Motorized injection system and method of use

Abstract

Systems and methods for injection into a cavity are provided. In some embodiments, the injection system includes an injection assembly, which includes a syringe barrel that defines a lumen between a proximal end and a distal end; and a second sealing element that is movably disposed in the lumen to dispense an injection from an injection chamber defined in the syringe barrel. The piercing element delivers the injection into a space in the tissue. The permeability of the tissue to the injection is lower than the permeability of the space to the injection. The injection system also includes: a support platform for supporting the injection assembly and anchoring the injection assembly relative to the injection site; a drive assembly for operating the injection assembly; one or more sensors for monitoring one or more forces on the injection assembly; and a controller that communicates with the one or more sensors to receive information related to one or more forces on the injection system.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Application Serial No. 63 / 064975, filed on August 13, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to a system and method capable of injecting into a cavity or space, and in particular, injecting through tissue into a cavity or space in the human body, such as the suprachoroidal space in ocular tissue. Background Art

[0004] The present disclosure relates to a device and method capable of delivering a variety of therapeutic agents to a cavity or space of the human body, and in particular to ocular tissue in the posterior segment of the eye, through the suprachoroidal space. Posterior segment eye diseases are the leading cause of permanent visual impairment affecting millions of people and can lead to blindness if not treated in time. It includes a variety of diseases such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema (DME), choroidal leukoplakia (CHM), retinal vein occlusion (RVO), uveitis and endophthalmitis. Although drug formulations can be used to prevent disease progression in many cases, systemic delivery cannot reach therapeutic concentrations in the posterior segment due to the blood-ocular barrier.

[0005] Recently, the suprachoroidal space (SCS) has been explored as a potential drug delivery route to the posterior part of the eye. The suprachoroidal space is a potential space between the sclera and the choroid. Drugs delivered in this space can bypass the eyeball and reach the posterior segment of the eye. This route of drug delivery has been shown to be more effective than intravitreal injection for the treatment of the posterior segment. However, the simplicity of intravitreal injection exceeds the surgical procedures required for previous choroidal delivery. Historically, choroidal delivery was achieved by creating a small incision using a scalpel, followed by delivery using a needle or cannula. Recently, microneedles with predefined, short lengths have been used to target the suprachoroidal space, which only allow penetration to a certain depth. Because scleral thickness varies significantly among patient populations, it is necessary to either draw the eye geometry in advance or to repeat trials when injecting with hollow microneedles. If the needle is too long, it can easily penetrate the thin suprachoroidal space to inject the drug into the vitreous body; and, if it is too short, it will be delivered to the sclera. The sclera is 10 times harder than the choroid and 200 times harder than the retina, making it even more challenging to penetrate the sclera without injecting the vitreous. In some instances, a small amount (approximately 100 microliters) of the therapeutic agent needs to be injected into the suprachoroidal space, and it needs to be injected with enough force to eliminate the positive resistance of the intraocular pressure pressing the choroid against the sclera to achieve extensive coverage of the posterior segment of the eye. This may be difficult to achieve using a conventional handheld syringe.

[0006] Therefore, there is a need for an improved system and method for choroidal drug delivery that accurately, consistently, and safely targets the suprachoroidal space and provides extensive coverage of the posterior segment of the eye. Summary of the invention

[0007] According to some aspects of the present disclosure, there is provided an injection system including an injection assembly, the injection assembly including: a syringe barrel, the syringe barrel defining a lumen between a proximal end and a distal end; and a second sealing element, the second sealing element being movably disposed in the lumen to dispense an injection from an injection chamber defined in the syringe barrel; and a piercing element, the piercing element being configured to deliver the injection to a space in the patient's tissue. The permeability of the tissue to the injection is lower than the permeability of the space to the injection. The injection system also includes: a support platform, the support platform being configured to support the injection assembly and anchor the injection assembly relative to the injection site; a drive assembly, the drive assembly being configured to operate the injection assembly; one or more sensors, the one or more sensors being configured to monitor one or more forces on the injection assembly; and a controller, the controller communicating with the one or more sensors to receive information related to one or more forces on the injection system. The controller is configured to operate the drive assembly based on the information to advance the piercing element through the tissue toward the space so that the injection remains in the injection chamber until the piercing element fluidly connects the injection chamber to the space.

[0008] In some embodiments, the injection assembly further includes a first sealing element, which is movably disposed in the lumen and is distal to the second sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and define an injection chamber between the first sealing element and the second sealing element. The piercing element can be in fluid communication with the injection chamber to deliver the injection from the injection chamber to the space in the patient's tissue. When a force is applied to the second sealing element in the distal direction, in response to a first reaction force as the piercing element advances through the tissue without delivering the injection through the piercing element, the first sealing element moves in the distal direction to advance the piercing element in the distal direction; and in response to a second reaction force when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the injection is delivered from the injection chamber through the piercing element.

[0009] In some embodiments, the drive assembly is linked to the second sealing element to apply force to the second sealing element, thereby translating the second element in the distal direction. In some embodiments, the drive assembly includes a linear actuator, which is linked to the second sealing element to apply force to the second sealing element, thereby translating the second element in the distal direction. In some embodiments, the drive assembly includes: a first driver and a second driver, the first driver is configured to translate the syringe barrel relative to the support platform, and the second driver is linked to the second sealing element to translate the second sealing element relative to the syringe barrel. One or more sensors may include: a first force sensor, the first force sensor is configured to measure the force on the syringe barrel, and one or more sensors may include: a second force sensor, the second force sensor is configured to measure the force on the second sealing element. In some embodiments, one or more sensors include one or more of the following: a pressure sensor, a force sensor, a stress sensor, a position sensor, or a low-rate sensor.

[0010] In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the first reaction force and the second reaction force. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the pre-insertion of the piercing element into the tissue, wherein the one or more feedback loops are configured to monitor the increase of the force on the piercing element, to detect the decline of the force on the piercing element, and to advance the piercing element to a predetermined distance based on the decline, so that the piercing element is embedded in the tissue. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the advancement of the piercing element through the tissue, and the one or more feedback loops are configured to measure the load on the second sealing element, and once the piercing element reaches the space in the tissue, the decline of the load is detected. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the injection of the injection into the space, wherein the one or more feedback loops are configured to control the speed or advancement distance of the second sealing element. In some embodiments, the controller is programmed to retract the piercing element to a predetermined distance when one or more sensors detect the decline of the load on the second sealing element. In some embodiments, the controller is programmed to control the stopping distance of the piercing element when the piercing element enters the space.

[0011] In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is the sclera and the space is the suprachoroidal space. In some embodiments, the tissue is the sclera and the choroid and the space is the intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye.

[0012] In some aspects, the present disclosure provides an injection system, the injection system includes an injection assembly, the injection assembly includes: a syringe barrel, the syringe barrel defines a lumen between a proximal end and a distal end; a first sealing element and a second sealing element, the first sealing element and the second sealing element are movably disposed in the lumen. The second sealing element is at the distal end of the first sealing element to define an injection chamber. The piercing element can be fluidly connected to the injection chamber and is configured to deliver an injection from the injection chamber to a space in the patient's tissue. The permeability of the tissue to the injection is lower than the permeability of the space to the injection. The injection system also includes: a support platform, the support platform is configured to support the injection assembly and anchor the injection assembly relative to the injection site; a drive assembly, the drive assembly is configured to translate one or both of the syringe barrel or the second sealing element relative to the support platform; one or more sensors, the one or more sensors are configured to monitor one or more forces on the injection assembly; and a controller, the controller communicates with the one or more sensors to receive information related to one or more forces on the injection system. A controller in communication with one or more sensors receives information about one or more forces on the injection system and is configured to control the drive assembly based on the information to advance the piercing element through the tissue toward the space, so that when the drive assembly translates the second sealing element in the distal direction, in response to a first reaction force as the piercing element advances through the tissue, the first sealing element moves in the distal direction to advance the piercing element in the distal direction without delivering an injectable agent through the piercing element; and in response to a second reaction force when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the injectable agent is delivered from the injection chamber through the piercing element.

[0013] In some embodiments, the drive assembly is configured to translate the syringe barrel and the second sealing element independently of each other relative to the support platform. In some embodiments, the drive assembly is linked to the second sealing element to apply a force to the second sealing element to translate the second element in the distal direction. In some embodiments, the drive assembly includes a linear actuator that is linked to the second sealing element to apply a force to the second sealing element to translate the second element in the distal direction. In some embodiments, the drive assembly includes: a first driver and a second driver, the first driver is configured to translate the syringe barrel relative to the support platform, and the second driver is linked to the second sealing element to translate the second sealing element relative to the syringe barrel.

[0014] In some embodiments, the one or more sensors include: a first force sensor configured to measure the force on the syringe barrel. In some embodiments, the one or more sensors include: a second force sensor configured to measure the force on the second sealing element. In some embodiments, the one or more sensors include: one or more of the following: a pressure sensor, a force sensor, a stress sensor, a position sensor, or a low rate sensor.

[0015] In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the first reaction force and the second reaction force. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the pre-insertion of the piercing element into the tissue. One or more feedback loops can be configured to monitor the increase of the force on the piercing element, to detect the decline of the force on the piercing element, and to advance the piercing member to a predetermined distance based on the decline, so that the piercing element is embedded in the tissue. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the advancement of the piercing element through the tissue, and the one or more feedback loops are configured to measure the load on the second sealing element, and once the piercing element reaches the space in the tissue, the decline of the load is detected. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the injection of the injection into the space, wherein one or more feedback loops are configured to control the speed or advancement distance of the second sealing element. In some embodiments, the controller is programmed to retract the piercing element to a predetermined distance when one or more sensors detect the decline of the load on the second sealing element. In some embodiments, the controller is programmed to control the stopping distance of the piercing element when the piercing element enters the space.

[0016] In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is the sclera and the space is the suprachoroidal space. In some embodiments, the tissue is the sclera and the choroid and the space is the intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye.

[0017] A method for delivering an injection is provided, which includes inserting a piercing element into a tissue. The piercing element can be configured to deliver the injection from an injection chamber to a space in the tissue, wherein the tissue has a density greater than the space, so that the permeability of the tissue to the injection is lower than the permeability of the space to the injection. The method also includes using a drive assembly to propel the piercing element through the tissue toward the space, using one or more sensors to monitor one or more forces on the piercing element, and controlling the drive assembly using a controller that communicates with the one or more sensors to propel the piercing element through the tissue toward the space, so that the injection remains in the injection cavity until the piercing element fluidically connects the injection chamber to the space.

[0018] In some embodiments, the piercing element is positioned on the distal end of an injection assembly, which includes: a syringe barrel defining a lumen between a proximal end and a distal end; and a first sealing element and a second sealing element, which are movably disposed in the lumen to dispense an injection from an injection chamber. In some embodiments, in response to a first reaction force of one or more forces on the piercing element as the piercing element is advanced through tissue, the first sealing element moves in a distal direction to advance the piercing element in a distal direction without delivering the injection through the piercing element. In some embodiments, in response to a second reaction force of one or more forces on the piercing element when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves in a distal direction, so that the injection is delivered from the injection chamber to the space through the piercing element.

[0019] In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is the sclera and the space is the suprachoroidal space. In some embodiments, the tissue is the sclera and the choroid and the space is the intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye.

[0020] A method for delivering an injection is provided, the method comprising: positioning an injection assembly near a tissue. The injection assembly comprises: a syringe barrel defining a lumen between a proximal end and a distal end; and a second sealing element movably disposed in the lumen to dispense the injection from an injection chamber defined in the syringe barrel; and a piercing element extending and configured to deliver the injection into a space in the tissue. The tissue has a density greater than the space, so that the permeability of the tissue to the injection is lower than the permeability of the space to the injection. The method also comprises using one or more sensors to monitor one or more forces on the injection assembly, and using a controller that communicates with the one or more sensors to control the injection assembly using the force on the injection system so that the piercing element is advanced through the tissue toward the space so that the injection remains in the injection chamber until the piercing element fluidly connects the injection chamber with the space.

[0021] In some embodiments, in response to a first reaction force in one or more forces on the piercing element when the piercing element is advanced through the tissue, the first sealing element moves in a distal direction to advance the piercing element in a distal direction without delivering the injection through the piercing element. In some embodiments, in response to a second reaction force in one or more forces on the piercing element when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves in a distal direction so that the injection is delivered from the injection chamber to the space through the piercing element. In some embodiments, the method further includes anchoring the injection assembly relative to the injection site in the tissue.

[0022] In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is the sclera and the space is the suprachoroidal space. In some embodiments, the tissue is the sclera and the choroid and the space is the intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] The present disclosure is further described in the following detailed description, by way of non-limiting examples of exemplary embodiments, with reference to the several drawings, wherein like reference numerals represent similar parts throughout the several views of the drawings, and wherein

[0024] Figure 1A An exemplary graph of time (or displacement) versus force is illustrated to show the forces experienced by a motorized injection system when administering a therapeutic agent into tissue;

[0025] Figure 1B illustrates an exemplary graph of piston position versus applied force to illustrate the forces experienced by a motorized injection system when administering a therapeutic agent into tissue;

[0026] Figure 2 An exemplary embodiment of a motorized injection system is illustrated;

[0027] Figure 3A and Figure 3B An exemplary embodiment of a drive assembly for a syringe barrel and a syringe plunger is illustrated;

[0028] Figure 4 An exemplary embodiment of a device for attaching and stabilizing a motorized injection system to an injection site is illustrated;

[0029] Figure 5A An exemplary embodiment of an injection system is illustrated;

[0030] Figure 5B Pictured Figure 5A Exemplary methods of using embodiments of the injection system;

[0031] Fig. 6A , Figure 6B , Figure 6C and Fig.6D An embodiment of the use of a motorized injection system with an automatic stop injector is illustrated;

[0032] Fig. 7A and Figure 7B It is shown Figure 6A-6D A flow chart of the use of the system shown in;

[0033] Fig. 8A , Figure 8B , Figure 8C , Fig.8D and Fig. 8E An embodiment of the use of a motorized injection system with an automatic stop injector is illustrated;

[0034] Fig. 9A and Fig. 9B It is shown Figure 8A-8E A flow chart of the use of the system shown in;

[0035] Fig. 10A , Fig. 10B , Fig. 10C , Fig. 10D and Fig.10E An embodiment of the use of a motorized injection system with an automatic stop injector is illustrated;

[0036] Fig.11A and Fig. 11B It is shown Figure 10A-10E A flow chart of the use of the system shown in;

[0037] Fig.12 An embodiment of an injection system of the present disclosure having a fast-fill port is shown;

[0038] Figure 13A-13B and Figure 14A-14B An exemplary process of filling an injection system of the present disclosure through a fast-fill port is illustrated;

[0039] Figure 15A-15B An exemplary process for backfilling the injection system of the present disclosure is shown;

[0040] Figure 16A-16B An exemplary process of filling an injection system of the present disclosure through a port in the proximal end is shown;

[0041] Figure 17A-Figure 17C An exemplary process of filling an injection system of the present disclosure through a port sealed with a self-sealing polymer is shown;

[0042] Figures 18A-18DAn embodiment of an injection system of the present disclosure having a port at the distal end is shown; and

[0043] Fig.19 is an exemplary embodiment of a computing system for use with various embodiments of the present disclosure.

[0044] Although the above-identified drawings illustrate the presently disclosed embodiments, other embodiments are contemplated as noted in the discussion. The present disclosure presents illustrative embodiments by way of representation and not limitation. Numerous other modifications and embodiments may be designed by those skilled in the art, which fall within the scope and spirit of the principles of the presently disclosed embodiments. DETAILED DESCRIPTION

[0045] The present disclosure provides a motorized injection system for delivering therapeutic agents into a potential space or cavity in a tissue. In some embodiments, such a system can be used to deliver drugs to the suprachoroidal space. In some embodiments, such a system is automated and consists of a sensor and a feedback loop. Thus, the system of the present disclosure can be configured to accurately, consistently and safely target the suprachoroidal space and provide extensive coverage of the posterior segment of the eye.

[0046] In some embodiments, the injection system includes: a syringe barrel for containing one or more injectables; a penetrating element (also referred to as a needle, but similar devices may be used) attached to the syringe barrel and in fluid communication with the syringe barrel; a sealing element (also referred to as a push plunger) that expels the injectable from the syringe barrel through the needle. As described in more detail below, the injection system may include a regular syringe or an auto-stop syringe with multiple sealing elements as described in more detail below.

[0047] Figure 1A and Figure 1B The forces experienced by a motorized injection system when administering a therapeutic agent into a tissue cavity through a piercing member or element (interchangeably referred to as a needle, but similar devices may be used). In stage I, the needle is pre-inserted into tissue (e.g., the sclera of the eye). Reference Figure 1A During the pre-insertion of the needle into the tissue (the injection system is moved towards the tissue), a load cell attached to the injection system records an increasing force until the needle pierces the tissue. When the tissue is pierced, there may be a drop in the load. Figure 1B, which shows the load applied after stage I is completed, once the insertion is completed, the contents of the injection system can be pressurized by advancing the push plunger. As the plunger advances, the load on the plunger can remain constant at this stage until the pressure in the syringe barrel begins to increase. Next, in stage II, the needle is pushed through the tissue toward the cavity (e.g., the suprachoroidal space of the eye). At this stage, due to the low water permeability of the tissue, the contents of the injection system remain pressurized. The load on the injection system increases, and may be stable. In stage III-a, the needle tip enters the cavity (e.g., the suprachoroidal space of the eye). Because the density of the cavity is less than the density of the tissue, the back pressure generated by the cavity relative to the needle is less than the back pressure generated by the tissue. Therefore, once the lumen of the needle opens into the cavity, the load on the plunger will decrease due to the reduction in back pressure. The decrease in back pressure indicates that the needle lumen is in the cavity, and the needle can (either by the system or due to the automatic adjustment design as discussed below) prevent the needle from being pushed deeper into the cavity. In some embodiments, the therapeutic agent may be pressurized to a pressure that is insufficient to expel the therapeutic agent into the tissue, but sufficient to expel the therapeutic agent into the cavity. Thus, once the needle opens into the cavity, the pressure of the pressurized therapeutic agent decreases, and when force is applied to the push plunger, the needle stops moving forward. In stage III-b, when force is applied to the needle plunger, the therapeutic agent is injected into the cavity at a preselected rate. The force required to administer the therapeutic agent may depend on the density and viscosity of the therapeutic agent, the friction or sliding force between the plunger and the drug chamber, the inner diameter of the drug chamber, the length of the needle, and the inner diameter of the needle. In some embodiments, once the needle reaches the cavity, the system may continue to advance the push plunger to inject the therapeutic agent into the cavity without interruption. In some embodiments, once the needle lumen reaches the cavity, the push plunger may be stopped, and then restarted to inject the therapeutic agent into the cavity.

[0048] refer to Figure 2 The motorized injection system 10 of the present disclosure includes a housing or support platform 12 that supports the injection system 14, a drive assembly or drive mechanism 16, and one or more sensors for measuring the load on the injection system or its components. The support platform 12 is configured to anchor the automatic injection system in a fixed position relative to the injection site. In some embodiments, the motorized injection system 10 may further include a controller that communicates with the drive assembly or one or more units to perform process control on the injection. In some embodiments, the controller can be configured to monitor the rate and force of the injection. In some embodiments, the controller can be configured to provide a feedback mechanism to the user. In some embodiments, the controller can be configured to trigger the movement of either the syringe or the push plunger or both in response to feedback from a separate one or more force sensors or tracking of the distance moved by the push plunger, the syringe, or the differential motion of one relative to the other.

[0049] In some embodiments, the injection system may include: a syringe including a syringe barrel defining a drug chamber for storing a therapeutic agent; a needle 15, which is fluidically connected to the drug chamber to administer the therapeutic agent from the drug chamber; and a plunger 11, which is slidably disposed in the syringe barrel and is configured to expel the therapeutic agent from the drug chamber through the needle 15.

[0050] In some embodiments, a standard syringe can be used so that the drug chamber can have a volume between about 0.1 ml and 20 ml, but larger or smaller syringes can also be used. In some embodiments, the drug chamber can have a volume of about 0.1 ml, 0.5 ml, 1 ml, 3 ml, 5 ml, or 10 ml before fluid displacement.

[0051] In some embodiments, the needle can be a standard needle between 34G and 25G. In some embodiments, the needle can be a standard 30G needle. As discussed above, various needle sizes can be used to deliver therapeutic treatments to the SCS. In some embodiments, particularly for higher viscosity preparations (e.g., greater than 10 centipoise), a needle with a larger lumen can be used. The pre-insertion step required to block fluid flow may set limits on the range of needle lumen diameters and bevel sizes that can be effectively used to target the SCS. In some embodiments, considering the minimum human scleral thickness, if the needle is inserted perpendicular to the scleral surface, the best results can be obtained by limiting the pre-insertion depth to less than or equal to about 0.5 mm (e.g., between about 0.05 mm and 0.5 mm). If inserted at an angle other than vertical, a needle with a longer bevel can be fully inserted without piercing the sclera. For example, based on geometric dependencies, a 30-gauge needle with a standard bevel (angle: 12 degrees, length: 1.45 mm) inserted into the surface at an angle less than or equal to about 20° will reach a depth of less than 0.5 mm when typically measured from the surface. Similarly, larger needles with longer bevel lengths can also be used. For a given needle size, a shorter bevel allows a larger range of pre-insertion angles. Broadly speaking, needles with an outer diameter less than about 0.5 mm of scleral thickness can be easily used to enter the SCS, and the angle of needle insertion is determined based on the length of the beveled tip. In some embodiments, the volume of the drug chamber is between 20 and 200 microliters. Needle For improved tactile and signal-to-noise ratio of the distance tracking element, in some embodiments, the stroke of the push plunger that delivers the therapeutic fluid or suspension is at least 1 cm in length. For some embodiments, the flow rate of the injection is targeted at an average of between 0.2 and 20 microliters per second. In some embodiments, the syringe barrel is lined with silicone oil, silicone rubber, rubber, glass, polytetrafluoroethylene, or polypropylene to minimize absorption of the therapeutic agent to the inner surface of the syringe barrel.

[0052] In some embodiments, the friction between the syringe barrel and the plunger can be designed to optimize the performance of the system. For example, the size of the system can be designed so that the static friction coefficient and the dynamic friction coefficient are approximately equal, so that there is no unexpected acceleration of the needle. On the other hand, the static friction coefficient can be higher than the dynamic friction coefficient, so that the needle stops in the cavity after it has a high force obstacle to overcome. The high static friction of the needle plunger also allows high fluid flow rates to be achieved during injection while maintaining the needle tip position. In some embodiments, once the lumen is exposed to the cavity, the needle-plunger-dynamic friction is enough to prevent the needle from moving. However, the dynamic coefficient can still be limited so that the internal pressure in the syringe barrel will not be high enough to cause the rupture of the tissue or the damage of the tissue.

[0053] refer to Figure 3A and Figure 3B In some embodiments, the drive assembly is configured to independently operate the syringe barrel (for example, for pre-inserting the needle into the tissue) and the syringe plunger. The drive assembly is designed to translate the syringe barrel toward the patient relative to the support platform 12 to pre-insert the needle into the tissue, and then away from the patient to withdraw the needle from the tissue. The drive assembly also applies a force on the plunger to translate the plunger within the syringe barrel to advance the needle through the tissue toward the cavity and dispense the therapeutic agent from the drug chamber. In some embodiments, the drive assembly may include separate drives for the syringe barrel and plunger. In some embodiments, each such drive may include a linear actuator linked to the syringe barrel or plunger and a force sensor for sensing the load on the syringe barrel or plunger. As shown in FIG. Figure 3A-3B As shown, the drive mechanism 20, 22 may include motors 24, 26, respectively, which are configured to drive the movement of the drive mechanism 20, 22 (such as, for example, through lead screws 25, 27 and actuators 32, 34). Each of the drive mechanisms 20, 22 may also include at least one load cell 28, 30 configured to sense the load on the syringe barrel or syringe plunger, respectively. In some embodiments, such a design can allow the system to advance the syringe barrel without advancing the plunger, and measure the force at the same time. For example, when the syringe barrel moves, the push plunger can move with it. When the needle is pre-inserted, the force is measured on the syringe barrel. After pre-insertion, the force is measured on the push plunger. During pre-insertion, once the force indicating the contact of the needle with the tissue is sensed, the needle will be moved forward by a set distance, thereby embedding the lumen of the needle into the tissue.

[0054] In some embodiments, the linear actuator can be a mechanical actuator, including, for example, a lead screw and nut or gear driven by a motor, but other designs can also be used. In some embodiments, a pneumatic actuator, a hydraulic actuator, an electromechanical actuator, a magnetic actuator or other types of linear actuators can also be used. In some embodiments, a single actuator can be used to drive both a syringe barrel and a plunger. The different movements of a syringe barrel and a plunger can be achieved by engaging / disengaging a gear mechanism. In some embodiments, the linear motion of the plunger can be achieved by applying hydraulic pressure.

[0055] refer to Figure 4 , the motorized injection system of the present disclosure may also include means for attaching and stabilizing the system relative to the injection site. In this way, with the syringe barrel secured in place by the attachment and stabilization system, the user can have both hands free while maintaining a fixed xy coordinate for injection. In other cases, the syringe barrel is only secured in the xy plane, and the syringe can be pushed or pulled toward or away from the eye in the z plane by the user to perform the injection. In some embodiments, for SCS injections, the motorized injection system may include an adjustable headband 200 that can be adjusted by a ratchet or other mechanism (such as, Figure 4 ) to fit the size. In some embodiments, other parts of the patient's face (such as the eye sockets, temples, chin, ears, nose, etc.) can be used to mount the system. In some embodiments, the motorized injection system can be attached to a fixed support, and the patient can press his or her face against the support (similar to an eye examination). Additionally or alternatively, the motorized injection system of the present disclosure may include a guide support 204 (such as a tripod, bipod, or monopod support) that is attached to the headband or to the motorized injection system 10 or to both the headband and the motorized injection system 10 to stabilize the injection system relative to the eye. In some embodiments, the motorized injection system of the present disclosure may further include a contact pad that can be pressed against the tissue being injected with the therapeutic agent to stabilize the insertion site or adjust the insertion angle. In some embodiments, the stabilizing tripod mentioned above can be used to fix the eye in place. For example, for ocular injections, such pads may be sized and shaped to prevent eye rotation when pressed against the sclera by the user (the relative angle of injection is controlled). In some embodiments, the component used to prevent significant rotation of the eye may be a separate device not attached to the motorized injection system.

[0056] Sensors and feedback loops

[0057] In some embodiments, the motorized system of the present disclosure includes a plurality of sensors that can measure one or more parameters throughout the injection process. One or more sensors can communicate with a controller to implement one or more feedback loops to control the various steps of the injection process. Various types of sensors or other mechanisms can be used to control the injection steps, including but not limited to force sensors and sensors such as pressure sensors, stress sensors and / or force sensors, which will be discussed in more detail below.

[0058] In some embodiments, the load applied by the drive assembly to the syringe barrel and the push plunger can be measured and transmitted to the controller. In some embodiments, one or more force sensors can be used to measure the load. Such force sensors can be embedded in the needle, needle plunger, push plunger or both, or otherwise configured to receive signals from the needle, needle plunger, push plunger or both. In some embodiments, such loads can be measured by the motor being subjected to torque based on its correlation with the current drawn by the motor. In some embodiments, the motorized injection system can further include one or more sensors to monitor the position or movement of the injection system as a whole or a separate syringe barrel or plunger. Such information can be used to, for example, determine the distance traveled by the injection system, syringe barrel or plunger, needle plunger in combination or individually. In some embodiments, the motorized system may include one or more sensors to monitor its position or speed in combination or individually when the syringe barrel or plunger moves. For example, such information can be used to control the flow rate of the therapeutic agent or to prevent the push plunger from overshooting the desired injection volume. In some embodiments, a high-precision flow sensor including a microfluidic mass flow sensor can be used to monitor the flow rate.

[0059] In some embodiments, the system of the present disclosure can also measure the pressure in the syringe. In some embodiments, pressure can be indirectly measured by monitoring the load on the plunger. In some embodiments, the system can be configured so that the coefficient of kinetic friction and the coefficient of static friction between the plunger and the syringe barrel are both close to 1, to more accurately sense fluid pressure. In some embodiments, the motorized injection system can further include one or more pressure sensors, force sensors or stress sensors, for directly measuring the pressure of the therapeutic agent in the drug chamber.

[0060] In some embodiments, the relative position of the push plunger relative to the needle plunger in the case of an auto-stop syringe or the relative position of the push piston relative to the needle hub in the case of a standard syringe is monitored to determine the volume of therapeutic agent drawn into the syringe or injected into the cavity. In some embodiments, the travel distance measured after pre-insertion can have a limit set to minimize the chance of overshoot.

[0061] In some embodiments, one or more feedback loops may be implemented based on the load distribution during phase I-III-a (as described above in conjunction with Figure 1A-1B Discussed). In some embodiments, the feedback loop can monitor the axial load on the system during the pre-insertion of the needle into the tissue in stage I. In some embodiments, the load cell can be configured to directly or indirectly measure the axial load experienced by the needle. During the pre-insertion period, the axial load on the needle increases as the needle is pushed into the tissue, and the axial load drops once the needle pierces the tissue. Therefore, in some embodiments, the feedback loop is configured to monitor the load on the needle to monitor the pre-insertion and determine when the needle enters the tissue. In some embodiments, the feedback loop can be configured to control the pressurization of the therapeutic agent in the drug chamber once the needle is embedded in the tissue. In some embodiments, the load on the plunger and / or the distance traveled by the plunger can be monitored to determine when the therapeutic agent is pressurized to the desired pressure. In some embodiments, the feedback loop is configured to monitor the movement of the needle through the tissue toward the cavity during stage II and enter stage III-a. In some embodiments, the pressure of the therapeutic agent in the syringe barrel can be monitored by, for example, measuring the load on the push plunger. In some embodiments, the applied load can be a high-frequency sinusoidal, and the response curve can be measured from the sensor to measure the internal pressure. The needle can be advanced through the tissue until the load on the plunger or the pressure of the therapeutic agent decreases, indicating that the needle has reached the cavity, so that the lumen of the needle is in fluid communication with the cavity, and the therapeutic agent can be delivered into the cavity. In some embodiments, a feedback loop can be provided to monitor the injection of the therapeutic agent into the cavity in stage III-b. In some embodiments, such a feedback loop can monitor the flow rate of the therapeutic agent by, for example, monitoring the travel speed of the plunger or the pressure of the therapeutic agent. In some embodiments, the feedback loop can monitor the distance traveled by the plunger (related to the desired injection volume). In some embodiments, the load on the plunger can be monitored as the plunger is advanced through the syringe barrel. When the plunger reaches the end of the barrel or reaches some other stopper that prevents any further distal movement of the plunger, the load on the plunger will begin to increase as the drive mechanism continues to apply force to the plunger in the distal direction. At the end of stage III-b, such an increase in the plunger load will indicate that the injection has been completed and the needle can be withdrawn from the patient.

[0062] Various embodiments of the present disclosure may include one or more of the feedback loops discussed above, depending on the level of design or control of the system desired by the user and other considerations.

[0063] Syringe design

[0064] In some embodiments, a regular syringe can be used for the motorized injection system of the present disclosure. Such a syringe can include a syringe barrel for containing one or more injections, a needle attached to the syringe barrel and in fluid communication with the barrel, and a plunger that discharges the injection from the syringe barrel through the needle.

[0065] In some embodiments, an adjustable injection system (also referred to as an auto-stop injection system) that automatically self-adjusts the depth of needle penetration into the tissue / cavity may be used. Figure 5A , the auto-stop syringe 300 may include: a syringe barrel 302 having a proximal end 302p and a distal end 302d; a push plunger 304, which is movably disposed in the syringe barrel 302 and forms a seal with the syringe barrel; a needle plunger 306, which is movably disposed in the syringe barrel, distal to the push plunger, so that the drug chamber is defined in the syringe barrel, between the push plunger and the needle plunger. In some embodiments, a needle plunger seat 310 may be provided to control the movement of the needle plunger in the proximal direction, and in some embodiments, the push plunger may be configured to be pushed through the needle plunger seat.

[0066] The movable needle 308 is supported by a needle plunger so that movement of the needle plunger can also move the needle, which is in fluid communication with the drug chamber to deliver the therapeutic agent from the drug chamber to the patient. A variety of techniques can be used to connect the needle to the needle plunger. In some embodiments, the needle is inserted into a rubber plunger and fixed with a waterproof adhesive. In some embodiments, the plunger can be molded around the needle. In some embodiments, a needle having a thread on the outer surface can be screwed into the plunger.

[0067] Figure 5BThe operation of the auto-stop syringe is further illustrated (the drive mechanism / support assembly is not shown). In stage I, the needle is pre-inserted into the tissue (e.g., the sclera of the eye). In some embodiments, the needle can be inserted tangentially into the sclera, with the needle tip pointing to the posterior segment of the eye. Next, in stage II, a force is applied to the push plunger, which pushes the needle plunger forward to advance the needle deeper through the tissue toward the cavity (e.g., the suprachoroidal space of the eye). In stage III-a, the needle tip enters the cavity, and once the lumen of the needle opens into the cavity, the needle plunger automatically stops, thereby limiting the depth of the needle penetration into the cavity. The precision and miniaturization of the auto-stop syringe allow the needle plunger to accurately aim and stop at a thin potential cavity (such as the suprachoroidal space). In stage III-b, as the operator continues to push the push plunger, the therapeutic agent in the drug chamber is delivered to the cavity while the needle maintains its position at the tissue-cavity interface. In some embodiments, the vector of fluid flow is parallel to the suprachoroidal space to provide extensive coverage of the posterior segment of the eye, rather than using fluid forces to radially displace choroidal and retinal tissue.

[0068] An exemplary auto-stop syringe for delivering a therapeutic agent to the suprachoroidal space is disclosed in U.S. application Ser. No. 16 / 469,567, filed on June 13, 2019, and PCT application Ser. No. PCT / US2020 / 051702, filed on September 20, 2020, all of which are incorporated herein by reference in their entirety. In some embodiments, design variables such as syringe geometry, needle geometry, flow rate, viscosity, and friction are relevant and can be designed as discussed in Chitnis, GD, Verma, MKS, Lamazouade, J. et al., "A resistance-sensing mechanical injector for the precise delivery of liquids to target tissue", Nat Biomed Eng 3, 621–631 (2019), which is incorporated herein by reference in its entirety. In some embodiments, insertion force can be considered to select various design variables. Thus, the system is capable of delivering drugs and gene therapies that benefit from localization to the SCS, including therapies for treating choroidal and retinal diseases and disorders. It should be noted that although the present disclosure describes a point-of-care injection system in conjunction with drug delivery to the SCS cavity, the presently disclosed systems and methods can be used to deliver therapeutic agents to other spaces or cavities of the human body.

[0069] In some embodiments, the auto-stop syringe is pre-filled with a therapeutic agent. In some embodiments, the therapeutic agent is contained in one or more vials that provide an interface to the syringe barrel via a fast-fill port (e.g., as described in co-pending PCT application PCT / US2020 / 051702, filed September 20, 2020, which is incorporated herein by reference in its entirety), where any valves that were manually turned during operation in the previous fill can be motorized or solenoid valves used in this fill.

[0070] Operation of the motorized injection system

[0071] The motorized injection system can be connected to the patient's head and / or eye before filling with the therapeutic agent or after filling with the therapeutic agent, depending on whether the filling process is automated. In some embodiments, an adjustable headband can be secured around the patient's head. In some embodiments, the distal end of the motorized injection system can be anchored to an external landmark around the orbit.

[0072] The position of the motorized injection system can be adjusted to achieve the desired angle of needle insertion (which will depend on the bevel) to embed the lumen into the tissue. Once the motorized injection system is in place, the tip of the needle can be located near the scleral surface (e.g., within about 2 centimeters, within about 1 centimeter, or within about 0.5 centimeters from the scleral surface). In some embodiments, such a distance can be between about 0.1 and about 2 cm, between about 0.1 and about 1 cm, or between about 0.1 and about 0.5 cm. In some embodiments, an acoustic or laser rangefinder can be used to assist in the initial positioning of the needle tip. Next, the user provides a signal via a button or touch screen to initiate the injection process.

[0073] Motorized syringe drive for automatic syringe stop

[0074] As a non-limiting example, refer to Figure 6A-6D and Figure 7A-7B The use of a motorized injection system with an auto-stop syringe is described.

[0075] refer to Fig. 6A, after the user initiates the injection process, the automatic stop syringe is advanced toward the surface of the eye. In some embodiments, to achieve this, the syringe barrel 102 and the push plunger 112 move in unison toward the eye at the same speed until the force sensor detects the needle 116 embedded in the sclera. During the advancement of the automatic stop syringe, for example, the load on the syringe barrel, the needle guide or the needle is sensed by a force sensor or a force sensor. In some embodiments, the advancement can be performed manually. Once the needle tip reaches the sclera, the load will increase with the contact force. In some embodiments, the load measured at this stage is the axial load experienced by the needle. The load continues to increase until the needle pierces the sclera, at which time the load drops. Once the load drops, the piercing of the sclera is signaled, and the automatic stop syringe and the floating needle are advanced until the lumen of the needle is completely embedded in the sclera. In some embodiments, in order to determine when the lumen of the needle is completely embedded, the system can rely on the fixed advancement of the needle after the scleral piercing is detected. In some embodiments, full insertion can be determined by slightly advancing the push plunger to see if it starts to build pressure or causes leakage.

[0076] Once the needle is embedded in the sclera, movement of the syringe barrel is stopped and the push plunger is advanced in the syringe barrel to pressurize the contents of the syringe barrel. In some embodiments, the push plunger is advanced a pre-specified or user-specified distance, or until a pre-specified or user-specified load is reached on a force sensor attached to the push plunger or its fixture, which confirms that the lumen of the needle is fully embedded in the sclera. In some embodiments, this step is skipped.

[0077] In some embodiments, an optional elastomeric contact pad 320 may be used to prevent rotation of the eye pressed against the sclera by an operator of the device (such as a physician). This may allow the relative angle of injection to be controlled.

[0078] refer to Figure 6B , with the needle pre-inserted into the sclera, the syringe barrel 102 is locked in place and the push plunger 112 is pushed forward to advance the needle tip through the sclera. Due to the low water permeability of the sclera, liquid is trapped in the auto-stop syringe, so the pressure in the syringe barrel is maintained as the needle is advanced through the sclera. Due to the back pressure generated by the dense tissue of the sclera, the therapeutic agent cannot be dispensed into the sclera. Conversely, advancing the push plunger also advances the needle plunger and the needle toward the SCS. The syringe barrel holder stops, and the plunger continues to move, forcing the second plunger (i.e., the needle plunger) toward the SCS.

[0079] refer to Figure 6CWhen the needle 116 reaches the SCS, the fluid pressure within the syringe barrel drops, which can be sensed by the push plunger force sensor or pressure sensor. In some embodiments, detection of the relative movement of the push plunger moving closer to the needle plunger can also be used or alternatively used to identify when the cavity is reached. Due to the reduced back pressure generated by the SCS compared to the back pressure generated by the sclera, the needle stops advancing, and instead, the therapeutic agent is expelled through the needle to the SCS. The push plunger 112 continues to be advanced at a predetermined or user-determined speed and / or a predetermined or user-determined distance to inject the therapeutic agent into the SCS in the form of a fixed volume of liquid.

[0080] refer to Fig.6D Once the push plunger 112 has moved a pre-specified or user-specified distance corresponding to the desired injection volume, or the push plunger senses an increased load corresponding to having reached the needle plunger, the push plunger fixture stops advancing. In some embodiments, such an increased load can be set depending on the static friction of the needle plunger so that the push plunger cannot advance the needle plunger.

[0081] After the therapeutic agent has been delivered to the SCS, the user can remove the syringe needle from the eye. In some embodiments, the syringe can be removed manually. In some embodiments, the entire auto-stop syringe is retracted from the eye until the needle no longer contacts the sclera. This can be achieved by returning the auto-stop syringe to the starting position, or by returning to at least the point where the needle tip initially sensed an increase in load corresponding to contacting the scleral surface.

[0082] In some embodiments, one or more feedback loops can be used to monitor the operation of the automatic stop syringe. In some embodiments, a first feedback loop can monitor the pre-insertion of the needle into the sclera. For example, during the insertion of the needle into the sclera (the entire syringe moves toward the eye), a force sensor attached to the needle or syringe barrel can record an increasing force until the needle pierces the sclera. Upon piercing, there is a drop in load, and the needle is then further advanced a predetermined distance until the lumen of the needle is embedded in the sclera, and then the advancement of the entire syringe is interrupted.

[0083] In some embodiments, a second feedback loop may be provided to monitor needle advancement through the sclera. For example, once needle pre-insertion is complete, the syringe barrel is locked in place, and the push plunger is advanced while the load on the push plunger is measured. The load on the push plunger increases, and the load may level off as the needle is advanced through the sclera. Once the needle lumen reaches the SCS, the load will drop.

[0084] In some embodiments, a third feedback loop may be provided to monitor the injection of the therapeutic agent into the SCS. For example, the push plunger may be advanced at a pre-specified speed until a specific distance (correlated with the desired injection volume) is reached, or until the push plunger reaches the needle plunger to avoid needle overshoot.

[0085] like Figure 7A-7B As described in more detail in , a method for delivering a therapeutic agent into an eye can begin with setting up an anchoring device in step 400. In step 402, a syringe containing a therapeutic agent can be loaded into a motorized syringe. In step 404, the motorized syringe containing the syringe can be loaded onto an anchoring mechanism connected to the patient (the needle does not contact the sclera). In step 406, the user can press a button or other mechanism to initiate the injection. In step 408, the entire syringe can be moved forward to engage the needle with the sclera. In step 410, if the syringe force sensor shows an increase in load, the syringe is moved forward a predetermined distance to pre-insert the needle and block the needle lumen with the sclera (step 412). If not, then the syringe continues to move forward (step 408) until the load increases.

[0086] Once the syringe barrel load sensor shows an increase in load, in step 414, the syringe barrel position is locked and the push plunger is moved forward relative to the syringe. In step 416, if the push plunger load sensor shows a load that is higher than the force required to inject into the SCS, then the push plunger is moved forward relative to the syringe (step 414). If the push plunger load sensor does not show a load that is higher than the force to inject into the SCS, then in step 418, the push plunger can continue to be pushed forward. If the load is similar to the force required to inject into the SCS, or if a drop in internal pressure is detected, the position of the push plunger is noted so that the distance moved by the push plunger can be monitored, which can be used, for example, to prevent the push plunger from hitting the needle plunger or to monitor the amount of injection delivered to the SCS.

[0087] In step 420, if the force measured by the push plunger load cell is maintained when the push plunger is moved forward, then it is determined based on the position of the push plunger whether the predetermined amount of therapeutic agent has been delivered (step 422). If it has not been delivered, the system continues to push the push plunger forward (step 418). If it has been delivered, the system stops pushing the push plunger forward (step 426). If the force measured by the push plunger load cell is not maintained when the push plunger is moved forward (step 420), then in step 424, if the load increases significantly, it indicates that all the therapeutic agent has been delivered and the push plunger is at the end of the injection chamber. Then, the system stops moving the push plunger forward (step 426).

[0088] Motorized syringe drive for standard syringes

[0089] As a non-limiting example, refer to Figure 8A-8E and Figure 9A-9B The use of a motorized injection system with an auto-stop syringe is described.

[0090] refer to Fig. 8A , after the user initiates the injection process, the entire syringe is advanced toward the surface of the eye by moving the barrel 502 of the syringe and pushing the plunger 504 at approximately the same speed until the force sensor detects that the needle is embedded in the sclera. During the advancement of the syringe, the force sensor contacting the barrel or needle 508 of the syringe is sensing the load. Once the needle tip reaches the sclera, the load will increase with the contact force. The load continues to increase until the needle pierces the sclera, at which point the load drops. Once the load drops, the piercing of the sclera is signaled, and the syringe and needle are advanced until the lumen of the needle is completely embedded in the sclera.

[0091] refer to Figure 8B Once the needle is embedded in the sclera, the syringe barrel 502 is held in place and remains stationary while the syringe plunger is advanced a pre-specified or user-specified distance, or until a pre-specified or user-specified load is reached on a load cell attached to the plunger or its fixture. This movement of the plunger increases the pressure of the therapeutic agent, which is recorded as a load on the syringe plunger.

[0092] refer to Figure 8C Next, the complete syringe is advanced into the sclera by the motorized syringe driver, causing the tip of the needle 508 to advance through the sclera. When the needle is blocked as a fluid outlet, the pressure within the syringe barrel is maintained, and due to the low water permeability of the sclera, the syringe is advanced through the sclera, causing the fluid to remain within the syringe until the lumen of the needle reaches the SCS.

[0093] refer to Fig.8D Once the lumen of the needle 508 reaches the SCS, the fluid pressure (i.e., load) on the push plunger decreases, as the lumen is no longer blocked and fluid can flow out, which is recorded by monitoring the load of the syringe plunger. Upon sensing the decrease in load on the syringe plunger, the syringe barrel stops in place. The push plunger is then advanced at a predetermined or user-determined speed to inject the therapeutic agent into the SCS.

[0094] refer to Fig. 8EThe push plunger fixture stops advancing once the push plunger 504 has moved a pre-specified or user-specified distance corresponding to the desired injection volume or entire payload, or the push plunger senses an increased load corresponding to having reached the end of the needle syringe barrel. The delivery of the entire payload can be detected using a load cell based on the increased force when the plunger engages the distal end of the syringe when the syringe is empty.

[0095] After the therapeutic agent has been delivered to the SCS, the user can remove the syringe needle from the eye. In some embodiments, the syringe can be removed manually. In some embodiments, the entire syringe is retracted from the eye until the needle no longer contacts the sclera. This can be achieved by returning the syringe to the starting position, or by returning to at least the point where the needle tip initially sensed an increase in load corresponding to contacting the scleral surface.

[0096] In some embodiments, one or more feedback loops may be used to monitor the operation of the automatic stop syringe. In some embodiments, a first feedback loop may be provided to monitor the insertion of the needle into the sclera. For example, when the needle is pre-inserted into the sclera (the entire syringe moves toward the eye), a force sensor attached to the needle or syringe barrel records an increasing force until the needle pierces the sclera, but then there is a drop in the load. After the drop is detected, the needle can then advance a predetermined distance until the lumen of the needle is embedded in the sclera and the syringe barrel can be stopped. In some embodiments, a second feedback loop may be provided to pressurize the contents of the syringe barrel. For example, once the pre-insertion is completed, the syringe barrel is locked in place and the plunger is pushed forward, while the load on the plunger or the pressure of the therapeutic agent is measured until a pre-specified load, distance or pressure is reached to pressurize the therapeutic agent. In some embodiments, a third feedback loop is provided to monitor the load on the needle when the needle is advanced through the sclera. In some embodiments, the load on the needle can be monitored indirectly. For example, once the fluid contents of the syringe are pressurized, the entire syringe is advanced until the load on the push plunger decreases, indicating that the lumen of the syringe has reached the SCS. In some embodiments, the load on the syringe can be monitored when the needle is fixed to the hub of the syringe, because such load indicates the load on the needle. In some embodiments, once the cavity is reached, a fourth feedback loop can be used to deliver the therapeutic agent to the SCS. For example, once the needle enters the SCS, the plunger is then advanced at a pre-specified speed until a specific distance (related to the desired injection volume) is reached, or until the push plunger reaches the needle plunger to avoid needle overshoot.

[0097] like Figure 9A-9BAs described in more detail in , a method for delivering a therapeutic agent into an eye can begin with setting up an anchoring device in step 600. In step 602, a syringe containing a therapeutic agent can be loaded into a motorized injector. In step 604, the motorized injector containing the syringe can be loaded onto an anchoring mechanism connected to the patient (the needle does not contact the sclera). In step 606, the user can press a button or other mechanism to initiate the injection. In step 608, the entire injector can be moved forward to engage the needle with the sclera. In step 610, if the injector load cell shows an increase in load, the injector moves forward a predetermined distance to pre-insert the needle and block the needle lumen with the sclera (step 612). If not, the injector continues to move forward (step 608) until the load increases.

[0098] In step 614, the push plunger is pushed to pressurize the internal fluid by a known amount, and in step 616, both the syringe and the push plunger are moved to move the entire syringe. In step 618, it is determined whether the push plunger load cell shows a drop in internal pressure. If so, and if the load is similar to the force required to inject into the SCS, or if a drop in internal pressure is detected, the position of the push plunger is noted and the push plunger continues to be pushed forward (step 620). If not, both the syringe and the push plunger are moved to move the entire syringe (step 616).

[0099] In step 622, if the force measured by the push plunger load cell is maintained when the push plunger is moved forward, it is determined whether the predetermined amount of therapeutic agent has been delivered based on the position of the push plunger (step 624). If it has not been delivered, the system continues to push the push plunger forward (step 626). If it has been delivered, the system stops pushing the push plunger forward (step 628). If the force measured by the push plunger load cell is not maintained when the push plunger is moved forward (step 622), then in step 626, if the load increases significantly, it indicates that all the therapeutic agent has been delivered and the push plunger is now in direct contact with the needle plunger. Then, the system stops moving the plunger forward (step 628).

[0100] Specifically, in some embodiments, in step 614, the plunger is pushed to pressurize the internal fluid by a known amount, and in step 616, both the syringe and the plunger are moved to move the entire syringe. In step 618, the internal fluid pressure is continuously checked. If the force sensor shows a drop in pressure, the position of the barrel is noted, the position of the barrel is maintained, and the plunger is continued to be pushed forward to deliver the therapeutic agent to the SCS space. In step 618, if the plunger force sensor has not yet recorded a drop in the load, the entire syringe is advanced. When the plunger force sensor does record a drop in the load, the syringe barrel stops advancing, and only the push plunger is advanced in step 620. The push plunger force sensor continues to be monitored (step 622). While the load on the push plunger is monitored, the push plunger is advanced, delivering the therapeutic agent until the desired volume of the therapeutic agent has been delivered (step 624), and the advancement of the push plunger is stopped (step 628). Alternatively, the push plunger load cell registers an increase in load, which indicates that the push plunger has reached the distal portion of the syringe (step 626), and advancement of the push plunger is stopped (step 628).

[0101] In some embodiments, reference Figure 10A-10E and Figure 11A-11B , after the lumen of the needle is embedded in the sclera, instead of advancing the complete syringe, the fixture attached to the syringe barrel is allowed to move freely and only the plunger fixture is advanced. Fig. 10A As shown, the syringe barrel 702 and plunger 704 can be moved in unison toward the eye until the force sensor detects that the needle 708 is embedded in the sclera. Fig. 10B In FIG. 7 , with the needle tip embedded, the syringe barrel 702 is held in place and the push plunger is advanced to create a fluid pressure recorded as the load on the push plunger. Fig. 10C Once the pre-load is reached on the push plunger 704, the stop on the syringe barrel is released allowing it to move freely and the push plunger is then advanced. Fig. 10D In the embodiment, when the lumen of needle 708 reaches the SCS, the load on push plunger 704 will decrease because the lumen is no longer blocked and fluid can flow out; the push plunger is then advanced to dispense the therapeutic agent into the SCS. Fig.10E In the embodiment of the present invention, the push plunger 704 can be advanced a set distance to deliver a known volume or can be pushed to deliver the entire payload. When the syringe is empty, when the plunger engages the distal end of the syringe, the delivery of the entire payload can be detected using a load cell based on the increased force.

[0102] In this way, when the lumen of the needle reaches the SCS, as indicated by the drop in the load on the push plunger load cell, the syringe barrel can then be locked into position and the syringe plunger can be advanced, injecting the therapeutic agent directly into the SCS, essentially creating an automatic stop needle based on a standard syringe when used in combination with a syringe driver. In such embodiments, a feedback loop can be provided to monitor the movement of the needle through the sclera. In some embodiments, the syringe barrel is not locked in place when it reaches the SCS, and the needle remains in the cavity as the push plunger is advanced due to the drop in fluid resistance at the needle lumen. For example, after the contents of the syringe barrel are pressurized, the mechanical stop on the syringe barrel is released. The plunger is then advanced, which advances the needle tip through the sclera until it reaches the SCS. Once there, the needle will stop automatically because the pressure within the syringe barrel will decrease due to the flow of fluid from the needle tip into the SCS.

[0103] like Figure 11A-11B As described in more detail in , a method for delivering a therapeutic agent into an eye can begin with setting up an anchoring device in step 800. In step 802, a syringe containing a therapeutic agent can be loaded into a motorized injector. In step 804, the motorized injector containing the syringe can be loaded onto an anchoring mechanism connected to the patient (the needle does not contact the sclera). In step 806, the user can press a button or other mechanism to initiate the injection. In step 808, the entire injector can be moved forward to engage the needle with the sclera. In step 810, if the injector load cell shows an increase in load, the injector is moved forward a predetermined distance to pre-insert the needle and block the needle lumen with the sclera (step 812). If not, the injector continues to move forward (step 808) until the load increases.

[0104] Once the syringe load cell shows an increase in load, step 814 includes pushing the push plunger without any axial movement restriction on the syringe, and both the syringe and the push plunger move forward. In step 816, if the push plunger load is similar to the force required to inject into the SCS, or if a drop in internal pressure is detected, the position of the push plunger is noted and the push plunger continues to be pushed forward. Optionally, the system can continue to push the push plunger forward while the syringe can be locked (step 818). If the push plunger load cell does not show a drop in internal pressure, the push plunger is pushed as indicated in step 814.

[0105] In step 820, if the force measured by the push plunger load cell is maintained when the push plunger is moved forward, then it is determined based on the position of the push plunger whether the predetermined amount of therapeutic agent has been delivered (step 822). If it has not been delivered, the system continues to push the push plunger forward while the syringe position is locked (step 818). If it has been delivered, the system stops pushing the push plunger forward (step 826). If the force measured by the push plunger load cell is not maintained when the push plunger is moved forward (step 820), then in step 824, if the load increases significantly, it indicates that all the therapeutic agent has been delivered and the push plunger is now in direct contact with the distal end of the syringe. Then, the system stops moving the push plunger forward (step 826).

[0106] Graphical User Interface

[0107] A graphical user interface is included in some embodiments. For example, such a user interface can allow a user to start an injection, monitor the injection through phases I-III-b, and abort the injection if necessary. In some embodiments, there is also a device to provide auditory feedback to the user. In some embodiments, lights, graphical displays, and / or sounds are used as indicators to indicate one or more of the following events: setting the angle of insertion, filling the syringe with therapeutic agent, priming the syringe to remove any trapped air, turning on the device, advancing the needle toward the sclera, when the sclera is pierced, when the SCS is reached, when the therapeutic agent has been delivered, when the needle has been withdrawn from the eye.

[0108] In some embodiments, the GUI allows the user to input certain patient parameters, including intraocular pressure, scleral thickness, eye size, etc. In some other embodiments, the GUI asks for patient information and generates a report after the injection is completed, and in further embodiments, the patient information is obtained via a one-dimensional or two-dimensional barcode scanner or a near field scanner (NFC-near field communication). In some embodiments, the injector can be connected to an external server to upload this information and / or download relevant information about the case (such as the disease being treated, the prescribed treatment, and dosage information).

[0109] In some embodiments, a display on the motorized syringe driver is used to display instructions to the user and request input from the user regarding when to advance to the next step of the injection process starting with filling the syringe and ending with completing the SCS injection. In some embodiments, the GUI also allows the user to input injection process parameters, such as, for example, the distance traveled by the system or its components, the threshold of pressure or load on the system or its components, the volume of therapeutic agent to be loaded, the volume of therapeutic agent to be delivered, the flow rate of the injection, the duration of the injection, the angle of the injection, or the maximum travel distance of the needle after scleral puncture. In some embodiments, the user can select the desired volume and / or rate of injection. In some embodiments, the position of the push plunger, needle tip and / or floating plunger and / or the load sensed by the needle tip force sensor and / or the push plunger force sensor are displayed.

[0110] In some embodiments, there is a camera focused on the surface of the tissue that provides a real-time magnified video picture to the user on a display so that they can witness the puncture of the sclera and the final withdrawal of the needle. In some embodiments, the camera can assist in pre-insertion, where the user manually pre-inserts the needle tip and then activates the automated system to complete the entire delivery of the therapeutic agent to the cavity. In some embodiments, the injector can include a scanner for a one-dimensional or two-dimensional barcode to record the disposable syringe and therapeutic agent used for injection.

[0111] Needle Stop Distance and Overshoot

[0112] As discussed above, in some embodiments, the motorized injection system of the present disclosure may be equipped with one or more safety features to limit or control needle overshoot. In some embodiments, additionally or alternatively, needle overshoot can be controlled by controlling the stopping distance of the needle plunger. The stopping distance is the distance that the needle plunger travels after the needle lumen reaches the cavity and begins to deliver the therapeutic agent. The stopping distance is determined by how fast the pressure of the syringe barrel drops below the friction resistance of the needle plunger. Such distances can be characterized as the relationship between the friction resistance of the needle plunger, the inner diameter of the needle, the length of the needle, the bevel of the needle, the diameter of the inner barrel of the syringe, the viscosity of the preparation, the force applied to the push plunger, and the mechanical properties of the device components (similar to the flow through the hollow needle by the Hagen-Poiseau equation). In some embodiments, the stopping distance can be predicted as a function of the time required to reduce the pressure and speed of the needle travel. The stopping distance may depend on the volume elasticity of the syringe assembly and the compressibility of the fluid. In some embodiments, the overshoot caused by the stopping distance can be controlled by using one or more safety features described above. In some embodiments, the stopping distance may depend on the time required to implement and actuate the motorized feedback loop. As long as a portion of the needle port overlaps the SCS, the payload will be delivered to the SCS. Therefore, the acceptable stopping distance is directly related to the lumen size and the bevel. For example, a 30G needle with a 0.160mm lumen diameter and a standard 12° bevel angle can overshoot approximately 0.8mm while maintaining lumen contact with the SCS. In order to obtain optimal fluid flow and maximize the overlap between the lumen and the SCS, the needle should be positioned so that the SCS is placed in the center of the lumen geometry, i.e., for a 30G needle with a 12° bevel angle, a stopping distance of approximately 0.4mm will position the SCS to the center of the lumen. A stopping distance less than 0.4mm is also acceptable.

[0113] In some embodiments, the stop distance overshoot is corrected by causing the motorized syringe driver to retract the barrel of the syringe to ensure that the SCS is placed in the center of the lumen geometry. For example, for a 30G needle with a 12° bevel angle, if the stop distance is greater than 0.4mm, the needle may be retracted to center it. In some embodiments, the barrel of the syringe is retracted a fixed distance to offset the volume elasticity of the syringe assembly and the compressibility of the fluid. In other embodiments, the retraction distance includes the position of the syringe barrel when the load drop on the plunger is first detected after passing through the sclera. In some embodiments, the retraction distance utilizes the scleral deformation measured in response to the contact of the needle before puncture. In some embodiments, the retraction distance utilizes the known or measured time required to detect and implement the motorized feedback loop for the syringe stop.

[0114] Automated Syringe Filling

[0115] In some embodiments, as described above, the auto-stop syringe of the present disclosure can be pre-filled with a therapeutic agent during manufacture. In some embodiments, the auto-stop syringe of the present disclosure can be filled with a therapeutic agent in a doctor's office, a pharmacy, or an operating room before administering the therapeutic agent to a patient. In some embodiments, the therapeutic agent can be provided in a vial for storage and can be transferred to the SCS system by the user only when the therapeutic agent is ready to be administered to the patient.

[0116] In some embodiments, Fig.12 As shown, the injection system of the present disclosure is provided with a fast filling port 900 to enable injection to be loaded into the injection chamber from a vial 902. In some embodiments, the fast filling port 900 includes a container 904, which is configured to receive the vial 902 to fluidly connect the vial to the injection chamber. In some embodiments, a hole or channel is created through the wall of the syringe barrel (e.g., by molding, machining, etc.) at the proximal end of the needle plunger 110, and the container 904 is placed on such a hole or channel.

[0117] In some embodiments, when the needle plunger is set in its initial position and the push plunger is contacted with the needle plunger, the quick filling port is fluidically connected to the syringe barrel at the position between the sealing elements. The side port filling needle 906 (preferably larger than the injection piercing element, such as No. 18 piercing element) is connected to the passage, partially or completely arranged in the passage. Such filling needles can be tilted to pierce the elastomer cap 903 of the vial 902 containing the therapeutic agent. In some embodiments, the opening of the filling piercing element of the quick filling port can be located on the side of the filling piercing element instead of the tip. The side port can be covered by a housing or a self-sealing piercing membrane 908 that blocks fluid flow when the closed position. Housing 908 can be arranged in a container and can be biased by a spring 910 to close the port of the filling needle when the vial is not present in its container. In some embodiments, safety cap 118 can be configured to provide an airtight seal when attached to an injection system.

[0118] In operation, Figure 13A-13B and Figure 14A-14BAs shown, the automatic stop syringe is coupled to the support platform and drive assembly of the motorized injection system. Next, bottle 902 is stuck in the container 904 of the quick filling port 900, which forces the sliding filling piercing element housing away from the side port of the filling piercing element. Then, the filling piercing element of the quick filling port penetrates the stopper of the bottle to fluidically connect the internal volume of the bottle with the syringe barrel by the side port of the filling piercing element. Subsequently, the filling piercing element of the quick filling port passes the stopper of the bottle to fluidically connect the internal volume of the bottle 902 with the syringe barrel by the side port of the filling piercing element. When the driving assembly is withdrawn by pushing the plunger, this allows therapeutic agent to flow into the syringe barrel from bottle 902. In certain embodiments, a safety cap is arranged on the piercing element of the injection system to fluidly seal the piercing element so that when the sealing element is withdrawn, bubbles will not be sucked into the syringe barrel either.

[0119] Once the auto-stop syringe is loaded with the desired amount of therapeutic agent, the vial can be removed from the container of the quick-fill port, which allows the sliding filling needle housing to rise to seal the side port of the filling needle, which also seals the syringe barrel. The safety cap can be removed to allow fluid to flow through the injection needle. The drive assembly can be activated to advance the push plunger until fluid appears at the tip of the injection needle, indicating that the injection needle has been purged of air. Subsequently, the auto-stop syringe is ready for use. This quick-fill port design can make it possible to fill the auto-stop syringe with a therapeutic agent in a physician's office while maintaining sterility outside a sterile facility.

[0120] In some embodiments, the auto-stop syringe of the present disclosure can be refilled with a therapeutic agent. This can occur during the initial manufacture of the syringe or in a physician's office immediately prior to use.

[0121] In some embodiments, Figure 15A-15B As shown, the push plunger 112 can be removed so that the therapeutic agent 114 can be added to the syringe barrel 102 through the back of the syringe barrel. The push plunger can then be inserted and pushed toward the needle plunger 110 to remove any air in the injection needle.

[0122] In some embodiments, Figure 16A-16BAs shown, the filling port 930 may be disposed in the proximal region of the syringe barrel 102 away from the push plunger 112. The therapeutic agent 114 may be added to the auto-stop syringe through the filling port 930, and then the push plunger 112 may be pushed through the filling port 930 so that the push plunger 112 seals the therapeutic fluid from the filling port. Specifically, another sterile syringe / needle may be used to add the therapeutic agent to the auto-stop syringe through the filling port while keeping the needle side down (the needle tip is blocked). In some embodiments, the total volume of the therapeutic agent may be about 80% of the volume between the plungers. Then, the push plunger may be advanced toward the needle plunger to remove air through the filling port. After the push plunger passes through the filling port (which blocks the filling port), the syringe may be flipped so that the needle side faces upward. Next, the push plunger is further advanced in the distal direction to release the remaining air from the syringe barrel and the injection needle.

[0123] In some embodiments, Figure 17A-Figure 17C As shown, a self-sealing seal or polymer 932 (e.g., silicone rubber or polytetrafluoroethylene) can be used to seal the fill port 930. In this way, the fill port can be filled with a separate, larger bore loading needle 934 of a standard syringe, while the syringe barrel of the auto-stop syringe can remain sealed throughout the entire process. When the loading needle is removed from the fill port, the fill port is sufficiently self-sealing to not leak under the pressure applied by the push plunger during use.

[0124] In some embodiments, Figure 18A-18B As shown, the filling port 950 can be arranged in the proximal part of the syringe barrel 102 at the front of the needle plunger 110. This enables the user to access the needle plunger using a push tool 952 (e.g., a long, thin, rigid object that fits in the hole and is long enough to reach the outside). In this way, the injection needle can be extended outward so that it can be pushed through the elastic bottle stopper, and then the injection can be drawn out of the push plunger and sucked into the syringe. The push plunger can then be further withdrawn in the proximal direction so that the needle plunger can be pushed back to its pre-insertion position in the syringe barrel.

[0125] Use of injection system

[0126] In some embodiments, the injection system of the present disclosure is used to deliver one or more viral gene delivery vectors, including but not limited to adeno-associated virus (AAV), variants or serotypes thereof, including but not limited to AAV serotypes 1-11, particularly AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 and AAV11, and recombinant serotypes such as Rec2 and Rec3, for the treatment of genetic disorders of retinal or choroidal diseases. AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8 and AAV9 can all show tropism for retinal tissues, including retinal pigment epithelial cells and photoreceptor cells, as described in https: / / www.retinalphysician.com / issues / 2020 / special-edition-2020 / vector-considerations-for-ocular-gene-therapy, which is incorporated herein by reference in its entirety. Exemplary diseases may include, but are not limited to, wet age-related macular degeneration, dry age-related macular degeneration (age-related macular degeneration, AMD), glaucoma, choroideremia, and other inherited vision diseases and disorders. In some embodiments, the injection system is used to deliver one or more viral delivery vectors, including but not limited to AAV or its variants, such as but not limited to photoreceptors, pigment cells, bipolar cells, ganglion cells, horizontal cells, amacrine cells, vascular endothelial cells, vascular smooth muscle cells, non-vascular smooth muscle cells, melanocytes, fibroblasts, resident immune-competent cells with anti-vascular endothelial growth factor (anti-VEGF) and anti-vascular endothelial growth factor receptor (anti-VEGFR) genes that produce one or more anti-VEGF proteins for treating wet AMD when transcribed, to transfect retinal and / or choroidal cells. In some embodiments, the gene therapy composition may also include a promoter of a gene of interest.

[0127] In some embodiments, the injection 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 end-deoxyribonucleic acid (ceDNA), polymer-DNA conjugates, or clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated protein 9 (Cas9) systems and variants thereof, and transcription activator-like effector nucleases (TALEN) and variants thereof, and zinc finger nucleases (ZFN) and variants thereof, and transposon-based gene delivery such as Sleeping Beauty (SB), piggyBac (PB), Tol2 or variants thereof. These gene therapies can be encapsulated in viral vectors, non-viral vectors or nanoparticles.

[0128] In some embodiments, the injection system is used to deliver one or more viral gene delivery vectors, non-viral gene delivery systems, or other gene therapies to achieve 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.

[0129] In some embodiments, the injection system is used to deliver small or large molecule therapeutics directed against VEGF or VEGFR, such as, but not limited to, aflibercept, pazopanib, bevacizumab, cabozantinib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandatanib, ramucirumab, lenvatinib, and bevacizumab.

[0130] In some embodiments, the injection system 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 a genetic eye disease or condition, including but not limited to MTP, HGD, SLC16A2, POLG, ALMS1, FGFR2, PRPS1, APTX, ATM, DNMT1, TGFBI, ACTB, FGFR2, BEST1, CYP4V2, NOD2, FOXL2, ABCC9, ERCC6, CYP27A1, CHS1, SH3BP2, HDAC6, CHM, SLC9A6, NSDHL, OPN1MW, OPN1LW, OPN1SW, KERA, IGBP1, OPA3, UGT1A1, FGFR2, FGFR3, ATP6V0A2, CTNS, EFEMP1, SALL4, ADAMTSL4, FBN1, ADAMTSL4, NR2E3, TGFBI, GLA, IKBKAP, LCAT, GALK1, GALT, GBA, GLB1, PORCN, TGFBI, OAT, ENG, CBS, MBTPS2, IKBKG, CNNM4, ATRX, GALC, TGFBI, HADHA, OCRL1, PLP1, B3GALTL, PAH, ARX, LO XL1, 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, RAILHBB, TIMP3, 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, FOXE3, PITX3, PITX2, FOXC1, CHD7, SEMA3E, ERCC6, ERCC8, CYP1B1, MYOC, MYOC, CYP1B1, FGFR1, FGFR2, FGFR1, FGFR2, NDN, SNRPN, PHYH, PEX7, CREBBP, EP300, OPA1, OPTN, SAG, GRK1, TWIST1, FGFR2, GPC3, OFD1, TSC1, TSC2, PRPH2, BEST1, WFS1, CISD2, COL4A5, COL4A4, COL4A3, UBE3A, CDKLS, MECP2, PTCH1, PTCH2, SUFU, NSD1, H19, KCNQ1OT1, CDKN1C, OPN1LW, OPN1MW, EYA1, SIX1, SIX5, KIF21A, PHOX2A, ARIX, TUBB3, SMC1A, HDAC8, COL5A1, COL5A2, COL3A1, TNXB, OPTN, ASB10, WDR36, MTND1, MTND4, MTNDS, MTND6, PAX6, PITX2, CYP1B1, FOXCl, DMPK, ZNF9, CNBP, NPC1, NPC2, SMPD1, TYR, OCA2, TYRP1 or SLC45A2, MC1R, COL1A1, COL1A2, CRTAP, LEPRE1, NPHP1, NPHP4 SDCCAG8, WDR19, CEP290, IQCB1, HESX1, OTX2, SOX2, COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, MYO7A, USH2A, EDN3, EDNRB, MITF, PAX3, SNAI2, SOX10, ADAMTS10, FBN1, LTBP2, XPA, XPC, ERCC2, ERCC3 and POLH.

[0131] In certain embodiments, the delivery system of the present disclosure can be used to deliver gene therapy to treat age-related macular degeneration (AMD) or diabetic macular edema (DME). In certain embodiments, the delivery system of the present disclosure is used for suprachoroidal space (SCS) delivery composition, and the composition includes AAV vector, and the AAV vector includes one or more genes blocking VEGFR-2, optionally with CAG promoter. In certain embodiments, other suitable promoters include but are not limited to: human bestrophin (hVMD2), cytomegalovirus (CMV), SV40, mGluR6, CB7, UbiC, RZ, RedO, Rho and Best1. In certain embodiments, such systems can include 25-34 piercing elements with polypropylene or glass syringes and fluoropolymers, silicone or rubber for promoting sealing element stoppers and floating sealing element stoppers. In certain embodiments, about 80-120 (e.g., 100) microliters of such gene therapy compositions can be delivered in 5-60 seconds. In some embodiments, the piercing 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 greater than 15 degrees, greater than 30 degrees, or even greater than 45 degrees. In some embodiments, the piercing element may be 25 gauge and higher, 27 gauge and higher, or 30 gauge and higher. In some embodiments, the needle has a secondary bevel for reducing cutting forces.

[0132] In some embodiments, the delivery system is used to deliver small molecule injections or large molecule injections, such as anti-VEGF drugs, which include but are not limited to: bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandins, tryptophan-tRNA synthetase-derived polypeptides, inosine monophosphate dehydrogenase (IMPDH) inhibitors and anti-PDGF for the treatment of AMD; as well as corticosteroids for the treatment of uveitis, chorioretinitis or other inflammatory eye diseases; botulinum toxin for various ocular applications; tyrosine kinase inhibitors (such as, vandetinib, axitinib, pazopanib, sunitinib, sorafenib) for the treatment of pterygium, dry eye or AMD; levobetaxolol or other beta adrenergic receptor antagonists and 5-HT1A agonists for the treatment of retinopathy.

[0133] In some embodiments, the injection system is used to deliver small molecule Wnt inhibitors to reduce angiogenesis. These small molecule Wnt inhibitors may include indazole-3-carboxamide compounds or analogs thereof (WO2013040215A1), y-diketones or salts or analogs thereof (WO2014130869A1), azaindazole compounds or analogs thereof (e.g., 3-(1h-benzo[d]imidazole-2-y1)-1h-pyrazolin[3,4-c]pyridine) (WO2016040180A1), N-(5-(3-(7-(3-fluorophenyl 1)-3H-imidazole[4,5-c]pyridine-2-y1)-1H-indazole-5-yl)pyridine-3-y1)-3-methylbutanamide, including its amorphous and polymorphic forms (WO201721 0407A1), isoquinoline-3-y1 carboxamides or salts or analogs, and including amorphous and polymorphic forms thereof (WO2017189823A2), diazonaphthalene-3-yl carboxamides or salts or analogs, and including amorphous and polymorphic forms thereof (US20190127370A1), 6-(5-membered heteroaryl)isoquinoline-3-y1-(5-membered heteroaryl)carboxamides or salts or analogs, and including amorphous and polymorphic forms thereof (WO2019084496A1), 6-(6-membered heteroaryl and aryl)isoquinoline-3-y1 carboxamides or salts or analogs, and including amorphous and polymorphic forms thereof (US201901257 40A1), 3-(3h-imidazole [4,5-b] pyridine-2-y1)-1h-pyrazolin[3,4-b] pyridine (US20190119303A1), Wnt inhibitors comprising an indazole core or salts or analogs, and including amorphous and polymorphic forms (WO2013151708A1), 1h-pyrazolo[3,4-b] pyridine or salts or analogs, including amorphous and polymorphic forms (WO2013166396A2), 2-(1h-indazole-3-y1)-3h-imidazole [4,5-b] pyridine or salts or analogs, and including amorphous and polymorphic forms (US20190055238A1 ), f3-diketone, y-diketone or y-hydroxyketone or its salt or analogue (WO2012024404A1), 3-(benzimidazole-2-y1)-indazole inhibitor or salt or analogue, and including amorphous and polymorphic forms (US10183929B2), 3-(1h-imidazole [4,5-c] pyridine-2-y1)-1h-pyrazolo [3,4-b] pyridine or salt or analogue, and including amorphous and polymorphic forms (US20180325910A1), 1H-pyrazolo [3,4-b] pyridine or salt or analogue, and including amorphous and polymorphic forms (CY-1119844-T1), 3-(1h-imidazole [4,5-c]pyridine-2-y1)-1h-pyrazolo[3,4-c]pyridine or salts or analogs, and including amorphous and polymorphic forms (US-2018250269-Al), N-(5-(3-(7-(3-fluorophenyl 1)-3H-imidazole[4,5-c]pyridine-2-y1)-1H-indazole-5-yl)pyridine-3-y1)-3-methylbutanamide or salts or analogs, and including amorphous and polymorphic forms (US20180133199A1), indazole-3-carboxamides or salts or analogs, and including amorphous and polymorphic forms (US-2018185343-A1 ), 3-(3h-imidazole [4,5-b] pyridine-2-y1)-1h-pyrazolo[3,4-c] pyridine or salts or analogs and including amorphous and polymorphic forms (US-2018201624-Al), 2-(1h-indazole-3-y1)-1h-imidazole [4,5-c] pyridine or salts or analogs and including amorphous and polymorphic forms (US-2018215753-A1), 3-(3H-imidazole [4,5-c] pyridine-2-y1)-1H-pyrazolino[3,4-c] pyridine or salts or analogs and including amorphous and polymorphic forms (US-10052331-B 2), 5-substituted indazole-3-carboxamides or salts or analogs and including amorphous and polymorphic forms (US-2018127377-A1), 3-(3H-imidazole [4,5-C] pyridine-2-y1)-1H-pyrazolino [4,3-B] pyridine or salts or analogs and including amorphous and polymorphic forms (US-10188634-B2), 3-(1H-imidazole [4,5-C] pyridine-2-y1)-1H-pyrazolino [4,3-B] pyridine or salts or analogs and including amorphous and polymorphic forms (US-10195185-B2), 3-(1h-pyrrole [2,3 -b]pyridine-2-y1)-1h-indazoles or salts or analogs and including amorphous and polymorphic forms (WO-2017024021-A1), 3-(1h-pyrrolo[2,3-c]pyridine-2-y1)-1h-pyrazolino[3,4-c]pyridines or salts or analogs and including amorphous and polymorphic forms (WO-2017023975-A1), 3-(1h-indo1-2-y1)-1h-pyrazolino[3,4-b]pyridines or salts or analogs and including amorphous and polymorphic forms (US-2018214428-A1), 3-(1h-pyrrolo[3,2-c]pyridine-2-y1)-1H-indazoles or salts or analogs and including amorphous and polymorphic forms (US-2018221350-A1), 3-(1h-indo1-2-y1)-1H-indazoles or salts or analogs and including amorphous and polymorphic forms (WO-2017023986-A1), 3-(1H-pyrrolo[2,3-b]pyridine-2-y1)-1H -pyrazolino[4,3-b]pyridines or salts or analogs and including amorphous and polymorphic forms (US-10206909-B2), 3-(1h-pyrrolo[3,2-c]pyridine-2-y1)-1h-pyrazolino[4,3-b]pyridines or salts or analogs and including amorphous and polymorphic forms (WO-2017024003-Al), 3-(1h-pyrrolo[3,2-c]pyridine- 2-y1)-1h-pyrazolino[3,4-b]pyridines or salts or analogs and including amorphous and polymorphic forms (US-2018221341-A1), 3-(3h-imidazole[4,5-b]pyridine-2-y1)-1h-pyrazolino[4,3-b]pyridines or salts or analogs and including amorphous and polymorphic forms (WO-2017024015-A1), 3-(1h-pyrrole [2,3-c]pyridine-2-y1)-1h-pyrazoline [3,4-b]pyridines or salts or analogs and including amorphous and polymorphic forms (US-2018221352-Al), 3-(1H-pyrrolo [3,2-C]pyridine-2-yL)-1H-pyrazoline [3,4-C]pyridines or salts or analogs and including amorphous and polymorphic forms (US-10206908-B2). Each of the references cited herein is incorporated by reference in its entirety. ,

[0134] In some embodiments, the injection system is used to deliver suspensions of injectable agents including microencapsulated agents, nanoencapsulated agents, pure protein nanoparticles, and poorly or insoluble agents.

[0135] In certain embodiments, the injection or encapsulated injection is delivered together with a residence time extension matrix. The matrix can be composed of a reverse thermal response hydrogel, a self-assembling hydrogel, a bioadhesive polymer network, a hydrogel, a hydrogel containing fibronectin, an enzyme response hydrogel, an ultrasound sensitive hydrogel, a pH sensitive hydrogel, a carbohydrate, a two or more component hydrogel, and a multi-component dual network hydrogel.

[0136] In some embodiments, the injection is delivered via an injection system together with a penetration enhancer such as, but not limited to, 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-hydroxybenzoyl)amino]caprylate (SNAC), 8-(N-2-hydroxy-5-chloro-benzoyl)-aminocaprylic acid (5 -CNAC), sodium caprate, sodium caprylate, omega 3 fatty acids, protease inhibitors, alkyl glycosides, chitosan, dodecyl-2-N, N-dimethylaminopropionate (DDAIP), N-methyl-2-pyrrolidone (NMP), azone, sulfoxides, surfactants, benzyl ammonium chloride, saponins, bile salts, bile acids, cell penetrating peptides, polyarginine, low molecular weight protamine, polyserine, capric acid, gelling agents, semifluorinated alkanes, terpenes, phospholipids, chelating agents, ethylenediaminetetraacetic acid (EDTA), citrates, crown ethers, and combinations thereof.

[0137] In some embodiments, an injection with one or more therapeutic agents is delivered via an injection system with one or more vasoconstrictors or after administration of one or more vasoconstrictors to reduce outflow of the injection via choroidal vessels, and one or more vasoconstrictors include but are not limited to 25I-NBOMe, amphetamine, AMT, antihistamines, caffeine, cocaine, dopamine, dobutamine, DOM, LSA, LSD, methylphenidate, methamphetamine, norepinephrine, oxymetazoline, phenylephrine, propylhexenamine, pseudoephedrine, stimulants, serotonin 5-hydroxytryptamine agonists, triptans, and tetrahydrozoline hydrochloride. In some embodiments, these agents can be administered into the SCS using the injection system of the present disclosure, or administered via intravitreal injection using a standard syringe. Vasoconstrictors can be delivered before, simultaneously with, or after administration of one or more therapeutic agents.

[0138] In some embodiments, the injectable delivered via the injection system achieves greater than 20%, 40%, 60% or 80% SCS coverage.

[0139] In some embodiments, the injectate delivered via the injection system achieves SCS coverage in less than 180, 120, 60, 30, or 15 minutes, with or without one or more vasoconstrictors for reducing outflow of the injectate via the choroidal vessels.

[0140] In some embodiments, the retention time of an injectable delivered via the injection system within the SCS is less than 180, 120, 60, 30, 15, 10, or 5 minutes.

[0141] In some embodiments, the injection is delivered via an injection system in an amount of less than 500, 400, 300, 200, or 100 microliters.

[0142] In some embodiments, the injectable is delivered via an injection system at a concentration of less than 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or 1%.

[0143] In some embodiments, the percentage of the dose of the injectable that is delivered to the subretinal space via the injection system is less than 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or 1%.

[0144] In some embodiments, the injection delivered via the injection system is administered at least once every 10 years, every 5 years, every 2 years, every 1 year, every 6 months, every 3 months, monthly, or weekly.

[0145] In some embodiments, the injection system is used to deliver one or more injectables to treat one or more of the ocular causes or effects of the following diseases, including, but not limited to: Abetalipoproteinemia (Bassen-Kornzweig syndrome), Alakptonuria, Allan-Hernton-Dudley syndrome, Alpers syndrome, Alström syndrome, Apel syndrome, Art syndrome (mental retardation, X-linked, syndrome 18), Ataxia-oculomotor dysmotility syndrome, Ataxia-telangiectasia (Louis-Barr syndrome), Autosomal Dominant Cerebellar Ataxia Deafness and Hypersomnia (Autosomal Dominant Cerebellar Ataxia Deafness and Hypersomnia), Narcolepsy (ADCADN), Avellino corneal dystrophy (combined granular lattice corneal dystrophy), Baraitser-Winter syndrome type 1, Beale-Stevensson syndrome, Best macular dystrophy, Bietti crystalline corneal retinal dystrophy, Blau syndrome, blepharophimosis, Ptosis, and inverted epicanthus Epicanthus Inversus (BPES), Cantu syndrome, craniofacial skeletal syndrome, xanthocephalic xanthomatosis, Sheddick-Don syndrome, jaw enlargement, scapular osteochondrodysplasia, unique brachial arthritis, hydrocephalus and microphthalmos, choroidal hyperplasia, Christiansen syndrome, CK syndrome, color blindness, green anomaly, color blindness, red anomaly, color blindness, tritanopia, flat cornea, corpus callosum, mental retardation, coloboma and micrognathia, Kestif syndrome, Crigler-Najjar, craniofacial stenosis syndrome, craniofacial stenosis syndrome with nigra syndrome (Crouzonodermoskeletal syndrome), cutis laxa, Debre type, cystic myositis, Doyne honeycomb dystrophy (Malattia Leventine), Duane radial line syndrome, ectopic macrophthalmia and pupil, ectopic microphthalmia, familial, ectopic microphthalmia, isolated, enhanced S-Cone syndrome, epithelial basement membrane corneal dystrophy (map dot fingerprint corneal dystrophy), Fabry disease (hereditary, lipodystrophy), familial dysautonomia, fish eye disease, galactokinase deficiency, galactosemia, Gaucher disease, GM1 gangliosidosis, type I, GM1 gangliosidosis, type II, GM1 gangliosidosis,Type III, Goltz syndrome, granular, corneal dystrophy (Groenouw type I), gyrate atrophy, hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), homocystinuria, IFAP syndrome with or without Blishek syndrome, pigmentary incontinence (Bloch-Sulzberger syndrome), Giardiac syndrome, Juberg Marsidi syndrome, Krabbe disease, lattice corneal dystrophy, LCHAD (long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiency, Reve, Pelitzow-Merzbach, Petergaard syndrome (Kraus-Kivling syndrome), phenylketonuria, Proud syndrome, pseudoexfoliation syndrome, Reis-Bucklers corneal dystrophy, Renpenning syndrome (mental retardation, X-linked, Renpenning type), retinoblastoma, retinoschisis, juvenile X-linked, Russell-Silver syndrome, mucopolysaccharidosis type IH (Huller syndrome), mucopolysaccharidosis type IH / S (Horra-Shay syndrome), IS type Mucopolysaccharidosis (Schaeus syndrome), Mucopolysaccharidosis type II (Hunter syndrome), Mucopolysaccharidosis type IIIA, Mucopolysaccharidosis type IIIC (Sanfilippo syndrome C), Mucopolysaccharidosis type IIID (Sanfilippo syndrome D), Mucopolysaccharidosis type IVA (Morquio syndrome A), Mucopolysaccharidosis type IVB (Morquio syndrome B), Mucopolysaccharidosis type VI, Sly syndrome, Muenke syndrome, Nail-patella syndrome, Nancy-Holland syndrome Native American myopathy, Neurofibromatosis type I, Neurofibromatosis type II, Neurofibromatosis Noonan syndrome, Neuropathy, Ataxia, and Retinitis. Retinitis, Pigmentosa, NARP), Norrie disease, hidden macular dystrophy, ocular albinism, oculopharyngeal muscular dystrophy, Sandhoff disease (GM2 gangliosidosis, type II), Schneider corneal dystrophy, Sengers syndrome, Smith-Mageni syndrome (chromosome 17p11.2 deletion syndrome), sickle cell anemia, Thorsby fundus dystrophy, spinocerebellar ataxia, X-linked 1, Stargardt disease / fundus disease, flat muscle, Sturge-Weber syndrome, thiocyanuria ( sulfite oxidase deficiency), syndromic microphthalmia 1 (Lenz microphthalmia syndrome), syndromic microphthalmia 2 (oculocardiodental syndrome), syndromic microphthalmia 3 (microphthalmia and esophageal atresia syndrome), syndromic microphthalmia 5, syndromic microphthalmia 6, syndromic microphthalmia 7 (Myers syndrome), syndromic microphthalmia 9 (Matthew Wood syndrome), syndromic microphthalmia 11, syndromic microphthalmia 12, syndromic microphthalmia 13, syndromic microphthalmia 14, Tarp syndrome, Tay-Sachs disease (GM2 gangliosidosis,I), Thiel-Behnke corneal dystrophy, Turner syndrome, tyrosinemia, II, association of Vacterl with hydrocephalus, Hippel-Lindau syndrome, Wanger syndrome, Watson syndrome, Wiakl-Wolf syndrome, Wilson's disease, color blindness, Alagille syndrome, aniridia syndrome, anterior stromal dysplasia, Axenfeld-Riegel syndrome, charged syndrome, Cockayne syndrome, glaucoma, congenital glaucoma, open-angle juvenile onset, Jackson-Weiss syndrome, Pfeiffer syndrome, Prader-Willi syndrome, Refsum disease, Rubinstein-Taybi syndrome, normal tension glaucoma, O'Sullivan's disease, craniosynostosis (Saethre Chotzen syndrome, Simpson-Golabi-Behmel syndrome, tuberous sclerosis, botryoid macular dysplasia, adult-onset, Wolfram syndrome, Allport syndrome, Angelman syndrome, Bard-Beedel syndrome, basal cell nevus syndrome, Beckwith syndrome, blue cone monochromacy, auriculo-auriculosyndrome, Charcot-Marie-Tooth disease, cone-rod dystrophy, congenital glycosylation disorder, extraocular muscle plexus fibrosis, congenital nystagmus, congenital stationary night blindness, corneal Langer syndrome, dyskeratosis congenita, Ehrlich disease Stanislavsky-Danlos syndrome, Fuch's endothelial corneal dystrophy, glaucoma, open-angle adult-onset, Hermansky-Pudlak syndrome, Joubert syndrome, Kearns-Sell syndrome, Leber congenital amaurosis, Leber hereditary optic neuropathy, Leigh syndrome, Peter anomaly retinitis pigmentosa, muscular dystrophy-sarcoglycanosis, myotonic dystrophy, Niemann-Pick disease, Noonan syndrome, neurogenic ceroid lipofuscinosis, oculocutaneous albinism, optic atrophy, oral-facial-digital syndrome, osteogenesis imperfecta, Senior-Locken syndrome, septic optical dysplasia (de Morsier syndrome), spastic paraplegia, Stickler syndrome, Treacher-Collins syndrome, Usher syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, and xeroderma pigmentosum.

[0146] In some embodiments, multiple injections can be performed over time to allow for the continuation of treatment. The injection of the therapeutic agent may be accompanied by another agent that can be delivered multiple times. For example, AAV delivery is limited by the immune response to AAV, which generally limits the use of AAV to a single treatment, a limitation that is generally associated with intravitreal injections, and although subretinal injections are immune privileged, damaged and diseased retinas cannot withstand multiple injections without trauma. Another agent that inhibits this response (such as ImmTOR) can be injected before, in combination with, or after AAV injection to mitigate the immune response and enable AAV treatment at multiple time points. This allows people to titrate the dose to the patient's response as needed.

[0147] In some embodiments, the administration route is by injection into the SCS. In some embodiments, the genetic disease or condition is diagnosed by gene sequencing, such as but not limited to: Sanger sequencing, next generation sequencing, high throughput screening, exome sequencing, Maxam-Gilbert sequencing, chain termination method, shotgun sequencing, bridge polymerase chain reaction, single molecule real-time sequencing, ion torrent sequencing, pyrophosphate sequencing, synthetic sequencing, combined probe anchor synthesis, ligation sequencing and nanopore sequencing. In some embodiments, the eye disease or condition is diagnosed by eye examination, ophthalmoscopy, ocular coherence tomography, retinal scanning, fluorescein staining, conjunctival staining, color vision testing, optic disc imaging, nerve fiber layer analysis, corneal topography, electrodiagnostic testing, fluorescein angiography, eye photography, mirror microscopy, field of view testing, ultrasound of the eye and combinations thereof.

[0148] In some embodiments, the patient presents with elevated intraocular pressure and is diagnosed with early juvenile primary open-angle glaucoma prior to significant optic nerve damage after ophthalmoscopy. A blood sample is drawn and sent for genetic testing to identify a mutation in the olfactory domain of the myosin (MYOC) gene (mutation Y437H) in the patient that may be involved in causing the disease, resulting in a diagnosis of myosin-associated primary open-angle glaucoma.

[0149] The patient is then treated with a systemic injection of microRNA complementary to the first 22 bases of the MYOC gene mRNA, formulated in an aqueous solution of a self-assembling hydrogel with beta-cyclodextrin and EDTA as penetration enhancers. Prior to use, the injection is stored as a lyophilized powder in a vial separate from the diluent. Following injection, the hydrogel self-assembles in the SCS after delivery, providing sustained delivery of the microRNA that inhibits myosin expression, leading to reduced accumulation of myosin in the trabecular meshwork, resulting in reduced intraocular pressure, thereby reducing the probability of sustained optic nerve damage in the patient.

[0150] In another specific embodiment, a male child has night blindness and is found on examination to have reduced visual fields and some retinal degeneration. A blood sample is drawn and sent for genetic testing to determine that the patient has a mutation in the CHM gene (comprising, for example, part or all of the CHM gene sequence as described in https: / / www.uniprot.org / uniprot / P24386, which is incorporated herein by reference in its entirety) encoding the RAB escort protein 1 (REP1), which supports the diagnosis of early stage choroideremia.

[0151] The patient is then treated by administration of an injection system, wherein, prior to injection, a lyophilized AAV2 vector is reconstituted with its aqueous diluent, the AAV2 vector comprising a retinal-specific promoter derived from the rhodopsin kinase (RK) promoter gene expressed in rods and cones, which is linked to the human CHM gene. Upon reconstitution, the injection solution contains approximately 1013 AAV vectors per milliliter. Once injected, the RK promoter and the human CHM gene will be stably transfected into photoreceptor cells, where the corrected form of REP 1 is expressed, thereby treating the patient's choroideremia.

[0152] In another specific embodiment, central vision defect occurs in elderly patients. In conventional retinal examination, drusen are detected. Fluorescein angiography shows choroidal vascular system leakage, which is confirmed by the presence of subretinal fluid accumulation observed by optical coherence tomography (OCT). The patient is diagnosed with early neovascular age-related macular degeneration (AMD).

[0153] The patient is then treated by systemic administration of a 21-24 nucleotide short interfering RNA (siRNA) sequence complementary to a portion of one or more of the following mRNAs, alone or in combination: vascular endothelial growth factor (VEGF), any isoform thereof, any isoform thereof including but not limited to VEGF-A, VEGF-A121, VEGF-A165, VEGF-A189, VEGF-A206, VEGF-B, VEGF-C, VEGF-D, VEGF receptors (VEGFRs), VEGFR-1, VEGFR-2, VEGFR-3, NOTCH regulated ankyrin repeat protein (NRARP), and other pro-angiogenic proteins encoding genes. The siRNA is delivered in a suspension in a liposome carrier. After delivery, the siRNA knocks down the expression of one or more pro-angiogenic proteins, thereby preventing additional choriocapillaris growth and causing capillary regression, thereby reducing choriocapillaris retinal and macular infiltration and improving central vision. In a specific embodiment, the siRNA is targeted to knock down VEGFR-2, which has a gene sequence as described in https: / / www.uniprot.org / uniport / P35968 or an isoform thereof, incorporated herein in its entirety.

[0154] In another specific embodiment, patients diagnosed with neovascular AMD or diabetic retinopathy are treated by injection system administration, wherein the AAV vector or other transfection vector contains a gene that, when transcribed, produces an RNA sequence complementary to at least a portion of the mRNA translated into VEGFR-2. When this gene therapy is delivered to the SCS, the choroidal capillaries (also referred to as choriocapillaries) contact the therapy delivered by targeting those cells that transfect and express VEGFR-2. During transfection, the transcribed siRNA or shRNA vector will knock down or knock out the production of VEGFR-2, thereby reducing new blood vessel formation to treat AMD or diabetic retinopathy.

[0155] In some embodiments, a physician may be provided with a suprachoroidal injection assembly or kit comprising (1) a volume of an injectable, including one or more therapeutic agent formulations, i.e., an active agent formulation, e.g., containing an effective amount of an agent for treating an eye condition of a patient; (2) an injection system as described above and (3) optionally, a syringe for facilitating ejection of the injectable into and through a membrane of the injection system.

[0156] As described earlier, the reagent formulation can include various forms, such as solutions and suspensions of various viscosities. The entire kit is sterile, including the formulation, injection system, and facilitating syringe.

[0157] In some embodiments, the total volume of the active agent preparation to be injected into the suprachoroidal space is preferably within the range of about 0.01-0.5 mL. In some embodiments, the active agent may be provided in a lyophilized form and an accompanying diluent to create a suspension at the time of injection. In some embodiments, the active agent may be premixed. In some embodiments, the injection system may be prefilled with a premixed preparation. In some embodiments, the user may fill the injection system immediately before administering the therapeutic preparation to the patient. In some embodiments, the injection system may include multiple chambers with frangible separations. In some embodiments, the piercing element has an initial penetration length of 0.01 to 3 mm, and the piercing element further extends while performing the injection. In some embodiments, the injection system and the injection facilitator may be preassembled with a prefilled preparation and are ready for use without any further components. In some embodiments, the entire kit is packaged in a single bag / tray to maintain sterility. In some embodiments, wherein the components are packaged separately or in combination. In some embodiments, the kit is sterilized together or separately by one of the sterilization methods, including but not limited to autoclaves, ethylene oxide, gamma rays, etc.

[0158] In some embodiments, the components are present in a secondary package. In some embodiments, the kit is stored as a collection at a sufficiently low temperature to extend the life of the active agent. In some embodiments, the formulation is stored separately at low temperature while the rest of the kit is stored at room temperature.

[0159] Computer system for injection system

[0160] The system of the present disclosure may include a controller for controlling the operation of the injection system of the present disclosure. In some embodiments, such a controller may be a computer system for collecting and analyzing sensor information used by the system to control the injection assembly. Any suitable computing system may be used to implement the computing devices and methods / functions described herein, and may be converted into a specific system for performing the operations and features described herein by modifying hardware, software, and firmware in a manner far beyond simply executing software on a general-purpose computing device, as will be appreciated by those skilled in the art. Fig.19 An illustrative example of such a computing device 1900 is depicted. Computing device 1900 is merely an illustrative example of a suitable computing environment and in no way limits the scope of the present invention. Fig.19 As indicated, a "computing device" may include a "workstation," "server," "laptop," "desktop," "handheld device," "mobile device," "tablet computer," or other computing device, as would be understood by one skilled in the art. Given that computing device 1900 is depicted for illustrative purposes, embodiments of the present invention may utilize any number of computing devices 900 in any number of different ways to implement a single embodiment of the present invention. Thus, embodiments of the present invention are not limited to a single computing device 1900, as would be appreciated by one skilled in the art, nor are they limited to a single type of implementation or configuration of the example computing device 1900.

[0161] Computing device 1900 may include bus 1910, which may be coupled directly or indirectly to one or more of the following illustrative components: memory 1912, one or more processors 1914, one or more presentation components 1916, input / output ports 1918, input / output components 1920, and power supply 1924. Those skilled in the art will appreciate that bus 1910 may include one or more buses, such as an address bus, a data bus, or any combination thereof. Those skilled in the art additionally appreciate that, depending on the intended application and use of a particular embodiment, multiple of these components may be implemented by a single device. Similarly, in some instances, a single component may be implemented by multiple devices. Thus, Fig.19 It is merely illustrative of an exemplary computing device that may be used to implement one or more embodiments of the present invention and in no way limits the present invention.

[0162] The computing device 1900 may include or interact with various computer-readable media. For example, the computer-readable media may include random access memory (RAM); read only memory (ROM); electronically erasable programmable read only memory (EEPROM); flash memory or other memory technology; CDROM, digital versatile disk (DVD) or other optical or holographic media; magnetic cassettes, magnetic tapes, disk storage devices or other magnetic storage devices that can be used to encode information and can be accessed by the computing device 1900.

[0163] Memory 1912 may include computer storage media in the form of volatile and / or non-volatile memory. Memory 1912 may be removable, non-removable, or any combination thereof. Exemplary hardware devices are devices such as hard drives, solid-state memory, optical drives, and the like. Computing device 1900 may include one or more processors that read data from components such as memory 1912, various I / O components 1920, and the like. Presentation component(s) 1916 presents data indications to a user or other device. Exemplary presentation components include display devices, speakers, printing components, vibration components, and the like.

[0164] I / O ports 1918 may enable computing device 1900 to be logically coupled to other devices, such as I / O components 1920. Some of I / O components 1920 may be built into computing device 1900. Examples of such I / O components 1920 include microphones, joysticks, recording devices, game pads, satellite dishes, scanners, printers, wireless devices, network devices, and the like.

[0165] In view of the foregoing description, various modifications and alternative embodiments of the present invention will be apparent to those skilled in the art. Therefore, this description is to be interpreted as illustrative only, and is for the purpose of teaching those skilled in the art to perform the best mode of the present invention. Without departing from the spirit of the present invention, the details of the structure may be substantially changed, and exclusive use of all modifications within the scope of the appended claims is reserved. Within this specification, embodiments have been described in a manner that enables writing of clear and concise specifications, but it is intended and will be appreciated that the embodiments may be combined or separated in various ways without departing from the present invention. The present invention is intended to be limited to the scope required by the appended claims and applicable legal rules.

[0166] It is also to be understood that the following claims are intended to cover all generic and specific features of the invention described herein and that all statements of the scope of the invention that may be said to come therebetween in a language.

Claims

1. An injection system, comprising: An injection assembly, the injection assembly comprising: a syringe barrel, the syringe barrel defining a lumen between a proximal end and a distal end; and a second sealing element, the second sealing element being movably disposed within the lumen to dispense an injection from an injection chamber defined in the syringe barrel; and a piercing element, the piercing element being configured to deliver the injection into a space in a patient's tissue, the permeability of the tissue to the injection being lower than the permeability of the space to the injection; a support platform configured to support the injection assembly and anchor the injection assembly relative to an injection site; a drive assembly configured to operate the injection assembly; one or more sensors configured to monitor one or more forces on the injection assembly; and A controller that communicates with the one or more sensors to receive information related to the one or more forces on the injection system and is configured to operate the drive assembly based on the information to advance the piercing element through the tissue toward the space so that the injectable agent is retained in the injection chamber until the piercing element fluidly connects the injection chamber with the space.

2. The injection system of claim 1, wherein: The injection assembly further comprises: a first sealing element, the first sealing element being movably disposed in the lumen and distal to the second sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and define the injection chamber between the first sealing element and the second sealing element, the piercing element being in fluid communication with the injection chamber to deliver the injection from the injection chamber to the space in the tissue of the patient, wherein, when a force is exerted on the second sealing element in the distal direction, In response to a first reaction force when the piercing element is advanced through the tissue, the first sealing element moves in the distal direction to advance the piercing element in the distal direction without delivering the injection through the piercing element, and In response to a second reaction force when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the injection is delivered from the injection chamber through the piercing element.

3. The injection system of claim 1, wherein: The drive assembly is linked to the second sealing element to exert the force on the second sealing element to translate the second sealing element in a distal direction.

4. The injection system of claim 1, wherein: The drive assembly includes a linear actuator linked to the second sealing element to exert the force on the second sealing element to translate the second sealing element in a distal direction.

5. The injection system of claim 1, wherein: The drive assembly includes a first driver configured to translate the syringe barrel relative to the support platform and a second driver linked to the second sealing element to translate the second sealing element relative to the syringe barrel.

6. The injection system of claim 5, wherein: The one or more sensors include a first load cell configured to measure a force on the syringe barrel.

7. The injection system of claim 5, wherein: The one or more sensors include a second load cell configured to measure a force on the second sealing element.

8. The injection system of claim 1, wherein: The one or more sensors include one or more of: a force sensor, a position sensor, or a low rate sensor.

9. The injection system of claim 8, wherein: The force sensor includes one or both of a pressure sensor and a strain sensor.

10. The injection system of claim 2, wherein: The controller is programmed to implement one or more feedback loops to monitor the first reaction force and the second reaction force.

11. The injection system of any one of claims 1 to 10, wherein: The controller is programmed to implement one or more feedback loops to monitor pre-insertion of the piercing element into the tissue, the one or more feedback loops being configured to monitor an increase in force on the piercing element, to detect a decrease in force on the piercing element, and to advance the piercing element a predetermined distance based on the decrease to embed the piercing element into the tissue.

12. The injection system of any one of claims 1 to 10, wherein: The controller is programmed to implement one or more feedback loops to monitor advancement of the piercing element through the tissue, the one or more feedback loops being configured to measure the load on the second sealing element and to detect a decrease in the load once the piercing element reaches the space in the tissue.

13. The injection system of any one of claims 1-10, wherein: The controller is programmed to implement one or more feedback loops to monitor the injection of the injectate into the space, the one or more feedback loops being configured to control the speed or advancement distance of the second sealing element.

14. The injection system of any one of claims 1-10, wherein: The controller is programmed to retract the piercing element a predetermined distance when the one or more sensors detect a decrease in the load on the second sealing element.

15. The injection system of any one of claims 1-10, wherein: The controller is programmed to control a stopping distance of the piercing element when the piercing element enters the space.

16. The injection system of any one of claims 1-10, wherein: The tissue is the conjunctiva and the space is the subconjunctival space.

17. The injection system of any one of claims 1-10, wherein: The tissue is the sclera and the space is the suprachoroidal space.

18. The injection system of any one of claims 1-10, wherein: The tissues are the sclera and the choroid and the space is the intravitreal space.

19. The injection system of any one of claims 1-10, wherein: The tissue is the cornea and the space is the anterior chamber of the eye.

20. An injection system comprising: An injection assembly, the injection assembly comprising: a syringe barrel, the syringe barrel defining a lumen between a proximal end and a distal end; a first sealing element and a second sealing element, the first sealing element and the second sealing element being movably disposed in the lumen, the second sealing element being distal to the first sealing element, to define an injection chamber; and a piercing element, the piercing element being fluidly connected to the injection chamber and configured to deliver an injectable agent from the injection chamber to a space in a patient's tissue, the permeability of the tissue to the injectable agent being lower than the permeability of the space to the injectable agent; a support platform configured to support the injection assembly and anchor the injection assembly relative to an injection site; a drive assembly configured to translate one or both of the syringe barrel or the second sealing element relative to the support platform; one or more sensors configured to monitor one or more forces on the injection assembly; and a controller in communication with the one or more sensors to receive information about the one or more forces on the injection system and configured to control the drive assembly based on the information to advance the piercing element through the tissue toward the space such that when the drive assembly translates the second sealing element in the distal direction, In response to a first reaction force when the piercing element is advanced through the tissue, the first sealing element moves in the distal direction to advance the piercing element in the distal direction without delivering the injection through the piercing element, and In response to a second reaction force when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the injection is delivered from the injection chamber through the piercing element.

21. The injection system of claim 20, wherein: The drive assembly is configured to translate the syringe barrel and the second sealing element independently of each other relative to the support platform.

22. The injection system of claim 20, wherein: The drive assembly is linked to the second sealing element to exert a force on the second sealing element to translate the second sealing element in the distal direction.

23. The injection system of claim 20, wherein: The drive assembly includes a linear actuator linked to the second sealing element to exert the force on the second sealing element to translate the second sealing element in the distal direction.

24. The injection system of claim 20, wherein: The drive assembly includes a first driver configured to translate the syringe barrel relative to the support platform and a second driver linked to the second sealing element to translate the second sealing element relative to the syringe barrel.

25. The injection system of claim 24, wherein: The one or more sensors include a first load cell configured to measure a force on the syringe barrel.

26. The injection system of claim 24, wherein: The one or more sensors include a second load cell configured to measure a force on the second sealing element.

27. The injection system of claim 20, wherein: The one or more sensors include one or more of: a force sensor, a position sensor, or a low rate sensor.

28. The injection system of claim 27, wherein: The force sensor includes one or both of a pressure sensor and a strain sensor.

29. The injection system of any one of claims 20-28, wherein: The controller is programmed to implement one or more feedback loops to monitor the first reaction force and the second reaction force.

30. The injection system of any one of claims 20-28, wherein: The controller is programmed to implement one or more feedback loops to monitor pre-insertion of the piercing element into the tissue, the one or more feedback loops being configured to monitor an increase in force on the piercing element, to detect a decrease in force on the piercing element, and to advance the piercing element a predetermined distance based on the decrease to embed the piercing element into the tissue.

31. The injection system of any one of claims 20-28, wherein: The controller is programmed to implement one or more feedback loops to monitor advancement of the piercing element through the tissue, the one or more feedback loops being configured to measure the load on the second sealing element and to detect a decrease in the load once the piercing element reaches a space in the tissue.

32. The injection system of any one of claims 20-28, wherein: The controller is programmed to implement one or more feedback loops to monitor the injection of the injectate into the space, the one or more feedback loops being configured to control the speed or advancement distance of the second sealing element.

33. The injection system of any one of claims 20-28, wherein: The controller is programmed to retract the piercing element a predetermined distance when the one or more sensors detect a decrease in the load on the second sealing element.

34. The injection system of any one of claims 20-28, wherein: The controller is programmed to control a stopping distance of the piercing element when the piercing element enters the space.

35. The injection system of any one of claims 20-28, wherein: The tissue is the conjunctiva and the space is the subconjunctival space.

36. The injection system of any one of claims 20-28, wherein: The tissue is the sclera and the space is the suprachoroidal space.

37. The injection system of any one of claims 20-28, wherein: The tissues are the sclera and the choroid and the space is the intravitreal space.

38. The injection system of any one of claims 20-28, wherein: The tissue is the cornea and the space is the anterior chamber of the eye.

39. A system for delivering an injection, comprising: a piercing element configured to be inserted into tissue to deliver an injectable agent from an injection chamber into a space in the tissue, the tissue having a density greater than a density of the space, such that a permeability of the tissue to the injectable agent is lower than a permeability of the space to the injectable agent; a drive assembly configured to advance the piercing element through the tissue toward the space; one or more sensors configured to monitor one or more forces on the piercing element; as well as A controller is in communication with the one or more sensors, the controller being configured to control the drive assembly to advance the piercing element through the tissue toward the space so that the injectable agent remains in the injection chamber until the piercing element fluidly connects the injection chamber with the space.

40. The system of claim 39, wherein the piercing element is positioned on a distal end of an injection assembly, the injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; and a first sealing element and a second sealing element, the first sealing element and the second sealing element being movably disposed in the lumen to dispense the injection from the injection chamber.

41. A system as described in claim 40, wherein in response to a first reaction force of one or more forces on the piercing element as the piercing element is advanced through the tissue, the first sealing element moves in a distal direction to advance the piercing element in the distal direction without delivering the injection through the piercing element.

42. A system as described in claim 40, in response to a second reaction force of one or more forces on the piercing element when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves in the distal direction, so that the injection is delivered from the injection chamber to the space through the piercing element.

43. The system of claim 41, wherein: The controller is programmed to implement one or more feedback loops to monitor the first reaction force.

44. The system of claim 42, wherein: The controller is programmed to implement one or more feedback loops to monitor the second reaction force.

45. The system of any one of claims 39-42, wherein: The controller is programmed to implement one or more feedback loops to monitor pre-insertion of the piercing element into the tissue, the one or more feedback loops being configured to monitor an increase in force on the piercing element, to detect a decrease in force on the piercing element, and to advance the piercing element a predetermined distance based on the decrease to embed the piercing element into the tissue.

46. ​​The system of any one of claims 40-42, wherein: The controller is programmed to implement one or more feedback loops to monitor advancement of the piercing element through the tissue, the one or more feedback loops being configured to measure the load on the second sealing element and to detect a decrease in the load once the piercing element reaches the space in the tissue.

47. The system of any one of claims 40-42, wherein: The controller is programmed to implement one or more feedback loops to monitor the injection of the injectate into the space, the one or more feedback loops being configured to control the speed or advancement distance of the second sealing element.

48. The system of any one of claims 40-42, wherein: The controller is programmed to retract the piercing element a predetermined distance when the one or more sensors detect a decrease in the load on the second sealing element.

49. The system of any one of claims 39-42, wherein: The controller is programmed to control a stopping distance of the piercing element when the piercing element enters the space.

50. The system of any one of claims 39-42, wherein: The tissue is the conjunctiva and the space is the subconjunctival space.

51. The system of any one of claims 39-42, wherein: The tissue is the sclera and the space is the suprachoroidal space.

52. The system of any one of claims 39-42, wherein: The tissues are the sclera and the choroid and the space is the intravitreal space.

53. The system of any one of claims 39-42, wherein: The tissue is the cornea and the space is the anterior chamber of the eye.

54. A system for delivering an injection, comprising: An injection assembly configured to be positioned adjacent to a tissue, the injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; and a second sealing element movably disposed within the lumen to dispense an injectable from an injection chamber defined in the syringe barrel; and a piercing element extending and configured to deliver the injectable into a space in the tissue, the tissue having a density greater than a density of the space, such that the permeability of the tissue to the injectable is lower than the permeability of the space to the injectable; one or more sensors configured to monitor one or more forces on the injection assembly; and A controller that communicates with the one or more sensors, the controller being configured to control the injection assembly using a force on the injection assembly to advance the piercing element through the tissue toward the space so that the injectable remains in the injection chamber until the piercing element fluidly connects the injection chamber with the space.

55. A system as described in claim 54, wherein in response to a first reaction force of the one or more forces on the piercing element as the piercing element is advanced through the tissue, the first sealing element moves in a distal direction to advance the piercing element in the distal direction without delivering the injectable agent through the piercing element.

56. A system as described in claim 54, in response to a second reaction force of the one or more forces on the piercing element when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves in the distal direction, so that the injection is delivered from the injection chamber to the space through the piercing element.

57. The system of claim 54, wherein: The injection assembly is further configured to be anchored relative to an injection site in the tissue.

58. The system of claim 55, wherein: The controller is programmed to implement one or more feedback loops to monitor the first reaction force.

59. The system of claim 56, wherein: The controller is programmed to implement one or more feedback loops to monitor the second reaction force.

60. The system of any one of claims 54-57, wherein: The controller is programmed to implement one or more feedback loops to monitor pre-insertion of the piercing element into the tissue, the one or more feedback loops being configured to monitor an increase in force on the piercing element, to detect a decrease in force on the piercing element, and to advance the piercing element a predetermined distance based on the decrease to embed the piercing element into the tissue.

61. The system of any one of claims 54-57, wherein: The controller is programmed to implement one or more feedback loops to monitor advancement of the piercing element through tissue, the one or more feedback loops being configured to measure the load on the second sealing element and to detect a decrease in the load once the piercing element reaches the space in the tissue.

62. The system of any one of claims 54-57, wherein: The controller is programmed to implement one or more feedback loops to monitor the injection of the injectate into the space, the one or more feedback loops being configured to control the speed or advancement distance of the second sealing element.

63. The system of any one of claims 54-57, wherein: The controller is programmed to retract the piercing element a predetermined distance when the one or more sensors detect a decrease in the load on the second sealing element.

64. The system of any one of claims 54-57, wherein: The controller is programmed to control a stopping distance of the piercing element when the piercing element enters the space.

65. The system of any one of claims 54-57, wherein: The tissue is the conjunctiva and the space is the subconjunctival space.

66. The system of any one of claims 54-57, wherein: The tissue is the sclera and the space is the suprachoroidal space.

67. The system of any one of claims 54-57, wherein: The tissues are the sclera and the choroid and the space is the intravitreal space.

68. The system of any one of claims 54-57, wherein: The tissue is the cornea and the space is the anterior chamber of the eye.

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