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 including 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 infusate from an infusion chamber defined in the syringe barrel. The piercing element delivers the infusate into a space within the tissue, the tissue being less permeable to the infusate than the space. The injection system also includes a support platform for supporting and anchoring the injection assembly to a site of injection, 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 in communication with the one or more sensors to receive information about the one or more forces on the injection system.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 064,975, filed August 13, 2020, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to systems and methods that allow injection into cavities or spaces, particularly into cavities or spaces through tissue within the human body, such as the suprachoroidal space within ocular tissue. [Background technology]

[0003] The present disclosure relates to devices and methods that enable the delivery of multiple therapeutic agents to cavities or spaces in the human body, particularly ocular tissues within the posterior segment of the eye through the suprachoroidal space. Posterior segment ocular diseases are a leading cause of permanent vision loss affecting millions of people and, if left untreated, can lead to blindness. These diseases include age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema (DME), choroidal atrophy (CHM), retinal vein occlusion (RVO), uveitis, and endophthalmitis. While pharmaceutical agents may be available to prevent disease progression in many cases, systemic delivery cannot achieve therapeutic concentrations in the posterior segment due to the blood-ocular barrier.

[0004] Recently, the suprachoroidal space (SCS) has been explored as a potential drug delivery route to the posterior segment of the eye. The suprachoroidal space is the potential space between the sclera and choroid. Drugs delivered into this space can travel around the eyeball and into the posterior segment of the eye. This route for drug delivery has been shown to be more effective for treating the posterior segment than intravitreal injection. However, the simplicity of intravitreal injection is superior to the surgical procedure previously required for suprachoroidal delivery. Historically, suprachoroidal delivery was achieved by creating a small incision using a scalpel, followed by delivery using a needle or cannula. More recently, microneedles with a predetermined short length that allows penetration only to a certain depth have been used to target the suprachoroidal space. Because scleral thickness varies significantly within the patient population, either premapping of the ocular geometry or trial and error is required during injection with hollow microneedles. If the needle is too long, it can easily penetrate the thin suprachoroidal space and inject the drug into the vitreous; if it is too short, it will deliver into the sclera. The sclera is 10 times stiffer than the choroid and 200 times stiffer than the retina, making it even more difficult to puncture the sclera without injecting into the vitreous. In some cases, a small amount (approximately 100 microliters) of therapeutic agent needs to be injected into the suprachoroidal space with enough force to displace the positive resistance of intraocular pressure that presses the choroid against the sclera to achieve broad coverage of the posterior segment of the eye. This can be difficult to achieve using a conventional handheld syringe.

[0005] Therefore, a need exists for improved systems and methods for suprachoroidal drug delivery that precisely, consistently, and safely target the suprachoroidal space and provide broad coverage of the posterior segment of the eye. Summary of the Invention [Means for solving the problem]

[0006] According to some aspects of the present disclosure, an injection system is provided that includes an injection assembly including a syringe barrel defining a lumen between a proximal end and a distal end, a second sealing element movably disposed within the lumen to dispense infusate from an infusion chamber defined in the syringe barrel, and a puncturing element configured to deliver the infusate into a space within a patient's tissue. The tissue has a lower permeability to the infusate than the space. The injection system also includes a support platform configured to support the injection assembly and anchor the injection assembly relative to a site of injection, 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 in communication with the one or more sensors to receive information about the one or more forces on the injection system. The controller is configured, based on the information, to operate the drive assembly to advance the puncturing element through the tissue toward the space such that the infusate remains within the infusion chamber until the puncturing element fluidly connects the infusion chamber with the space.

[0007] In some embodiments, the injection assembly further includes a first seal element movably disposed within the lumen distal to the second seal element, the first seal element and the second seal element forming a seal with the lumen and defining an infusion chamber therebetween. The puncture element is in fluid communication with the infusion chamber and is capable of delivering infusate from the infusion chamber into a space within the patient's tissue. When a force is applied to the second seal element in a distal direction, in response to a first counter force as the puncture element advances through the tissue, the first seal element moves distally, advancing the puncture element distally without delivering infusate through the puncture element; and in response to a second counter force when the infusion chamber is fluidly connected to the space, the first seal element remains stationary and infusate is delivered from the infusion chamber through the puncture element.

[0008] In some embodiments, the drive assembly is coupled to the second seal element and applies a force to the second seal element, translating the second element in a distal direction. In some embodiments, the drive assembly comprises a linear actuator coupled to the second seal element and applies a force to the second seal element, translating the second element in a distal direction. In some embodiments, the drive assembly comprises a first drive configured to translate the syringe barrel relative to the support platform and a second drive coupled to the second seal element and translating the second seal element relative to the syringe barrel. The one or more sensors can comprise a first load cell configured to measure a force on the syringe barrel, and the one or more sensors can comprise a second load cell configured to measure a force on the second seal element. In some embodiments, the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor, or a flow rate sensor.

[0009] In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring the first and second reaction forces. In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncture element into tissue, the one or more feedback loops configured to monitor an increase in force on the puncture element, detect a decrease in force on the puncture element, and, based on the decrease, cause advancement of the puncture element a predetermined distance to embed the puncture element into the tissue. In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncture element through tissue, the one or more feedback loops configured to measure a load on the second seal element and detect a decrease in load when the puncture element reaches a space within the tissue. In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring injection of infusate into the space, the one or more feedback loops configured to control a speed or advancement distance of the second seal element. In some embodiments, the controller is programmed to cause retraction of the puncturing element a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element, hi some embodiments, the controller is programmed to control a stopping distance of the puncturing element as it enters the space.

[0010] 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 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.

[0011] In some aspects, the present disclosure provides an injection system comprising an injection assembly including a syringe barrel defining a lumen between a proximal end and a distal end, and first and second seal elements movably disposed within the lumen. The second seal element is distal to the first seal element and defines an infusion chamber. A piercing element is fluidly connected to the infusion chamber and configured to deliver an infusate from the infusion chamber into a space within the patient's tissue, the tissue having a lower permeability to the infusate than the space. The injection system also includes a support platform configured to support the injection assembly and anchor the injection assembly relative to a site of injection; a drive assembly configured to translate one or both of the syringe barrel or the second seal 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 assembly. A controller in communication with the one or more sensors is configured to receive information about one or more forces on the injection system and, based on the information, control the drive assembly to advance the puncturing element through the tissue toward the space when the drive assembly translates the second sealing element distally such that: in response to a first reaction force as the puncturing element advances through the tissue, the first sealing element moves distally, advancing the puncturing element distally without delivering infusate through the puncturing element, and in response to a second reaction force when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and infusate is delivered from the infusion chamber through the puncturing element.

[0012] In some embodiments, the drive assembly is configured to translate the syringe barrel and the second seal element independently of one another relative to the support platform. In some embodiments, the drive assembly is coupled to the second seal element and applies a force to the second seal element, causing it to translate in a distal direction. In some embodiments, the drive assembly comprises a linear actuator coupled to the second seal element and applies a force to the second seal element, causing it to translate in a distal direction. In some embodiments, the drive assembly comprises a first drive device configured to translate the syringe barrel relative to the support platform and a second drive device coupled to the second seal element and causing it to translate in a distal direction.

[0013] In some embodiments, the one or more sensors comprise a first load cell configured to measure a force on the syringe barrel. In some embodiments, the one or more sensors comprise a second load cell configured to measure a force on the second seal element. In some embodiments, the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor, or a flow rate sensor.

[0014] In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring the first and second reaction forces. In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncture element into tissue. The one or more feedback loops can be configured to monitor an increase in force on the puncture element, detect a decrease in force on the puncture element, and, based on the decrease, cause advancement of the puncture member a predetermined distance to embed the puncture element into the tissue. In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncture element through tissue, the one or more feedback loops configured to measure a load on the second seal element and detect a decrease in load when the puncture element reaches a space within the tissue. In some embodiments, the controller is programmed to implement one or more feedback loops for monitoring infusion of infusate into the space, the one or more feedback loops configured to control a speed or advancement distance of the second seal element. In some embodiments, the controller is programmed to cause retraction of the puncturing element a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element, hi some embodiments, the controller is programmed to control a stopping distance of the puncturing element as it enters the space.

[0015] 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 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.

[0016] A method of delivering infusate is provided, comprising inserting a puncturing element into tissue. The puncturing element is configured to deliver the infusate from an infusion chamber into a space within the tissue, where the tissue can have a density greater than the space such that the tissue has a lower permeability to the infusate than the space. The method also includes advancing the puncturing element through the tissue toward the space using a drive assembly, monitoring one or more forces on the puncturing element using one or more sensors, and controlling the drive assembly using a controller in communication with the one or more sensors to advance the puncturing element through the tissue toward the space such that the infusate remains within the infusion chamber until the puncturing element fluidly connects the infusion chamber with the space.

[0017] In some embodiments, the puncture element is positioned on the distal end of an infusion assembly comprising a syringe barrel defining a lumen between a proximal end and a distal end, and first and second seal elements movably disposed within the lumen to dispense infusate from the infusion chamber. In some embodiments, in response to a first counter force of one or more forces on the puncture element as it advances through tissue, the first seal element moves distally, advancing the puncture element distally without delivering infusate through the puncture element. In some embodiments, in response to a second counter force of one or more forces on the puncture element when the infusion chamber is fluidly connected to the space, the first seal element remains stationary and the second seal element moves distally such that infusate is delivered from the infusion chamber through the puncture element and into the space.

[0018] 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 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.

[0019] A method of delivering infusate is provided, comprising positioning an injection assembly adjacent to tissue. The injection assembly comprises a syringe barrel defining a lumen between a proximal end and a distal end, a second sealing element movably disposed within the lumen to dispense infusate from an infusion chamber defined in the syringe barrel, and an extending piercing element configured to deliver the infusate into a space within the tissue. The tissue has a density greater than the space such that the tissue has a lower permeability to the infusate than the space. The method also includes monitoring one or more forces on the injection assembly using one or more sensors, and controlling the injection assembly using the forces on the injection system using a controller in communication with the one or more sensors to advance the piercing element through the tissue toward the space such that the infusate remains within the infusion chamber until the piercing element fluidly connects the infusion chamber with the space.

[0020] In some embodiments, in response to a first of the one or more forces acting against the puncture element as it advances through the tissue, the first sealing element moves distally, advancing the puncture element distally without delivering infusate through the puncture element. In some embodiments, in response to a second of the one or more forces acting against the puncture element when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves distally such that infusate is delivered from the infusion chamber through the puncture element and into the space. In some embodiments, the method further includes anchoring the injection assembly relative to a site of infusion within the tissue.

[0021] 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 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. The present invention provides, for example, the following. (Item 1) 1. An injection system comprising: an injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; a second sealing element movably disposed within the lumen to dispense infusate from an infusion chamber defined within the syringe barrel; and a piercing element configured to deliver the infusate into a space within a patient's tissue, the tissue being less permeable to the infusate than the space; a support platform configured to support the injection assembly and anchor the injection assembly relative to a site of injection; a drive assembly configured to operate the injection assembly; and one or more sensors configured to monitor one or more forces on the injection assembly; a controller configured to communicate with the one or more sensors to receive information about the one or more forces on the injection system, and to operate the drive assembly based on the information to advance the piercing element through the tissue toward the space such that the infusate remains within the infusion chamber until the piercing element fluidly connects the infusion chamber with the space; and An injection system comprising: (Item 2) the injection assembly further comprises a first sealing element movably disposed within the lumen distal to the second sealing element, the first sealing element and the second sealing element forming a seal with the lumen and defining the infusion chamber therebetween, the piercing element being in fluid communication with the infusion chamber and delivering the infusate from the infusion chamber into the space within the tissue of the patient; When a force is applied to the second sealing element in a 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 carrying the infusate through the piercing element; 2. The injection system of claim 1, wherein in response to a second reaction force when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and the infusion agent is conveyed from the infusion chamber through the piercing element. (Item 3) Item 1. The injection system of item 1, wherein the drive assembly is coupled to the second seal element to apply the force against the second seal element to translate the second element in a distal direction. (Item 4) Item 10. The injection system of item 1, wherein the drive assembly comprises a linear actuator coupled to the second seal element to apply the force against the second seal element and translate the second element in a distal direction. (Item 5) 2. The injection system of claim 1, wherein the drive assembly comprises a first drive device configured to translate the syringe barrel relative to the support platform, and a second drive device coupled to the second seal element to translate the second seal element relative to the syringe barrel. (Item 6) Item 6. The injection system of item 5, wherein the one or more sensors include a first load cell configured to measure a force on the syringe barrel. (Item 7) Item 6. The injection system of item 5, wherein the one or more sensors include a second load cell configured to measure a force on the second sealing element. (Item 8) Item 10. The infusion system of item 1, wherein the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor, or a flow rate sensor. (Item 9) Item 3. The injection system of item 2, wherein the controller is programmed to implement one or more feedback loops for monitoring the first reaction force and the second reaction force. (Item 10) 10. The injection system of any one of items 1 to 9, wherein the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncturing element into the tissue, the one or more feedback loops being configured to detect a decrease in force on the puncturing element and, based on the decrease, monitor an increase in force on the puncturing element to cause advancement of the puncturing element a predetermined distance to embed the puncturing element in the tissue. (Item 11) 10. The injection system of any one of items 1 to 9, wherein the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncturing element through the tissue, the one or more feedback loops configured to measure a load on the second sealing element and detect a decrease in the load when the puncturing element reaches the space within the tissue. (Item 12) 10. The injection system of any one of items 1 to 9, wherein the controller is programmed to implement one or more feedback loops for monitoring injection of the infusate into the space, the one or more feedback loops configured to control a speed or an advancement distance of the second sealing element. (Item 13) 10. The injection system of any one of items 1 to 9, wherein the controller is programmed to cause retraction of the puncture element a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element. (Item 14) 10. The injection system according to any one of items 1 to 9, wherein the controller is programmed to control a stopping distance of the puncture element when the puncture element enters the space. (Item 15) 10. The injection system according to any one of items 1 to 9, wherein the tissue is the conjunctiva and the space is the subconjunctival space. (Item 16) 10. The injection system according to any one of items 1 to 9, wherein the tissue is the sclera and the space is the suprachoroidal space. (Item 17) 10. The injection system according to any one of items 1 to 9, wherein the tissues are the sclera and choroid, and the space is the intravitreal space. (Item 18) 10. The injection system according to any one of items 1 to 9, wherein the tissue is the cornea and the space is the anterior chamber of the eye. (Item 19) 1. An injection system comprising: an injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; first and second sealing elements movably disposed within the lumen, the second sealing element being distal to the first sealing element and defining an infusion chamber; and a piercing element fluidly connected to the infusion chamber and configured to deliver an infusate from the infusion chamber into a space within a patient's tissue, the tissue having a lower permeability to the infusate than the space; a support platform configured to support the injection assembly and anchor the injection assembly relative to a site of injection; a drive assembly configured to translate one or both of the syringe barrel or the second seal element relative to the support platform; one or more sensors configured to monitor one or more forces on the injection assembly; a controller configured to communicate with the one or more sensors to receive information about the one or more forces on the injection system, and to control the drive assembly based on the information to advance the puncture element through the tissue toward the space, whereby when the drive assembly translates the second sealing element distally; 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 carrying the infusate through the piercing element; In response to a second reaction force when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and the infusion agent is conveyed from the infusion chamber through the piercing element. Controller and An injection system comprising: (Item 20) 20. The injection system of claim 19, wherein the drive assembly is configured to translate the syringe barrel and the second seal element independently of each other relative to the support platform. (Item 21) 20. The injection system of claim 19, wherein the drive assembly is coupled to the second seal element to apply the force against the second seal element and translate the second element in the distal direction. (Item 22) 20. The injection system of claim 19, wherein the drive assembly comprises a linear actuator coupled to the second seal element to apply the force against the second seal element and translate the second element in the distal direction. (Item 23) 20. The injection system of claim 19, wherein the drive assembly comprises a first drive configured to translate the syringe barrel relative to the support platform, and a second drive coupled to the second seal element to translate the second seal element relative to the syringe barrel. (Item 24) Item 24. The injection system of item 23, wherein the one or more sensors include a first load cell configured to measure a force on the syringe barrel. (Item 25) Item 24. The injection system of item 23, wherein the one or more sensors include a second load cell configured to measure a force on the second sealing element. (Item 26) 20. The infusion system of claim 19, wherein the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor, or a flow rate sensor. (Item 27) 27. The injection system of any one of items 19 to 26, wherein the controller is programmed to implement one or more feedback loops for monitoring the first reaction force and the second reaction force. (Item 28) 27. The injection system of any one of items 19 to 26, wherein the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncturing element into the tissue, the one or more feedback loops being configured to detect a decrease in force on the puncturing element and, based on the decrease, monitor an increase in force on the puncturing element to cause advancement of the puncturing element a predetermined distance to embed the puncturing element in the tissue. (Item 29) 27. The injection system of any one of items 19 to 26, wherein the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncturing element through the tissue, the one or more feedback loops configured to measure a load on the second sealing element and detect a decrease in the load when the puncturing element reaches the space within the tissue. (Item 30) 27. The injection system of any one of items 19 to 26, wherein the controller is programmed to implement one or more feedback loops for monitoring injection of the infusate into the space, the one or more feedback loops configured to control a speed or an advancement distance of the second sealing element. (Item 31) 27. The injection system of any one of items 19 to 26, wherein the controller is programmed to cause retraction of the puncture element a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element. (Item 32) 27. The injection system of any one of items 19 to 26, wherein the controller is programmed to control a stopping distance of the puncture element when the puncture element enters the space. (Item 33) 27. The injection system according to any one of items 19 to 26, wherein the tissue is the conjunctiva and the space is the subconjunctival space. (Item 34) 27. The injection system according to any one of items 19 to 26, wherein the tissue is the sclera and the space is the suprachoroidal space. (Item 35) 27. The injection system according to any one of items 19 to 26, wherein the tissues are the sclera and choroid, and the space is the intravitreal space. (Item 36) 27. The injection system according to any one of items 19 to 26, wherein the tissue is the cornea and the space is the anterior chamber of the eye. (Item 37) 1. A method of delivering an injectable agent, comprising: inserting a piercing element into tissue, the piercing element configured to deliver an infusate from an infusion chamber into a space within the tissue, the tissue having a density greater than the space such that the tissue is less permeable to the infusate than the space; advancing the piercing element through the tissue toward the space using a drive assembly; monitoring one or more forces on the lancing element using one or more sensors; using a controller in communication with the one or more sensors, controlling the drive assembly to advance the piercing element through the tissue toward the space such that the infusate remains within the infusion chamber until the piercing element fluidly connects the infusion chamber with the space; A method comprising: (Item 38) Item 38. The method of item 37, wherein the piercing element is positioned on a distal end of an injection assembly comprising a syringe barrel defining a lumen between a proximal end and a distal end, and first and second sealing elements movably disposed within the lumen to dispense the infusate from the injection chamber. (Item 39) 39. The method of claim 38, wherein in response to a first reaction force of the one or more forces on the piercing element as the piercing element advances through the tissue, the first sealing element moves distally to advance the piercing element in the distal direction without carrying the infusate through the piercing element. (Item 40) Item 39. The method of item 38, wherein in response to a second counter force of the one or more forces on the piercing element when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves distally such that the infusate is transported from the infusion chamber through the piercing element and into the space. (Item 41) 41. The method of any one of items 37 to 40, wherein the controller is programmed to implement one or more feedback loops for monitoring the first reaction force and the second reaction force. (Item 42) 41. The method of any one of items 37 to 40, wherein the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncturing element into the tissue, the one or more feedback loops being configured to detect a decrease in force on the puncturing element and, based on the decrease, monitor an increase in force on the puncturing element to cause advancement of the puncturing element a predetermined distance to embed the puncturing element in the tissue. (Item 43) 41. The method of any one of items 37 to 40, wherein the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncturing element through the tissue, the one or more feedback loops configured to measure a load on the second sealing element and detect a decrease in the load when the puncturing element reaches the space within the tissue. (Item 44) 41. The method of any one of items 37 to 40, wherein the controller is programmed to implement one or more feedback loops for monitoring injection of the infusate into the space, the one or more feedback loops being configured to control a speed or an advancement distance of the second sealing element. (Item 45) 41. The method of any one of items 37 to 40, wherein the controller is programmed to cause retraction of the puncturing element by a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element. (Item 46) 41. The method according to any one of items 37 to 40, wherein the controller is programmed to control a stopping distance of the lancing element when the lancing element enters the space. (Item 47) 41. The method according to any one of items 37 to 40, wherein the tissue is the conjunctiva and the space is the subconjunctival space. (Item 48) 41. The method according to any one of items 37 to 40, wherein the tissue is the sclera and the space is the suprachoroidal space. (Item 49) 41. The method according to any one of items 37 to 40, wherein the tissues are the sclera and choroid, and the space is the intravitreal space. (Item 50) 41. The method according to any one of items 37 to 40, wherein the tissue is the cornea and the space is the anterior chamber of the eye. (Item 51) 1. A method of delivering an injectable agent, comprising: positioning an injection assembly adjacent to tissue, the injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; a second sealing element movably disposed within the lumen to dispense an infusate from an injection chamber defined within the syringe barrel; and a piercing element extending therefrom configured to deliver the infusate into a space within the tissue, the tissue having a density greater than the space such that the tissue is less permeable to the infusate than the space; monitoring one or more forces on the injection assembly using one or more sensors; controlling the injection assembly using the force on the injection assembly using a controller in communication with the one or more sensors to advance the piercing element through the tissue toward the space such that the infusate remains within the injection chamber until the piercing element fluidly connects the injection chamber with the space using a controller in communication with the one or more sensors; A method comprising: (Item 52) Item 52. The method of item 51, wherein in response to a first reaction force of the one or more forces on the piercing element as the piercing element advances through the tissue, a first sealing element moves distally to advance the piercing element in the distal direction without carrying the infusate through the piercing element. (Item 53) Item 52. The method of item 51, wherein in response to a second counter force of the one or more forces on the piercing element when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves distally such that the infusate is transported from the infusion chamber through the piercing element and into the space. (Item 54) 52. The method of claim 51, further comprising anchoring the injection assembly to a site of injection within the tissue. (Item 55) 55. The method of any one of items 51 to 54, wherein the controller is programmed to implement one or more feedback loops for monitoring the first reaction force and the second reaction force. (Item 56) 55. The method of any one of items 51 to 54, wherein the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncturing element into the tissue, the one or more feedback loops being configured to detect a decrease in force on the puncturing element and, based on the decrease, monitor an increase in force on the puncturing element to cause advancement of the puncturing element a predetermined distance to embed the puncturing element in the tissue. (Item 57) 55. The method of any one of items 51 to 54, wherein the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncturing element through the tissue, the one or more feedback loops configured to measure a load on the second sealing element and detect a decrease in the load when the puncturing element reaches the space within the tissue. (Item 58) 55. The method of any one of items 51 to 54, wherein the controller is programmed to implement one or more feedback loops for monitoring injection of the infusate into the space, the one or more feedback loops being configured to control a speed or an advancement distance of the second sealing element. (Item 59) 55. The method of any one of items 51 to 54, wherein the controller is programmed to cause retraction of the puncturing element a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element. (Item 60) 55. The method according to any one of items 51 to 54, wherein the controller is programmed to control a stopping distance of the lancing element when the lancing element enters the space. (Item 61) 55. The method according to any one of items 51 to 54, wherein the tissue is the conjunctiva and the space is the subconjunctival space. (Item 62) 55. The method according to any one of items 51 to 54, wherein the tissue is the sclera and the space is the suprachoroidal space. (Item 63) 55. The method according to any one of items 51 to 54, wherein the tissues are the sclera and choroid, and the space is the intravitreal space. (Item 64) 55. The method according to any one of items 51 to 54, wherein the tissue is the cornea and the space is the anterior chamber of the eye. [Brief explanation of the drawings]

[0022] The present disclosure is further described in the following detailed description with reference to several drawings, in which like reference numerals represent similar parts throughout the several views of the drawings, and in which:

[0023] [Figure 1A] FIG. 1A illustrates an exemplary graph of force versus time (or displacement) to show the forces experienced by a motorized injection system when administering a therapeutic agent into tissue.

[0024] [Figure 1B] FIG. 1B illustrates an exemplary graph of piston position versus applied force to show the forces experienced by a motorized injection system when administering a therapeutic agent into tissue.

[0025] [Figure 2] FIG. 2 illustrates an exemplary embodiment of a motorized injection system.

[0026] [Figure 3A] 3A and 3B illustrate an exemplary embodiment of a drive assembly for a syringe barrel and syringe plunger. [Figure 3B] 3A and 3B illustrate an exemplary embodiment of a drive assembly for a syringe barrel and syringe plunger.

[0027] [Figure 4] FIG. 4 illustrates an exemplary embodiment of a means for attaching and stabilizing a motorized injection system to an injection site.

[0028] [Figure 5A] FIG. 5A illustrates an exemplary embodiment of an injection system.

[0029] [Figure 5B]FIG. 5B illustrates an exemplary method of use of one exemplary embodiment of the injection system of FIG. 5A.

[0030] [Figure 6A] 6A, 6B, 6C, and 6D illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 6B] 6A, 6B, 6C, and 6D illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 6C] 6A, 6B, 6C, and 6D illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 6D] 6A, 6B, 6C, and 6D illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe.

[0031] [Figure 7A] 7A and 7B are flow charts illustrating the use of the system shown in FIGS. 6A-6D. [Figure 7B] 7A and 7B are flow charts illustrating the use of the system shown in FIGS. 6A-6D.

[0032] [Figure 8A] 8A, 8B, 8C, 8D, and 8E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 8B] 8A, 8B, 8C, 8D, and 8E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 8C] 8A, 8B, 8C, 8D, and 8E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 8D] 8A, 8B, 8C, 8D, and 8E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 8E]8A, 8B, 8C, 8D, and 8E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe.

[0033] [Figure 9A] 9A and 9B are flow charts illustrating the use of the system shown in FIGS. 8A-8E. [Figure 9B] 9A and 9B are flow charts illustrating the use of the system shown in FIGS. 8A-8E.

[0034] [Figure 10A] 10A, 10B, 10C, 10D, and 10E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 10B] 10A, 10B, 10C, 10D, and 10E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 10C] 10A, 10B, 10C, 10D, and 10E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 10D] 10A, 10B, 10C, 10D, and 10E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe. [Figure 10E] 10A, 10B, 10C, 10D, and 10E illustrate one embodiment of the use of a motorized injection system with an auto-stop syringe.

[0035] [Figure 11A] 11A and 11B are flow charts illustrating the use of the system shown in FIGS. 10A-10E. [Figure 11B] 11A and 11B are flow charts illustrating the use of the system shown in FIGS. 10A-10E.

[0036] [Figure 12] FIG. 12 illustrates an embodiment of an injection system of the present disclosure having a quick fill port.

[0037] [Figure 13A] 13A-13B and 14A-14B illustrate an exemplary process for filling an infusion system of the present disclosure through a quick fill port. [Figure 13B] 13A-13B and 14A-14B illustrate an exemplary process for filling an infusion system of the present disclosure through a quick fill port. [Figure 14A] 13A-13B and 14A-14B illustrate an exemplary process for filling an infusion system of the present disclosure through a quick fill port. [Figure 14B] 13A-13B and 14A-14B illustrate an exemplary process for filling an infusion system of the present disclosure through a quick fill port.

[0038] [Figure 15A] 15A-15B illustrate an exemplary process for backfilling an infusion system of the present disclosure. [Figure 15B] 15A-15B illustrate an exemplary process for backfilling an infusion system of the present disclosure.

[0039] [Figure 16A] 16A-16B show an exemplary process for filling the infusion system of the present disclosure through a port at the proximal end. [Figure 16B] 16A-16B show an exemplary process for filling the infusion system of the present disclosure through a port at the proximal end.

[0040] [Figure 17A] 17A-17C illustrate an exemplary process for filling an infusion system of the present disclosure through a port sealed with a self-sealing polymer. [Figure 17B] 17A-17C illustrate an exemplary process for filling an infusion system of the present disclosure through a port sealed with a self-sealing polymer. [Figure 17C]17A-17C illustrate an exemplary process for filling an infusion system of the present disclosure through a port sealed with a self-sealing polymer.

[0041] [Figure 18A] 18A-18D show an embodiment of an injection system of the present disclosure having a port at the distal end. [Figure 18B] 18A-18D show an embodiment of an injection system of the present disclosure having a port at the distal end. [Figure 18C] 18A-18D show an embodiment of an injection system of the present disclosure having a port at the distal end. [Figure 18D] 18A-18D show an embodiment of an injection system of the present disclosure having a port at the distal end.

[0042] [Figure 19] FIG. 19 is an exemplary embodiment of a computing system for use in conjunction with various embodiments of the present disclosure.

[0043] While the above-identified drawings set forth embodiments of the presently disclosed subject matter, other embodiments are also contemplated, as noted in the discussion. The present disclosure presents illustrative embodiments by way of representation, not limitation. Numerous other modifications and embodiments can be devised by those skilled in the art which fall within the scope and spirit of the principles of the presently disclosed subject matter. DETAILED DESCRIPTION OF THE INVENTION

[0044] Detailed Description The present disclosure provides a motorized injection system for the delivery of therapeutic agents into potential spaces or cavities within tissue. In some embodiments, such a system can be used for drug delivery to the suprachoroidal space. In some embodiments, such a system is automated and comprises sensors and a feedback loop. The system of the present disclosure can thus be configured to precisely, consistently, and safely target the suprachoroidal space and provide broad coverage of the posterior segment of the eye.

[0045] In some embodiments, the injection system includes a syringe barrel for holding one or more infusates, a piercing element (also referred to as a needle, although similar devices can be used) attached to the syringe barrel in fluid communication with the syringe barrel, and a sealing element (also referred to as an ejection plunger) for expelling the infusate from the syringe barrel through the needle. As described in more detail below, the injection system can include a regular syringe or an auto-stop syringe with multiple sealing elements as described in more detail below.

[0046] 1A and 1B illustrate the forces experienced by a motorized injection system when administering a therapeutic agent into a tissue cavity through a puncturing member or element (interchangeably referred to as a needle, although similar devices can also be used). In Phase I, the needle is pre-inserted into the tissue (e.g., the sclera of the eye). Referring to FIG. 1A, during pre-insertion of the needle into the tissue (movement of the injection system toward the tissue), a load cell attached to the injection system detects an increasing force until the needle punctures the tissue. Once the tissue is punctured, there may be a drop in load. Referring to FIG. 1B, which shows the applied load after completion of Phase I, once insertion is complete, the contents of the injection system may be pressurized by advancing the extrusion plunger. The load on the plunger may remain constant in this phase as the plunger advances until pressure within the syringe barrel begins to increase. Next, in Phase II, the needle is advanced 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 may increase and plateau. In stage III-a, the needle tip enters a cavity (e.g., the suprachoroidal space of the eye). Because the density of the cavity is lower than that of the tissue, the cavity generates a backpressure on the needle that is lower than the backpressure generated by the tissue. Thus, when the needle lumen opens into the cavity, the load on the plunger decreases due to the decrease in backpressure. This decrease in backpressure indicates that the needle lumen is within the cavity, and the needle can be prevented from advancing further into the cavity (either by the system or due to an autoregulation design as discussed below). In some embodiments, the therapeutic agent can be pressurized to a pressure that is insufficient to release the therapeutic agent into the tissue, but sufficient to release the therapeutic agent into the cavity. Thus, the pressure of the pressurized therapeutic agent will decrease when the needle is released into the cavity, and the needle will not move forward when force is applied to the extrusion plunger. In step III-b, the therapeutic agent is injected into the cavity at a preselected rate when force is applied to the needle plunger.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 medication chamber, the inner diameter of the medication chamber, the length of the needle, and the inner diameter of the needle. In some embodiments, once the needle reaches the cavity, the system can continue to advance the pusher plunger, continuously injecting the therapeutic agent into the cavity. In some embodiments, the pusher plunger can be stopped once the needle lumen reaches the cavity and then restarted to inject the therapeutic agent into the cavity.

[0047] Referring to FIG. 2 , the motorized injection system 10 of the present disclosure includes a housing or support platform 12 that supports an injection system 14, a drive assembly or mechanism 16, and one or more sensors for measuring loads on the injection system or its components. The support platform 12 is configured to anchor the automated injection system in a fixed position relative to the site of injection. In some embodiments, the motorized injection system 10 can further include a controller in communication with the drive assembly or one or more cells for process control of 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 movement of either the syringe, the ejector plunger, or both in response to feedback from a load cell or multiple load cells alone, or in combination with tracking the distance traveled by the differential movement of the ejector plunger, the syringe, or one relative to the other.

[0048] In some embodiments, the injection system may include a syringe comprising a syringe barrel defining a medicine chamber for storing a therapeutic agent, a needle 15 in fluid communication with the medicine chamber for administering the therapeutic agent from the medicine chamber, and a plunger 11 slidably disposed within the syringe barrel and configured to expel the therapeutic agent from the medicine chamber through the needle 15.

[0049] In some embodiments, a standard syringe can be used so that the medication chamber can have a volume of about 0.1 ml to 20 ml, although larger or smaller syringes can also be used. In some embodiments, the medication chamber can have a volume of about 0.1 ml, 0.5 ml, 1 ml, 3 ml, 5 ml, or 10 ml prior to fluid displacement.

[0050] In some embodiments, the needle may be a standard 34G to 25G needle. In some embodiments, the needle may be a standard 30G needle. Various needle sizes can be used to deliver therapeutic treatments to the SCS, as discussed above. In some embodiments, needles with larger lumens may be used, particularly for formulations with higher viscosities, e.g., above 10 centipoise. 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, keeping in mind the minimum human scleral thickness, optimal results can be obtained by limiting the pre-insertion depth to less than or equal to about 0.5 millimeters (e.g., about 0.05 mm to 0.5 mm) when the needle is inserted perpendicular to the scleral surface. When inserted at angles other than perpendicular, needles with longer bevels can be inserted sufficiently without puncturing through the sclera. For example, based on geometric correlation, a 30-gauge needle inserted at a standard bevel (angle: 12 degrees, length: 1.45 mm) less than or equal to approximately 20 degrees relative to the surface will reach a depth of less than 0.5 millimeters when measured normal to the surface. Similarly, larger needles with longer bevel lengths can also be used. A shorter bevel allows for a wider range in pre-insertion angles for a given needle size. Roughly speaking, needles with an outer diameter less than approximately 0.5 millimeters of scleral thickness can be easily used to access the SCS, with the angle of needle insertion determined based on the bevel tip length. In some embodiments, the volume of the medication chamber is 20 to 200 microliters. For improved tactile sensation and signal-to-noise ratio for the distance tracking element, in some embodiments, the stroke length of the extrusion plunger for delivering the treatment fluid or suspension is at least 1 centimeter in length. For some embodiments, the injection flow rate is targeted to average 0.2 to 20 microliters per second.In some embodiments, the syringe barrel is lined with silicone oil, silicone rubber, rubber, glass, polytetrafluoroethylene, or polypropylene to minimize adsorption of the therapeutic agent to the interior surface of the syringe barrel.

[0051] In some embodiments, the friction between the syringe barrel and plunger can be designed to optimize the performance of the system. For example, the system can be sized so that the static and kinetic coefficients of friction are approximately equal, so that there is no unintended acceleration of the needle. On the other hand, the static friction coefficient can be higher than the kinetic friction coefficient if the needle has a high-force barrier to overcome after stopping within the cavity. High static friction of the needle plunger also allows for high fluid flow rates during injection while maintaining needle tip position. In some embodiments, the needle-plunger kinetic friction is high enough to prevent needle motion as soon as the lumen is exposed to the cavity. However, the kinetic coefficient can still be limited so that the internal pressure inside the syringe barrel is not so high as to cause tissue destruction or damage.

[0052] 3A and 3B, in some embodiments, the drive assembly is configured to independently operate the syringe barrel (e.g., for pre-inserting the needle into tissue) and the syringe plunger. The drive assembly is designed to translate the syringe barrel relative to the support platform 12 toward the patient to pre-insert the needle into tissue and then away from the patient to withdraw the needle from the tissue. The drive assembly also applies a force to the plunger, translating the plunger within the syringe barrel and advancing the needle through the tissue toward the cavity and dispensing the therapeutic agent from the medication 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 coupled to the syringe barrel or plunger and a load cell for sensing a load on the syringe barrel or plunger. As shown in FIGS. 3A-3B , drive mechanisms 20, 22 can include motors 24, 26 configured to drive movement of drive mechanisms 20, 22, such as through lead screws 25, 27 and actuators 32, 34, respectively. Drive mechanisms 20, 22 can also each include at least one load cell 28, 30 configured to sense a load on the syringe barrel or syringe plunger, respectively. In some embodiments, such a design can enable the system to advance the syringe barrel while measuring force without advancing the plunger. For example, as the syringe barrel moves, the ejector plunger can move with it. During needle pre-insertion, force is measured on the syringe barrel. After pre-insertion, force is measured on the ejector plunger. During pre-insertion, force is sensed, indicating contact between the needle and tissue, and the needle is then moved forward a set distance to embed the needle lumen in the tissue.

[0053] In some embodiments, the linear actuator may be a mechanical actuator, for example, comprising a lead screw and nut or gears driven by an electric motor, although other designs may be used. In some embodiments, pneumatic, hydraulic, electromechanical, magnetic, or other types of linear actuators may also be used. In some embodiments, a single actuator may be used to drive both the syringe barrel and plunger. Differential motion of the syringe barrel and plunger can be achieved by engaging / disengaging gear mechanisms. In some embodiments, linear motion of the extrusion plunger can be accomplished by applying hydraulic pressure.

[0054] Referring to FIG. 4, the motorized injection system of the present disclosure can also include a means for mounting and stabilizing the system relative to the injection site. In this way, the user can have a free hand while maintaining fixed x-y coordinates for injection, in some cases where the syringe barrel is held in place by the mounting and stabilizing system. In other cases, the syringe barrel is fixed only in the x-y plane, and the syringe can be pushed or pulled by the user in the z-plane toward or away from the eye for injection. In some embodiments, for SCS injections, the motorized injection system can include an adjustable headband 200 that can be fitted to a size by a ratchet or other mechanism, such as the ratchet size adjuster 202 shown in FIG. 4. In some embodiments, other parts of the patient's face, such as the eye sockets, temples, chin, ears, or nose, can be used to mount the system. In some embodiments, the motorized injection system can be attached to a stationary brace, allowing the patient to press their face against the brace (similar to an eye exam). Additionally or alternatively, the motorized injection system of the present disclosure can include a guide support 204, such as a tripod, bipod, or monopod support, attached to either the headband, the motorized injection system 10, or both, to stabilize the injection system around the eye. In some embodiments, the motorized injection system of the present disclosure can further include a contact pad that can be pressed against the tissue into which the therapeutic agent is being injected to stabilize the injection site or adjust the insertion angle. In some embodiments, the stabilizing tripod mentioned above can be used to hold the eye in a fixed position. For example, with respect to ocular injection, such a pad can be sized and shaped to prevent upward rotation of the eye when pressed against the sclera by the user (controlling the relative angle of injection). In some embodiments, the component used to prevent significant rotation of the eye can be a separate device not attached to the motorized injection system.

[0055] Sensors and Feedback Loops

[0056] In some embodiments, the motorized system of the present disclosure includes multiple sensors that can measure one or more parameters throughout the injection process. The one or more sensors may be in communication with a controller to implement one or more feedback loops for controlling various steps of the injection process. As will be discussed in more detail below, various types of sensors or other mechanisms can be used to control the injection steps, including, but not limited to, sensors such as load cells and pressure sensors, strain sensors, and / or force sensors.

[0057] In some embodiments, the load applied by the drive assembly on the syringe barrel and the ejector plunger may be measured and communicated to a controller. In some embodiments, the load may be measured using one or more load cells. Such load cells may be embedded in or otherwise configured to receive signals from the needle, the needle plunger, the ejector plunger, or both. In some embodiments, such load may be measured by the torque experienced by the motor based on its correlation with the current drawn by the motor. In some embodiments, the motorized injection system may further include one or more sensors for monitoring the position or movement of the injection system as a whole or an individual syringe barrel or plunger. Such information may be used, for example, in combination or individually, to determine the distance traveled by the injection system, the syringe barrel, or the plunger, or the needle plunger. In some embodiments, the motorized system may include one or more sensors for monitoring the position or speed at which the syringe barrel or plunger moves, in combination or individually. For example, such information may be used to control the flow rate of a therapeutic agent or to prevent the ejector plunger from overshooting the desired injection volume. In some embodiments, the flow rate may be monitored using a high precision flow sensor, including a microfluidic mass flow sensor.

[0058] In some embodiments, the system of the present disclosure can also measure the pressure within the syringe. In some embodiments, the pressure can be measured indirectly by monitoring the load on the plunger. In some embodiments, the system can be configured so that both the kinetic and static coefficients of friction between the plunger and the syringe barrel are close to 1 to more accurately sense fluid pressure. In some embodiments, the motorized injection system may further include one or more pressure, force, or strain sensors for direct measurement of the pressure of the therapeutic agent within the medication chamber.

[0059] In some embodiments, the relative position of the ejector plunger to either the needle plunger in the case of an auto-stop syringe or 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 distance of travel measured following pre-insertion can have limits set to minimize the chance of overshoot.

[0060] In some embodiments, one or more feedback loops may be implemented based on the load distribution during phases I-III-a (as discussed above in connection with FIGS. 1A-1B). In some embodiments, the feedback loop can monitor the axial load on the system during pre-insertion of the needle into the tissue in phase I. In some embodiments, the load cell can be configured to directly or indirectly measure the axial load experienced by the needle. During pre-insertion, the axial load on the needle increases as the needle is pushed into the tissue and decreases once the needle pierces the tissue. Thus, in some embodiments, the feedback loop is configured to monitor the load on the needle, monitor 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 medication chamber once the needle is implanted 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 a desired pressure. In some embodiments, the feedback loop is configured to monitor the movement of the needle through the tissue toward the cavity during phase II and into phase III-a. In some embodiments, the pressure of the therapeutic agent within the syringe barrel can be monitored, for example, by measuring the load on the extrusion plunger. In some embodiments, the applied load can be sinusoidal at high frequency, and a response curve can be measured from a 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 may monitor the flow rate of the therapeutic agent, for example, by monitoring the speed of plunger advancement or the pressure of the therapeutic agent.In some embodiments, a feedback loop may monitor the distance traveled by the plunger (which correlates to the desired injection volume). In some embodiments, the load on the plunger can be monitored as the plunger advances through the syringe barrel. When the plunger reaches the end of the barrel or some other stop that prevents 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. Such an increase in plunger load at the end of phase III-b will indicate that the injection is complete and the needle can be removed from the patient.

[0061] Various embodiments of the present disclosure may include one or more of the feedback loops discussed above, depending on the design of the system or the level of control desired by the user, among other considerations.

[0062] Syringe Design

[0063] In some embodiments, a conventional syringe may be used in the motor-operated injection system of the present disclosure. Such a syringe may include a syringe barrel for holding one or more infusates, a needle attached to the syringe barrel in fluid communication with the barrel, and a plunger for expelling the infusate from the syringe barrel through the needle.

[0064] In some embodiments, an adjustable injection system (also referred to as an auto-stop injection system) can be used that automatically self-adjusts the depth to which the needle penetrates into the tissue / cavity. Referring to FIG. 5A , an auto-stop syringe 300 may include a syringe barrel 302 having a proximal end 302 p and a distal end 302 d, a pusher plunger 304 movably disposed within the syringe barrel 302 and forming a seal therewith, and a needle plunger 306 movably disposed within the syringe barrel distal to the pusher plunger such that a medication chamber is defined within the syringe barrel between the pusher and the needle plunger. In some embodiments, a needle plunger seat 310 can be provided to control movement of the needle plunger in the proximal direction, and in some embodiments, the pusher plunger may be configured to be advanced past the needle plunger seat.

[0065] A movable needle 308 is supported by the needle plunger such that movement of the needle plunger can also move the needle, which is in fluid communication with the medication chamber to deliver the therapeutic agent from the medication chamber to the patient. The needle can be connected to the needle plunger using several techniques. In some embodiments, the needle is inserted into a rubber plunger and secured with a waterproof adhesive. In some embodiments, the plunger can be molded around the needle. In some embodiments, a needle with threads on its exterior can be threaded into the plunger.

[0066] FIG. 5B further illustrates the operation of an auto-stop syringe (drive mechanism / support assembly not shown). In stage I, the needle is pre-inserted into 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 toward the posterior segment of the eye. Next, in stage II, force is applied to the pusher plunger, which pushes the needle plunger forward, advancing the needle deeper through the tissue toward a cavity (e.g., the suprachoroidal space of the eye). In stage III-a, the needle tip enters the cavity, and the needle plunger automatically stops when the needle lumen opens into the cavity, thus limiting the depth to which the needle penetrates into the cavity. The precision and compactness of the auto-stop syringe allow the needle plunger to precisely target and stop at thin potential cavities such as the suprachoroidal space. In step III-b, as the operator continues to push the extrusion plunger, the therapeutic agent in the medication chamber is delivered into the cavity while the needle holds its position at the tissue-cavity interface. In some embodiments, the fluid flow vector is parallel to the suprachoroidal space to provide broad coverage of the posterior segment of the eye, instead of using fluid forces to radially displace choroidal and retinal tissue.

[0067] Exemplary auto-stop syringes for use in delivering therapeutic agents into the suprachoroidal space are disclosed in U.S. Application No. 16 / 469,567, filed June 13, 2019, and PCT Application No. PCT / US2020 / 051702, filed September 20, 2020, both of which are incorporated herein by reference in their entireties. In some embodiments, design variables such as syringe geometry, needle geometry, flow rate, viscosity, and frictional forces 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 in its entirety. In some embodiments, insertion force can be considered to select various design variables. As a result, the present system is capable of delivering drugs and gene therapies that benefit from localization to the SCS, including those that treat diseases and disorders of the choroid and retina. While the present disclosure describes the present injection system in the context of drug delivery to the SCS cavity, it should be noted that the disclosed systems and methods may also be used to deliver therapeutic agents to other gaps or cavities in the human body.

[0068] 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 interface with the syringe barrel via a rapid-fill port (e.g., as described in co-pending PCT Application No. PCT / US2020 / 051702, filed September 20, 2020, which is incorporated herein by reference in its entirety), and any valves that were manually turned during operation in the previous fill may be motorized or use solenoid valves in this fill.

[0069] Operation of the motorized injection system

[0070] Either prior to filling with therapeutic agent or after filling with therapeutic agent, depending on whether the filling process is automated, the motorized injection system can be connected to the patient's head and / or eye. 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 external landmarks around the orbit.

[0071] The position of the motorized injection system can be adjusted to achieve the desired angle of needle insertion, which will depend on the bevel angle, to implant the lumen into the tissue. Once the motorized injection system is in place, the needle tip can be positioned near the surface of the sclera, for example, within about 2 centimeters, about 1 centimeter, or about 0.5 centimeters of the surface of the sclera. In some embodiments, such a distance can be about 0.1 to about 2 cm, about 0.1 to about 1 cm, or about 0.1 to about 0.5 cm. In some embodiments, an acoustic or laser distance meter can be used to assist in the initial positioning of the needle tip. The user then provides a signal via a button or touchscreen to begin the injection process.

[0072] Motorized syringe drive device for automatic shut-off syringes

[0073] As a non-limiting example, the use of a motorized injection system with an auto-stop syringe will be described with reference to Figures 6A-6D and 7A-7B.

[0074] Referring to FIG. 6A , after the user initiates the injection process, the auto-stop syringe is advanced toward the surface of the eye. In some embodiments, to accomplish this, the syringe barrel 102 and extrusion plunger 112 are moved together toward the eye at the same speed until a load cell detects the needle 116 embedded in the sclera. During advancement of the auto-stop syringe, the load on the syringe barrel, needle guide, or needle is sensed, for example, by a load cell or force sensor. In some embodiments, this advancement can be performed manually. Once the needle tip reaches the sclera, the load will increase along 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 punctures the sclera, at which point the load decreases. Once the load decreases, indicating scleral puncture, the auto-stop syringe and floating needle are advanced until the needle lumen is fully embedded in the sclera. In some embodiments, the system can rely on a fixed advancement of the needle after detecting a scleral puncture to determine when the needle lumen is fully embedded. In some embodiments, full insertion can be determined by slightly advancing the ejector plunger and seeing if this begins to build pressure or leads to leakage.

[0075] Once the needle is implanted into the sclera, movement of the syringe barrel is stopped and the ejector plunger is advanced within the syringe barrel to pressurize the contents of the syringe barrel. In some embodiments, the ejector plunger is advanced a predefined or user-defined distance or until a predefined or user-defined load is reached on a load cell attached to the ejector plunger or its fixture, confirming that the lumen of the needle is fully implanted within the sclera. In some embodiments, this step is omitted.

[0076] In some embodiments, an optional elastomeric contact pad 320 can be used to prevent upward movement of the eye by being pressed against the sclera by an operator of the device, such as a physician, which can allow the relative angle of injection to be controlled.

[0077] Referring to FIG. 6B , once the needle is pre-inserted into the sclera, the syringe barrel 102 is locked in place and the extrusion plunger 112 is advanced forward to advance the needle tip through the sclera. Pressure within the syringe barrel is maintained while the needle advances through the sclera due to the sclera's low water permeability trapping fluid inside the auto-stop syringe. The therapeutic agent cannot be dispensed into the sclera due to backpressure created by the dense tissue of the sclera. Instead, advancing the extrusion plunger also advances the needle plunger and needle toward the SCS. The syringe barrel holder stops and the plunger continues to move, thereby urging a second plunger (i.e., the needle plunger) toward the SCS.

[0078] Referring to FIG. 6C , when the needle 116 reaches the SCS, the fluid pressure within the syringe barrel drops, which can be sensed by a load cell or pressure sensor in the extrusion plunger. In some embodiments, detection of the relative motion of the extrusion plunger moving closer to the needle plunger can also, or alternatively, be used to identify when the cavity is reached. Due to the decrease in backpressure generated by the SCS compared to the backpressure generated by the sclera, the needle stops advancing, and instead, the therapeutic agent is expelled through the needle and into the SCS. The extrusion plunger 112 continues to be advanced at a predetermined or user-determined rate and / or a predetermined or user-determined distance to inject a fixed volume of the therapeutic agent in liquid form into the SCS.

[0079] 6D, the ejector plunger lock will not advance once the ejector plunger 112 has moved a predefined or user-defined distance corresponding to the desired injection volume or the ejector plunger senses an increased load corresponding to reaching the needle plunger. In some embodiments, such increased load can be set depending on the static friction of the needle plunger such that the ejector plunger cannot advance the needle plunger.

[0080] 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 away from the eye until the needle no longer contacts the sclera. This can be accomplished by returning the auto-stop syringe to its starting position, or at least to the point where the needle tip first sensed contact with the scleral surface and a corresponding increase in load.

[0081] In some embodiments, one or more feedback loops can be used to monitor the operation of the auto-stop syringe. In some embodiments, a first feedback loop can monitor the pre-insertion of the needle into the sclera. For example, during needle insertion into the sclera (movement of the entire syringe toward the eye), a load cell attached to the needle or syringe barrel can detect increasing force until the needle punctures the sclera. Upon puncture, there is a drop in load, and the needle is then further advanced a predetermined distance until the needle lumen is embedded in the sclera, and then the advancement of the entire syringe is stopped.

[0082] In some embodiments, a second feedback loop can be provided to monitor the advancement of the needle through the sclera. For example, once needle pre-insertion is complete, the syringe barrel is locked in place and the ejector plunger is advanced while the load on the ejector plunger is measured. The load may increase on the ejector plunger and plateau as the needle advances through the sclera. The load decreases once the needle lumen reaches the SCS.

[0083] In some embodiments, a third feedback loop may be provided to monitor the infusion of the therapeutic agent into the SCS. For example, the extrusion plunger can be advanced at a predefined rate until a specific distance (correlated to the desired injection volume) is reached, or until the extrusion plunger reaches the needle plunger to avoid needle overshoot.

[0084] As illustrated in more detail in FIGS. 7A-7B, 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 the therapeutic agent can be loaded into a motorized injector. In step 404, the motorized injector containing the syringe can be loaded onto an anchoring mechanism that connects to a patient (the needle does not contact the sclera). In step 406, a user can press a button or other mechanism to begin 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's load cell indicates an increased 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, the syringe continues to move forward until the load increases (step 408).

[0085] If the load cell of the syringe barrel indicates an increased load, the syringe barrel position is locked and the ejector plunger is moved forward relative to the syringe in step 414. If the load cell of the ejector plunger indicates a load higher than the force required to inject into the SCS in step 416, the ejector plunger is moved forward relative to the syringe (step 414). If the load cell of the ejector plunger does not indicate a load higher than the force to inject into the SCS, the ejector plunger can continue to be pushed forward in step 418. 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 ejector plunger is noted and therefore the distance traveled by the ejector plunger can be monitored, which can be used, for example, to prevent the ejector plunger from hitting the needle plunger or to monitor the amount of injectate delivered to the SCS.

[0086] If the force measured by the pusher plunger's load cell is maintained as the pusher plunger moves forward in step 420, it is determined based on the pusher plunger's position whether a predetermined amount of therapeutic agent has been delivered (step 422). If not, the system continues to push the pusher plunger forward (step 418). If yes, the system stops pushing the pusher plunger forward (step 426). If the force measured by the pusher plunger's load cell is not maintained as the pusher plunger is moved forward (step 420), then in step 424, if the load increases significantly, this indicates that all of the therapeutic agent has been delivered and the pusher plunger is at the end of the injection chamber. The system then stops moving the pusher forward (step 426).

[0087] Motorized syringe drive for standard syringes

[0088] As a non-limiting example, the use of a motorized injection system with an auto-stop syringe will be described with reference to Figures 8A-8E and 9A-9B.

[0089] 8A, after the user initiates the injection process, the entire syringe is advanced toward the surface of the eye by moving the syringe barrel 502 and extrusion plunger 504 at approximately the same speed until the load cell detects the needle embedded in the sclera. During syringe advancement, a load cell contacting the syringe barrel or needle 508 senses a load. When the needle tip reaches the sclera, the load will increase with the contact force. The load continues to increase until the needle punctures the sclera, at which point the load decreases. When the load decreases, indicating scleral puncture, the syringe and needle are advanced until the needle lumen is fully embedded in the sclera.

[0090] 8B, once the needle is implanted into the sclera, the syringe barrel 502 is held in place and remains stationary while the syringe plunger is advanced a predefined or user-defined distance or until a predefined or user-defined load is reached on a load cell attached to the extrusion plunger or its fixture. This movement of the plunger increases the pressure of the therapeutic agent, which is sensed as a load on the syringe plunger.

[0091] 8C, the entire syringe is then advanced into the sclera by the motorized syringe drive, advancing the tip of needle 508 through the sclera. Pressure within the syringe barrel is maintained while the needle is blocked as fluid outflow and the syringe is advanced through the sclera due to the sclera's low water permeability keeping fluid inside the syringe until the needle lumen reaches the SCS.

[0092] 8D, once the lumen of needle 508 reaches the SCS, the lumen is no longer blocked and fluid can flow out, so the fluid pressure (i.e., load) on the extrusion plunger decreases, which is recorded by the load monitoring syringe plunger. In response to sensing the decrease in load on the syringe plunger, the syringe barrel stops in place. The extrusion plunger is then advanced at a predetermined or user-determined rate to inject the therapeutic agent into the SCS.

[0093] 8E, the ejector plunger fixture will not advance once the ejector plunger 504 has traveled a predefined or user-defined distance corresponding to the desired injection volume or full payload, or the ejector plunger senses an increased load corresponding to reaching the end of the syringe barrel. Delivery of the full payload can be detected using a load cell based on the increased force with which the plunger engages the distal end of the syringe when the syringe is empty.

[0094] 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 manually removed. In some embodiments, the entire syringe is retracted away from the eye until the needle no longer contacts the sclera. This can be accomplished by returning the syringe to its starting position, or at least to the point where the needle tip first sensed contact with the scleral surface and a corresponding increase in load.

[0095] In some embodiments, one or more feedback loops can be used to monitor the operation of the auto-stop syringe. In some embodiments, a first feedback loop can be provided to monitor the insertion of the needle into the sclera. For example, as the needle is pre-inserted into the sclera (moving the entire syringe toward the eye), a load cell attached to the needle or syringe barrel detects an increasing force until the needle punctures the sclera, and then there is a drop in load. After the drop is detected, the needle can be advanced a predetermined distance until the needle lumen is embedded in the sclera, and the syringe barrel can be stopped. In some embodiments, a second feedback loop can be provided to pressurize the contents of the syringe barrel. For example, once pre-insertion is complete, the syringe barrel is locked in place, and the extrusion plunger is advanced while the load on the plunger or pressure of the therapeutic agent is measured until a pre-defined 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 as it is advanced through the sclera. In some embodiments, the load on the needle can be monitored indirectly. For example, when the fluid contents of the syringe are pressurized, the entire syringe is advanced until the load on the ejector plunger decreases, indicating that the lumen of the syringe has reached the SCS. In some embodiments, when the needle is secured to the syringe hub, the load on the syringe can be monitored, as 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 advanced at a predefined rate until a specific distance (correlated to the desired injection volume) is reached, or until the ejector plunger reaches the needle plunger to avoid needle overshoot.

[0096] As illustrated in more detail in FIGS. 9A-9B, 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 the 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 that connects to a patient (the needle does not contact the sclera). In step 606, a user can press a button or other mechanism to begin the injection. In step 608, the entire syringe can be moved forward to engage the needle with the sclera. In step 610, if the syringe load cell indicates an increased load, the syringe is moved forward a predetermined distance to pre-insert the needle and block the needle lumen with the sclera (step 612). If not, the syringe continues to move forward until the load increases (step 608).

[0097] In step 614, the extrusion plunger is pushed to pressurize the internal fluid by a known amount, and in step 616, both the syringe and extrusion plunger are moved to move the entire syringe. In step 618, it is determined whether the load cell of the extrusion plunger indicates 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 extrusion plunger is noted and the extrusion plunger continues to be pushed forward (step 620). If not, both the syringe and extrusion plunger are moved, moving the entire syringe (step 616).

[0098] If the force measured by the pusher plunger's load cell is maintained as the pusher plunger moves forward in step 622, it is determined based on the pusher plunger's position whether a predetermined amount of therapeutic agent has been delivered (step 624). If not, the system continues to push the pusher plunger forward (step 626). If yes, the system stops pushing the pusher plunger forward (step 628). If the force measured by the pusher plunger's load cell is not maintained as the pusher plunger is moved forward (step 622), then in step 626, if the load increases significantly, this indicates that all of the therapeutic agent has been delivered and the pusher plunger is now in direct contact with the needle plunger. The system then stops moving the plunger forward (step 628).

[0099] In particular, 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 barrel and plunger are moved to move the entire syringe. In step 618, the internal fluid pressure is continuously checked. If the load cell indicates a drop in pressure, the position is noted, the barrel position is held, and the plunger continues to be pushed forward, delivering therapeutic agent into the SCS space. In step 618, if the plunger load cell has not yet detected a drop in load, the entire syringe is advanced. In step 620, once the plunger load cell now detects a drop in load, the syringe barrel is no longer advanced and only the extrusion plunger is advanced. The extrusion plunger load cell continues to be monitored (step 622). While the load on the extrusion plunger is monitored, the extrusion plunger is advanced, delivering therapeutic agent until the desired volume of therapeutic agent is delivered (step 624), at which point the advancement of the extrusion plunger is stopped (step 628). Alternatively, the load cell of the ejector plunger detects an increase in load, indicating that the ejector plunger has reached the distal portion of the syringe (step 626), and stops the advancement of the ejector plunger (step 628).

[0100] 10A-10E and 11A-11B, instead of advancing the entire syringe after the needle lumen is implanted in the sclera, a fixture attached to the syringe barrel is allowed to move freely, and only the ejector plunger fixture is advanced. As shown in FIG. 10A, the syringe barrel 702 and plunger 704 can be moved together toward the eye until the load cell detects the needle 708 embedded in the sclera. In FIG. 10B, once the needle tip is embedded, the syringe barrel 702 is held in place and the ejector plunger is advanced, generating fluid pressure that is sensed as a load on the ejector plunger. In FIG. 10C, once the pre-pressurized load on the ejector plunger 704 is reached, a stop on the syringe barrel is released to allow it to move freely, and the ejector plunger is then advanced. In Figure 10D, once the lumen of the needle 708 reaches the SCS, the load on the extrusion plunger 704 decreases because the lumen is no longer blocked and fluid can flow out, and the extrusion plunger is then advanced to dispense the therapeutic agent into the SCS. In Figure 10E, the extrusion plunger 704 can be advanced a set distance to deliver a known volume, or can be pushed in to deliver the entire payload. Delivery of the entire payload can be detected using a load cell based on the increased force as the plunger engages the distal end of the syringe when the syringe is empty.

[0101] In this way, once the needle lumen reaches the SCS, as represented by a drop in load on the pusher plunger load cell, the syringe barrel can be locked in place and the syringe plunger can be advanced, injecting the therapeutic agent directly into the SCS, essentially creating an auto-stop needle from a standard syringe when used in combination with a syringe driver. In such embodiments, a feedback loop may be provided to monitor the movement of the needle through the sclera. In some embodiments, the syringe barrel does not lock in place upon reaching the SCS, and the needle remains in the cavity as the pusher plunger is advanced due to a decrease in fluid resistance in the needle lumen. For example, after the contents of the syringe barrel are pressurized, a 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. At that point, the needle will automatically stop because the pressure inside the syringe barrel is reduced by the outflow of fluid from the needle tip into the SCS.

[0102] As illustrated in more detail in FIGS. 11A-11B, 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 the 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 that connects to a patient (the needle does not contact the sclera). In step 806, a user can press a button or other mechanism to begin the injection. In step 808, the entire syringe can be moved forward to engage the needle with the sclera. In step 810, if the syringe's load cell indicates an increased load, the syringe is moved forward a predetermined distance to pre-insert the needle and block the needle lumen with the sclera (step 812). If not, the syringe continues to move forward until the load increases (step 808).

[0103] If the syringe load cell indicates an increase in load, step 814 includes pushing the ejector plunger without any axial movement restraint on the syringe, and both the syringe and the ejector plunger move forward. In step 816, if the load on the ejector plunger is similar to the force required to inject into the SCS or if a drop in internal pressure is detected, the position of the ejector plunger is noted and the ejector plunger continues to be pushed forward. Optionally, the system may continue to push the ejector plunger forward while the syringe may be locked (step 818). If the ejector plunger load cell does not indicate a drop in internal pressure, the ejector plunger is pushed as shown in step 814.

[0104] If the force measured by the pusher plunger load cell is maintained as the pusher plunger moves forward in step 820, it is determined based on the pusher plunger position whether a predetermined amount of therapeutic agent has been delivered (step 822). If not, the system continues to push the pusher plunger forward while the syringe position is locked (step 818). If yes, the system stops pushing the pusher plunger forward (step 826). If the force measured by the pusher plunger load cell is not maintained as the pusher plunger is moved forward (step 820), then in step 824, if the load increases significantly, this indicates that all of the therapeutic agent has been delivered and the pusher plunger is now in direct contact with the distal end of the syringe. The system then stops moving the pusher forward (step 826).

[0105] Graphical User Interface

[0106] A graphical user interface is included in some embodiments. For example, such a user interface may allow a user to start the injection, monitor the injection through phases I-III-b, and stop the injection if necessary. In some embodiments, there is also a means of providing auditory feedback to the user. In some embodiments, lights, graphical displays, and / or sounds are used as indicators to represent 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 punctured, when the SCS is reached, when the therapeutic agent has been delivered, and when the needle is removed from the eye.

[0107] 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 requests patient information and generates a report after completing the injection, and in further embodiments, the patient information is obtained via a one- or two-dimensional barcode scanning device or a near-field scanning device (NFC - Near Field Communication). In some embodiments, the injector can connect to an external server and upload this information and / or download relevant information about the case, such as the disease being treated, the prescribed therapeutic drug, and dosage information.

[0108] In some embodiments, a display on the motorized syringe drive is used to display instructions to the user and request input from the user regarding when to proceed to the next step in the injection process, starting with filling the syringe and ending with the completion of the SCS injection. In some embodiments, the GUI also allows the user to input injection process parameters, such as the distance traveled by the system or its components, thresholds for 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 distance the needle will advance following scleral puncture. In some embodiments, the user can select the desired volume and / or rate of injection. In some embodiments, the positions of the ejector plunger, needle tip, and / or floating plunger, and / or the load sensed by the load cell at the needle tip and / or the load cell at the ejector plunger are displayed.

[0109] In some embodiments, there is a camera focused on the surface of the tissue that provides the user with a real-time magnified video image on the display so that the user can visualize the puncture of the sclera and the final removal of the needle. In some embodiments, the camera can assist with pre-insertion, where the user manually pre-inserts the needle tip and then activates the automated system to complete the delivery of the therapeutic agent to the cavity. In some embodiments, the injector may include a scanning device for one-dimensional or two-dimensional barcodes to log the disposable syringe and therapeutic agent used for injection.

[0110] Needle stop distance and overshoot

[0111] As discussed above, in some embodiments, the motorized injection system of the present disclosure can be equipped with one or more safety features to limit or control needle overtravel. In some embodiments, additionally or alternatively, needle overtravel can be controlled by controlling the stopping distance of the needle plunger. The stopping distance is the distance the needle plunger travels after the needle lumen reaches the cavity and begins delivering the therapeutic agent. The stopping distance is determined by the degree to which the pressure within the syringe barrel quickly drops below the frictional resistance of the needle plunger. Such a distance can be characterized as the relationship between the frictional resistance of the needle plunger, the needle inner diameter, the needle length, the needle bevel, the syringe inner barrel diameter, the formulation viscosity, the force applied to the extrusion plunger, and the mechanical properties of the device components (similar to how flow through a hollow needle is characterized by the Hagen-Poiseuille equation). In some embodiments, the stopping distance may be predicted as a function of the time required to reduce pressure and the speed at which the needle was traveling. The stop distance may depend on the volume elasticity of the syringe assembly and the compressibility of the fluid. In some embodiments, overshoot due to the stop distance can be controlled by using one or more safety features described above. In some embodiments, the stop distance may depend on the time required to implement and activate a motorized feedback loop. As long as a portion of the needle opening overlaps with the SCS, payload will be delivered to the SCS. Therefore, an acceptable stop distance is directly related to the lumen size and bevel. For example, a 30G needle with a lumen diameter of 0.160 mm and a standard 12° bevel angle can overshoot by approximately 0.8 mm while maintaining lumen contact with the SCS. For optimal fluid flow and maximum overlap between the lumen and SCS, the needle should be positioned so that the SCS is centered in the lumen geometry; i.e., for a 30G needle with a 12° bevel angle, a stop distance of approximately 0.4 mm would center the SCS in the lumen. A stopping distance of less than 0.4 mm is also acceptable.

[0112] In some embodiments, stop distance overshoot is corrected by having the motorized syringe drive retract the syringe barrel to ensure the SCS is centered within the lumen geometry. For example, for a 30G needle with a 12° bevel angle, if the stop distance exceeds 0.4 mm, the needle may be retracted back to center it. In some embodiments, the syringe barrel is retracted a fixed distance to counteract the volumetric elasticity of the syringe assembly and the compressibility of the fluid. In other embodiments, the retraction distance incorporates the position of the syringe barrel when a drop in load on the extrusion plunger is first detected after traversing the sclera. In some embodiments, the retraction distance utilizes measured deformation of the sclera in response to contact by the needle prior to puncture. In some embodiments, the retraction distance utilizes a known or measured time required to detect and implement a syringe stop motorized feedback loop.

[0113] Automated Syringe Filling

[0114] In some embodiments, the auto-stop syringes of the present disclosure may be pre-filled with a therapeutic agent during manufacture, as described above. In some embodiments, the auto-stop syringes of the present disclosure may be filled with a therapeutic agent at a doctor's office, pharmacy, or operating room prior to administering the therapeutic agent to a patient. In some embodiments, the therapeutic agent may be provided in a vial for storage and transferred by a user to the SCS system only when the therapeutic agent is ready to be administered to a patient.

[0115] 12, an injection system of the present disclosure comprises a quick-fill port 900 to allow loading of infusate into the injection chamber from a vial 902. In some embodiments, the quick-fill port 900 includes a container 904 configured to receive the vial 902 and fluidly connect the vial to the injection chamber. In some embodiments, a hole or passage is created (e.g., through molding, machining, etc.) through the wall of the syringe barrel proximal to the needle plunger 110, and the container 904 is placed across such hole or passage.

[0116] In some embodiments, when the needle plunger is set to its initial position and the ejector plunger is brought into contact with the needle plunger, the quick fill port is fluidly connected to the syringe barrel at a site between the sealing elements. Connected to the passageway and partially or completely disposed therein is a side port filling needle 906 (preferably larger than an injection piercing element, such as an 18-gauge piercing element). Such a filling needle may be beveled to pierce the elastomeric cap 903 of the therapeutic agent-containing vial 902. In some embodiments, the quick fill port's filling piercing element may have its opening on the side of the filling piercing element rather than at the tip. This side port may be covered by a casing or self-sealing piercing membrane 908 that blocks fluid flow when in a closed position. The casing 908 may be disposed within the container and may be biased by a spring 910 to close the filling needle port when a vial is not present in the container. In some embodiments, the safety cap 118 may be configured to provide an airtight seal when attached to the injection system.

[0117] In operation, as shown in Figures 13A-13B and 14A-14B, the auto-stop syringe is coupled to the support platform and drive assembly of the motorized injection system. Next, a vial 902 is snapped into the container 904 of the quick fill port 900, which pushes the sliding fill piercing element casing away from the side port of the fill piercing element. The fill piercing element of the quick fill port then penetrates through the stopper of the vial, fluidly connecting the interior volume of the vial with the syringe barrel through the side port of the fill piercing element. The puncture needle of the quick fill port then penetrates through the stopper of the vial, fluidly connecting the interior volume of the vial 902 with the syringe barrel through the side port of the fill needle. This allows therapeutic agent to flow from the vial 902 into the syringe barrel when the ejector plunger is withdrawn by the drive assembly. In some embodiments, a safety cap is provided over the piercing element of the injection system to fluidly seal the piercing element so that air bubbles are not similarly drawn into the syringe barrel when the pushing seal element is removed.

[0118] Once the auto-stop syringe is filled with the desired amount of therapeutic agent, the vial can be removed from the container of the quick-fill port, allowing the sliding fill needle casing to rise to seal the side port of the fill needle, which also seals the syringe barrel. The safety cap can be removed to allow fluid flow through the injection needle. The drive assembly can be activated to advance the ejector plunger until fluid appears at the tip of the injection needle, indicating that air has been purged from the injection needle. The auto-stop syringe is then ready for use. This quick-fill port design can enable the auto-stop syringe to be filled with therapeutic agent in a physician's office while maintaining sterility outside of a sterile facility.

[0119] In some embodiments, the self-stop syringes of the present disclosure can be backfilled with a therapeutic agent, which can be done during the initial manufacturing of the syringe or in a physician's office immediately prior to use.

[0120] 15A-15B, the ejector plunger 112 can be removed so that the therapeutic agent 114 can be added to the syringe barrel 102 through the rear of the syringe barrel. The ejector plunger can then be inserted and pushed toward the needle plunger 110 to remove any air in the injection needle.

[0121] In some embodiments, as shown in FIGS. 16A-16B , a fill port 930 may be provided in a proximal region of the syringe barrel 102 distal to the extrusion plunger 112. The therapeutic agent 114 can be added to the auto-stop syringe through this fill port 930, and then the extrusion plunger 112 can be pushed past the fill port 930 so that the extrusion plunger 112 seals the therapeutic fluid away from the fill port. In particular, the therapeutic agent can be added to the auto-stop syringe through the fill port using another sterile syringe / needle while holding it needle-side down (the needle tip is blocked). In some embodiments, the total volume of the therapeutic agent can be approximately 80% of the volume between the plungers. The extrusion plunger can then be advanced toward the needle plunger, removing air through the fill port. After the extrusion plunger passes past the fill port and blocks it, the syringe can be inverted so that the needle is up. The ejector plunger is then advanced further distally, expelling any remaining air from the syringe barrel and out of the injection needle.

[0122] 17A-17C, the fill port 930 may be sealed using a self-sealing seal or polymer 932 (e.g., silicone rubber or polytetrafluoroethylene). In this way, the fill port can be filled using 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 process. Once the loading needle is removed from the fill port, the fill port self-seals sufficiently to prevent leakage under the pressure applied by the ejector plunger during use.

[0123] In some embodiments, as shown in FIGS. 18A-18D , a fill port 950 may be provided in the distal portion of the syringe barrel 102 in front of the needle plunger 110. This allows a user to access the needle plunger with a pushing tool 952 (e.g., a long, thin, rigid object long enough to fit into the hole and reach outward). In this way, the injection needle can be extended outward so that it can be pushed through the elastomeric vial stopper, and the therapeutic agent can then be drawn into the syringe by withdrawing the pushing plunger. The pushing plunger can then be further withdrawn in the proximal direction so that the needle plunger can be pushed back to its pre-inserted position within the syringe barrel.

[0124] Use of the injection system

[0125] In some embodiments, the injection system of the present disclosure is used to deliver a viral gene delivery vector or vectors, including, but not limited to, adeno-associated virus (AAV), AAV serotypes 1-11, particularly variants or serotypes thereof, including AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, and AAV11, as well as recombinant serotypes such as Rec2 and Rec3, to treat genetic disorders of the retina or choroid. AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9 can all exhibit tropism for retinal tissues, including the retinal pigment epithelium and photoreceptors, as described at https: / / www.retinalphysician.com / issues / 2020 / special-edition-2020 / vector-considerations-for-ocular-gene-therapy (incorporated herein by reference in its entirety). Exemplary diseases include, but are not limited to, wet age-related macular degeneration, dry age-related macular degeneration (AMD), glaucoma, total choroidal atrophy, and other inherited vision diseases and disorders. In some embodiments, the injection system delivers a viral delivery vector or vectors, including, but not limited to, AAV or variants thereof, to retinal and / or choroidal cells, including, but not limited to, photoreceptors, pigment cells, bipolar cells, ganglion cells, horizontal cells, and amacrine cells, vascular endothelial cells, vascular smooth muscle cells, non-vascular smooth muscle cells, melanocytes, fibroblasts, and resident immunocompetent cells, to transduce anti-vascular endothelial growth factor (anti-VEGF) and anti-vascular endothelial growth factor receptor (anti-VEGFR) genes that, when transcribed, produce an anti-VEGF protein or proteins for treating wet AMD. In some embodiments, the gene therapy composition may also include a promoter for the gene of interest.

[0126] 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), microribonucleic 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, transcription activator-like effector nucleases (TALENs) and variants thereof, zinc finger nucleases (ZFNs) and variants thereof, and transposon-based gene delivery, such as Sleeping Beauty (SB), PiggyBac (PB), Tol2 or variants thereof. These gene therapies can be packaged in viral vectors, non-viral vectors, or nanoparticles.

[0127] In some embodiments, the injection system is used to deliver a viral gene delivery vector or vectors, non-viral gene delivery system, or other gene therapy that achieves a gene transduction efficiency of less than 0.001%, 0.01%, 0.1%, 1%, 3%, 5%, 10%, 25%, 50%, 75%, or 90% in retinal and / or choroidal cells.

[0128] In some embodiments, the infusion system is used to deliver small or large molecule therapies targeted against VEGF or VEGFR, including, but not limited to, Ziv-aflibercept, pazopanib, bevacizumab, cabozantinib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, and bevacizumab.

[0129] In some embodiments, the infusion system may be used to target the following genes to confer a therapeutic effect on a genetic ocular disease or disorder: 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, P ORCN, TGFBI, OAT, ENG, CBS, MBTPS2, IKBKG, CNNM4, ATRX, GALC, TGFBI, HADHA, OCRL1, PLP1, B3GALTL, PAH, ARX, LOXL1, TGFBI, PQBP1, RB1, IDUA, IDS, SGS H, NAGLU, HGSNAT, GNS, GALNS, GLB1, ARSB, GUSB, FGFR3, LMX1B, NHS, STAC3, NF1, NF2, NF1, MT-ATP6, NDP, RP1L1, GPR143, PABN1, HEXB, UBIAD1, AGK, RAI L, HBB, 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, CYP 1B1, 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, PHOX 2A, 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, T YR, 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.

[0130] In some embodiments, the delivery system of the present disclosure may be used to deliver gene therapy for treating age-related macular degeneration (AMD) or diabetic macular edema (DME). In some embodiments, the delivery system of the present disclosure is used for suprachoroidal (SCS) delivery of a composition comprising an AAV vector containing one or more genes for blocking VEGFR-2, optionally with a CAG promoter. In some 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 some embodiments, such a system may include a 25-34 gauge puncture element with a polypropylene or glass syringe and fluoropolymer, silicone, or rubber for the push-type and floating seal element stoppers. In some embodiments, approximately 80-120 (e.g., 100) microliters of such a gene therapy composition can be delivered over 5-60 seconds. In some embodiments, the piercing elements 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 elements may be 25 gauge and greater, 27 gauge and greater, or 30 gauge or greater. In some embodiments, the needles have a secondary bevel to reduce cutting forces.

[0131] In some embodiments, the delivery system is utilized to deliver small or large molecule injectables such as anti-VEGF agents, including, but not limited to, bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrins, anti-prostaglandins, tryptophanyl-tRNA synthetase-derived polypeptides, inosine monophosphate dehydrogenase (IMPDH) inhibitors, and anti-PDGF agents for treating AMD, as well as corticosteroids for treating uveitis, chorioretinitis, or other inflammatory ocular diseases, botulinum toxin for various ocular applications, tyrosine kinase inhibitors (such as vandetanib, axitinib, pazopanib, sunitinib, sorafenib, etc.) for treating pterygium, dry eye, or AMD, levobetaxolol or other beta-adrenergic receptor antagonists and 5-HT1A agonists for treating retinal pathologies.

[0132] In some embodiments, the infusion system is used to deliver small molecule Wnt inhibitors to reduce angiogenesis. These small molecule Wnt inhibitors 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-y)-1h-pyrazolo[3,4- c]pyridine) (Patent No. W02016040180A1), N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine-2-yl)-1H-indazole-5-yl)pyridine-3-yl)-3-methylbutanamide (including its amorphous and polymorphic forms) (Patent No. W02017210407A1), isoquinoline-3-yl carboxamide or a salt or analogue thereof, including amorphous and polymorphic forms (Patent No. W02017189823A2), diazanaphthalen-3-yl carboxamide or a salt or analogue thereof, including amorphous and polymorphic forms (Patent No. US20190127370A1), 6-(5-membered heteroaryl)isoquinoline-3-yl1-(5-membered heteroaryl)carboxamide or a salt or analogue thereof, including amorphous and polymorphic forms (Patent No. W02019084496A1), 6-(6-membered heteroaryl and aryl)isoquinolin-3-yl carboxamides or salts or analogs (including amorphous and polymorphic forms) (US20190125740A1), 3-(3h-imidazo[4,5-b]pyridine-2-yl)-1h-pyrazolo[3,4-b]pyridine (US20190119303A1), Wnt inhibitors containing an indazole core or salts or analogs (including amorphous and polymorphic forms) (WO213151708A1), 1h-pyrazolo[3,4-b]pyridine or salts or analogs (including amorphous and polymorphic forms) (WO213166396A2), 2-(1h-indazole-3-yl)-3h-imidazo[4,5-b]pyridine or a salt or analogue (including amorphous and polymorphic forms) (US20190055238A1), f3-diketone, y-diketone or y-hydroxyketone or a salt or analogue thereof (W02012024404A1), 3-(benzimidazol-2-yl)-indazole inhibitor or a salt or analogue (including amorphous and polymorphic forms) (US10183929B2), 3-(1h-imidazo[4,5-c]pyridine-2-yl)-1h-pyrazolo[3,4-b]pyridine or a salt or analogue (amorphous and polymorphic forms) (US10183929B2), and polymorphic forms) (US20180325910A1), 1H-pyrazolo[3,4-b]pyridine or a salt or analogue (including amorphous and polymorphic forms) (CY-1119844-T1), 3-(1h-imidazo[4,5-c]pyridine-2-yl)-1h-pyrazolo[3,4-c]pyridine or a salt or analogue (including amorphous and polymorphic forms) (US2018250269-Al), N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine-2-yl))-1H-indazole

[0010] 3-(3h-imidazo[4,5-b]pyridine-2-yl)-1h-pyrazolo[3,4-c]pyridine or salts or analogues (including amorphous and polymorphic forms) (US20180133199A1), indazole-3-carboxamide or salts or analogues (including amorphous and polymorphic forms) (US2018185343-A1), 3-(3h-imidazo[4,5-b]pyridine-2-yl)-1h-pyrazolo[3,4-c]pyridine or salts or analogues (including amorphous and polymorphic forms) (US2018201624-A1), 2-(1h-indazole -3-y1)-1h-imidazo[4,5-c]pyridine or a salt or analogue, including amorphous and polymorphic forms (US-2018215753-A1), 3-(3H-imidazo[4,5-C]pyridine-2-y1)-1H-pyrazolo[3,4-C]pyridine or a salt or analogue, including amorphous and polymorphic forms (US-10052331-B2), 5-substituted indazole-3-carboxamide or a salt or analogue, including amorphous and polymorphic forms (US-2018127377-A1), 3-(3H-imidazo[4,5-C]pyridine-2-y1)-1H-pyrazolo[4,3-B]pyridine or a salt or analogue, including amorphous and polymorphic forms (US-10188634-B2), 3-(1H-imidazo[4,5-C]pyridine-2-y1)-1H-pyrazolo[4,3-B]pyridine or a salt or analogue, including amorphous and polymorphic forms (US-10195185-B2), 3-(1h-pyrrolo[2,3-b]pyridine-2-y1)-1h-indazole or a salt or analogue, including amorphous and polymorphic forms (US-10195185-B2), 7024021-A1), 3-(1h-pyrrolo[2,3-c]pyridine-2-y1)-1h-pyrazolo[3,4-c]pyridine or a salt or analogue (including amorphous and polymorphic forms) (WO-2017023975-A1), 3-(1h-indo1-2-y1)-1h-pyrazolo[3,4-b]pyridine or a salt or analogue (including amorphous and polymorphic forms) (US-2018214428-A1), 3-(1h-pyrrolo[3,2-c]pyridine-2-y1)-1h-indazole or a salt or analogue (including amorphous and polymorphic forms) (US-2018214428-A1). (including polymorphic forms) (US-2018221350-A1), 3-(1h-indo1-2-y1)-1h-indazole or a salt or analogue (including amorphous and polymorphic forms) (WO-2017023986-A1), 3-(1H-pyrrolo[2,3-B]pyridine-2-y1)-1H-pyrazolo[4,3-B]pyridine or a salt or analogue (including amorphous and polymorphic forms) (US-10206909-B2), 3-(1h-pyrrolo[3,2-c]pyridine-2-y1)-1h-pyrazolo[4,3-b]pyridine or a salt or analogues (including amorphous and polymorphic forms) (Publication No. WO-2017024003-Al), 3-(1h-pyrrolo[3,2-c]pyridine-2-yl)-1h-pyrazolo[3,4-b]pyridine or salts or analogues (including amorphous and polymorphic forms) (Publication No. US-2018221341-A1), 3-(3h-imidazo[4,5-b]pyridine-2-yl)-1h-pyrazolo[4,3-b]pyridine or salts or analogues (including amorphous and polymorphic forms) (Publication No. WO-2017024015-A1), 3-(1h-pyrrolo[2,3-(1H-pyrrolo[3,2-C]pyridine-2-YL)-1H-pyrazolo[3,4-C]pyridine or a salt or analogue (including amorphous and polymorphic forms) (US-2018221352-AI), 3-(1H-pyrrolo[3,2-C]pyridine-2-YL)-1H-pyrazolo[3,4-C]pyridine or a salt or analogue (including amorphous and polymorphic forms) (US-10206908-B2). Each of the references cited herein is incorporated by reference in its entirety.

[0133] In some embodiments, the infusion system is utilized to deliver suspensions of infusates containing microencapsulated drugs, nanoencapsulated drugs, pure protein nanoparticles, and poorly water-soluble or water-insoluble drugs.

[0134] In some embodiments, the injectable or encapsulated injectable is delivered with a residence time-extending matrix, which can be comprised of an inverse thermosensitive hydrogel, a self-assembling hydrogel, a bioadhesive polymer network, a hydrogel, a fibronectin-containing hydrogel, an enzyme-responsive hydrogel, an ultrasound-sensitive hydrogel, a pH-sensitive hydrogel, a carbohydrate, a two or more component hydrogel, and a multi-component double network hydrogel.

[0135] In some embodiments, the injectable agent may be any of the following, including 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 fats, etc. They are delivered via an infusion system along with penetration enhancers, including fatty acids, protease inhibitors, alkyl glycosides, chitosan, dodecyl-2-N,N-dimethylaminopropionic acid (DDAIP), N-methyl-2-pyrrolidone (NMP), azone, sulfoxides, surfactants, benzyl alkonium chloride, saponins, bile salts, bile acids, cell-penetrating peptides, polyarginine, low molecular weight protamine, polyserine, capric acid, gelling agents, semi-fluorinated alkanes, terpenes, phospholipids, chelating agents, ethylenediaminetetraacetic acid (EDTA), citric acid, crown ethers, and combinations thereof.

[0136] In some embodiments, the injectate containing one or more therapeutic agents is delivered via an infusion system in conjunction with or following administration of one or more vasoconstrictors, including, but not limited to, 25I-NBOMe, amphetamine, AMT, antihistamines, caffeine, cocaine, dopamine, dobutamine, DOM, LSA, LSD, methylphenidate, mephedrone, norepinephrine, oxymetazoline, phenylephrine, propylhexidine, pseudoephedrine, stimulants, serotonin 5-hydroxytryptamine agonists, triptans, and tetrahydrozoline hydrochloride, to reduce injectate outflow through the choroidal vessels. In some embodiments, these agents may be administered into the SCS using the infusion system of the present disclosure or via intravitreal injection using a standard syringe. The vasoconstrictor may be delivered before, simultaneously with, or after administration of the one or more therapeutic agents.

[0137] In some embodiments, the infusate delivered via the infusion system achieves greater than 20%, 40%, 60%, or 80% SCS coverage.

[0138] In some embodiments, the infusate delivered via the infusion system, with or without one or more vasoconstrictors to reduce infusate outflow through the choroidal vessels, achieves SCS coverage in less than 180, 120, 60, 30, or 15 minutes.

[0139] In some embodiments, the infusate delivered via the infusion system has a residence time within the SCS of less than 180, 120, 60, 30, 15, 10, or 5 minutes.

[0140] In some embodiments, the infusate is delivered via the infusion system in less than 500, 400, 300, 200, or 100 microliters.

[0141] In some embodiments, the infusate is delivered via the infusion system at a concentration of less than 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or 1%.

[0142] In some embodiments, the percent dosage of the injectable agent delivered via the injection system that is delivered to the subretinal space is less than 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or 1%.

[0143] In some embodiments, the infusion agent delivered via the infusion system is administered at least once every 10 years, once every 5 years, once every 2 years, once every year, once every 6 months, once every 3 months, once every month, or once every week.

[0144] In some embodiments, the infusion system is used to treat the following conditions, including but not limited to: abetalipoproteinemia (Bassen-Kornzweig syndrome), alkaptonuria, Allan-Herndon-Dudley syndrome, Alpers syndrome, Alström syndrome, Apert syndrome, Aerts syndrome (mental retardation, X-linked, syndromic 18), ataxic oculomotor apraxia syndrome, ataxia telangiectasia (Louis-Bar syndrome), autosomal dominant cerebellar ataxia with deafness and narcolepsy (ADCADN), Avellino corneal dystrophy (complex granular lattice corneal dystrophy), ), Baraita-Winters syndrome type 1, Behr-Stevenson syndrome, Best macular dystrophy, Bietti crystalline corneal dystrophy, Blau syndrome, blepharophimosis, ptosis, and inverted epicanthal folds (BPES), Cantu syndrome, cerebro-ocular-facial-skeletal syndrome, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, cherubism, chondrodysplasia with flat vertebrae, characteristic brachydactyly, hydrocephalus, and microphthalmia, total choroidal atrophy, Christianson syndrome, CK syndrome, deuteranopia, protanopia, tritanopia, cornea planus, mental retardation, ocular coloboma, and Agenesis of the corpus callosum with micrognathia, Kosteff syndrome, Crigler-Najjar syndrome, Crouzon syndrome, Crouzon syndrome with acanthosis nigricans (Crouzon exoskeletal syndrome), cutis laxa, Deble's type, cystinosis, Doyne honeycomb dystrophy (Malatti aventinase), Okihiro syndrome, lens and pupil deviation, ectopia lentis, familial ectopia lentis, isolated S-cone hyperactivity syndrome, epithelial basement membrane corneal dystrophy (geographic-punctate-fingerprint corneal dystrophy), Fabry disease (hereditary ectopic lipidosis), familial dysautonomia, LCAT deficiency, Galactosyltransferase (GLA), cytokinase deficiency, galactosemia, Gaucher disease, GM1-gangliosidosis type I, GM1-gangliosidosis type II, GM1-gangliosidosis type III, Goltz syndrome, granular corneal dystonia (Grenaau type 1), gyrate atrophy, hereditary hemorrhagic telangiectasia (Osler-Lendt-Weber disease), homocystinuria, IFAP syndrome with or without Brecheck syndrome, incontinentia pigmenti (Bloch-Sulzberger syndrome), Jalili syndrome, Uberg-Marsidi syndrome, Krabbe disease, lattice corneal dystrophy,LCHAD (long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiency, Lowe, Pelizaeus-Merzbach, Peters-Plas syndrome (Kraus-Kiblin syndrome), phenylketonuria, Proud syndrome, pseudoexfoliation syndrome, Reiss-Buckler corneal dystrophy, Renpenning syndrome (mental retardation, X-linked, Renpenning type), retinoblastoma, retinoschisis, juvenile X-linked, Russell-Silver syndrome, mucopolysaccharidosis type IH (Hurler syndrome), mucopolysaccharidosis type IH / S (Hurler-Scheie syndrome), mucopolysaccharidosis type IS (Scheie syndrome), mucopolysaccharidosis type II (Hunter syndrome), Mucopolysaccharidosis IIIA (Sanfilippo syndrome A), Mucopolysaccharidosis IIIB (Sanfilippo syndrome B), Mucopolysaccharidosis IIIC (Sanfilippo syndrome C), Mucopolysaccharidosis IIID (Sanfilippo syndrome D), Mucopolysaccharidosis IVA (Morquio syndrome A), Mucopolysaccharidosis IVB (Morquio syndrome B), Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome), Mucopolysaccharidosis VII (Sly syndrome), Moonke syndrome, Nail-Patella syndrome, Nance-Horan syndrome, Native American myopathy, Neurofibromatosis I, Neurofibromatosis II, God Transfibromatosis Noonan syndrome, neuropathy, ataxia, and retinitis pigmentosa (NARP), Norrie disease, occult macular dystrophy, ocular albinism, oculopharyngeal muscular dystrophy, Sandhoff disease (GM2-gangliosidosis type II), Schneider corneal dystrophy, Senger syndrome, Smith-Magenis syndrome, (chromosome 17p11.2 deletion syndrome), sickle cell anemia, Sorsby's fundus dystrophy, spinocerebellar ataxia, X-linked type 1, Stargardt disease / fundus flava, Sturge-Weber syndrome, sulfocystenuria (sulfite oxidase deficiency), syndrome Syndromic microphthalmia 1 (Lenz microphthalmia syndrome), syndromic microphthalmia 2 (ocular-facial-cardiac-dental syndrome), syndromic microphthalmia 3 (microphthalmia and esophageal atresia syndrome), syndromic microphthalmia 5, syndromic microphthalmia 6, syndromic microphthalmia 7 (Midas 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 type 1), Thiel-Behnke corneal dystrophy, Turner syndrome, tyrosinemia type 2, VACTERL association with hydrocephalus,von Hippel-Lindau syndrome, Wagner syndrome, Watson syndrome, Wiercker-Wolff syndrome, Wilson's disease, color vision deficiency, Alagille syndrome, aniridia, anterior segmental dysplasia, Axenfeld-Rieger syndrome, Charge syndrome, Cockayne syndrome, glaucoma, open-angle juvenile-onset congenital glaucoma, Jackson-Weiss syndrome, Pfeiffer syndrome, Pruder-Willi syndrome, Refsum disease, Rubinstein-Taybi syndrome, normal-tension glaucoma, Oguchi disease, Saetre-Hochschen syndrome, Simpson-Golabi-Behmel syndrome, tuberous sclerosis, adult-onset vitelliform macular degeneration, Wolfram syndrome, Alport syndrome, Angelman syndrome, Bardet-Biedl syndrome, basal cell nevus syndrome, Beckwith-Wiedemann syndrome, blue-cone total achromatopsia, branchio-oto-renal syndrome, Charcot-Marie-Tooth disease, cone-rod dystrophy, congenital glycosylation disorders, congenital fibrosis of the extraocular muscles, congenital nystagmus, congenital stationary night blindness, Cornell syndrome It is used to deliver one or more injectables to treat one or more of the ocular causes or consequences of diseases including Lier-de-Lange syndrome, dyskeratosis congenita, Ehlers-Danlos syndrome, Fuchs endothelial corneal dystrophy, open-angle adult-onset glaucoma, Hermansky-Pudlak syndrome, Joubert syndrome, Kearns-Sayre syndrome, Leber congenital amaurosis, Leber hereditary optic neuropathy, Leigh syndrome, Peters anomaly retinitis pigmentosa, muscular dystrophy-dystroglycanopathy, myotonic dystonia, Niemann-Pick disease, Noonan syndrome, neuronal ceroid lipofuscinosis, oculocutaneous albinism, optic atrophy, orofacial-digital syndrome, osteogenesis imperfecta, Senior-Loken syndrome, septo-optic dysplasia (Domorsia syndrome), spastic paraplegia, Stickler syndrome, Treacher-Collins syndrome, Usher syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, and xeroderma pigmentosum.

[0145] In some embodiments, multiple injections may be performed over time to allow for continuation of therapy. Therapeutic injections may be accompanied by another agent that allows for multiple deliveries. For example, AAV delivery is limited by an immune response to AAV, which typically limits AAV use to a single treatment, a limitation commonly associated with intravitreal injections, and subretinal injections are immune privileged, but damaged and diseased retinas do not tolerate multiple injections without trauma. Another agent that suppresses this response (such as ImmTOR) can be injected prior to, in combination with, or after AAV injection to mitigate the immune response and allow for AAV therapy at multiple time points. This allows for dosage to be titrated to patient response as needed.

[0146] In some embodiments, the route of administration is via injection into the SCS. In some embodiments, the genetic disease or disorder is diagnosed by genetic sequencing, including but not limited to, Sanger sequencing, next-generation sequencing, high-throughput screening, exome sequencing, Maxam-Gilbert sequencing, chain termination reaction (CTRA), shotgun sequencing, bridge polymerase chain reaction (PCR), single-molecule real-time sequencing, ion torrent sequencing, pyrosequencing, sequencing by synthesis, combinatorial probe-anchored synthesis, sequencing by ligation, and nanopore sequencing. In some embodiments, the ocular disease or disorder is diagnosed by eye examination, ophthalmoscopy, ocular coherence tomography, retinal scanning, fluorescein staining, conjunctival staining, color vision testing, optic nerve disc imaging, nerve fiber layer analysis, corneal topography, electrodiagnostic testing, fluorescein angiography, ocular photography, specular microscopy, visual field testing, ocular ultrasound, and combinations thereof.

[0147] In some embodiments, a patient presents with elevated intraocular pressure and is diagnosed with early-stage juvenile primary open-angle glaucoma after being examined with an ophthalmoscope, before significant optic nerve damage has occurred. A blood sample is taken and sent for genetic testing, which determines that the patient has a mutation in the olfactomedin domain of the myocilin (MYOC) gene, i.e., mutation Y437H, which is likely involved in causing the disease and leads to a diagnosis of myocilin-associated primary open-angle glaucoma.

[0148] The patient is then treated using an injection system to administer a microRNA complementary to the first 22 bases of the mRNA for the MYOC gene, formulated in an aqueous solution of a self-assembling hydrogel with betacyclodextrin 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 within the SCS after delivery, providing sustained delivery of the microRNA that suppresses myocilin expression, leading to reduced accumulation of myocilin in the trabecular meshwork and reduced intraocular pressure, thereby reducing the patient's chance of sustaining optic nerve damage.

[0149] In another specific embodiment, a male child presents with night blindness and, upon examination, is found to have reduced visual fields and some degree of retinal degeneration. A blood sample is taken and sent for genetic testing, which determines that the patient has a mutation in the CHM gene, for example, encoding RAB escort protein 1 (REP1), including part or all of the CHM gene sequence as described in https: / / www.uniprot.org / uniprot / P24386 (incorporated herein by reference in its entirety), which aids in the diagnosis of early global choroidal atrophy.

[0150] The patient is then treated by administering a freeze-dried AAV2 vector containing a retina-specific promoter derived from the rhodopsin kinase (RK) promoter gene, which is expressed in rods and cones and is linked to the human CHM gene, with the aqueous diluent prior to injection. Upon reconstitution, the injectate solution contains approximately 1,013 AAV vectors per milliliter. Upon injection, the RK promoter and human CHM are stably transfected into photoreceptor cells, where the corrected form of REP1 is expressed, thereby treating the patient's choroidal atrophy.

[0151] In another specific embodiment, an elderly patient presents with central visual impairment. Following a routine retinal examination, drusen are detected. Fluorescein angiography demonstrates leaky choroidal vessels, confirmed by the presence of subretinal fluid accumulation observed on optical coherence tomography (OCT). The patient is diagnosed with early neovascular age-related macular degeneration (AMD).

[0152] The patient is then treated by administering, using an infusion system, 21-24 nucleotide short interfering RNA (siRNA) sequences complementary to portions of the mRNA of one or more of the following genes, alone or in combination: vascular endothelial growth factor (VEGF), any of its subtypes including, but not limited to, VEGF-A, VEGF-A121, VEGF-A165, VEGF-A189, VEGF-A206, VEGF-B, VEGF-C, VEGF-D, VEGF receptor (VEGFR), VEGFR-1, VEGFR-2, and VEGFR-3; NOTCH-regulated ankyrin repeat protein (NRARP); and other pro-angiogenic proteins. The siRNA is delivered in suspension in a liposome carrier. Following delivery, the siRNA knocks down expression of angiogenesis-promoting protein or proteins, thereby preventing additional choriocapillaris growth and causing capillary regression, resulting in reduced choriocapillaris retinal and macular infiltration and improved central vision. In a specific embodiment, the siRNA is targeted to knock down VEGFR-2, having a gene sequence as described at https: / / www.uniprot.org / uniport / P35968 (incorporated herein in its entirety), or an isoform thereof.

[0153] In another specific embodiment, a patient diagnosed with neovascular AMD or diabetic retinopathy is treated by administering an AAV vector or other gene transfer vector containing a gene that, when transcribed, produces an RNA sequence complementary to at least a portion of the mRNA that translates into VEGFR-2. When this gene therapy is delivered to the SCS, the choriocapillaris, also known as the choriocapillaris, comes into contact with the delivered therapeutic agent, which targets the gene transfer to those cells that express VEGFR-2. In response to gene transfer, the transcribed siRNA or shRNA vector knocks down or knocks out VEGFR-2 production, thereby reducing angiogenesis and treating AMD or diabetic retinopathy.

[0154] In some embodiments, a physician may be presented with a suprachoroidal injection assembly or kit that includes: (1) a volume of injectate comprising one or more therapeutic agent formulations, i.e., active drug formulations containing an effective amount of a drug useful for treating a patient's ocular condition, for example; (2) an injection system as described above; and (3) optionally, an injector for facilitating the release of the injectate into and through the injection system membrane.

[0155] As explained above, the pharmaceutical formulation can be in various forms, such as solutions and suspensions of various viscosities. The entire kit, including the formulation, injection system, and facilitating injector, is sterile.

[0156] In some embodiments, the total volume of the active drug formulation to be injected into the suprachoroidal space is preferably in the range of about 0.01 to 0.5 mL. In some embodiments, the active drug may be provided in lyophilized form and accompanying diluent to create a suspension at the time of injection. In some embodiments, the active drug may be premixed. In some embodiments, the injection system may be preloaded with the premixed formulation. In some embodiments, the user may load the injection system immediately prior to administering the therapeutic formulation to the patient. In some embodiments, the injection system may include multiple chambers with frangible separation. In some embodiments, the piercing element has an initial penetration length of 0.01 to 3 mm, and the piercing element extends further during injection. In some embodiments, the injection system and injection facilitator may be preassembled with the preloaded formulation and ready to use without any further assembly. In some embodiments, the entire kit is packaged in a single pouch / tray to maintain sterility. In some embodiments, the components are packaged separately or combined. In some embodiments, the kits are sterilized together or separately by one of several sterilization methods including, but not limited to, autoclave, ethylene oxide, gamma radiation, and the like.

[0157] In some embodiments, the components are present in secondary packaging. In some embodiments, the kit is stored as a set at a temperature low enough to extend the shelf life of the active pharmaceutical agent. In some embodiments, the formulations are stored separately at low temperatures while the remainder of the kit is stored at room temperature.

[0158] Computer system for use with an injection system - Patent Application 20070122967

[0159] The system of the present disclosure may include a controller for controlling the operation of the infusion 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 infusion assembly. Any suitable computing system may be used to implement the computing devices and methods / functionality described herein, and, as will be understood by those skilled in the art, may be converted into a specific system for performing the operations and features described herein through hardware, software, and firmware modifications in a manner that goes significantly beyond simply running software on a general-purpose computing device. An illustrative example of such a computing device 1900 is depicted in FIG. 19. The computing device 1900 is merely an illustrative example of a suitable computing environment and does not limit the scope of the present invention in any way. The "computing device" as represented by FIG. 19 may include a "workstation," a "server," a "laptop," a "desktop," a "handheld device," a "mobile device," a "tablet computer," or other computing device, as will be understood by those 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 1900 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, or to a single type of implementation or configuration of an exemplary computing device 1900, as will be understood by those skilled in the art.

[0160] Computing device 1900 may include a bus 1910 that may be directly or indirectly coupled 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 understand 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 will additionally understand that, depending on the intended application and use of a particular embodiment, more than one of these components may be implemented by a single device. Similarly, in some cases, a single component may be implemented by multiple devices. Thus, FIG. 19 is merely an illustration of an exemplary computing device that may be used to implement one or more embodiments of the present invention and does not limit the invention in any way.

[0161] Computing device 1900 may include or interact with a variety of computer-readable media. For example, 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, CD-ROM, digital versatile disk (DVD) or other optical or holographic media, magnetic cassettes, magnetic tape, magnetic disk storage, or other magnetic storage devices that may be used to encode information and that may be accessed by computing device 1900.

[0162] The memory 1912 can include computer storage media in the form of volatile and / or nonvolatile memory. The memory 1912 can be removable, non-removable, or any combination thereof. Exemplary hardware devices are devices such as hard drives, solid-state memory, optical disk drives, and the like. The computing device 1900 can include one or more processors that read data from components such as the memory 1912, various I / O components 1920, and the like. The presentation component 1916 presents an indication of the data to a user or other device. Exemplary presentation components include a display device, a speaker, a printing component, a vibrating component, and the like.

[0163] I / O ports 1918 may allow computing device 1900 to be logically coupled to other devices, such as I / O components 1920, some of which may be built into computing device 1900. Examples of such I / O components 1920 include microphones, joysticks, recording devices, gamepads, satellite dishes, scanning devices, printers, wireless devices, networking devices, and the like.

[0164] Various modifications and alternative embodiments of the present invention will be apparent to those skilled in the art in view of the foregoing description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the best mode of carrying out the invention. Details of construction may vary substantially without departing from the spirit of the invention, and the exclusive use of all modifications that come within the scope of the appended claims is reserved. While embodiments have been described herein in a manner that permits a clear and concise specification to be written, it is intended and should be understood that the embodiments can be combined or separated in various ways without departing from the invention. It is intended that the present invention be limited only to the extent required by the appended claims and applicable legal provisions.

[0165] It is also to be understood that the following claims are intended to cover all general and specific features of the invention described herein, and all language of the scope of the invention that may be considered to fall therebetween as a matter of language.

Claims

1. 1. An injection system, comprising: an injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; a second sealing element movably disposed within the lumen to dispense an infusate from an infusion chamber defined within the syringe barrel; and a piercing element configured to deliver the infusate into a space within a patient's tissue, the tissue being less permeable to the infusate than the space; a first sealing element movably disposed within the lumen distal to the second sealing element, the first sealing element and the second sealing element forming a seal with the lumen and defining the infusion chamber therebetween, the piercing element being in fluid communication with the infusion chamber to deliver the infusate from the infusion chamber into the space within the tissue of the patient; a support platform configured to support the injection assembly and anchor the injection assembly relative to a site of injection; a drive assembly configured to operate the injection assembly, the drive assembly configured to apply a force to the second seal element, the force moving the first seal element and the second seal element forward within the syringe barrel, the first seal element being mechanically configured to cease forward movement in response to a decrease in resistance after the piercing element enters the space, thereafter the force moving only the second seal element forward, thereby dispensing the infusate from the injection chamber; and one or more sensors configured to monitor one or more forces on the injection assembly; a controller in communication with the one or more sensors to receive information regarding the one or more forces on the injection system, the controller being configured to operate the drive assembly based on the received information to advance the puncturing element through the tissue toward the space by translating the syringe barrel relative to the support platform such that the infusate remains within the injection chamber until the puncturing element fluidly connects the injection chamber with the space; and An injection system comprising:

2. When a force is applied to the second sealing element in a 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 carrying the infusate through the piercing element; 2. The injection system of claim 1, wherein 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 agent is transported from the injection chamber through the piercing element.

3. 2. The injection system of claim 1, wherein the drive assembly is coupled to the second seal element such that application of the force to the second seal element causes distal translation of the second seal element.

4. 2. The injection system of claim 1, wherein the drive assembly comprises a linear actuator coupled to the second seal element to apply the force to the second seal element, thereby translating the second seal element in a distal direction.

5. 2. The injection system of claim 1, wherein the drive assembly comprises a first drive configured to translate the syringe barrel relative to the support platform, and a second drive coupled to the second seal element to translate the second seal element relative to the syringe barrel.

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

8. The infusion system of claim 1 , wherein the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor, or a flow rate sensor.

9. 3. The infusion system of claim 2, wherein the controller is programmed to implement one or more feedback loops for monitoring the first counter force and the second counter force.

10. 10. The injection system of claim 1, wherein the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncture element into the tissue, the one or more feedback loops being configured to monitor an increase in force on the puncture element, detect a decrease in force on the puncture element, and, based on the decrease, cause advancement of the puncture element a predetermined distance to embed the puncture element into the tissue.

11. 10. The injection system of claim 1, wherein the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncturing element through the tissue, the one or more feedback loops being configured to measure a load on the second sealing element and detect a decrease in the load when the puncturing element reaches the space within the tissue.

12. 10. The injection system of claim 1, wherein the controller is programmed to implement one or more feedback loops for monitoring the injection of the infusate into the space, the one or more feedback loops configured to control a speed or an advancement distance of the second sealing element.

13. 10. The injection system of claim 1, wherein the controller is programmed to cause retraction of the puncture element a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element.

14. The injection system of any one of claims 1 to 9, wherein the controller is programmed to control a stopping distance of the puncturing element when the puncturing element enters the space.

15. The injection system of any one of claims 1 to 9, wherein the tissue is the conjunctiva and the space is the subconjunctival space.

16. The injection system of any one of claims 1 to 9, wherein the tissue is the sclera and the space is the suprachoroidal space.

17. The injection system of any one of claims 1 to 9, wherein the tissues are the sclera and choroid and the space is the intravitreal space.

18. The injection system of any one of claims 1 to 9, wherein the tissue is the cornea and the space is the anterior chamber of the eye.

19. 1. An injection system, comprising: an injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; first and second sealing elements movably disposed within the lumen, the first sealing element distal to the second sealing element so as to define an injection chamber; and a piercing element fluidly connected to the injection chamber, the piercing element configured to deliver an infusate from the injection chamber into a space within a patient's tissue, the tissue being less permeable to the infusate than the space; a support platform configured to support the injection assembly and anchor the injection assembly relative to a site of injection; a drive assembly configured to translate the syringe barrel and the second seal element relative to the support platform; one or more sensors configured to monitor one or more forces on the injection assembly; a controller in communication with the one or more sensors to receive information regarding the one or more forces on the injection system, the controller configured to control the drive assembly to advance the puncture element through the tissue toward the space based on the received information, whereby when the drive assembly translates the second sealing element distally: 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 carrying the infusate through the piercing element; a controller, wherein in response to a second reaction force when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and the infusate is conveyed from the infusion chamber through the piercing element; Equipped with the drive assembly is configured to apply a force to the second sealing element, the force moving the first sealing element and the second sealing element forward within the syringe barrel, the first sealing element being mechanically configured to cease forward movement in response to a decrease in resistance after the puncture element enters the space, and thereafter the force moving only the second sealing element forward thereby dispensing the infusate from the infusion chamber.

20. 1. A system for delivering an infusate, the system comprising: a piercing element configured to be inserted into tissue and to deliver infusate from an infusion chamber into a space within the tissue, the tissue having a greater density than the space such that the tissue is less permeable to the infusate than the space; a first sealing element supporting the piercing element, the first sealing element configured to advance the piercing element through the tissue in response to a force from a second sealing element and to discontinue advancement based on a change in backpressure or a change in tissue resistance when the piercing element reaches the space; 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 lancing element; a controller in communication with the one or more sensors, the controller configured to control the drive assembly to advance the piercing element through the tissue toward the space by translating the syringe barrel relative to a support platform configured to support the injection assembly and anchor the injection assembly relative to a site of injection such that the infusate remains within the injection chamber until the piercing element fluidly connects the injection chamber with the space; and Equipped with The drive assembly is configured to apply a force to the second sealing element, the force moving the first sealing element and the second sealing element forward within the syringe barrel, and after the puncture element enters the space, the force moving only the second sealing element forward to dispense the infusate from the infusion chamber.

21. 21. The system of claim 20, wherein the piercing element is positioned on a distal end of an injection assembly comprising a syringe barrel defining a lumen between a proximal end and a distal end, and first and second sealing elements movably disposed within the lumen to dispense the infusion agent from the injection chamber.

22. 22. The system of claim 21, wherein in response to a first reaction force of the one or more forces on the piercing element as the piercing element advances through the tissue, the first sealing element moves distally to advance the piercing element in the distal direction without carrying the infusate through the piercing element.

23. 22. The system of claim 21, wherein in response to a second counter force of the one or more forces on the puncture element when the infusion chamber is fluidly connected to the space, the first sealing element remains stationary and the second sealing element moves distally such that the infusion agent is transported from the infusion chamber through the puncture element and into the space.

24. 24. The system of any one of claims 20 to 23, wherein the controller is programmed to implement one or more feedback loops for monitoring the first reaction force and the second reaction force.

25. 24. The system of claim 20, wherein the controller is programmed to implement one or more feedback loops for monitoring pre-insertion of the puncturing element into the tissue, the one or more feedback loops being configured to monitor an increase in force on the puncturing element, detect a decrease in force on the puncturing element, and, based on the decrease, cause advancement of the puncturing element a predetermined distance to embed the puncturing element into the tissue.

26. 24. The system of claim 20, wherein the controller is programmed to implement one or more feedback loops for monitoring advancement of the puncturing element through the tissue, the one or more feedback loops configured to measure a load on the second sealing element and detect a decrease in the load when the puncturing element reaches the space within the tissue.

27. 24. The system of claim 20, wherein the controller is programmed to implement one or more feedback loops for monitoring injection of the infusate into the space, the one or more feedback loops configured to control a speed or advancement distance of the second sealing element.

28. 24. The system of any one of claims 20 to 23, wherein the controller is programmed to cause retraction of the puncturing element a predetermined distance when the one or more sensors detect a decrease in load on the second sealing element.

29. The system of any one of claims 20 to 23, wherein the controller is programmed to control a stopping distance of the lancing element as the lancing element enters the space.

30. The system of any one of claims 20 to 23, wherein the tissue is the conjunctiva and the space is the subconjunctival space.

31. The system of any one of claims 20 to 23, wherein the tissue is the sclera and the space is the suprachoroidal space.

32. The system of any one of claims 20 to 23, wherein the tissues are the sclera and choroid and the space is the intravitreal space.

33. The system of any one of claims 20 to 23, wherein the tissue is the cornea and the space is the anterior chamber of the eye.

34. 1. A system for delivering an infusate, the system comprising: an injection assembly configured to be positioned adjacent to tissue, the injection assembly comprising: a syringe barrel defining a lumen between a proximal end and a distal end; first and second sealing elements movably disposed within the lumen to dispense an infusate from an infusion chamber defined in the syringe barrel; and an extending piercing element configured to deliver the infusate into a space within the tissue, the tissue having a greater density than the space such that the tissue is less permeable to the infusate than the space; one or more sensors configured to monitor one or more forces on the injection assembly; a controller in communication with the one or more sensors, the controller configured to control the injection assembly using the force on the injection assembly to advance the piercing element through the tissue toward the space such that the infusate remains in the injection chamber until the piercing element fluidly connects the injection chamber with the space; and a drive assembly configured to apply a force to the second seal element, the force moving the first seal element and the second seal element forward within the syringe barrel, the first seal element being mechanically configured to cease forward movement in response to a decrease in resistance after the piercing element enters the space, and thereafter the force moving only the second seal element forward to dispense the infusate from the infusion chamber; and A system comprising:

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