndrome with or without Breschek syndrome, pigmented incontinence (Bloch-Sulzberger S syndrome), Jalilli syndrome, Jouberg-Marsidi syndrome, Krabbe disease, lattice corneal dystrophy, LCHAD (long-chain 3-hydroxyacyl-core dehydrogenase) deficiency, Lowe, Pelizaeus-Merzbacher, Peters-Plus syndrome (Krause-Kivlinketonuria syndrome), , Pelizaeus-Merzbacher syndrome, Gaffabruption syndrome, Reiss-Buckler corneal dystrophy, Renpenning syndrome (mental retardation, X-linked, Renpenning type), retinoblastoma, retinal schizophrenia, adolescent X-linked, Russell-Silver syndrome, mucopolysaccharidosis syndrome type IH (Hurler type), IH / S (Hurler-Scheie syndrome), Mucopolysaccharidosis Type IS (Scheie syndrome), Mucopolysaccharidosis Type II (Hunter syndrome), Mucopolysaccharidosis Type IIIA (Sanfilippo syndrome A), Mucopolysaccharidosis Type IIIB (Sanfilippo syndrome B), Scisan Mucolipopolysaccharidosis IIIC (C), Mucopolysaccharidosis Type IIID (Sanfilippo syndrome D), Mucopolysaccharidosis Type IVA (Morquio syndrome A), Mucopolysaccharidosis Type IVB (Morquio syndrome B), Mucopolysaccharidosis Type 6 (Maroteaux-Lamy syndrome), Mucopolysaccharidosis Type 7 (Sly syndrome), Muenke syndrome, Onychopatella syndrome, Nance-Horan syndrome, Native American myopathy, Neurofibromatosis Type 1, Neurofibromatosis Type 2, Neurofibromatosis-Noonan syndrome, Neuropathy, Ataxia and retinitis, Pigmentary disorders (NAP), Nory's disease, Latent macular abnormality, Albinism, ophthalmopharyngeal muscular dystrophy, Sandhoff disease (GM2-gangliosidosis, type II), Schneider corneal dystrophy, Senger syndrome, Smith-Magenis syndrome, (chromosome 17p11.2 deficiency syndrome), sickle cell anemia, Sorbi fundus dystrophy, spinocerebellar ataxia,X-linked 1, Stargardt disease / fundus, Flavimaculatus, Sturge-Weber syndrome, Sulfocystinuria (microdeficiency of sulfite oxidase 1), Microphthalmia syndrome), Microphthalmia syndrome 2 (Oculofacial heart disease syndrome), Microphthalmia syndrome 3 (Microphthalmia and esophageal atresia syndrome), Microophthalmic syndrome ophthalmology 5, Microphthalmia syndrome 6, Microphthalmia syndrome 7, (Midas syndrome), Microphthalmia syndrome 9 (Matthewwood syndrome), Microphthalmia syndrome 11, Microphthalmia syndrome 12, Microphthalmia syndrome 13, Microphthalmia syndrome 14, GM2-gangliosidosis, Type I), Thiel-Behnke corneal dystrophy, Turner syndrome, Tyrosinemia, Type II, Vacterl's hyperhydraulic syndrome, von Hippel-Lindau syndrome, Wagner syndrome, Watson Syndrome, Wicker-Wolf syndrome, Wilson's disease, color blindness, Alagille syndrome, aniridia, pansegmental mesenchymal dysplasia, Axenfeld-Rieger syndrome, anterograde syndrome, Cocaine syndrome, glaucoma, congenital, glaucoma, open-angle pediatric onset, Jackson-Weiss syndrome, Pfeiffer syndrome, Prader-Willi syndrome, Refsum disease, Rubinstein-Taibee syndrome, normal-tension glaucoma, Oguchi disease, Satre-Schochen syndrome, Simpson-Gollaby-Bemmel syndrome, tuberous sclerosis, yolk-sac macular dystrophy, adult onset, Wolfram syndrome, Alport syndrome, Angelman syndrome, Bardet-Biedl syndrome, basal cell nevus syndrome, Beckwith-Wiedemann syndrome, Blue-Cone Monochromacy, Branchiootorenal syndrome, Charcot-Marie-Tooth disease, Cone-Rod dystrophy, congenital disorder Glycation, congenital fibrosis of the extraocular muscles, congenital nystagmus, congenital stationary night blindness, Cornelia de Lange syndrome, congenital keratotic dystrophy, Ehlers-Danlos syndrome, Fuch's endothelial corneal dystrophy, glaucoma, open-angle adult onset, Hermansy-Pudlak, Joubernst syndrome - Sayer syndrome, Leber congenital amaurosis, Leber hereditary optic neuropathy, Leigh syndrome, Peters variant retinitis pigmentosa,It is used to deliver one or more injectable agents to treat one or more of the ophthalmic causes or effects of diseases including, but not limited to, muscular dystrophy-glycanopathy, myotonic dystrophy, Niemann-Pick disease, Noonan syndrome, neuroceroid lipopharyngeal atrophy, oculocutaneous albinism, facial digital syndrome, osteogenesis imperfecta, Seer's Loken syndrome, septic optic dysplasia (de Mors syndrome), spastic paraplegia, Stickler syndrome, Treacher Collins syndrome, Usher syndrome, Waardenburg syndrome, Weil-Marcesani syndrome, and xeroderma pigmentosum.

[0131] In some embodiments, multiple infusions may be performed over time to allow for the continuation of treatment. The infusion of the therapeutic agent may be accompanied by other agents that enable multiple deliveries. For example, AAV delivery is generally limited by an immune response to AAV that limits treatment to a single time, which is a limitation typically associated with intravitreal injection; while subretinal injection is immune-privileged, damaged and diseased retinas do not tolerate multiple treatments. Trauma-free injection. To mitigate the immune response and enable AAV therapy at multiple time points, other agents that suppress this response (e.g., ImmTOR) may be infused before, in combination with, or after the AAV infusion. This allows the dose to be titrated according to the patient's response as needed.

[0132] In some embodiments, the route of administration is injection into the SCS. In some embodiments, genetic diseases or disorders are diagnosed by Sanger sequencing, next-generation sequencing, high-throughput screening, exome sequencing, Maxam-Gilbert sequencing, chain termination methods, shotgun sequencing, bridge polymerase chain reaction, single molecule real-time sequencing, ion torrent sequencing, pyrosequencing, sequencing by synthesis, combination probe anchor synthesis, sequencing by ligation, and nanopore sequencing. In some embodiments, ocular diseases or disorders are diagnosed by ophthalmic examination, ophthalmoscopy, ocular coherence tomography, retinal scanning, fluorescein staining, conjunctival staining, color vision testing, optic disc imaging, neurofiber layer analysis, corneal topography, and electro-examination. They are diagnosed by gene sequencing, including but not limited to diagnostic tests, fluorescein angiography, eye photography, mirror microscopy, visual field testing, ocular ultrasound, and combinations thereof:

[0133] In some embodiments, the patient exhibits elevated intraocular pressure and is diagnosed with early-stage pediatric primary open-angle glaucoma after ophthalmoscopic examination before significant optic nerve damage occurs. After injection, the hydrogel self-assembles in the SCS after delivery to provide continuous delivery of microRNA that inhibits myocillin expression, thereby reducing myocillin accumulation in the trabecular mesh, and consequently reducing intraocular pressure and the likelihood of optic nerve damage in the patient.

[0134] In another specific embodiment, a male child exhibited night blindness and was found to have reduced visual field and slight retinal degeneration upon examination. A blood sample was taken and sent for genetic testing to determine if the patient had a mutation in their CHM gene, including, for example, part or all of the CHM gene sequence as described in https: / / www.uniprot.org / uniprot / P24386, the full text of which is incorporated herein by reference, which encodes RAB escort protein 1 (REP1), which supports the diagnosis of early-stage chorioretinopathy.

[0135] The patient is then treated by administering an infusion system, in which a lyophilized AAV2 vector containing a retinal-specific promoter derived from the rhodopsin kinase (RK) promoter gene, which is linked to the human CHM gene and expressed in rods and cones, is subsequently reconstituted with an aqueous diluent. Upon reconstitution, the infusion solution contains approximately 10¹³ AAV vectors per milliliter. Once injected, the RK promoter and the human CHM gene will stably transfect photoreceptor cells, where a modified form of REP 1 will be expressed to treat the patient's choriorethromycin.

[0136] In another specific embodiment, an elderly patient presents with central vision defects. Drusen are detected during a routine retinal examination. Fluorescein angiography reveals a leaking choroidal vascular system confirmed by the presence of subretinal fluid accumulation observed on OCT (Optical Coherence Tomography). The patient is diagnosed with early-stage neovascular age-related macular degeneration (AMD).

[0137] The patient is then treated by administering, via an infusion system, any subtype containing but not limited to vascular endothelial growth factor (VEGF), VEGF-A, VEGF-A121, VEGF-A165, VEGF-A189, VEGF-A206, VEGF-B, VEGF-C, VEGF-D, VEGF receptor (VEGFR), VEGFR-1, VEGFR-2, VEGFR-3, NOTCH-regulated ankyrin repeat protein (NRARP), and other angiogenesis-promoting proteins encoding these genes, either alone or in combination. The siRNA is delivered as a suspension on a liposomal carrier. After delivery, the siRNA knocks down the expression of the angiogenesis-promoting proteins or proteins, thereby preventing further choroidal capillary growth and inducing capillary regression, which reduces choroidal capillary retinal and macular infiltration and improves central vision. In certain embodiments, siRNA is targeted to knock down VEGFR-2, which has a gene sequence or isoform thereof as described in https: / / www.uniprot.org / uniport / P35968, the whole of which is incorporated herein.

[0138] In another specific embodiment, a patient diagnosed with neovascular AMD or diabetic retinopathy is treated by administering an injection system containing a gene that generates an RNA sequence complementary to at least a portion of the mRNA translated into VEGFR-2 when an AAV vector or other transfection vector is transcribed. When this gene therapy is delivered to the SCS, the choroidal capillaries, also known as choroidal capillaries, come into contact with the delivered therapeutic agent that targets transfection of cells expressing VEGFR-2. Upon transfection, the transcribed siRNA or shRNA vector reduces neovascularization to treat AMD or diabetic retinopathy by knocking down or knocking out VEGFR-2 production.

[0139] A physician may be provided with a choroidal infusion assembly or kit comprising (1) a volume of an infusion agent containing one or more therapeutic formulations, i.e., an active formulation containing an effective amount of a drug useful for treating, for example, the condition of a patient's eye; (2) an infusion system as described above; and (3) optionally, an injector for facilitating the release of the infusion agent into and through the infusion system membrane.

[0140] As mentioned above, the formulation may include various forms such as solutions and suspensions of various viscosities. The entire kit, including the formulation, injection system, and facilitating injector, is sterile.

[0141] In some embodiments, the total volume of the activator formulation to be injected into the supracorachaelinal space is preferably in the range of approximately 0.01–0.5 mL. In some embodiments, the activator may be provided in a lyophilized form and with an accompanying diluent to form a suspension at the time of injection. In some embodiments, the activator may be pre-mixed. In some embodiments, the infusion system may be pre-filled with the pre-mixed formulation. In some embodiments, the user may fill the infusion system immediately before administering the therapeutic agent to the patient. In some embodiments, the infusion system may include multiple chambers with brittle separation. In some embodiments, the puncture element has an initial penetration length of 0.01 to 3 mm and expands further during the infusion. In some embodiments, the infusion system and the injection promoter may be pre-assembled with the pre-filled formulation and may be ready for use without any additional assembly. In some embodiments, the entire kit is packaged in a single pouch / tray to maintain sterility. In some embodiments, the components are packaged individually or in combination. In some embodiments, the kit is sterilized together or separately by one of the sterilization methods including, but not limited to, an autoclave, ethylene oxide, gamma rays, etc.

[0142] In some embodiments where the components are present in a secondary package. In some embodiments, the kit is stored as a set at a temperature low enough to extend the shelf life of the active pharmaceutical agent. In some embodiments, the formulation is stored separately at a low temperature, while the rest of the kit is stored at room temperature.

[0143] Numerous variations and optional embodiments of the present invention will be apparent to those skilled in the art in light of the foregoing description. Accordingly, this description should be interpreted merely as illustrative and is intended to instruct those skilled in the art of the best mode for carrying out the present invention. Details of the structure may be substantially altered without departing from the spirit of the invention, and exclusive use of any modifications within the scope of the appended claims is reserved. Although embodiments within this specification have been described in a manner that allows for a clear and concise specification, it is intended and understood that embodiments may be combined or separated in various ways without being separated from the present invention. The present invention is intended to be limited only to the extent required by the appended claims and applicable legal rules.

[0144] The following claims should be understood to include all general and specific features of the invention as described herein, and all statements of the scope of the invention that may be said to exist between them as a matter of language.

Claims

Claim 1 In an infusion system, an infusion barrel forming a lumen between a proximal end and a distal end; a first sealing element movably disposed within the lumen; a second sealing element movably disposed within the lumen adjacent to the first sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and form an infusion chamber between them; a puncture element extending from the distal end of the first sealing element, wherein the puncture element is in fluid communication with the infusion chamber to deliver an infusion agent from the infusion chamber to a space within the patient's tissue; and a unidirectional stop disposed within the infusion barrel between the first sealing element and the second sealing element, wherein the unidirectional stop is configured to prevent proximal movement of the first sealing element past the unidirectional stop, and simultaneously, the second sealing element passes through the unidirectional stop and contacts the first sealing element. An injection system comprising, wherein one or more of an injector barrel, a first sealing element, a second sealing element, and a unidirectional stop are configured such that the second sealing element contacts the first sealing element while preventing the first sealing element from moving past the unidirectional stop to a proximal portion of the first sealing element. Claim 2 An injection system according to claim 1, wherein the unidirectional stop comprises a section of an injector barrel having a reduced diameter, the diameter of a first sealing element is sufficiently larger than the reduced diameter so as not to allow the first sealing element to pass through the section, and a second sealing element is configured to pass through the section and contact the first sealing element. Claim 3 An injection system according to claim 1, characterized in that the unidirectional stop comprises a portion of the inner surface of the injector barrel having a friction coefficient sufficient to prevent proximal movement of the first sealing element. Claim 4 An injection system according to claim 1, characterized in that the unidirectional stop includes a mechanical stop. Claim 5 An injection system according to claim 1, wherein the unidirectional stop comprises a foldable stop disposed between a first sealing element and a second sealing element, wherein the foldable stop is configured to prevent the first sealing element from moving proximally past the foldable stop, and wherein when a force is applied distally to the foldable stop, the foldable stop is folded so that the second sealing element can pass through the foldable stop and come into contact with the first sealing element. Claim 6 An injection system according to claim 1, wherein the first sealing element is characterized in that the first frictional force or sliding force against the first sealing element in the proximal direction is greater than the second frictional force or sliding force against the first sealing element in the distal direction, and is greater than the force for inserting the puncture element into the tissue. Claim 7 An injection system according to claim 1, characterized in that, in a relaxed state, the first sealing element has a size 1.01 to 2 times larger than the lumen size of the injector barrel. Claim 8 An injection system according to claim 1, characterized in that, in a relaxed state, the first sealing element has a size 1.01 to 1.10 times larger than the lumen size of the injector barrel. Claim 9 An injection system according to claim 1, characterized in that the inner surface of the injector barrel is modified to increase friction between the inner surface of the injector barrel and the first sealing element. Claim 10 An injection system according to claim 1, further comprising a locking device positioned at the distal end of a first sealing element and configured to selectively secure the first sealing element in place. Claim 11 An injection system according to claim 10, wherein the locking device comprises a sealed compartment defined in the lumen of an injector barrel distal to a first sealing element, an incompressible material inside the compartment, and a valve for releasing the incompressible material from the compartment, wherein when the valve is closed, distal movement of the first sealing element is prevented, and when the valve is opened, distal movement of the first sealing element is allowed. Claim 12 An injection system according to claim 1, further comprising a touch trigger mechanism disposed between a first sealing element and a second sealing element, wherein the touch trigger mechanism is configured to deploy when the first sealing element contacts the second sealing element in order to prevent distal movement of the first sealing element. Claim 13 An injection system according to claim 1, further comprising a filling port disposed on the surface of an injector barrel and fluidly communicating with an injection chamber. Claim 14 An infusion system according to claim 13, wherein the charging port comprises: a receptacle disposed on the outer surface of an injector barrel and configured to receive a vial; a channel connecting the receptacle and the infusion chamber; a self-sealing member configured to seal the channel; and a puncture element disposed in the receptacle, wherein the puncture element is configured to penetrate the self-sealing member to fluidly connect the vial containing the injectable agent received in the receptacle and the infusion chamber. Claim 15 An infusion system according to claim 14, wherein the puncture element is movable relative to a receptacle, so that when a vial is received in the receptacle, the puncture element moves toward the infusion chamber to penetrate a self-sealing member and fluidically connect the vial to the infusion chamber, and when the vial is removed from the receptacle, the puncture element moves away from the infusion chamber, thereby enabling the self-sealing member to seal the flow path. Claim 16 An injection system according to claim 1, characterized in that a support element is positioned around a distal portion of a puncture element, and the support element is configured to be movable relative to the puncture element and the injector barrel. Claim 17 An injection system according to claim 1, wherein the injection chamber comprises a first chamber and a second chamber, and the sealing portion of the second sealing element fluidly isolates the first chamber from the second chamber, thereby fluidly connecting the first and second chambers according to the movement of the sealing portion. Claim 18 An injection system according to claim 1, wherein the injection chamber comprises a first chamber and a second chamber, wherein the first chamber and the second chamber are fluidly isolated from each other when the second sealing element is in an initial position, and the first chamber and the second chamber are fluidly connected by the movement of the second sealing element. Claim 19 An injection system according to claim 1, characterized in that the second sealing element engages with the first sealing element and is configured to draw the first sealing element and the puncture element into the injector barrel. Claim 20 A kit for injecting an injectable agent into tissue, comprising an injection system, wherein the injection system comprises: an injector barrel forming a lumen between a proximal end and a distal end; a first sealing element movably disposed within the lumen; a second sealing element movably disposed within the lumen adjacent to the first sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and form an injection chamber between them; a puncture element extending from the distal end of the first sealing element, wherein the puncture element is in fluid communication with the injection chamber to deliver the injectable agent from the injection chamber to a space within the patient's tissue; A kit characterized by comprising: a unidirectional stop disposed between a first sealing element and a second sealing element within an injector barrel, wherein the unidirectional stop is configured to allow the second sealing element to pass through the unidirectional stop and contact the first sealing element while preventing the first sealing element from moving proximally past the unidirectional stop, and at least one of the injector barrel, the first sealing element, the second sealing element, and the unidirectional stop is configured to allow the second sealing element to contact the first sealing element while preventing the first sealing element from moving proximally past the unidirectional stop; and a volume of an injectable fluid comprising one or more injectable formulations. Claim 21 A kit according to claim 20, characterized in that the injection system further comprises a locking device positioned at the distal end of a first sealing element and configured to selectively secure the first sealing element. Claim 22 A kit according to claim 20, wherein the injection system further comprises a touch trigger mechanism between a first sealing element and a second sealing element, and the touch trigger mechanism is configured to deploy when the first sealing element contacts the second sealing element to prevent distal movement of the first sealing element. Claim 23 A kit according to claim 20, characterized in that the injection system further comprises a filling port disposed on the surface of an injector barrel and fluidly communicating with an injection chamber. Claim 24 A kit according to claim 23, wherein the filling port comprises: a receptacle disposed on the outer surface of an injector barrel and configured to receive a vial; a channel connecting the receptacle and the injection chamber; a self-sealing member configured to seal the channel; and a puncture element disposed in the receptacle, wherein the puncture element is configured to penetrate the self-sealing member to fluidly connect the vial received in the receptacle with the injection chamber. Claim 25 A kit according to claim 20, wherein the injection chamber comprises a first chamber and a second chamber, and the sealing portion of the second sealing element is configured to fluidly isolate the first chamber from the second chamber so that the movement of the sealing portion fluidly connects the first and second chambers. Claim 26 A kit according to claim 20, wherein the injection chamber comprises a first chamber and a second chamber, wherein the first chamber and the second chamber are fluidly isolated from each other when the second sealing element is in an initial position, and the first and second chambers are fluidly connected by the movement of the second sealing element. 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