Device and methods for implant delivery

Abstract

An applicator device including a reusable component and a disposable component is disclosed. The disposable unit is configured to deliver a formulation and a disposable optical fiber. The reusable component includes a reusable fiber position control configured to control a position of the disposable optical fiber, a reusable fiber optics connection configured to direct an output from a laser source through the applicator device, and a reusable syringe plunger position control configured to control delivery of the formulation from a syringe located in the disposable unit. Methods for assembling and using the applicator device to deliver a formulation and form a therapeutic implant in a patient's eye are also disclosed.

Description

DEVICE AND METHODS FOR IMPLANT DELIVERYCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This nonprovisional application claims the benefit and priority, under 35 U.S.C. § 119(e) and any other applicable laws or statutes, to U.S.Provisional Patent Application Serial No. 63 / 735575 filed on December 18, 2024, the entire disclosure of which is hereby expressly incorporated herein by reference.TECHNICAL FIELD

[0002] The present disclosure relates generally to devices and methods of using the devices for delivering a formulation to the treatment site. More particularly, the present disclosure relates to devices and methods of using the devices for delivering a formulation to form a contained therapeutic implant to the eye.BACKGROUND

[0003] Patients benefit from having access to implants that control drug delivery, and research is underway to develop implants that exhibit biocompatibility and biodegradability. The ability to modulate the physicochemical properties of an implant, such as the rate of drug diffusion, the rate of implant degradation, and its compatibility with a wide range of therapeutic agents, would be beneficial in providing therapy. Moreover, when using implants in drug delivery applications, the therapeutic agent is preferably retained in its implanted medium for extended time periods. While small molecule therapeutics have been incorporated into formulations that may control the release of the agent over periods of multiple hours to multiple days or even weeks, there would be a benefit for patients to have access to implantablecontrolled release dosage forms that are capable of delivering pharmaceutically effective dosages for a time frame on the order of multiple months or longer. Given the increased use of large molecule agents including biologies such as proteins and antibodies for patient treatment, an implantable controlled release dosage form that maintains integrity, stability, and affords loading capacity for effective release over multiple months for such agents would be of benefit.

[0004] When a subject suffers from a disorder that requires repeated administration of an implant, implant location and / or space constraints within the administration site of the subject may limit the usefulness of implants. Particularly, when implants do not exhibit appropriate degradation rates in comparison with the longevity of the pharmaceutically effective dosage delivered from the implant, the usefulness or convenience is limited. The controlled release of therapeutic agents from the implants and the degradation of such implants is critical to efficient treatment.

[0005] This disclosure is directed to devices and method of using the devices to efficiently deliver such implants to the site of treatment. More specifically, this disclosure is directed to devices and methods of efficiently delivering an implant to the eye.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] The detailed description particularly refers to the following figures, in which:

[0007] FIG. 1 is an illustration of an applicator device of the present disclosure being used to form a therapeutic implant in a patient’s eye;

[0008] FIG. 2 is an illustration of an applicator device including a handheld applicator and a benchtop unit connected to the handheld applicator via an umbilical tether;

[0009] FIG. 3 is an illustration of an applicator device including a handheld applicator and a benchtop unit further connected to a computing device;

[0010] FIG. 4 A is a perspective view of a handheld applicator;

[0011] FIG. 4B is a perspective view of a handheld applicator with portions removed to show the internal structure;

[0012] FIG. 5 is a perspective view of a disposable unit of a handheld applicator;

[0013] FIG. 6 is a cross-sectional view of a disposable unit of a handheld applicator;

[0014] FIG. 7 is a cross-sectional view of a disposable unit of a handheld applicator illustrating fluid and fiber inlets;

[0015] FIG. 8 is a cross-sectional view of a disposable unit illustrating a fiber guide;

[0016] FIG. 9 is a cross-sectional view of a disposable unit illustrating a fluid seal;

[0017] FIG. 10 is an illustration of an exploded view of the disposable unit of the handheld applicator;

[0018] FIG. 11 is an illustration of communication between one or more controllers in an electronic box in a benchtop unit a computing device;

[0019] FIG. 12 illustrates a therapeutic implant formed when using the applicator device of FIG. 2 with a formulation of 7.5 % w / w to 10 % w / w PLGA, 15% w / w Cryo OVA (Irg 819 1% w / w)

[0020] FIG. 13 is a graph illustrating the success rate of the applicator device of FIG. 2 as function of formulation viscosity;

[0021] FIG. 14A illustrates a therapeutic implant formed when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, no Triacetin + 1% Irg 819;

[0022] FIG. 14B illustrates a therapeutic implant formed when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 2.5 % Triacetin + 1% Irg 819;

[0023] FIG. 14C illustrates a therapeutic implant formed when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 5% Triacetin + 1% Irg 819;

[0024] FIG. 14D illustrates a therapeutic implant formed when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 7.5% Triacetin + 1% Irg 819;

[0025] FIG. 14E illustrates a therapeutic implant formed when using the applicator device of FIG. 2 with a formulation of pPD32 containing 8.8% PLGA, 15% OVA, 8.8% Triacetin + 1% Irg 819;

[0026] FIG. 14F illustrates a therapeutic implant formed when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 10% Triacetin + 1% Irg 819;

[0027] FIG. 15A illustrates a therapeutic implant formed in PBS when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 7.5% Triacetin + 1% Irg 819;

[0028] FIG. 15B illustrates a therapeutic implant formed in low viscosity artificial vitreous humor (300 cP) when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 8.8% Triacetin + 1% Irg 819;

[0029] FIG. 15C illustrates a therapeutic implant formed in high viscosity artificial vitreous humor (1900 cP) when using the applicator device of FIG. 2 with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 10% Triacetin + l% Irg 819;

[0030] FIG. 16A illustrates the formation of a therapeutic implant using dynamic operation of the applicator device of FIG. 2 using a first method;

[0031] FIG. 16B illustrates the syringe speed, the fiber speed, the laser current, and fiber position as a function of time when using the first method illustrated in FIG. 16A;

[0032] FIG. 17A illustrates the formation of a therapeutic implant using dynamic operation of the applicator device of FIG. 2 using a second method;

[0033] FIG. 17B illustrates the syringe speed, the fiber speed, the laser current, and fiber position as a function of time when using the second method illustrated in FIG. 17A;

[0034] FIG. 17C illustrates the diameter of the therapeutic implant formed in FIG. 17A; and

[0035] FIG. 17D illustrated the change in the diameter of the therapeutic implant formed in FIG. 17A as a function of the therapeutic implant volume.DETAILED DESCRIPTION OF THE DRAWINGS

[0036] While the concepts of the present disclosure are susceptible to various modifications and alternative forms, specific exemplary embodiments thereof have been shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that there is no intent to limit the concepts of the present disclosure to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, andalternatives falling within the spirit and scope of the invention as defined by the appended claims.

[0037] This disclosure is directed to systems and methods for delivering and curing an implant and / or for delivering a therapeutic formulation to a patient, and preferably to the eye of a patient. In some embodiments, a formulation is injected into the eye and photo-crosslinked by the controlled delivery of a curing light in-situ. In some embodiments, the formulation forms a generally spherical therapeutic implant when injected into the eye and is cured to form a solid mass by the curing light. In some embodiments, the formulation is composed of polymeric materials or macromers including but not limited to a photo-cross linkable polymer.

[0038] In one embodiment, as illustrated in FIG. 1, an applicator device 10 is used to deliver a formulation 12 to an eye 14 of a patient that is cured (partially or full) in-situ to afford an implant 16 that contains a therapeutic agent. As illustrated in FIG. 2, the applicator device 10 includes a handheld applicator 20 and a benchtop unit 22 connected to the handheld applicator 20 via an umbilical tether 24. The applicator device 10 can deliver the formulation 12 into the eye 14 as well as cure the injected formulation 12 at the point of delivery. The applicator device 10 can cause the formulation 12 to form the cured (partial or fully) therapeutic implant 16 (FIG. 1) in the eye 14, the implant allowing for sustained release of one or more drug products included in the therapeutic implant 16, the sustained release occurring over an extended period.

[0039] The mass of the therapeutic implant 16 delivered by applicator device 10 may be much larger than intravitreal implants known in the art. In some embodiments, the therapeutic implants 16 may be greater than 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, or 10 times the massof existing implants (about 10 mg to about 80 mg). In some embodiments, the therapeutic implants 16 may be greater than 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, or 80 times the mass of existing implants. As an increased mass allows for more drug to be loaded into the therapeutic implant 16 for sustained release, the use of the applicator device 10 decreases the frequency of injections into the eye 14 that is required for treatment. Use of the applicator device 10 thereby improves therapeutic outcomes as well as patient experience.

[0040] Referring to FIG. 2, the applicator device 10 further includes a laser controller 26 and a foot pedal 28. The handheld applicator 20 combines the formulation 12 with an output of a laser source 30 to deliver and cure the formulation 12 and form the therapeutic implant 16 within the eye 14.

[0041] As shown in FIGS. 3 and 11, the benchtop unit 22 comprises an electronics box 32 that contains a power supply 34, one or more motor controllers 36, ethernet networking 38, one or more USB hubs 40, one or more laser sources 30, and a data acquisition interface 42, which allows a computing device 44 to connect over the USB hubs 40 and control the applicator device 10.

[0042] The electronics box 32 may be implemented, in some cases, in communication with hardware, firmware, software, or any combination thereof present in or outside the applicator device 10. The electronics box 32 may have a display 18 in communication with the one or more motor controllers 36.

[0043] The one or more motor controllers 36 for monitoring and / or controlling the laser source 30, the handheld applicator 20, and / or other components of the applicator device 10 may be implemented, in some cases, in communication with hardware, firmware, software, or any combination thereof present in or outside the applicator device 10. Information may be transferredto the one or more controllers 36 using any one or more communication technology (e.g., wired or wireless communications) and associated protocols (e.g., Ethernet, InfiniBand®, Wi-Fi®, Bluetooth®, WiMAX, 3G, 4G LTE, 5G, etc.) to affect such communication.

[0044] As shown in FIG. 11, the one or more controllers 36 may be in communication with the computing device 44 through the USB hub 40. The computing device 44 may be embodied as any type of computation or computer device capable of performing the functions described herein, including, but not limited to, a server (e.g., stand-alone, rack-mounted, blade, etc.), a network appliance (e.g., physical or virtual), a high-performance computing device, a web appliance, a distributed computing system, a computer, a processor-based system, a multiprocessor system, a smartphone, a tablet computer, a laptop computer, a notebook computer, and a mobile computing device.

[0045] The one or more controllers 36 may include one or more of an input / output (I / O) subsystem 130, a memory device 132, a processor 134, a data storage device 136, and communication subsystem 138 that may be connected to each other, in communication with each other, and / or configured to be connected and / or in communication with each other through wired, wireless and / or power line connections and associated protocols (e.g., Ethernet, InfiniBand®, Bluetooth®, Wi-Fi®, WiMAX, 3G, 4G LTE, 5G, etc.).

[0046] The processor 134 may be embodied as any type of computational processing tool or equipment capable of performing the functions described herein. For example, the processor 134 may be embodied as a single or multicore processor(s), digital signal processor, microcontroller, or other processor or processing / controlling circuit. The memoiy device 132 may be embodied as anytype of volatile or non-volatile memory or data storage capable of performing the functions described herein.

[0047] In operation, the memory device 132 may store various data and software used during operation of the one or more controllers 36 such as operating systems, applications, programs, libraries, and drivers. The memory device 132 may be communicatively coupled to the processor 134 via the I / O subsystem 130, which may be embodied as circuitry and / or components to facilitate input / output operations with the processor 134, the memory device 132, and other components of the one or more controllers 36. Additionally, or alternatively, in some embodiments, the electronics box 32 may be connected to an external memory device.

[0048] For example, the I / O subsystem 130 may be embodied as, or otherwise include, memory controller hubs, input / output control hubs, sensor hubs, host controllers, firmware devices, communication links (i.e., point-to- point links, bus links, wires, cables, light guides, printed circuit board traces, etc.) and / or other components and subsystems to facilitate the input / output operations.

[0049] In one embodiment, the memory device 132 may be directly coupled to the processor 134, for example via an integrated memory controller hub. Additionally, in some embodiments, the I / O subsystem 130 may form a portion of a system-on-a-chip and be incorporated, along with the processor 134, the memory device 132, and / or other components of the one or more controllers 36, on a single integrated circuit chip.

[0050] The data storage device 136 may be embodied as any type of device or devices configured for short-term or long-term storage of data such as, for example, memory devices and circuits, memory cards, hard disk drives, solid-state drives, or other data storage devices. The one or more controllers 36 may also include the communication subsystem 138, which may be embodied as any communication circuit, device, or collection thereof, capable of enabling communications between the one or more controllers 36 and other remote devices over the computer network.

[0051] The laser controller 26 may be configured to receive one or more commands from the electronics box 32 over the one or more USB hubs 40 and then relay these into signals to control the one or more laser sources 30 and a temperature-controlled mount 46 of the laser sources 30.

[0052] Referring to FIGS. 2 and 3, the umbilical tether 24 includes about one or more electrical conductors 48 and one or more optical fibers 50. The umbilical tether 24 carries the light from the laser source 30 to the handheld applicator 20 along with the electrical signals for one or more motors 52 and one or more LEDs 54. The foot pedal 28 includes a switch 56 that interfaces with the electronics box 32 and is a hands-free interface for starting delivery of the formulation 12. The one or more motors 52 may be non-captive stepper motors 52 configured to deliver any fluid, and preferably high viscosity fluids. The one or more motors 52 may deliver about 5 pL to about 300 pL of the formulation 12, including any volume or range comprised therein at up to about 20,000 cP. The one or more motors 52 may deliver about 5 pL to about 25 pL, about 25 pL to about 50 pL of the formulation 12, about 50 pL to about 75 pL about 75 pL to about 100 pL, about 100 pL to about 150 pL about 150 pL to about 200 pL, about 200 pL to about 250 pL, or about 250 pL to about 300 pL including any volume or range comprised therein at up to about 20,000 cP.

[0053] The one or more motors 52 may deliver about 15 pL to about 25 pL of the formulation 12 of about 1000 cP to about 2000 cP, about 2000 cP to about3000 cP, about 4000 cP to about 5000 cP, about 5000 cP to about 6000 cP, about 6000 cP to about 7000 cP, about 7000 cP to about 8000 cP, about 8000cP to about 9000 cP, about 9000 cP to about 10000 cP, about 10000 cP to about 11000 cP, about l lOOOcP to about 12000 cP, about 12000 cP to about 13000 cP, about 13000 cP to about 14000 cP, about 14000 cP to about 15000 cP about 15000 cP to about 16000 cP, about 16000 cP to about 17000 cP, about 17000cP to about 18000 cP about 18000 cP to about 19000 cP, or about 19000 cP to about 20000 cP.

[0054] Referring to FIGS. 1-4, a user using the applicator device 10 can pierce the eye 14 using a needle 60 attached to the handheld applicator 20 and then activate the applicator device 10 using the connected foot pedal 28. The signals from the electronics box 32 and laser controller 26 actuate a first motor 52a within the handheld applicator 20, which delivers the formulation 12 contained in the applicator device 10 into the eye 14. The signals then actuate a second motor 52b, that advances a disposable optical fiber(s) 50’ up to about 5 mm from the tip of the needle 60, where 0 mm is just inside the tip of the needle 60 and 5 mm is about 3 mm beyond the tip of the needle. In some embodiments, the disposable optical fiber(s) 50’ may be extended past the tip of the needle 60. The laser controller is activated to provide optical power through to the end of the disposable optical fiber 50’ at the tip of the needle 60, which cures the delivered formulation 12 to form the therapeutic implant 16. In some embodiments, movement of the optical fiber 50’ and / or light delivery from the laser source 30 may occur whilst formulation 12 is being delivered to the eye 14.

[0055] Feedback is provided to the user throughout this process, via the two status LEDs 54 on top of the handheld applicator 20. Disposable is used to describe any component of the handheld applicator 20 that is used once for onlyone patient. Reusable is used to describe any component of the handheld applicator 20 that is used more once for one patient and / or for multiple patients.

[0056] Referring to FIGS. 4A and 4B, in the illustrative embodiment, the handheld applicator 20 includes a disposable unit 62, a reusable fiber position control 64, a reusable fiber optics connection 66, a reusable syringe plunger position control 68, and one or more caseworks, frameworks, and connectors (e.g., screws, nuts etc.) 70. The disposable unit 62 may be replaced after each injection. As shown in FIGS. 4 and 5, the disposable unit includes a syringe 84, the needle 60, and a fluid optic manifold 78. The fluid optic manifold 78 connects the optical fiber 50’ to a fluid channel 86 configured to supply the formulation 12. The needle 60 is integrated with the optical fiber 50’ and configured to flow the formulation 12 to the implant site in the eye 14.

[0057] In some embodiments, control over the position of the optical fiber 50’ ensures that the tip of the optical fiber 50’ starts and ends at the same point relative to the tip of the needle 60 for each disposable unit 62. The optical fiber 50’ is preferably configured to be moveable so that the optical fiber 50’ can be extended and retracted during delivery of the formulation 12. Movability of the optical fiber 50’ ensures that the injection profile is not compromised by the presence of the optical fiber 50’ and that the tip of the optical fiber 50’ is positioned in the therapeutic implant 16 during curing. In some embodiments, the optical fiber 50’ may always be positioned in the needle 60. In some embodiments, the optical fiber 50’ may be moved out of the needle 60.

[0058] In some embodiments, the optical fiber 50’ is advanced forward using linear motion from the non-captive motor 52b and retracted under the action of a return spring 72 positioned in the disposable unit 62 as shown in FIG. 4B. The disposable unit 62 contains a hard stop surface 80 on the fluidoptic manifold 78, which the motor 52b uses to set a home position as part of its delivery routine. The fiber position control 64 illustrated in FIGS. 4A and 4B controls the position of the optical fiber 50’ in the needle 60. The fiber position control 64 is comprised of the non-captive motor 52b, that transfers linear motion through a connecting arm 124 to a rod 125 and then through a fiber movement fork 126 to the spring 72 in the disposable unit 62. The fiber position control 64 allows the setting and the adjustment of the axial position of the optical fibers 50’. The non-captive motor 52b moves the fiber movement fork 126 back and forth to control the position of optical fibers 50 and / or 50’.

[0059] The fiber optics connection 66 illustrated in FIGS. 3-5, allows the reusable optical fiber 50 to transmit light to the reusable optical fiber 50’ in the disposable unit 62 through a second reusable optical fiber 50” located in the handheld applicator 20 and extending from the caseworks, frameworks, and connectors 70 to the fiber optics connection 66. In some embodiments, the fiber position control 64 may also allow the setting and the adjustment of the axial position of the optical fibers 50”. The non-captive motor 52b may move the fiber movement fork 126 back and forth to control the position of optical fibers 50”.

[0060] A fiber connector 74 is fitted inside a carriage 76 positioned in a linear track so the fiber connector 74 can slide as the optical fiber 50’ moves in the needle 60. The fiber optics connection 66 allows transfer of light into the fluid optic manifold 78. In some embodiments, the fiber connector 74 is configured to be a clip-in connector 74 to minimize time required to swap the disposable units 62.

[0061] The fiber optics connection 66 is configured to direct the output of the laser source 30, through the handheld applicator 20 unit via the disposable unit 62 to the tip of the needle 60. There may be a connection point between thedisposable unit 62 and the handheld applicator 20 so the disposable unit 62 may be replaced. There may also be another connection point between the handheld applicator 20 and the benchtop unit 22, so the handheld applicator 20 and the umbilical tether 24 may be stored separately.

[0062] When the disposable unit 62 is disconnected, the fiber connector 74 within the handheld applicator 20 is configured to be retractable to allow the disposable unit 62 to be released. Retracting the handheld applicator 20 may cause any excess optical fiber 50’ to be pushed in an uncontrolled way into the handheld applicator 20, which poses the risk of the optical fiber 50’ breaking. To avoid this, the handheld applicator 20 includes fiber guides 90 (see FIG. 8) to control the fiber path and bending radius. This ensures that the optical fiber 50’ does not make a tighter bend than its minimum bend radius.

[0063] The fluid optic manifold 78 shown in FIGS. 5-8 combines fluid flow of the formulation 12 and the optical fiber 50’ into a single outlet 88. The fluid optic manifold 78 includes the fiber guide 90 to assist threading of optical fiber 50’ into the needle 60 and the spring-loaded fiber connector 74 to ensure consistent fiber position at the start of any procedure. The optical fiber 50’ is housed in the fluid optic manifold 78 and in the needle 60.

[0064] As shown in FIGS. 5, 6, and 10, the fluid optic manifold 78 comprises manifold caps 92, 94 that allow for the controlled movement of a connector collar 96. The manifold caps 92, 94 include an upper cap 92 and a lower cap 94 that are separate from a manifold body 98. The manifold body 98 allows the joining of the fluid channel 86 and the fiber guide 90. The manifold body 98 includes a threaded front end 100 configured to connect to the needle 60 and a threaded rear end 102 configured to connect to the syringe 84. The manifold body 98 further includes a locating feature 104 for the spring 72. Themanifold body 98 comprises a narrow neck region 106 to fit with a disposable unit housing 108 shown in FIG. 4A. FIG. 10 illustrates an exploded view of the disposable unit 62 of the handheld applicator 20.

[0065] The connector collar 96 allows for movement of the position of the optical fiber 50’ in the needle 60. The optical fiber 50’ is connected by glue to the fiber connector 74. Fiber movement is controlled by the fiber movement fork 126 that is configured to advance the optical fiber 50’ and is further controlled by the spring 72 that is configured to retract the optical fiber 50’. The spring 72 ensures contact of the connector collar 96 with the fiber movement fork 126 to control fiber movement. The spring 72 ensures contact of the connector collar 96 with the fiber movement fork 126 to control fiber movement.

[0066] Referring to FIGS. 4-6, the syringe plunger position control 68 includes the non-captive motor 52a that is connected to a linear stage 97 and that is configured to push on a syringe plunger 82 to control the delivered volume from the syringe 84. The non-captive motor 52a moves a plunger carriage 99 to advance the syringe plunger 82. The non-captive motor 52a, maintains accurate positional control while exerting a high output force, which is required due to the high viscosity of the formulation 12.

[0067] The syringe plunger position control 68 allows precise control of delivered volume of formulation 12 during both priming and delivery phases. The priming phase comprises the movement of the formulation 12 to the end of the needle 60 and the delivery phase comprises the movement of the formulation 12 out of the needle 60. The Formulation 12 may also be ejected from the needle during the priming phase to check for the presence of air bubbles.

[0068] The one or more caseworks, frameworks, and connectors 70 holds the components, prevents external light from curing the formulation 12, and allows electrical and optical connections to be made.

[0069] The syringe 84 holds and dispenses the formulation 12. The syringe 84 allows transfer of high delivery forces to formulation 12. The syringe plunger 82 may be refurbished between injections. The purpose of the syringe plunger 82 is to transfer the linear force output from the motor 52a, in the syringe plunger position control 68 to drive the formulation 12 out of the syringe 84 and through the disposable unit 62. The syringe plunger 82 may be comprised of steel to ensure that the syringe plunger 82 is stiff enough to not deflect during delivery. The syringe plunger 82 may comprise one or more O-ring seals 110 to ensure that a seal is maintained throughout operation.

[0070] The disposable unit 62 further comprises a fiber ferrule 112 that includes a running surface for the fiber fluid seal to prevent the formulation 12 from escaping during delivery.

[0071] Referring to FIG. 7, in the illustrative embodiment, the disposable unit 62 includes a fluid optic manifold 78 that contains a fluid inlet 116, a fiber inlet 114, and the single combined outlet 88. The purpose of the fluid optic manifold 78 as described above is to combine fluid delivery and the optical fiber into a single output, such that both are present at the exit of the needle 60. This allows the formulation 12 and the visible light output from the optical fiber 50’ to be co-located in the eye 14, ensuring that the formulation 12 can be cured into the therapeutic implant 16. Additionally, a single output ensures that there is only one incision into the sclera of the eye 14, minimising the risk of damage to the eye 14.

[0072] The fluid optic manifold 78 also determines the position of the tip of the optical fiber 50’ within a sphere of the formulation 12, once delivered, ensuring that the visible light is directed into the therapeutic implant 16. The position of the optical fiber 50’ and / or optical fiber 50” may be determined through the movement of the connector collar 96, which may be spring-loaded and connected by epoxy to the blue optical connector.

[0073] Tight alignment of fiber connector 74 to fiber ferrule 112 permits the optical fiber 50’ to travel forwards and backwards without breaking. Such movement preferably involves minimal friction and minimal axial misalignment between the moving optical fiber 50’ and the static fluid optic manifold 78. In some embodiments, a known position for the optical fiber 50’ is provided so that the applicator motor 52b can set a datum for every disposable unit 62. In doing so, the hard stop surface 80 may be present within the fluid optic manifold 78, allowing the optical fiber 50’ to be advanced fully forwards, setting a known “home” position, and ensuring that each optical fiber 50’ extends the same amount from the tip of the needle 60.

[0074] Referring to FIG. 8, in the illustrative embodiment, the disposable unit 62 includes the fiber guide 90. In some embodiments, the fiber guide 90 is configured to direct the tip of the optical fiber 50’ as it is assembled from the fiber inlet 114 side and towards the tip of the needle 60. Due to the fragility of the optical fiber 50’ in some embodiments, this gradual reduction in crosssection up to the needle 60 minimizes the areas where the optical fiber 50’ could snag, thereby lowering the risk of the tip of the optical fiber 50’ breaking during the assembly process. Additionally, the tapered shape of the fiber guide 90 profile aids delivery of the formulation 12 by avoiding any step change in cross- sectional area. Therefore, there is a lower risk of air pockets forming asformulation 12 passes through the disposable unit 62, so there is no disruption to formulation 12 delivered out the tip of the needle 60.

[0075] Referring to FIG. 9, in the illustrative embodiment, the disposable unit 62 includes a fluid seal 118. The fluid seal 118 comprises the fiber ferrule 112 having a small gap 122 between a ferrule bore 120 and the optical fiber 50’ such that the gap 122 allows clearance for the optical fiber 50’ to move and air to pass through. The size of the gap 122 may depend on the viscosity of the formulation 12 and total pressure applied to the handheld applicator 20. The gap 122 may be sized between about 0.5 mm to about 0.005 mm, including any size or range comprised therein. In other embodiments, the gap 122 may be smaller than 0.005 mm or larger than 0.5 mm. However, due to the cross- sectional area of this gap 122 being smaller, and preferably several orders of magnitude smaller, than the area of the bore of the needle 60, the formulation 12 will preferentially flow out of the tip of the needle 60 because of the high resistance to fluid flow around the fluid seal 118.

[0076] The purpose of the fluid seal 118 is to allow the optical fiber 50’ to move forwards and backwards in the axial direction, whilst also providing a seal around the optical fiber 50’ for the formulation 12. During the priming phase, due to the geometry of the fluid path defined by the fluid channel 86 joining to the fiber path defined by the fiber guide 90, there is a chance that air at this interface may be pushed out of the tip of the needle 60. Therefore, it is preferable for the fluid seal 118 to allow air to escape through the fluid seal 118 but not allow the escape of any formulation 12.

[0077] In one embodiment, the applicator device 10 may be comprised of resin. In one embodiment, the applicator device 10 may be comprised of plastic. For example, the applicator device 10 may be comprised of Polypropylene (PP),Polyethylene (PE), Polycarbonate (PC), Acrylonitrile Butadiene Styrene (ABS), Polyether ether ketone (PEEK), Polyoxymethylene (POM), Cyclic olefin polymer (COP), Cyclic olefin copolymer (COC), or any resin designed to mimic the properties of any of the above.

[0078] In one embodiment, the applicator device 10 may be, in whole or in part, manufactured by 3D printing, injection molding, machining, vacuum casting, or resin casting.

[0079] In one embodiment, the applicator device 10 may be operated by implementing an operating algorithm with one or more variable parameters. The variable parameters in the operating algorithm may include but is not limited to formulation flow rate, formulation volume, fiber speed, degree of fiber movement, timing of fiber movement, formulation delivery time, lag time between formulation delivery and start of curing, light / laser current, light / laser power, light / laser pulsing, and / or curing time.

[0080] In some embodiment the operating algorithm used to deliver the formulation 12 in the therapeutic implant 16 includes a dynamic operation of the applicator device 10. The operating algorithm may control the delivery rates and positioning of both the formulation 12 and the optical fiber 50’. This control ensures the formation of the contained and generally spherical therapeutic implant 16 in aqueous media with minimal to no leakage of the drug or other components from the formulation 12 or impact to the eye 14 during curing or implant formation. Such control may also reduce the leakage of light from formulation 12 during curing. This may be beneficial if formulation 12 is administered to an area of the patient that is sensitive to certain wavelengths of light, such as the patient’s eye, during curing of formulation 12. Accordingly, patient safety is improved by such operation of the applicator device 10. Theparameters of the operating algorithm may depend on the composition of the formulation 12 and changes in the formulation 12 and / or the therapeutic implant 16 during the duration of delivery.

[0081] In some embodiments, the operating algorithm may include controlling a rate of delivery of the formulation 12 by controlling the movement of the syringe plunger 82. In some embodiments, the rate of delivery of the formulation 12 may vary with time as the formulation 12 is being delivered through the needle 60 to the eye 14. In some embodiments, the rate of delivery of the formulation 12 may depend on the composition of the formulation 12 including the viscosity of the formulation 12. In some embodiments, the applicator device 10 is configured to be capable of delivering about 5-50 microliters of a formulation 12 possessing a range of viscosities (e.g., about 1,000- about 40,000 cP) through a narrow-gauge needle 60 (e.g., a 22, 23, 24, 25, 26, 27, 28, 29, or 30 gauge needle; preferably a 25 or 27 gauge needle).

[0082] In some embodiments, the formulation 12 may have a viscosity of about 500 cP to about 20000 cP at a shear rate of about 100 s -1, including any viscosity or range comprised therein. For example, the formulation 12 may have a viscosity of about 500 cP to about 1000 cP, about 1000 cP to about 2000 cP, about 2000 cP to about 3000 cP, about 3000 cP to about 4000 cP, about 4000 cP to about 5000 cP, about 5000 cP to about 6000 cP, about 6000 cP to about 7000 cP, about 7000 cP to about 8000 cP, about 8000 cP to about 9000 cP, about 9000 cP to about 10000 cP, about 10000 cP to about 11000 cP, about 11000 cP to about 12000 cP, about 12000 cP to about 13000 cP, about 13000 cP to about 14000 cP, about 14000 cP to about 15000 cP, about 15000 cP to about 16000 cP, about 16000 cP to about 17000 cP, about 17000 cP to about 18000 cP, about 18000 cP to about 19000 cP, or about 19000 cP to about 20000cP, at a shear rate of about 100 s1. In some embodiments, the formulation 12 may have a viscosity less than about 6000 cP at a shear rate of about 100 s1. In some embodiments, the formulation 12 may have a viscosity less than about500 cP or more than about 20000 cP at a shear rate of about 100 s1.

[0083] In some embodiments, the formulation 12 may include a biodegradable polymer such as a polypropylene fumarate), a lactide / glycolide copolymer (PLGA), a polylactic acid (PLA), a polyglycolic acid (PGA), a polycaprolactone (PCL), a lactide / caprolactone copolymer (PLC), a poly(L-lactide) (PLLA), a polyorthoester type IV, a polyhydroxyalkanoate (PHA), chitosan, collagen, or mixtures, copolymers, or block copolymers of the aforementioned biodegradable polymers. In more preferable embodiments, the biodegradable polymer is a lactide / glycolide co-polymer (PLGA) that is poly-DL-(lactide-co- glycolide). In even more preferable embodiments, the biodegradable polymer is a lactide / glycolide co-polymer (PLGA) that is poly-DL-(lactide-co-glycolide) (75:25).

[0084] In some embodiments, the biodegradable polymer may have an average molecular weight of 10 kDa, 11 kDa, 12 kDa, 13 kDa, 14 kDa, 15 kDa, 16 kDa, 17 kDa, 18 kDa, 19 kDa, 20 kDa, 21 kDa, 22 kDa, 23 kDa, 24 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, 55 kDa, 60 kDa, 65 kDa, 70 kDa, 75 kDa, 80 kDa, 85 kDa, 90 kDa, 95 kDa, 100 kDa, 110 kDa, 120 kDa, 130 kDa, 140 kDa, 150 kDa, 160 kDa, 170 kDa, 180 kDa, 190 kDa, 200 kDa, or about any of the aforementioned molecular weights (e.g., about lOkDa, about 15 kDa, about 20 kDa, about 40 kDa, about 60 kDa, about 100 kDa, or about 150 kDa), or a range bounded by any of the aforementioned molecular weights or about any of the aforementioned molecular weights (e.g., 10-30 kDa, 15-25 kDa, 10-100 kDa, about 10-30 kDa, about 15-25 kDa, or about 10-100 kDa). Insome embodiments, the biodegradable polymer may have an average molecular weight of less than 10 kDa.

[0085] In some embodiments, the biodegradable polymer may have an average molecular weight of greater than 10 kDa, greater than 11 kDa, greater than 12 kDa, greater than 13 kDa, greater than 14 kDa, greater than 15 kDa, greater than 16 kDa, greater than 17 kDa, greater than 18 kDa, greater than 19 kDa, greater than 20 kDa, greater than 21 kDa, greater than 22 kDa, greater than 23 kDa, greater than 24 kDa, greater than 25 kDa, greater than 30 kDa, greater than 35 kDa, greater than 40 kDa, greater than 45 kDa, greater than 50 kDa, greater than 55 kDa, greater than 60 kDa, greater than 65 kDa, greater than 70 kDa, greater than 75 kDa, greater than 80 kDa, greater than 85 kDa, greater than 90 kDa, greater than 95 kDa, greater than 100 kDa, or about any of the aforementioned molecular weights (e.g., greater than about lOkDa, greater than about 15 kDa, greater than about 20 kDa, greater than about 40 kDa, greater than about 60 kDa, or greater than about 100 kDa), or a range bounded by any of the aforementioned molecular weights or about any of the aforementioned molecular weights (e.g., greater than 10-15 kDa, greater than 15-19 kDa, greater than 10-20 kDa, greater than about 10-15 kDa, greater than about 15-19 kDa, or greater than about 10-20 kDa).

[0086] In some embodiments, the biodegradable polymer may have an average molecular weight of less than 10 kDa, less than 15 kDa, less than 20 kDa, less than 21 kDa, less than 22 kDa, less than 23 kDa, less than 24 kDa, less than 25 kDa, less than 30 kDa, less than 35 kDa, less than 40 kDa, less than 45 kDa, less than 50 kDa, less than 55 kDa, less than 60 kDa, less than 65 kDa, less than 70 kDa, less than 75 kDa, less than 80 kDa, less than 85 kDa, less than 90 kDa, less than 95 kDa, less than 100 kDa, less than 110 kDa, lessthan 120 kDa, less than 130 kDa, less than 140 kDa, less than 150 kDa, less than 160 kDa, less than 170 kDa, less than 180 kDa, less than 190 kDa, less than 200 kDa, or about any of the aforementioned molecular weights (e.g., less than about 20 kDa, less than about 25 kDa, less than about 30 kDa, less than about 40 kDa, less than about 60 kDa, less than about 100 kDa, or less than about 150 kDa), or a range bounded by any of the aforementioned molecular weights or about any of the aforementioned molecular weights (e.g., less than 20-25 kDa, less than 25-30 kDa, less than 25- 100 kDa, less than about 20-25 kDa, less than about 25-30 kDa, or less than about 25- 100 kDa).

[0087] In some embodiments, the formulation 12 may include PLGA as the biodegradable polymer. In some embodiments, the amount of PLGA in the formulation 12 may range from about 0.001% w / w to about 40% w / w about 1%- 15% w / w, about 5%-10% w / w, or about 7.5% w / w, including any percentage or range comprised therein. In some embodiments, the amount of PLGA in the formulation 12 may range from about 0.001% w / w to about 0.01% w / w, about 0.01% w / w to about 0.1% w / w, about 0.1% w / w to about 1% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 5% w / w, about 5% w / w to about 6% w / w, about 6% w / w to about 7% w / w, about 7% w / w to about 8% w / w, about 8% w / w to about 9% w / w, about 9% w / w to about 10% w / w, about 10% w / w to about 11% w / w, about 11% w / w to about 12% w / w, about 12% w / w to about 13% w / w, about 13% w / w to about 14% w / w, about 14% w / w to about 15% w / w, about 15% w / w to about 16% w / w, about 16% w / w to about 17% w / w, about 17% w / w to about 18% w / w, about 18% w / w to about 19% w / w, about 19% w / w to about 20% w / w, about 20% w / w to about 22% w / w, about 22% w / w to about 24% w / w, about 24% w / w to about 26% w / w, about 26% w / w toabout 28% w / w, about 28% w / w to about 30% w / w, about 30% w / w to about 32% w / w, about 32% w / w to about 34% w / w, about 34% w / w to about 36% w / w, about 36% w / w to about 38% w / w, or about 38% w / w to about 40% w / w. In some embodiments, the formulation 12 may include micronized PLGA. In some embodiments, the formulation 12 may include alternatives to PLGA such as those described above.

[0088] In some embodiments, the formulation 12 may include a curing agent or a cross-linking agent. In some embodiments, the formulation 12 may include a photoreactive cross-linking agent. In some embodiments, cross-linking agent is a photoinitiator such as Irgacure 819, Irgacure 2959, lithium phenyl- 2,4,6-trimethylbenzoylphosphinate (LAP). In some embodiments, the amount of the curing agent or cross-linking agent in the formulation 12 may range from about 0.01% w / w to about 5% w / w, about 0.1% w / w to about 2.5% w / w, about 0.5% w / w to about 1.5% w / w, or about 1% w / w, including any percentage or range comprised therein. In some embodiments, the curing agent or crosslinking agent is present in the formulation 12 in the amount of 0.01% (w / w), 0.02% (w / w), 0.03% (w / w), 0.04% (w / w), 0.05% (w / w), 0.06% (w / w), 0.07% (w / w), 0.08% (w / w), 0.09% (w / w), 0.1% (w / w), 0.2% (w / w), 0.3% (w / w), 0.4% (w / w), 0.5% (w / w), 0.6% (w / w), 0.7% (w / w), 0.8% (w / w), 0.9% (w / w), 1% (w / w), 1.1% (w / w), 1.2% (w / w), 1.3% (w / w), 1.4% (w / w), 1.5% (w / w), 1.6% (w / w), 1.7% (w / w), 1.8% (w / w), 1.9% (w / w), 2% (w / w), 2. 1% (w / w), 2.2% (w / w), 2.3% (w / w), 2.4% (w / w), 2.5% (w / w), 2.6% (w / w), 2.7% (w / w), 2.8% (w / w), 2.9% (w / w), 3% (w / w), 3.1% (w / w), 3.2% (w / w), 3.3% (w / w), 3.4% (w / w), 3.5% (w / w), 3.6% (w / w), 3.7% (w / w), 3.8% (w / w), 3.9% (w / w), 4% (w / w), 4.1% (w / w), 4.2% (w / w), 4.3% (w / w), 4.4% (w / w), 4.5% (w / w), 4.6% (w / w), 4.7% (w / w), 4.8% (w / w), 4.9% (w / w), 5% (w / w), or about any of the aforementioned percentages (e.g., about0.5% (w / w) or about 1% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., 0.1%-5% (w / w), 0.2%-4% (w / w), 0.3%-3% (w / w), 0.4%-2% (w / w), 0.5%-1.5% (w / w), 0.6%- 1.3% (w / w), 0.7%-1.2% (w / w), 0.8%- 1.2% (w / w), 0.9%- l. l% (w / w), about 0.1%- 5% (w / w), about 0.5%- l% (w / w), about 0.8%-1.2% (w / w), or about 0.9%-l. l% (w / w)). In some embodiments, the curing agent or cross-linking agent is present in the formulation 12 in the amount of 1% (w / w). In some embodiments, the curing agent or cross-linking agent is present in the composition in the amount of about 1% (w / w).

[0089] In some embodiments, the curing agent or cross-linking agent is present in the formulation 12 in the amount of less than 0.1% (w / w), less than 0.2% (w / w), less than 0.3% (w / w), less than 0.4% (w / w), less than 0.5% (w / w), less than 0.6% (w / w), less than 0.7% (w / w), less than 0.8% (w / w), less than 0.9% (w / w), less than 1% (w / w), less than 1.1% (w / w), less than 1.2% (w / w), less than 1.3% (w / w), less than 1.4% (w / w), less than 1.5% (w / w), less than 1.6% (w / w), less than 1.7% (w / w), less than 1.8% (w / w), less than 1.9% (w / w), less than 2% (w / w), less than 2. 1% (w / w), less than 2.2% (w / w), less than 2.3% (w / w), less than 2.4% (w / w), less than 2.5% (w / w), less than 2.6% (w / w), less than 2.7% (w / w), less than 2.8% (w / w), less than 2.9% (w / w), less than 3% (w / w), less than 3.1% (w / w), less than 3.2% (w / w), less than 3.3% (w / w), less than 3.4% (w / w), less than 3.5% (w / w), less than 3.6% (w / w), less than 3.7% (w / w), less than 3.8% (w / w), less than 3.9% (w / w), less than 4% (w / w), less than 4.1% (w / w), less than 4.2% (w / w), less than 4.3% (w / w), less than 4.4% (w / w), less than 4.5% (w / w), less than 4.6% (w / w), less than 4.7% (w / w), less than 4.8% (w / w), less than 4.9% (w / w), less than 5% (w / w), or less than about any of the aforementioned percentages (e.g., less than about 0.6% (w / w) or less thanabout 1. 1% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., less than 0.1%-5% (w / w), less than 0.2%-4% (w / w), less than 0.3%-3% (w / w), less than 0.4%-2% (w / w), less than 0.5%- 1.5% (w / w), less than 0.6%- 1.3% (w / w), less than 0.7%-1.2% (w / w), less than 0.8%-1.2% (w / w), less than 0.9%- l. l% (w / w), less than about 0.1%-5% (w / w), less than about 0.5%-l% (w / w), less than about 0.8%-1.2% (w / w), or less than about 0.9%-l. l% (w / w)).

[0090] In some embodiments, the curing agent or cross-linking agent is present in the formulation 12 in the amount of greater than 0. 1% (w / w), greater than 0.2% (w / w), greater than 0.3% (w / w), greater than 0.4% (w / w), greater than 0.5% (w / w), greater than 0.6% (w / w), greater than 0.7% (w / w), greater than 0.8% (w / w), greater than 0.9% (w / w), greater than 1% (w / w), greater than 1.1% (w / w), greater than 1.2% (w / w), greater than 1.3% (w / w), greater than 1.4% (w / w), greater than 1.5% (w / w), greater than 1.6% (w / w), greater than 1.7% (w / w), greater than 1.8% (w / w), greater than 1.9% (w / w), greater than 2% (w / w), greater than 2.1% (w / w), greater than 2.2% (w / w), greater than 2.3% (w / w), greater than 2.4% (w / w), greater than 2.5% (w / w), greater than 2.6% (w / w), greater than 2.7% (w / w), greater than 2.8% (w / w), greater than 2.9% (w / w), greater than 3% (w / w), greater than 3.1% (w / w), greater than 3.2% (w / w), greater than 3.3% (w / w), greater than 3.4% (w / w), greater than 3.5% (w / w), greater than 3.6% (w / w), greater than 3.7% (w / w), greater than 3.8% (w / w), greater than 3.9% (w / w), greater than 4% (w / w), greater than 4.1% (w / w), greater than 4.2% (w / w), greater than 4.3% (w / w), greater than 4.4% (w / w), greater than 4.5% (w / w), greater than 4.6% (w / w), greater than 4.7% (w / w), greater than 4.8% (w / w), greater than 4.9% (w / w), greater than 5% (w / w), or greater than about any of the aforementioned percentages (e.g., greater thanabout 0.4% (w / w) or greater than about 0.9% (w / w)), or a range bounded by any of the aforementioned percentages or about any of the aforementioned percentages (e.g., greater than 0. l%-0.4% (w / w), greater than 0.2%-0.4% (w / w), greater than 0.3%-0.4% (w / w), greater than 0.4%-0.5% (w / w), greater than 0.5%-0.9% (w / w), greater than 0.6%-0.9% (w / w), greater than 0.7%-0.9% (w / w), greater than 0.8%-0.9% (w / w), greater than about 0.1%-0.4% (w / w), greater than about 0.2%-0.44% (w / w), greater than about 0.3%-0.4% (w / w), greater than about 0.4%-0.5% (w / w), greater than about 0.5%-0.9% (w / w), greater than about 0.6%-0.9% (w / w), greater than about 0.7%-0.9% (w / w), or greater than about 0.8%-0.9% (w / w)).

[0091] In some embodiments, in some embodiments, the curing agent or cross-linking agent is present in the formulation 12 in an amount sufficient for crosslinking the crosslinkable macromer(s) in the composition. This is readily determined by following the synthetic methods for crosslinking disclosed herein while increasing and / or decreasing the amount of cross-linking agent included in any particular composition.

[0092] In some embodiments, the crosslinkable macromer(s) are comprised of monomers of polyethylene glycol diacrylate or polyethylene glycol diaciylate and dithiothreitol (“DTT”) in which the ratio of PEGDA (“P”) to DTT (“D”) may be varied in molar inputs for the preparation of the macromer. Thus, a crosslinkable macromer designated as “PD48” or “PD 48” or “48 PD” refers to a crosslinkable macromer prepared from the monomers of polyethylene glycol diacrylate and dithiothreitol in a molar ratio of 1 polyethylene glycol diacrylate to 0.48 dithiothreitol. Such nomenclature may be utilized in the examples of this application. In some embodiments, the cross-linkable macromer compositioncomprises PD16, PD24, PD32, PD40, PD48, PD56, PD64, PD72, PD80, PD88, orPD96 macromers or mixtures thereof.

[0093] In some embodiments, the cross-linkable macromer composition has been purified to remove unreacted material from its synthesis. For macromers prepared from PEGDA and DTT, such purified macromers are referred to “pPD” macromers in which unreacted or residual PEGDA from the preparation of the macromers has been reduced. For pPD macromers, the amount of residual PEGDA is generally about 25% or less (w / w), about 20% or less (w / w), about 15% or less (w / w), about 10% or less (w / w), about 5% or less (w / w), about 1% (w / w) or less, or more preferably, about 0.5% (w / w) or less. Accordingly, in some embodiments, the cross-linkable macromer composition is pPD 16, pPD24, pPD32, pPD40, pPD48, pPD56, pPD64, pPD72, pPD80, pPD88, or pPD96

[0094] In some embodiments, the formulation 12 may include additional excipients for improving therapeutic implant 16 formation and / or reducing the viscosity of the formulation 12. In some embodiments, the formulation 12 may include additional excipients such as triacetin, triethyl acetyl citrate, and / or tributyl citrate. In some embodiments, the formulation 12 may include water. In some embodiments, the water in the formulation may be less than 2% w / w, less than 1 % w / w or less than 0.5% w / w.

[0095] Exemplary therapeutic agents for inclusion in the embodiments disclosed herein include, but are not limited to, polypeptides, nucleic acids, such as DNA, RNA, and siRNA, growth factors, steroid agents, antibodies, antimicrobial agents, antibiotics, antiretroviral drugs, anti-inflammatory agents, antitumor agents, anti-angiogeneic agents, pain relievers, local anesthetics, and chemotherapeutic agents.

[0096] In some embodiments, the formulation 12 may include one or more active ingredients. In some embodiments, the active ingredients may be selected from a group including but not limited to AFL, faricimab, suzetrigine, naltrexone, ketorolac, naphazoline, lidocaine, bupivacaine, bevacizumab, aflibercept (or a biosimilar thereof such as ALT-L9, MYL- 1701P (aflibercept-jbvf), SB 15 (aflibercept-yszy) , FYB203 (aflibercept-mrbb), SOK583A19 (aflibercept-abzv), ABP-938 (aflibercept-ayyh) , QL1207, P041, or CT-P42), pegaptanib, brimonidine, dorzolamide, azithromycin, rapamycin, bepotastine besilate, diclofenac, besifloxacin, cysteamine hydrochloride, fluocinolone acetonide, difluprednate, aflibercept, tasimelteon, ocriplasmin, enoxaparin sodium, ranibizumab, trastuzumab, rituximab, gentuzumab, ozagamicin, cetuximab, sorafenib, dasatinib, sunitinib, nilotinib, pazopanib, latanoprost, timolol, bimatoprost, pegaptanib, ofloxacin, cephazolin, phenylephrine, dexamethasone, triamcinolone acetonide, levofloxacin, cyclophosphamide, melphalan cyclosporine, methotrexate, azathioprine ketorolac, travoprost, verteporfin, tafluprost, ketotifen fumarate, foscarnet, amphotericin B, fluconazole, voriconazole, ganciclovir, acyclovir, gatifloxacin, vitamin (vitamin A, vitamin C, and vitamin E), zinc, copper, lutein, zeaxanthin, non-opioid analgesics (including but not limited to acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) including but not limited to ibuprofen), opioid analgesics (including but not limited to morphine, oxycodone), sodium channel blockers (including but not limited to suzetrigine, tetrodotoxin, saxitoxin, neosaxitoxin), adjuvant analgesics including but not limited to antidepressants (e.g., amitriptyline), anticonvulsants (e.g., gabapentin), muscle relaxants (e.g., cyclobenzaprine), corticosteroids (e.g., dexamethasone, prednisone), and / or local anesthetics (e.g., bupivacaine, ropivacaine) , any biosimilars thereof or combinations thereof.

[0097] In some embodiments, the active ingredients may be used for treating advanced neovascular age-related macular degeneration (AMD), retinopathy of prematurity (ROP), geographic atrophy (GA), neovascular age- related macular degeneration, retinal vein occlusion (RVO), age-related macular degeneration (AMO), pain, inflammation, cataracts, allergies, diabetic retinopathy (DR), macular edema, diabetic macular edema (DME), cytomegalovirus (CMV), retinitis, retinitis pigmentosa, uveitis, dry-eye syndrome, keratitis, glaucoma, blepharitis, blephariconjunctivtis, ocular hypertension, conjunctivitis, cystinosis, vitreomacular adhesion, corneal neovascularisation, corneal ulcers, post-surgical ocular inflammations, and post-surgical wounds. In some embodiments, the amount of the active agent in the formulation 12 may range from about 2% w / w to about 50% w / w, including any percentage or range comprised therein.

[0098] In some embodiments, the photoinitiator in the formulation 12 is capable of initiating crosslinking using visible light. In some embodiments, the photoinitiator is capable of initiating crosslinking of the crosslinkable macromer using light having a wavelength of 405 nm or about 405 nm. In some embodiments, the photoinitiator is capable of initiating crosslinking of the crosslinkable macromer using light having a wavelength of from about 200 nm to about 550 nm, from about 250 nm to about 550 nm, from about 300 nm to about 550 nm, from about 350 nm to about 550 nm, from about 400 nm to about 550 nm, from about 450 nm to about 550 nm, from about 500 nm to about 550 nm, or about any of the aforementioned ranges (e.g., from about 400 nm to 550 nm). In some embodiments, the photoinitiator is capable of initiating crosslinking of the crosslinkable macromer using light having a wavelength that is greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, or greater than about any of the aforementioned wavelengths (e.g., greater than about 400 nm), or greater than a range bounded by any of the aforementioned wavelengths or greater than a range of about any of the aforementioned wavelengths (e.g., greater than 300-350 nm or greater than about 300-350 nm).

[0099] In some embodiments, the photoinitiator in the formulation 12 is capable of initiating crosslinking at a wavelength in the range of about 380 nm to about 700 nm. In some embodiments, the photoinitiator is capable of initiating using light having a wavelength that is less than 700 nm, less than 650 nm, less than 600 nm, less than 550 nm, less than 500 nm, less than 450 nm, less than 400 nm, less than 350 nm, less than 300 nm, less than 250 nm, less than 200 nm, or less than about any of the aforementioned wavelengths (e.g., less than about 450 nm), or less than a range bounded by any of the aforementioned wavelengths or less than a range of about any of the aforementioned wavelengths (e.g., less than 450-500 nm or less than about 450- 500 nm).

[0100] In some embodiments, the operating algorithm may include controlling a rate of translation of the optical fiber 50’ through the fiber guide 90 into the needle 60. The optical fiber 50’ may be located within the central lumen of the needle 60, permitting the delivery of visible light for photo-curing the formulation 12. Such control of the location of the optical fiber 50’ ensures the optical fiber 50’ is not positioned in the therapeutic implant 16 when the therapeutic implant 16 is cured. In one embodiment, the optical fiber 50’ may move inside the needle 60 at the center of needle bevel during formulation 12 delivery. In some embodiments, the optical fiber 50’ may move inside the needle 60 after formulation 12 delivery. In one embodiment, the optical fiber 50’ speedmay be about 0.1 mm / s to about 2 mm / s, including any percentage or range comprised therein.

[0101] In some embodiments, the operating algorithm may include controlling the flow rate of the formulation 12. In one embodiment, the flow rate of the formulation 12 may be about 1 pL / s to about 20 pL / s, including any speed or range comprised therein. In one embodiment, the flow rate of the formulation 12 may be about 2 pL / s to about 4 pL / s, including any speed or range comprised therein.

[0102] In some embodiments, the operating algorithm may include controlling the intensity of the laser source 30 as a function of the position of the optical fiber 50’. In one embodiment, the intensity of the laser source 30 may depend on the size of the disposable unit 62.

[0103] In some embodiments, the operating algorithm may include controlling the laser current. In one embodiment, the laser current used may be about 10 mA to about 100 mA, including any current or range comprised therein,

[0104] In some embodiments, the time of curing or crosslinking of the formulation 12 may depend on the composition of the formulation 12, rate of delivery of the formulation 12, the intensity of the laser source 30, and / or the laser current. In some embodiments, the curing or crosslinking of the formulation 12 may be accomplished within about 1 second to about 10 minutes, including any time or range comprised therein. In some embodiments, the curing or crosslinking of the formulation 12 may be accomplished within about 1 second to about 5 seconds, about 5 seconds to about 10 seconds, about 10 seconds to about 15 seconds, about 15 seconds to about 20 seconds, about 20 seconds to about 25 seconds, about 25 seconds to about 30 seconds, about 30 seconds to about 35 seconds, about 35 seconds to about 40 seconds, about 40seconds to about 45 seconds, about 45 seconds to about 50 seconds, about 50 seconds to about 55 seconds, about 55 seconds to about 60 seconds, about 60 seconds to about 2 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 4 minutes, about 4 minutes to about 5 minutes, about 5 minutes to about 6 minutes, about 6 minutes to about 7 minutes, about 7 minutes to about 8 minutes, about 8 minutes to about 9 minutes, or about 9 minutes to about 10 minutes.

[0105] In some embodiments, the curing or crosslinking of the formulation 12 may be accomplished in less than 5 seconds, less than 10 seconds, less than 15 seconds, less than 20 seconds, less than 25 seconds, less than 30 seconds, less than 35 seconds, less than 40 seconds, less than 45 seconds, less than 50 seconds, less than 55 seconds, less than 1 minute, less than 2 minutes, less than 3 minutes, less than 4 minutes, less than 5 minutes, less than 6 minutes, less than 7 minutes, less than 8 minutes, less than 9 minutes, less than 10 minutes, or a range bounded by any of the aforementioned times or about any of the aforementioned times (e.g., less than 5-45 seconds, less than 5 seconds to 1 minute, less than about 5-45 seconds, less than about 5 seconds to 1 minute). In some embodiments, curing or cross-linking provides a matrix. In more preferred embodiments, curing or cross-linking provides a homogenous matrix.

[0106] In some embodiments, the therapeutic implant 16 may be formed within about 1 second to about 5 seconds, about 5 seconds to about 10 seconds, about 10 seconds to about 15 seconds, about 15 seconds to about 20 seconds, about 20 seconds to about 25 seconds, about 25 seconds to about 30 seconds, about 30 seconds to about 35 seconds, about 35 seconds to about 40 seconds, about 40 seconds to about 45 seconds, about 45 seconds to about 50 seconds, about 50 seconds to about 55 seconds, about 55 seconds to about 60 seconds,about 60 seconds to about 2 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 4 minutes, about 4 minutes to about 5 minutes, about 5 minutes to about 6 minutes, about 6 minutes to about 7 minutes, about 7 minutes to about 8 minutes, about 8 minutes to about 9 minutes, or about 9 minutes to about 10 minutes.

[0107] In some embodiments, the mass of the therapeutic implant 16 formed may range from about 5 mg to about 150mg, including any percentage or range comprised therein.

[0108] In one embodiment, the formulation 12 volume may range from about 5 piL to about 300 pL, including any volume or range comprised therein. In one embodiment, the formulation volume may range from about 5 pL to about 10 pL, about 10 pL to about 15 pL, about 15 pL to about 20 pL, about 20 pL to about 25 pL, or about 25 pL to about 30 pL.

[0109] In one embodiment, the formulation 12 delivery time may be about 1 second to about 300 seconds including any time or range comprised therein. In one embodiment, the lag time between formulation 12 delivery and the start of curing may be about 0 seconds to about 120 seconds, including any time or range comprised therein.

[0110] In some embodiments, the delivery rate of the formulation 12, laser power, and / or position of the optical fiber 50’ may vary during the course of formulation delivery. Such embodiments may be utilized to facilitate therapeutic implant 16 formation and detachment from the delivery needle 60.

[0111] While the disclosure has been illustrated and described in detail in the drawings and foregoing description, such an illustration and description is to be considered as exemplary and not restrictive in character, it being understood that only illustrative embodiments have been shown and describedand that all changes and modifications that come within the spirit of the disclosure are desired to be protected.

[0112] There is a plurality of advantages of the present disclosure arising from the various features of the devices and assemblies described herein. It will be noted that alternative embodiments of the devices and assemblies of the present disclosure may not include all of the features described yet still benefit from at least some of the advantages of such features. Those of ordinary skill in the art may readily devise their own implementations of the devices and assemblies that incorporate one or more of the features of the present invention and fall within the spirit and scope of the present disclosure as defined by the appended claims.

[0113] Example 1: Characterization of therapeutic implant formation

[0114] Table 1 characterizes the therapeutic implant formed based on shape of the therapeutic implant when using the applicator device 10.Table 1: Therapeutic implant shape rating

[0115] Example 2: Therapeutic implant formation using the applicator device and pPD48

[0116] Therapeutic implant formation was observed when a formulation of pPD48 containing 7.5 % w / w to 10 % w / w PLGA, 15% w / w Cryo OVA (Irg 819 1% w / w) was used in the applicator device 10. FIG. 12 illustrates the formation of a therapeutic implant 200 with 10 id of such formulation.

[0117] Example 3: Determination of Formulation Viscosity for effective use of applicator device

[0118] FIG. 13 illustrates the success rate of using the applicator device 10 with formulations of different viscosities. As illustrated, a formulation with a viscosity of less than about 6000 cP at 100 s1shear rate results in effective use of one embodiment of the applicator device 10.

[0119] Example 4: Therapeutic implant formation using the applicator device and pPD32

[0120] pPD32 (PEGDA-700:DTT macromer having prepared with a molar ratio of 1 mole PEGDA-700 to 0.32 mole DTT that has been purified to remove residual PEGDA to less than 0.5% w / w) has a much lower viscosity than pPD48. pPD32 has a viscosity of about 1800 cP and pPD48 viscosity has a viscosity of about 3200 cP. pPD32 was evaluated for therapeutic implant formation using the applicator device 10. FIG. 14A illustrates a therapeutic implant 202 (therapeutic implant score: 3; therapeutic implant mass: 14.2 mg) formed in phosphate buffered saline (“PBS”) with a formulation of pPD32 containing 7.5% PLGA, 15% ovalbumin as a model therapeutic (“OVA”), no Triacetin + 1% Irg 819. FIG. 14B illustrates a therapeutic implant 204 (therapeutic implant score: 3, 4; therapeutic implant mass: 14.6 mg) formed in PBS with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 2.5 % Triacetin + 1% Irg 819. FIG. 14Cillustrates a therapeutic implant 206 (therapeutic implant score: 4; therapeutic implant mass: 13 mg) formed in PBS with a formulation of pPD32 containing7.5% PLGA, 15% OVA, 5% Triacetin + 1% Irg 819. FIG. 14D illustrates a therapeutic implant 208 (therapeutic implant score: 5; therapeutic implant mass: 11.3 mg) formed in PBS with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 7.5% Triacetin + 1% Irg 819. FIG. 14E illustrates a therapeutic implant 210 (therapeutic implant score: 3, 4; therapeutic implant mass: 9.2 mg) formed in PBS with a formulation of pPD32 containing 8.8% PLGA, 15% OVA, 8.8% Triacetin + 1% Irg 819. FIG. 14F illustrates a therapeutic implant 212 (therapeutic implant score: 3, 4; therapeutic implant mass: 10.4 mg) formed in PBS with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 10% Triacetin + 1% Irg 819.

[0121] Spherical drug-loaded, pPD-based therapeutic implant were formed in Artificial Vitreous Humor (300 - 1900 cP) using the applicator device 10. FIG. 15A illustrates a therapeutic implant 214 formed in PBS with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 7.5% Triacetin + 1% Irg 819. FIG. 15B illustrates a therapeutic implant 216 formed in low viscosity artificial vitreous humor (300 cP) with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 8.8% Triacetin + 1% Irg 819. FIG. 15C illustrates a therapeutic implant 218 formed in high viscosity artificial vitreous humor (1900 cP) with a formulation of pPD32 containing 7.5% PLGA, 15% OVA, 10% Triacetin + 1% Irg 819.

[0122] Example 5: Therapeutic implant formation using dynamic operation of the applicator device

[0123] The formulation was injected at an applicator device injection speed of about 4 pL / second with a 405 nm laser operating at low power for about 2 seconds after the initiation of formulation delivery while the optical fiber is movedabout 1 mm beyond the tip of the needle of the applicator device. The laser power is increased to full power after all the formulation has been injected. FIG. 16B illustrates the syringe speed, the fiber speed, the laser current, and fiber position as a function of time. FIG. 16A illustrates the formation of a therapeutic implant 220. The wet mass of the therapeutic implant 220 formed was about 44.7 mg. FIG. 16B illustrates the syringe speed, the fiber speed, the laser current, and fiber position as a function of time.

[0124] The formulation was injected at an applicator device injection speed of about 4 pL / second with a 405 nm laser operating at low power for about 2 seconds after the initiation of formulation delivery while the optical fiber is moved about 2 mm beyond the tip of the needle of the applicator device. The laser power is increased to full power after all the formulation has been injected. FIG. 17B illustrates the syringe speed, the fiber speed, the laser current, and fiber position as a function of time. FIG. 17A illustrates the formation of a therapeutic implant 222. The wet mass of the therapeutic implant 222 formed was about 62.5 mg and the wet volume of the therapeutic implant 222 formed was about 53 gL. The therapeutic implant 222 had a dry mass of about 49.2 mg and a dry volume of about 49 gL. FIG. 17C shows the diameter of the wet therapeutic implant 222 measured using a Keyence microscope. FIG. 17D shows the change in the diameter of the therapeutic implant (depot diameter) as a function of the therapeutic implant volume (depot volume).

Claims

CLAIMS:

1. An applicator device comprising: a handheld applicator comprising: a disposable unit configured to deliver a formulation and a disposable optical fiber, a reusable fiber position control configured to control a position of the disposable optical fiber, a reusable fiber optics connection configured to direct an output from a laser source through the applicator device, and a reusable syringe plunger position control configured to control delivery of the formulation from a syringe located in the disposable unit.

2. The applicator device of claim 1, wherein the disposable unit comprises a fluid optic manifold that connects the disposable optical fiber to a fluid channel that is configured to supply the formulation.

3. The applicator device of claim 2, wherein the disposable unit comprises a fiber guide configured to direct a tip of the disposable optical fiber from a fiber inlet to an outlet.

4. The applicator device of claim 3, wherein the fluid channel and the fiber guide are joined at the outlet at a first end.

5. The applicator device of claim 1, wherein the disposable unit comprises a needle integrated with the disposable optical fiber and configured to flow the formulation to an implant site in an eye.

6. The applicator device of claim 1, wherein the reusable fiber optics connection comprises a fiber connector positioned in a carriage, the fiber connector configured to connect the disposable optical fiber to a reusable optical fiber and direct the output of the laser source to the disposable optical fiber in a needle of the disposable unit.

7. The applicator device of claim 6, wherein the disposable optical fiber is positioned in a fiber ferrule aligned with the fiber connector, and wherein the disposable optical fiber is configured to be movable forward and backward in the fiber ferrule.

8. The applicator device of claim 7, wherein the disposable unit comprises a fluid seal including a gap between a ferrule bore of the fiber ferrule and the disposable optical fiber, the gap sized to allow the disposable optical fiber to move, air to pass through, and prevent the formulation to pass through.

9. The applicator device of claim 1, wherein the reusable fiber position control is configured to control the position of the disposable optical fiber in a needle of the disposable unit, and wherein the reusable fiber position control comprises a non-captive motor configured to transfer linear motion through a connecting arm to a rod and then through a fiber movement fork to a spring in the disposable unit.

10. The applicator device of claim 1, wherein the reusable syringe plunger position control comprises a non-captive motor that is connected to a linear stage that is configured to push on a syringe plunger to control delivery of the formulation from the syringe.

11. The applicator device of claim 1, further comprising an electronics box connected to the handheld applicator via an umbilical tether.

12. The applicator device of claim 1, wherein the formulation has a viscosity less than about 7000 cP.

13. A method of treating an eye disease comprising: delivering a formulation through a needle in a handheld applicator to an eye; delivering a light through a disposable optical fiber in the handheld applicator to the formulation; curing the formulation by controlling an intensity of the light delivered through an optical fiber; and forming a therapeutic implant in the eye.

14. The method of claim 13 further comprising, controlling a delivery rate of the formulation and the optical fiber so that the therapeutic implant formed is generally spherical.

15. The method of claim 13, wherein the handheld applicator comprises a disposable unit configured to deliver the formulation and the disposable optical fiber.

16. The method of claim 15, wherein the handheld applicator comprises a reusable fiber position control configured to control a position of the disposable optical fiber, a reusable fiber optics connection configured to direct an output from a laser source through the handheld applicator, and a reusable syringe plunger position control configured to control delivery of the formulation from a syringe located in the disposable unit.

17. The method of claim 16, wherein the disposable unit comprises a fluid optic manifold that connects the disposable optical fiber to a fluid channel that is configured to supply the formulation.

18. The method of claim 17, wherein the disposable unit comprises a fiber guide configured to direct a tip of the optical fiber from a fiber inlet to an outlet.

19. The method of claim 18, wherein the fluid channel and the fiber guide are joined at the outlet at a first end.

20. The method of claim 15, wherein the disposable unit comprises the needle integrated with the disposable optical fiber and configured to flow the formulation to an implant site in the eye.

21. The method of claim 16, wherein the reusable fiber optics connection comprises a fiber connector positioned in a carriage, the fiber connector configured to connect the disposable optical fiber to a reusable opticalfiber and direct the output of the laser source to the disposable optical fiber in the needle.

22. The method of claim 21, wherein the optical fiber is positioned in a fiber ferrule aligned with the fiber connector, and wherein the optical fiber is configured to be movable forward and backward in the fiber ferrule.

23. The method of claim 22, wherein the disposable unit comprises a fluid seal including a gap between a ferrule bore of the fiber ferrule and the optical fiber, the gap sized to allow the optical fiber to move, air to pass through, and prevent the formulation to pass through.

24. The method of claim 16, wherein the reusable fiber position control is configured to control the position of the disposable optical fiber in the needle of the disposable unit, and wherein the reusable fiber position control comprises a non-captive motor configured to transfer linear motion through a connecting arm to a rod and then through a fiber movement fork to a spring in the disposable unit.

25. The method of claim 16, wherein the reusable syringe plunger position control comprises a non-captive motor that is connected to a linear stage that is configured to push on a syringe plunger to control delivery of the formulation from the syringe.

26. The method of claim 13, wherein the formulation has a viscosity of less than about 7000 cP.

27. The method of claim 13, wherein the therapeutic implant has a mass of about 5 mg to about 150 mg.

28. The method of claim 13, wherein the formulation comprises a curing agent.

29. The method of claim 13, wherein the therapeutic implant is formed within about 60 seconds.

30. A handheld applicator configured to deliver a formulation, comprising: a reusable fiber position control configured to control a position of a disposable optical fiber, a reusable fiber optics connection configured to direct an output from a laser source through the handheld applicator, and a reusable syringe plunger position control configured to control delivery of the formulation from a syringe located in the handheld applicator.

31. The handheld applicator of claim 30, further comprising a fluid optic manifold that connects the disposable optical fiber to a fluid channel that is configured to supply the formulation.

32. The handheld applicator of claim 31, further comprising a fiber guide configured to direct a tip of the disposable optical fiber from a fiber inlet to an outlet.

33. The handheld applicator of claim 32, wherein the fluid channel and the fiber guide are joined at the outlet at a first end.

34. The handheld applicator of claim 30, further comprising a needle integrated with the disposable optical fiber and configured to flow the formulation to an implant site in an eye.

35. The handheld applicator of claim 30, wherein the reusable fiber optics connection comprises a fiber connector positioned in a carriage, the fiber connector configured to connect the disposable optical fiber to a reusable optical fiber and direct the output of the laser source to the disposable optical fiber in a needle.

36. The handheld applicator of claim 35, wherein the disposable optical fiber is positioned in a fiber ferrule aligned with the fiber connector, and wherein the disposable optical fiber is configured to be movable forward and backward in the fiber ferrule.

37. The handheld applicator of claim 36, further comprising a fluid seal including a gap between a ferrule bore of the fiber ferrule and the disposable optical fiber, the gap sized to allow the disposable optical fiber to move, air to pass through, and prevent the formulation to pass through.

38. The handheld applicator of claim 30, wherein the reusable fiber position control is configured to control the position of the disposableoptical fiber in a needle of the handheld applicator, and wherein the reusable fiber position control comprises a non-captive motor configured to transfer linear motion through a connecting arm to a rod and then through a fiber movement fork to a spring in the handheld applicator.

39. The handheld applicator of claim 30, wherein the reusable syringe plunger position control comprises a non-captive motor that is connected to a linear stage that is configured to push on a syringe plunger to control delivery of the formulation from the syringe.

40. The handheld applicator of claim 30, wherein an electronics box is connected to the handheld applicator via an umbilical tether.

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