Thin multi-dose injection system and method

Abstract

To provide a suitable thin multi-medicament injection system and method.SOLUTION: A low-profile fluid injection system and method for injecting fluid into a tumor in a body comprising an elongate member, a plurality of fluid delivery members, and a plurality of fluid reservoirs. Each of the plurality of fluid reservoirs may be fluidly coupled to a single fluid delivery lumen of a single fluid delivery member such that each of the fluid delivery members is fluidly independent from all other fluid delivery members. The plurality of fluid delivery members may be configured to extend out of the distal end of the elongate member and into the tumor when the system is positioned within the body of the patient. A fluid delivery mechanism may be operably coupled to the plurality of fluid reservoirs for delivering fluid from the plurality of fluid reservoirs to the plurality of fluid delivery members and injecting the fluid into the tumor.SELECTED DRAWING: Figure 2

Description

[Background technology]

[0001] (cross reference) This application claims the benefit of U.S. Provisional Application No. 62 / 679,589, filed June 1, 2018, which is incorporated herein by reference in its entirety for all purposes.

[0002] (background) A fundamental problem in anticancer drug development is that antitumor efficacy in preclinical cancer models may not translate to efficacy in patients or patient outcomes. In many cases, drugs may be tested in preclinical in vitro or in vivo systems that cannot accurately represent clinical disease. In vitro cell culture-based systems, for example, often provide static, homogeneous testing conditions that cannot account for the effects of altering tumor microenvironment conditions or cellular heterogeneity. While in vivo animal model-based systems may provide slightly better translation to the clinic, their predictive utility is often hindered by differences in the tumor microenvironment (particularly genetic, molecular, immune, and cellular differences), varying growth conditions, and various other factors compared to clinical human tumors. Summary of the Invention [Problem to be solved by the invention]

[0003] (summary) Therefore, it would be desirable to provide improved methods, systems, and devices for testing drug candidates for efficacy in clinical tumors. Proposed embodiments of such systems may provide for in situ injection of one or more drug candidates into discrete, mapped locations of a clinical tumor for simultaneous assessment of the drug candidates in growing tumors in living subjects. The effect of the drug may be observed as a spatially defined tumor response following resection or biopsy of the injected tumor tissue. In this way, the efficacy of multiple drug candidates may be assessed directly in a clinical setting, which may lead to improved prediction of therapeutic response to systemic drug delivery.

[0004] Furthermore, it would also be desirable if improved methods, systems, and devices for drug candidate testing could reach subcutaneous tumors in a minimally invasive manner. Proposed embodiments of such systems may be compatible with existing non- or minimally invasive surgical access devices or introducers, such as, for example, biopsy instrumentation, laparoscopic instruments, intravascular catheters, or the like. Alternatively, or in combination, embodiments of such systems may be equipped with their own introducers to provide access to the tumor site of interest. The systems described herein may be configured to access superficial tumors and / or those tumors that are less accessible and / or located deeper inside the body.

[0005] It would also be desirable if improved methods, systems, and devices for drug candidate testing allowed for simplified loading of drug candidates. Proposed embodiments of such systems may include, for example, one or more cartridges containing one or more drug candidates therein. Each cartridge may be preloaded with a drug candidate and configured for insertion into a delivery system that delivers the drug candidate from the cartridge to a tumor site of interest.

[0006] At least some of these objectives will be met by the exemplary embodiments described below. Not necessarily all such aspects or advantages will be achieved by any particular embodiment. Thus, various embodiments may be implemented in a manner that achieves or optimizes one advantage or group of advantages taught herein without necessarily achieving other aspects or advantages that may also be taught or suggested herein.

[0007] The present disclosure relates generally to medical devices, systems, and methods, and more particularly to methods and apparatus used to inject one or more fluids, such as one or more drug candidates or combinations, into tissue. [Means for solving the problem]

[0008] An aspect of the present disclosure provides a fluid injection system. In some embodiments, the fluid injection system includes an elongate member having a proximal end and a distal end. In some embodiments, the elongate member includes an inner wall defining a lumen therein. In some embodiments, the fluid injection system includes a plurality of fluid delivery members. In some cases, the plurality of fluid delivery members are disposed within the lumen of the elongate member. In some cases, the plurality of fluid delivery members have a retracted configuration and an extended configuration. In some embodiments, the plurality of fluid delivery members are configured to extend out from the distal end of the elongate member in the extended configuration. In some embodiments, the plurality of fluid delivery members each include a distal end, a proximal end, an exit port at the distal end, and an inner wall defining a fluid delivery lumen therein. In some embodiments, the fluid delivery lumen is fluidly coupled to the exit port. In some embodiments, each fluid delivery lumen is fluidly independent from all other fluid delivery lumens of the plurality of fluid delivery members. In some embodiments, the fluid injection system includes a plurality of fluid delivery channels. In some embodiments, each of the multiple fluid delivery channels is fluidly coupled to one or more fluid delivery lumens of the multiple fluid delivery members. In some embodiments, a fluid delivery mechanism is operably coupled to the multiple fluid delivery channels, and actuation of the fluid delivery mechanism causes fluid to pass from the multiple fluid delivery channels to the multiple fluid delivery members and out the exit port.

[0009] In some embodiments, actuation of the fluid delivery mechanism is operably coupled to the plurality of fluid delivery members such that delivery of fluid occurs simultaneously with retraction of the fluid delivery members from the extended configuration to the retracted configuration. In some embodiments, the fluid delivery mechanism comprises a fluid delivery rod. In some embodiments, the plurality of fluid delivery members are configured to retract from the extended configuration to the retracted configuration simultaneously with fluid delivery from the fluid delivery members. In some embodiments, the plurality of fluid delivery members are configured to be fully enclosed within the lumen of the elongate member in the retracted configuration.

[0010] In some embodiments, the elongate member comprises a sheath, a hypotube shaft, or a needle. In some embodiments, the elongate member comprises a metal. In some embodiments, the elongate member comprises a flexible material. In some embodiments, the elongate member comprises a rigid material. In some embodiments, the elongate member has a length in a range of about 4 cm to about 250 cm. In some embodiments, the elongate member has a length in a range of about 4 cm to about 20 cm. In some embodiments, the elongate member has a length in a range of about 4 cm to about 20 cm. In some embodiments, the elongate member has a length in a range of about 100 cm to about 250 cm. In some embodiments, the elongate member has an outer diameter in a range of about 0.9 mm to about 3.5 mm. In some embodiments, the elongate member has an outer diameter in a range of about 2 mm to about 4 mm. In some embodiments, the elongate member has an outer diameter in a range of about 3 French to about 10 French. In some embodiments, the elongate member has an outer diameter sized to fit within a working channel of a conventional biopsy access needle, a conventional endoscope, or a conventional vascular access sheath. In some embodiments, the elongate member comprises a needle with a gauge number in the range of about 10 to about 20.

[0011] In some embodiments, the plurality of fluid delivery members comprises at least two fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises a plurality of needles or tubes. In some embodiments, the plurality of fluid delivery members comprises a plurality of pencil-tip needles, blunt-tip needles, or bevel-tip needles. In some embodiments, the plurality of fluid delivery members comprises a metal or plastic. In some embodiments, the plurality of fluid delivery members comprises a shape memory alloy. In some embodiments, the plurality of fluid delivery members comprises a flexible material. In some embodiments, the plurality of fluid delivery members comprises a rigid material. In some embodiments, each of the plurality of fluid delivery members has an outer diameter in the range of about 0.05 mm to about 0.50 mm. In some embodiments, each of the plurality of fluid delivery members has an outer diameter of about 0.25 mm. In some embodiments, each of the plurality of fluid delivery members is a needle with a gauge of about 28 to about 33. In some embodiments, each of the plurality of fluid delivery members is a needle with a gauge of about 31. In some embodiments, the fluid delivery lumens of the plurality of fluid delivery members each have a volume within a range of about 0.1 μl to about 10 μl. In some embodiments, the plurality of fluid delivery members each have a length extending from the distal end of the elongate member to the proximal end of the elongate member. In some embodiments, the plurality of fluid delivery members each have a length within a range of about 4 cm to about 250 cm. In some embodiments, the plurality of fluid delivery members each have a length extending out from the distal end of the elongate member in the extended configuration within a range of about 5 mm to about 40 mm. In some embodiments, the plurality of fluid delivery members each comprise at least one additional outlet port fluidly coupled to the fluid delivery lumen. In some embodiments, in the extended configuration, the plurality of fluid delivery members each angle away from the longitudinal axis of the elongate member. In some embodiments, the plurality of fluid delivery members each angle away from the longitudinal axis of the elongate member at an angle within a range of about 10° to about 90°.

[0012] In some embodiments, the distal end of the elongate member comprises an angle element positioned to guide the plurality of fluid delivery members and angle them away from the longitudinal axis of the elongate member in the extended configuration, hi some embodiments, in the extended configuration, each of the plurality of fluid delivery members is angled away from the longitudinal axis of the elongate member such that the distance between the distal ends of each of the plurality of fluid delivery members is within the range of about 1 mm to about 10 mm.

[0013] In some embodiments, the system further comprises a handle adjacent the proximal end of the elongate member.

[0014] In some embodiments, the system further comprises an actuator adjacent the proximal end of the elongate member and operably coupled to the plurality of fluid delivery members, wherein actuation of the actuator transitions the plurality of fluid delivery members from a retracted configuration to an extended configuration or from an extended configuration to a retracted configuration. In some embodiments, the actuator is configured to retract the plurality of fluid delivery members from the extended configuration to the retracted configuration at a rate in the range of about 0.1 mm / sec to about 10 mm / sec. In some embodiments, the actuator comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the actuator is manually operated. In some embodiments, the actuator is automatically operated.

[0015] In some embodiments, the fluid delivery mechanism is actuated by an actuator. In some embodiments, the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the fluid delivery mechanism comprises one or more of a plunger or a pump. In some embodiments, the fluid delivery mechanism is manually operated. In some embodiments, the fluid delivery mechanism is automatically operated. In some embodiments, the fluid delivery mechanism is configured to deliver fluid out of the outlet port at a flow rate in a range of about 0.1 μl / sec to about 10 μl / sec.

[0016] In some embodiments, the system is configured for fluid delivery from about 1 cm to about 300 cm below the skin surface. In some embodiments, the system is configured for fluid delivery from about 1 cm to about 30 cm below the skin surface. In some embodiments, the system is configured for fluid delivery from about 4 cm to about 20 cm below the skin surface. In some embodiments, the system is configured for fluid delivery from about 100 cm to about 250 cm below the skin surface.

[0017] In some embodiments, the plurality of fluid delivery channels comprises fluid delivery lumens of a plurality of fluid delivery members. In some embodiments, the fluid delivery lumens of the plurality of fluid delivery members are a plurality of fluid delivery channels. In some embodiments, the fluid delivery mechanism comprises a plurality of fluid delivery mechanisms, each of the plurality of fluid delivery mechanisms operably coupled to a single fluid delivery channel of the plurality of fluid delivery channels.

[0018] In some embodiments, the system further comprises an imaging system for perioperative imaging of the fluid injection system in use.

[0019] In some embodiments, the system further comprises one or more cartridges fluidly coupled to one or more of the fluid delivery lumens or one or more of the plurality of fluid delivery channels, hi some embodiments, each of the plurality of fluid delivery channels has a volume in the range of about 10 μl to about 500 μl.

[0020] In some embodiments, the system further comprises a population of fluorescent tracking microspheres (FTMs). In some embodiments, the fluorescent tracking microspheres have a diameter of between 5 micrometers and 10 micrometers. In some embodiments, the fluorescent tracking microspheres comprise polystyrene. In some embodiments, the system further comprises a plurality of populations of fluorescent tracking microspheres (FTMs).

[0021] In some embodiments, the system further comprises a volume selector.In some embodiments, the system further comprises a plurality of cartridges.

[0022] An aspect of the present disclosure provides a method of injecting fluids into a tumor in a patient's body, the method including: providing a fluid injection system comprising: an elongate member having a proximal end and a distal end; a plurality of fluid delivery members disposed within a lumen of the elongate member; and a plurality of fluid delivery channels, each fluid delivery channel being fluidly coupled to a single fluid delivery lumen of each of the plurality of fluid delivery members; inserting the distal end of the elongate member into the body with the plurality of fluid delivery members retracted; positioning the distal end of the elongate member in close proximity to the tumor with the plurality of fluid delivery members retracted; extending the plurality of fluid delivery members from the distal end of the elongate member into the tumor; and injecting a plurality of fluids into the tumor from the plurality of fluid delivery members, each of the plurality of fluid delivery members being fluidically independent of all other of the plurality of fluid delivery members.

[0023] In some embodiments, the method further includes retracting the plurality of fluid delivery members from the tumor into the distal end of the elongate member. In some embodiments, the retracting the plurality of fluid delivery members occurs concurrently with the injecting of the plurality of fluids. In some embodiments, the retracting the plurality of fluid delivery members includes retracting the plurality of fluid delivery members such that the plurality of fluid delivery members are fully enclosed within the lumen of the elongate member. In some embodiments, the retracting the plurality of fluid delivery members includes retracting the plurality of fluid delivery members at a rate in the range of about 0.1 mm / sec to about 10 mm / sec.

[0024] In some embodiments, the method further includes removing the distal end of the elongate member from the body with the plurality of fluid delivery members retracted. In some embodiments, the method further includes resecting at least a portion of the tumor for analysis. In some embodiments, the method further includes loading a plurality of fluids into the plurality of fluid delivery channels prior to inserting the distal end of the elongate member into the body. In some embodiments, the method further includes imaging the fluid injection system before and after surgery.

[0025] In some embodiments, the elongate member comprises a sheath, a hypotube shaft, or a needle. In some embodiments, the elongate member comprises a metal. In some embodiments, the elongate member comprises a flexible material. In some embodiments, the elongate member comprises a rigid material. In some embodiments, the elongate member has an outer diameter in the range of about 0.9 mm to about 3.5 mm. In some embodiments, the elongate member comprises a needle with a gauge in the range of about 10 to about 20.

[0026] In some embodiments, inserting the distal end of the elongate member into the body includes inserting the distal end of the elongate member into a working channel of a conventional biopsy access needle, a conventional endoscope, or a conventional vascular access sheath that is pre-positioned within the body.

[0027] In some embodiments, the plurality of fluid delivery members comprises at least two fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. In some embodiments, the plurality of fluid delivery members comprises a plurality of needles or tubes. In some embodiments, the plurality of fluid delivery members comprises a metal or plastic. In some embodiments, the plurality of fluid delivery members comprises a shape memory alloy. In some embodiments, the plurality of fluid delivery members comprises a flexible material. In some embodiments, the plurality of fluid delivery members comprises a rigid material. In some embodiments, each of the plurality of fluid delivery members has an outer diameter of about 0.05 mm to about 0.50 mm. In some embodiments, each of the plurality of fluid delivery members is a needle with a gauge number of about 28 to about 33.

[0028] In some embodiments, injecting the plurality of fluids comprises injecting the plurality of fluids at a flow rate in the range of about 0.1 μl / sec to about 10 μl / sec, hi some embodiments, injecting the plurality of fluids comprises injecting a volume of each of the plurality of fluids from each of the plurality of fluid delivery members in the range of about 10 μl to about 500 μl.

[0029] In some embodiments, each of the plurality of fluid delivery members has a length extending from the distal end of the elongate member to the proximal end of the elongate member, hi some embodiments, each of the plurality of fluid delivery members has a length in the range of about 4 cm to about 250 cm.

[0030] In some embodiments, extending the plurality of fluid delivery members comprises extending a length of each of the plurality of fluid delivery members from the distal end of the elongate member into the tumor within a range of about 5 mm to about 40 mm. In some embodiments, extending the plurality of fluid delivery members comprises extending the plurality of fluid delivery members from the distal end of the elongate member such that the plurality of fluid delivery members are angled away from a longitudinal axis of the elongate member.

[0031] In some embodiments, the distal end of the elongate member comprises an angle element positioned to guide the plurality of fluid delivery members and angle them away from the longitudinal axis of the elongate member in the extended configuration.

[0032] In some embodiments, injecting multiple fluids comprises creating multiple distinct fluid columns within the tumor.

[0033] In some embodiments, the fluid injection system used in the method further comprises a handle having a fluid delivery mechanism thereon, the fluid delivery mechanism operably coupled to the plurality of fluid delivery channels, and injecting the plurality of fluids comprises actuating the fluid delivery mechanism. In some embodiments, the fluid delivery mechanism comprises manually actuating the fluid delivery mechanism. In some embodiments, actuating the fluid delivery mechanism comprises automatically actuating the fluid delivery mechanism. In some embodiments, the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the fluid delivery mechanism comprises one or more of a plunger or a pump. In some embodiments, the fluid injection system further comprises an actuator adjacent a proximal end of the extension member and operably coupled to the plurality of fluid delivery members. In some embodiments, extending the plurality of fluid delivery members comprises actuating the actuator.

[0034] In some embodiments, activating the actuator comprises manually activating the actuator. In some embodiments, injecting the plurality of fluids comprises activating the actuator. In some embodiments, activating the actuator comprises automatically activating the actuator. In some embodiments, the actuator comprises a mechanical actuator or an electromechanical actuator. In some embodiments, the actuator comprises one or more of a thumbwheel or an electric actuator. In some embodiments, injecting the plurality of fluids comprises injecting the plurality of fluids from about 0.2 cm to about 20 cm below the skin surface. In some embodiments, injecting the plurality of fluids comprises injecting the plurality of fluids from about 1 cm to about 30 cm below the skin surface. In some embodiments, injecting the plurality of fluids comprises injecting the plurality of fluids from about 4 cm to about 20 cm below the skin surface. In some embodiments, injecting the plurality of fluids comprises injecting the plurality of fluids from about 100 cm to about 250 cm below the skin surface. In some embodiments, the plurality of fluids comprises one or more therapeutic agents. In some embodiments, injecting a plurality of fluids comprises injecting a different fluid into the tumor from each of a plurality of fluid delivery members. In some embodiments, injecting a plurality of fluids comprises injecting the same fluid into the tumor from each of a plurality of fluid delivery members. In some embodiments, the tumor is located within the patient's skin, breast, brain, prostate, colon, rectum, kidney, pancreas, lung, liver, heart, stomach, intestine, ovary, testicle, cervix, lymph node, thyroid, esophagus, head or neck, eye, bone, or bladder. In some embodiments, the plurality of fluids comprises a population of fluorescent tracking microspheres (FTMs). In some embodiments, the plurality of fluids comprises a plurality of populations of fluorescent tracking microspheres. (Incorporated by reference)

[0035] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0036] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description and accompanying drawings that set forth illustrative embodiments, in which the principles of the disclosure are utilized. The present invention provides, for example, the following. (Item 1) 1. A fluid injection system comprising: an elongate member having a proximal end and a distal end, the elongate member including an inner wall defining a lumen therein; a plurality of fluid delivery members disposed within the lumen of the elongate member, the plurality of fluid delivery members having a retracted configuration and an extended configuration, the plurality of fluid delivery members configured to extend out of the distal end of the elongate member in the extended configuration; each of the plurality of fluid delivery members comprising a distal end, a proximal end, an exit port at the distal end, and an interior wall defining a fluid delivery lumen therein, the fluid delivery lumen being fluidly coupled to the exit port; each of the fluid delivery lumens being fluidly independent from all other fluid delivery lumens of the plurality of fluid delivery members; a plurality of fluid delivery members; a plurality of fluid delivery channels, each of the plurality of fluid delivery channels fluidly coupled to one or more fluid delivery lumens of the plurality of fluid delivery members; a fluid delivery mechanism operably coupled to the plurality of fluid delivery channels, actuation of the fluid delivery mechanism causing fluid to pass from the plurality of fluid delivery channels to the plurality of fluid delivery members and out the outlet port; A system comprising: (Item 2) Item 10. The system of item 1, wherein actuation of the fluid delivery mechanism is operably coupled to the plurality of fluid delivery members such that delivery of fluid occurs simultaneously with retraction of the fluid delivery members from the extended configuration to the retracted configuration. (Item 3) 3. The system of claim 1, wherein the fluid delivery mechanism comprises a fluid delivery rod. (Item 4) Item 10. The system of item 1, wherein the plurality of fluid delivery members are configured to retract from the extended configuration to the retracted configuration simultaneously with fluid delivery from the fluid delivery members. (Item 5) 5. The system of any one of items 1-4, wherein the plurality of fluid delivery members are configured to be completely enclosed within the lumen of the elongate member in the retracted configuration. (Item 6) 6. The system of any one of items 1-5, wherein the elongate member comprises a sheath, a hypotube shaft, or a needle. (Item 7) 7. The system of any one of claims 1-6, wherein the elongated member comprises a metal. (Item 8) 8. The system of any one of claims 1-7, wherein the elongated member comprises a flexible material. (Item 9) 9. The system of any one of claims 1-8, wherein the elongated member comprises a rigid material. (Item 10) 10. The system of any one of items 1-9, wherein the extension member has a length in the range of about 4 cm to about 250 cm. (Item 11) Item 11. The system of item 10, wherein the extension member has a length in the range of about 4 cm to about 20 cm. (Item 12) Item 11. The system of item 10, wherein the extension member has a length in the range of about 100 cm to about 250 cm. (Item 13) 13. The system of any one of items 1-12, wherein the elongate member has an outer diameter in the range of about 0.9 mm to about 3.5 mm. (Item 14) Item 14. The system of item 13, wherein the elongate member has an outer diameter in the range of about 2 mm to about 4 mm. (Item 15) 15. The system of any one of claims 1-14, wherein the elongated member has an outer diameter within a range of about 3 French to about 10 French. (Item 16) 16. The system of any one of items 1-15, wherein the elongate member has an outer diameter sized to fit within a working channel of a conventional biopsy access needle, a conventional endoscope, or a conventional vascular access sheath. (Item 17) 17. The system of any one of items 1-16, wherein the elongate member comprises a needle with a gauge number in the range of about 10 to about 20. (Item 18) 18. The system of any one of items 1-17, wherein the plurality of fluid delivery members comprises at least two fluid delivery members. (Item 19) Item 19. The system of item 18, wherein the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. (Item 20) 20. The system of any one of items 1-19, wherein the plurality of fluid delivery members comprises a plurality of needles or tubes. (Item 21) 21. The system of any one of items 1-20, wherein the plurality of fluid delivery members comprises a plurality of pencil-tip needles, blunt-tip needles, or bevel-tip needles. (Item 22) 22. The system of any one of items 1-21, wherein the plurality of fluid delivery members comprises metal or plastic. (Item 23) 23. The system of any one of claims 1-22, wherein the plurality of fluid delivery members comprises a shape memory alloy. (Item 24) 24. The system of any one of claims 1-23, wherein the plurality of fluid delivery members comprises a flexible material. (Item 25) 25. The system of any one of claims 1-24, wherein the plurality of fluid delivery members comprises a rigid material. (Item 26) 26. The system of any one of items 1-25, wherein each of the plurality of fluid delivery members has an outer diameter in the range of about 0.05 mm to about 0.50 mm. (Item 27) Item 27. The system of item 26, wherein each of the plurality of fluid delivery members has an outer diameter of about 0.25 mm. (Item 28) 28. The system of any one of items 1-27, wherein each of the plurality of fluid delivery members is a needle with a gauge number of about 28 to about 33. (Item 29) Item 29. The system of item 28, wherein each of the plurality of fluid delivery members is a needle with a gauge number of about 31. (Item 30) 30. The system of any one of items 1-29, wherein the fluid delivery lumens of the plurality of fluid delivery members each have a volume in the range of about 0.1 μl to about 10 μl. (Item 31) 31. The system of any one of items 1-30, wherein each of the plurality of fluid delivery members has a length extending from a distal end of the elongate member to a proximal end of the elongate member. (Item 32) 32. The system of any one of items 1-31, wherein each of the plurality of fluid delivery members has a length in the range of about 4 cm to about 250 cm. (Item 33) 33. The system of any one of items 1-32, wherein each of the plurality of fluid delivery members has a length extending out from the distal end of the elongate member in the extended configuration in the range of about 5 mm to about 40 mm. (Item 34) Item 34. The system of any one of items 1-33, wherein each of the plurality of fluid delivery members comprises at least one additional outlet port fluidly coupled to the fluid delivery lumen. (Item 35) 35. The system of any one of claims 1-34, wherein in the extended configuration, each of the plurality of fluid delivery members is angled away from the longitudinal axis of the elongate member. (Item 36) Item 36. The system of item 35, wherein each of the plurality of fluid delivery members is angled away from the longitudinal axis of the elongate member at an angle in the range of about 10° to about 90°. (Item 37) 37. The system of any one of items 1-36, wherein the distal end of the elongate member comprises an angle element positioned to guide the plurality of fluid delivery members and angle them away from the longitudinal axis of the elongate member in the extended configuration. (Item 38) 38. The system of any one of items 1-37, wherein in the extended configuration, each of the plurality of fluid delivery members is angled away from the longitudinal axis of the elongated member such that the distance between the distal ends of each of the plurality of fluid delivery members is within a range of about 1 mm to about 10 mm. (Item 39) Item 39. The system of any one of items 1-38, further comprising a handle adjacent the proximal end of the elongate member. (Item 40) 40. The system of any one of items 1-39, further comprising an actuator adjacent a proximal end of the elongate member and operably coupled to the plurality of fluid delivery members, wherein actuation of the actuator transitions the plurality of fluid delivery members from the retracted configuration to the extended configuration or from the extended configuration to the retracted configuration. (Item 41) Item 41. The system of item 40, wherein the actuator is configured to retract the plurality of fluid delivery members from the extended configuration to the retracted configuration at a rate in a range of about 0.1 mm / sec to about 10 mm / sec. (Item 42) Item 41. The system of item 40, wherein the actuator comprises a mechanical actuator or an electromechanical actuator. (Item 43) Item 41. The system of item 40, wherein the actuator is manually operated. (Item 44) Item 41. The system of item 40, wherein the actuator is automatically operated. (Item 45) Item 41. The system of item 40, wherein the fluid delivery mechanism is actuated by the actuator. (Item 46) 46. ​​The system of any one of claims 1-45, wherein the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. (Item 47) 47. The system of any one of items 1-46, wherein the fluid delivery mechanism comprises one or more of a plunger or a pump. (Item 48) Item 48. The system of any one of items 1-47, wherein the fluid delivery mechanism is manually operated. (Item 49) Item 49. The system of any one of items 1-48, wherein the fluid delivery mechanism is automatically operated. (Item 50) 50. The system of any one of items 1-49, wherein the fluid delivery mechanism is configured to deliver fluid out of the outlet port at a flow rate in the range of about 0.1 μl / sec to about 10 μl / sec. (Item 51) 51. The system of any one of items 1-50, wherein the system is configured for fluid delivery from about 1 cm to about 300 cm below the skin surface. (Item 52) Item 52. The system of item 51, wherein the system is configured for fluid delivery from about 1 cm to about 30 cm below the skin surface. (Item 53) Item 52. The system of item 51, wherein the system is configured for fluid delivery from about 4 cm to about 20 cm below the skin surface. (Item 54) Item 52. The system of item 51, wherein the system is configured for fluid delivery from about 100 cm to about 250 cm below the skin surface. (Item 55) 55. The system of any one of items 1-54, wherein the plurality of fluid delivery channels comprise fluid delivery lumens of the plurality of fluid delivery members. (Item 56) Item 56. The system of item 55, wherein the fluid delivery lumens of the plurality of fluid delivery members are the plurality of fluid delivery channels. (Item 57) 57. The system of any one of items 1-56, wherein the fluid delivery mechanism comprises a plurality of fluid delivery mechanisms, each of the plurality of fluid delivery mechanisms operably coupled to a single fluid delivery channel of the plurality of fluid delivery channels. (Item 58) 58. The system of any one of items 1-57, further comprising an imaging system for perioperative imaging of the fluid injection system in use. (Item 59) 59. The system of any one of items 1-58, further comprising one or more cartridges fluidly coupled to one or more of the fluid delivery lumens or one or more of the plurality of fluid delivery channels. (Item 60) 60. The system of any one of items 1-59, wherein each of the plurality of fluid delivery channels has a volume in the range of about 10 μl to about 500 μl. (Item 61) 61. The system of any one of items 1-60, further comprising a population of fluorescent tracking microspheres (FTM). (Item 62) Item 62. The system of item 61, wherein the fluorescent tracking microspheres have a diameter of 5 micrometers to 10 micrometers. (Item 63) 63. The system of claim 61 or 62, wherein the fluorescent tracking microspheres comprise polystyrene. (Item 64) 64. The system of any one of items 1-63, further comprising a plurality of populations of fluorescent tracking microspheres (FTM). (Item 65) 65. The system of any one of items 1-64, further comprising a volume selector. (Item 66) Item 67. The system of any one of items 1-65, further comprising a plurality of cartridges. 1. A method of injecting a fluid into a tumor in a patient's body, the method comprising: providing a fluid injection system comprising: an elongate member having a proximal end and a distal end; a plurality of fluid delivery members disposed within a lumen of the elongate member; and a plurality of fluid delivery channels, each of the plurality of fluid delivery channels fluidly coupled to a single fluid delivery lumen of each of the plurality of fluid delivery members; inserting a distal end of the elongate member into the body with the plurality of fluid delivery members retracted; positioning the distal end of the elongate member in close proximity to the tumor with the plurality of fluid delivery members retracted; extending the plurality of fluid delivery members from a distal end of the elongate member into the tumor; injecting a plurality of fluids into the tumor from the plurality of fluid delivery members, each of the plurality of fluid delivery members being fluidically independent of every other of the plurality of fluid delivery members; A method comprising: (Item 68) Item 68. The method of item 67, further comprising retracting the plurality of fluid delivery members from the tumor into the distal end of the elongate member. (Item 69) Item 69. The method of item 68, wherein retracting the plurality of fluid delivery members occurs concurrently with injecting the plurality of fluids. (Item 70) Item 69. The method of item 68, wherein retracting the plurality of fluid delivery members comprises retracting the plurality of fluid delivery members such that the plurality of fluid delivery members are fully enclosed within the lumen of the elongate member. (Item 71) Item 69. The method of item 68, wherein retracting the plurality of fluid delivery members comprises retracting the plurality of fluid delivery members at a rate in the range of about 0.1 mm / sec to about 10 mm / sec. (Item 72) 72. The method of any one of items 61-71, further comprising removing the distal end of the elongate member from the body with the plurality of fluid delivery members retracted. (Item 73) 73. The method of any one of items 61-72, further comprising excising at least a portion of the tumor for analysis. (Item 74) 74. The method of any one of claims 61-73, further comprising loading the plurality of fluids into the plurality of fluid delivery channels prior to inserting the distal end of the elongate member into the body. (Item 75) 75. The method of any one of items 61-74, further comprising imaging the fluid injection system before and after surgery. (Item 76) 76. The method of any one of items 61-75, wherein the elongate member comprises a sheath, a hypotube shaft, or a needle. (Item 77) 77. The method of any one of items 61-76, wherein the elongate member comprises a metal. (Item 78) 78. The method of any one of items 61-77, wherein the elongate member comprises a flexible material. (Item 79) 79. The method of any one of items 61-78, wherein the elongated member comprises a rigid material. (Item 80) 80. The method of any one of items 61-79, wherein the elongate member has an outer diameter in the range of about 0.9 mm to about 3.5 mm. (Item 81) 81. The method of any one of items 61-80, wherein the elongate member comprises a needle with a gauge number in the range of about 10 to about 20. (Item 82) 82. The method of any one of items 61-81, wherein inserting the distal end of the elongate member into the body comprises inserting the distal end of the elongate member into a working channel of a conventional biopsy access needle, a conventional endoscope, or a conventional vascular access sheath that is pre-positioned within the body. (Item 83) 83. The method of any one of items 61-82, wherein the plurality of fluid delivery members comprises at least two fluid delivery members. (Item 84) Item 84. The method of item 83, wherein the plurality of fluid delivery members comprises 2 to 20 fluid delivery members. (Item 85) 85. The method of any one of items 61-84, wherein the plurality of fluid delivery members comprises a plurality of needles or tubes. (Item 86) 86. The method of any one of items 61-85, wherein the plurality of fluid delivery members comprises metal or plastic. (Item 87) 87. The method of any one of items 61-86, wherein the plurality of fluid delivery members comprises a shape memory alloy. (Item 88) 88. The method of any one of items 61-87, wherein the plurality of fluid delivery members comprises a flexible material. (Item 89) 89. The method of any one of items 61-88, wherein the plurality of fluid delivery members comprises a rigid material. (Item 90) Item 89. The method of any one of items 61-89, wherein each of the plurality of fluid delivery members has an outer diameter of about 0.05 mm to about 0.50 mm. (Item 91) 91. The method of any one of items 61-90, wherein each of the plurality of fluid delivery members is a needle with a gauge number of about 28 to about 33. (Item 92) Item 93. The method of any one of Items 61-91, wherein injecting the plurality of fluids comprises injecting the plurality of fluids at a flow rate within a range of about 0.1 μL / sec to about 10 μL / sec. 93. The method of any one of items 61-92, wherein injecting the plurality of fluids comprises injecting a volume of each of the plurality of fluids from each of the plurality of fluid delivery members in a range of about 10 μl to about 500 μl. (Item 94) Item 94. The method of any one of items 61-93, wherein each of the plurality of fluid delivery members has a length extending from a distal end of the elongate member to a proximal end of the elongate member. (Item 95) Item 95. The method of any one of items 61-94, wherein each of the plurality of fluid delivery members has a length in the range of about 4 cm to about 250 cm. (Item 96) 96. The method of any one of items 61-95, wherein extending the plurality of fluid delivery members comprises extending a length of each of the plurality of fluid delivery members from the distal end of the elongated member into the tumor within a range of about 5 mm to about 40 mm. (Item 97) Item 97. The method of any one of items 61-96, wherein extending the plurality of fluid delivery members comprises extending the plurality of fluid delivery members from a distal end of the elongate member such that the plurality of fluid delivery members are angled away from a longitudinal axis of the elongate member. (Item 98) Item 68. The method of any one of items 61-97, wherein the distal end of the elongate member comprises an angle element positioned to guide the plurality of fluid delivery members and angle them away from the longitudinal axis of the elongate member in the extended configuration. (Item 99) 99. The method of any one of items 61-98, wherein injecting the plurality of fluids comprises creating a plurality of distinct fluid columns within the tumor. (Item 100) 99. The method of claim 68, wherein the fluid injection system further comprises a handle having a fluid delivery mechanism thereon, the fluid delivery mechanism operably coupled to the plurality of fluid delivery channels, and wherein injecting the plurality of fluids comprises actuating the fluid delivery mechanism. (Item 101) Item 101. The method of item 100, wherein actuating the fluid delivery mechanism comprises manually actuating the fluid delivery mechanism. (Item 102) Item 101. The method of item 100, wherein activating the fluid delivery mechanism includes automatically activating the fluid delivery mechanism. (Item 103) Item 101. The method of item 100, wherein the fluid delivery mechanism comprises a mechanical actuator or an electromechanical actuator. (Item 104) Item 101. The method of item 100, wherein the fluid delivery mechanism comprises one or more of a plunger or a pump. (Item 105) Item 61-104. The method of any one of items 61-104, wherein the fluid injection system further comprises an actuator adjacent to a proximal end of the elongated member and operably coupled to the plurality of fluid delivery members, and extending the plurality of fluid delivery members comprises actuating the actuator. (Item 106) Item 106. The method of item 105, wherein actuating the actuator includes manually actuating the actuator. (Item 107) Item 106. The method of item 105, wherein injecting the plurality of fluids includes actuating the actuator. (Item 108) Item 106. The method of item 105, wherein activating the actuator includes automatically activating the actuator. (Item 109) Item 106. The method of item 105, wherein the actuator comprises a mechanical actuator or an electromechanical actuator. (Item 110) Item 106. The method of item 105, wherein the actuator comprises one or more of a thumbwheel or an electric actuator. (Item 111) 111. The method of any one of items 61-110, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 0.2 cm to about 20 cm below the skin surface. (Item 112) Item 112. The method according to item 111, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 1 cm to about 30 cm below the skin surface. (Item 113) Item 112. The method according to item 111, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 4 cm to about 20 cm below the skin surface. (Item 114) Item 112. The method according to item 111, wherein injecting the plurality of fluids comprises injecting the plurality of fluids from about 100 cm to about 250 cm below the skin surface. (Item 115) 115. The method of any one of items 61-114, wherein the plurality of fluids comprises one or more therapeutic agents. (Item 116) Item 117. The method of any one of items 61-115, wherein injecting the plurality of fluids comprises injecting a different fluid into the tumor from each of the plurality of fluid delivery members. 117. The method of any one of items 61-116, wherein injecting the plurality of fluids comprises injecting the same fluid into the tumor from each of the plurality of fluid delivery members. (Item 118) 118. The method of any one of paragraphs 61-117, wherein the tumor is located in the patient's skin, breast, brain, prostate, colon, rectum, kidney, pancreas, lung, liver, heart, stomach, intestine, ovary, testicle, cervix, lymph node, thyroid, esophagus, head or neck, eye, bone, or bladder. (Item 119) 119. The method of any one of items 61-118, wherein the plurality of fluids comprises a population of fluorescent tracking microspheres (FTM). (Item 120) 119. The method of any one of items 67-119, wherein the plurality of fluids comprises a plurality of populations of fluorescent tracking microspheres. [Brief explanation of the drawings]

[0037] [Figure 1] FIG. 1 shows a schematic diagram of a low-profile fluid injection system, according to an embodiment.

[0038] [Figure 2] FIG. 2 shows a schematic diagram of a low-profile fluid injection system with an extended delivery member, according to an embodiment.

[0039] [Figure 3] FIG. 3 shows a schematic diagram of a low-profile fluid injection system, according to an embodiment.

[0040] [Figure 4A] FIG. 4A shows a schematic diagram of a portion of a low-profile fluid injection system and cartridge, according to an embodiment.

[0041] [Figure 4B] FIG. 4B shows a schematic diagram illustrating loading of a low-profile fluid injection system with a cartridge, according to an embodiment.

[0042] [Figure 5A] FIG. 5A shows a schematic diagram of a low-profile fluid injection system, according to an embodiment.

[0043] [Figure 5B] FIG. 5B shows a schematic diagram of a low-profile fluid injection system with an extended delivery member, according to an embodiment.

[0044] [Figure 5C] FIG. 5C shows a schematic diagram of a portion of the low-profile fluid injection system shown in FIG. 5B, according to an embodiment.

[0045] [Figure 6A] FIG. 6A shows a schematic diagram of a low-profile fluid injection system, according to an embodiment.

[0046] [Figure 6B] FIG. 6B illustrates a portion of the low-profile fluid injection system shown in FIG. 6A, according to an embodiment.

[0047] [Figure 7]FIG. 7 shows an image of the internal workings of a low-profile fluid injection system, according to an embodiment.

[0048] [Figure 8] FIG. 8 shows a schematic diagram of a low-profile fluid injection system, according to an embodiment.

[0049] [Figure 9] FIG. 9 illustrates a cross-sectional view of an elongate member of a low-profile fluid injection system, according to an embodiment.

[0050] [Figure 10A] FIG. 10A shows a schematic diagram of a low-profile fluid injection system with a fluid delivery member in an unextended configuration, according to an embodiment.

[0051] [Figure 10B] FIG. 10B shows the system of FIG. 10A with a fluid delivery member in an extended configuration, according to an embodiment.

[0052] [Figure 11A] FIG. 11A shows an exemplary elongate member with a fluid delivery member in an unextended configuration, according to an embodiment.

[0053] [Figure 11B] FIG. 11B illustrates an exemplary elongate member with a fluid delivery member in an extended configuration, according to an embodiment.

[0054] [Figure 12A] FIG. 12A shows a distal end of an exemplary elongated member with a fluid delivery member in an unextended configuration, according to an embodiment.

[0055] [Figure 12B] FIG. 12B illustrates a distal end of an exemplary elongate member with a fluid delivery member in an extended configuration, according to an embodiment.

[0056] [Figure 13A]FIG. 13A shows a schematic representation of a target tissue following injection with a low-profile fluid injection system, depicted in cross section perpendicular to the longitudinal axis of the system, according to an embodiment.

[0057] [Figure 13B] FIG. 13B shows a perspective view of an injection column within a target tissue following injection with a low-profile fluid injection system, according to an embodiment.

[0058] [Figure 13C] FIG. 13C shows a perspective view of an injection column within a target tissue following injection with a low-profile fluid injection system, according to an embodiment.

[0059] [Figure 14] FIG. 14 shows a schematic diagram of a low-profile fluid injection system with a fluid delivery member extended inside a target tissue, according to an embodiment.

[0060] [Figure 15A] FIG. 15A shows an exemplary low-profile fluid injection system with a fluid delivery member in an unextended configuration inside a simulated target tissue, according to an embodiment.

[0061] [Figure 15B] FIG. 15B illustrates the exemplary system of FIG. 15A with a fluid delivery member extended into a simulated target tissue, according to an embodiment.

[0062] [Figure 15C] FIG. 15C shows the system of FIG. 15A during fluid injection into a simulated target tissue and simultaneous retraction of the fluid delivery member, according to an embodiment.

[0063] [Figure 16A] FIG. 16A shows a schematic diagram of a low-profile fluid injection system prior to fluid injection with a fluid delivery member in an unextended configuration, according to an embodiment.

[0064] [Figure 16B]FIG. 16B shows a schematic diagram of a low-profile fluid injection system prior to fluid injection with a fluid delivery member in an extended configuration, according to an embodiment.

[0065] [Figure 16C] FIG. 16C shows a schematic diagram of a low-profile fluid injection system after fluid injection with a fluid delivery member in an unextended configuration, according to an embodiment.

[0066] [Figure 16D] FIG. 16D shows a schematic diagram of a low-profile fluid injection system prior to fluid injection with a fluid delivery member in an extended configuration, according to an embodiment.

[0067] [Figure 16E] FIG. 16E shows the system of FIG. 16D after simultaneous fluid injection and retraction of the fluid delivery member, according to an embodiment.

[0068] [Figure 17] FIG. 17 shows exemplary steps of a method for injecting fluid into a tumor in a subject's body using a fluid injection system, according to an embodiment.

[0069] [Figure 18A] FIG. 18A shows an image of a low-profile fluid injection system with a volume selector, according to an embodiment.

[0070] [Figure 18B] FIG. 18B shows an image of a volume selector, according to an embodiment.

[0071] [Figure 19A] FIG. 19A shows a schematic diagram of a low-profile fluid injection system with a tip cap, according to an embodiment.

[0072] [Figure 19B] FIG. 19B shows a schematic diagram of a tip cap, according to an embodiment.

[0073] [Figure 20A]FIG. 20A shows a cartridge, according to an embodiment.

[0074] [Figure 20B] FIG. 20B shows a cartridge, according to an embodiment.

[0075] [Figure 21] 21A-21D show methods for delivering and detecting one or more agents in a target tissue, according to embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0076] (Detailed explanation) In the following detailed description, reference is made to the accompanying drawings, which form a part of this specification. In the figures, like symbols typically identify like components unless context dictates otherwise. The illustrative embodiments described in the detailed description, the figures, and the claims are not intended to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the scope of the subject matter presented herein. In general, it will be readily understood that aspects of the present disclosure as described herein and illustrated in the drawings can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated herein.

[0077] Although certain embodiments and examples are disclosed below, the inventive subject matter extends beyond the specifically disclosed embodiments to other alternative embodiments and / or applications, as well as modifications and equivalents thereof. Accordingly, the scope of the claims appended hereto is not limited by any of the specific embodiments described below. For example, in any method or process disclosed herein, the acts or operations of the method or process may be performed in any suitable order and are not necessarily limited to any particular disclosed order. Various operations may, in turn, be described as multiple discrete operations in a manner that may be helpful in understanding certain embodiments; however, the order of description should not be construed to imply that these operations are order-dependent. Additionally, structures, systems, and / or devices described herein may be described as integrated components or as separate components.

[0078] For purposes of comparing various embodiments, certain aspects and advantages of these embodiments are described. Not necessarily all such aspects or advantages are achieved by any particular embodiment. Thus, for example, various embodiments may be implemented in a manner that achieves or optimizes one advantage or group of advantages as taught herein, without necessarily achieving other aspects or advantages as may also be taught or suggested herein.

[0079] The present disclosure describes low-profile fluid injection devices and systems, and methods for their use. The low-profile fluid injection devices and systems disclosed herein can provide advantages over existing devices, systems, and methods, for example, in diagnostic and / or therapeutic applications. In some cases, the low-profile fluid injection systems disclosed herein (e.g., system 100) are used for drug delivery to cancer in situ. Those skilled in the art will understand that the devices, systems, and methods disclosed herein can be used in multiple anatomical areas and multiple surgical procedures. It will also be understood by those skilled in subcutaneous injections, such as a physician (e.g., a doctor) or a non-physician medical professional (e.g., a phlebotomist, clinical technician, nurse, practical nurse, or physician's assistant). The devices may be used, for example, for preclinical, ex vivo, or in vitro drug testing. The methods may be performed on human tissue or tissue samples, or on animal tissue or tissue samples.

[0080] FIG. 1 illustrates a low-profile fluid injection system 100 comprising an actuator 250 and an elongated member 110. As will be understood by one of ordinary skill in the art, the dimensions and configuration of the low-profile fluid injection system disclosed herein enable minimally invasive delivery of one or more fluids (which may include, for example, therapeutic and / or diagnostic agents) to a target tissue. As disclosed herein, one or more fluids may be loaded into a chamber 400 (e.g., in one or more cartridges 432) and delivered to the target tissue (e.g., tumor tissue or a portion thereof) via one or more fluid delivery members 320 housed within the elongated member 110. The elongated member 110 can be connected to a housing of the fluid injection system 100 at a proximal end 113 of the elongated member 110. In some cases, the proximal end 113 of the elongated member 110 can comprise a distal coupling 190. The distal coupling 190 can be an attachment interface (e.g., a clip or a luer lock connector). In some cases, a coaxial sheath can be slid over elongate member 110 and coupled to distal coupling 190 .

[0081] The actuator 250 can be one of a variety of means for actuating the syringe body 260 and fluid delivery member 320 within the housing of the fluid injection system 100 (which may include a contoured outer wall with a handgrip 170 (or handle)). Often, the actuator 250 includes a lever arm connected to an actuator post 254 that drives the syringe body 260 inside the housing of the fluid injection system 100 via a syringe rod 257. In various embodiments, the actuator 250 can be operated manually (e.g., by squeezing the actuator 250 against the housing of the fluid injection system 100). In some cases, the actuator 250 may include a mechanized actuator in which some or all of the force used in actuating the syringe body 260 can be provided by an electromechanical mechanism. Actuation of the actuator 250 can extend one or more fluid delivery members from the distal end 114 of the elongated member 110 (e.g., into tissue of interest, such as target tumor tissue).

[0082] 2 shows the low-profile fluid injection system 100 with the lever arm of the actuator 250 engaged (e.g., depressed). Engaging (e.g., depressing) the actuator 250 can cause one or more fluid delivery members 320 to extend out from the elongated member 110 through the distal end 114 of the elongated member 110. The fluid delivery members 320 can be deflected (e.g., spread) away from the longitudinal axis of the fluid injection system 100. A representative example of multiple fluid delivery members 320 spread as they extend from the distal end 114 of the elongated member 110 is shown in FIG. 2. In some cases, the distal end 114 of the elongate member may include one or more angle elements 115 (e.g., magnifying mechanisms) that may deflect the one or more fluid delivery members 320 away from the longitudinal axis of the fluid injection system 100 when the actuator 250 is engaged (e.g., when the syringe body 260 is actuated distally within the housing of the fluid injection system 100). The angle elements 115 may include one or more guides that may include angled channels through which the fluid delivery members 320 may pass. Representative examples of angle elements 115 are shown in FIGS. 12A and 12B. In some embodiments, the one or more fluid delivery members 320 may extend in a straight line with the longitudinal axis of the fluid injection system 100 when the actuator 250 is engaged. When the actuator 250 is engaged, the fluid delivery member 320 extends in a straight line with the longitudinal axis of the fluid injection system 100. In some cases, the distal end 114 of the elongate member 110 includes a guide element that is not angled (e.g., through which the fluid delivery member 320 can pass).

[0083] In some cases, the distal end 114 is shaped to penetrate (e.g., puncture) tissue. For example, the distal end 114 can have a pointed or sharp end, for example, for penetrating skin or fibrous tissue. In many cases, the distal end 114 can have a bullet-shaped or rounded end. While such a bullet-shaped or rounded end of the distal end 114 may be sufficient for penetrating skin or fibrous tissue, a bullet-shaped or rounded distal end 114 may be advantageous for advancing the elongated member through tissue within a tissue or subject because it may avoid damaging (e.g., puncturing) other tissue, such as an internal organ. In some cases, a guide element, such as an angled element 115, can be shaped to aid in the penetration of the elongated member 110 into or through tissue.

[0084] In some cases, the lever arm of the actuator 250 may be placed (e.g., by fully engaging the actuator 250) in alignment with (e.g., contacting) a lever arm recess 172 on the housing of the fluid injection system 100. The lever arm recess 172 can allow the actuator 250 to be depressed to a position more flush with the surface of the housing of the fluid injection system 100, which can help a user of the fluid injection system 100 maintain stable control over the fluid injection system 100 during use. A representative example of a lever arm recess 172 is shown in FIG. 1.

[0085] 3 shows a cross-sectional image of the low-profile fluid injection system 100. The actuator 250 of the low-profile fluid injection system 100 can include an actuator coupling 252. The actuator coupling 252 can be coupled to an actuator post 254 (e.g., rotatably coupled, e.g., the actuator coupling 252 is a hinge joint). The actuator post 254 can be coupled to a post coupling 256 (e.g., rotatably coupled, e.g., the post coupling 256 is a hinge joint). The post coupling 256 can be coupled to a syringe rod 257 and / or a syringe body 260. In some cases, the post coupling is fixedly attached to the syringe rod 257 and / or the syringe body 260, e.g., no rotation or translation is permitted between the post coupling 256 and the syringe rod 257, the syringe body 260, or both the syringe rod 257 and the syringe body 260.

[0086] Engaging the actuator 250 (e.g., depressing the lever arm of the actuator 250) can cause the strut 254 (e.g., in some cases via the syringe rod 257) to apply a force to the syringe body 260, which causes the syringe body 260 to slidably translate through the interior of the fluid injection system 100 (e.g., via the syringe body shaft 268), e.g., distally along the longitudinal axis of the fluid injection system 100 (see, e.g., FIGS. 5A, 5B, and 5C). In some cases, disengaging the actuator 250 (e.g., releasing the lever arm of the actuator 250) can allow the syringe body to translate proximally along the longitudinal axis of the fluid injection system 100 (see, e.g., FIGS. 6A and 6B). In some cases, engaging the actuator 250 can slidably translate the syringe rod 257 through the interior of the fluid injection system 100 (e.g., syringe rod shaft 520), e.g., in a distal direction along the longitudinal axis of the fluid injection system 100. In some cases, disengaging the actuator 250 (e.g., releasing the lever arm of the actuator 250) can allow the syringe rod 257 to translate fully or partially through the interior of the fluid injection system 100, e.g., in a proximal direction along the longitudinal axis of the fluid injection system 100. The lever arm of the actuator 250 can be coupled (e.g., rotatably coupled) to the housing of the fluid injection system 100 by an actuator hinge 251. In some cases, actuation of the actuator 250 rotates the lever arm of the actuator 250 about the actuator hinge 251.

[0087] In some cases, the housing of the fluid injection system 100 can include a strut channel 255 to allow the actuator strut 254 to move along a longitudinal axis (e.g., during actuation of the actuator 250). The housing of the fluid injection system 100 can include an actuator coupling cutout 253. In some cases, the actuator coupling cutout 253 is molded and positioned within the housing of the fluid injection system 100 to receive the actuator coupling 242 (e.g., when the lever arm of the actuator 250 is depressed). In some cases, the actuator coupling cutout 253 can allow the actuator coupling 252 to move within a maximum radius of the housing of the fluid injection system 100 (e.g., this can allow the actuator 250 to be depressed to a point where it is flush with or in contact with the exterior surface of the housing of the fluid injection system 100).

[0088] One or more fluid delivery members can be coupled to the syringe body 260. Translation of the syringe body 260 through the syringe body shaft 268 can translate the one or more fluid delivery members 320 distally through the extension member 110. In some cases, the distance the syringe body 260 and / or the one or more fluid delivery members 320 translate distally or proximally along the longitudinal axis of fluid injection can depend on the degree to which the actuator 250 is engaged (e.g., depressed) or disengaged (e.g., released). In some cases, engaging the actuator 250 extends the one or more fluid delivery members 320 distally from the distal end 114 of the extension member 110.

[0089] A syringe body spring 264 can be used to resist distal translation of the syringe body 260 along the longitudinal axis of the fluid injection system 100. In some cases, the syringe body spring 264 is disposed between a distal end 269 of the syringe body shaft 268 and a shoulder 266 of the syringe body 260. Actuation of the actuator 250 (e.g., engaging the actuator 250 by, for example, depressing a lever arm of the actuator 250) can cause compression of the syringe body spring 264 (e.g., by translating the syringe body 260 such that the syringe body shoulder 266 is brought closer to the distal end 269 of the syringe body shaft 268). Disengaging the actuator 250 (e.g., releasing the lever arm of the actuator 250) can allow the syringe body spring to extend, causing the syringe body 260 to translate proximally along the longitudinal axis of the fluid injection system 100. Syringe rod 257 may translate with syringe body 260 when actuator 250 is disengaged. Proximal translation of syringe rod 257 and / or proximal translation of syringe body 260 can, for example, cause actuator post 254 (e.g., via post coupling 256 and actuator coupling 252) to apply a force to actuator 250, causing actuator 250 to assume an unengaged (e.g., undepressed) configuration when actuator 250 is disengaged (e.g., as shown in FIG. 3 ).

[0090] Syringe body spring 264 can be held in a compressed state when actuator 250 is not engaged (e.g., when actuator 250 is in an unengaged configuration). For example, syringe body spring 264 can be held in a compressed state between the distal end of syringe body shaft 268 and syringe body 260. In some cases, syringe body 260 is biased against syringe shaft shoulder 267 by syringe body spring 264. In some cases, syringe body shaft 268 and syringe rod shaft 520 are connected interior spaces of fluid injection system 100. In some cases, syringe shaft shoulder 267 represents the distal end of syringe rod shaft 520 and the proximal end of syringe body shaft 260. The length and / or spring constant of syringe body spring 264 may be designed or selected so that a desired force is required to actuate actuator 250. For example, syringe body spring 264 may be selected to have a length and / or spring constant such that excessive force is not required to actuate actuator 250, which may otherwise reduce a user's control over the position and / or orientation of the device during use or may lead to incomplete actuation of actuator 250. In certain embodiments, it is useful to select syringe body spring 264 to have a length and / or spring constant such that actuator 250 will not actuate under its own weight or if inadvertently bumped, which may lead to unintended extension of fluid delivery member 320 and / or squeezing of fluid from fluid delivery member 320.

[0091] The low-profile fluid injection system 100 can include one or more fluid delivery members 320. The fluid delivery members 320 can include channels through which fluid can flow. Often, the fluid injection system 100 includes multiple fluid delivery members 320. For example, the fluid injection system 100 can include 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-40, 40-50, or more than 50 fluid delivery members 320. By increasing the number of fluid delivery members 320 included in the fluid injection system 100, more target tissue sites can be infused with fluid. The fluid injection system 100 can inject fluid into the target tissue in a well-controlled pattern (e.g., a pattern that can include one or more columnar fluid injections). In some cases, a fluid injection system 100 comprising multiple fluid delivery members 320 will allow multiple different fluids to be injected into one or more portions of a target tissue (e.g., so that the effect of each injection can be compared, e.g., ex vivo, in situ, in vivo, or in vitro).

[0092] The fluid delivery member 320 can comprise part of a fluid path (e.g., a continuous fluid path or a valved fluid path) from a fluid source (e.g., cartridge 432) to a target tissue (e.g., to an injection site within the target tissue adjacent to or near the distal end of the fluid delivery member 320). In some cases, the proximal end 327 of the fluid delivery member 320 is at a greater radial distance from the longitudinal axis of the fluid injection system 100 than the distal end 328 of the fluid delivery member 320. The fluid delivery member 320 can comprise one or more bends, which can be advantageous in minimizing the diameter of the elongated member (e.g., to reduce the size of the access pathway used to advance the elongated member 110 into or through tissue). In some cases, the number and / or angle of bends in the fluid delivery member 320 depends on the radius at which the proximal end of the fluid delivery member 320 is derived from the longitudinal axis of the fluid injection system 100. In some cases, the radius at which the proximal end of fluid delivery member 320 is derived from the longitudinal axis of fluid injection system 100 depends on the thickness and / or diameter of one or more of syringe body 260, syringe body spring 264, syringe body shaft 268, syringe rod shaft 520, or cartridge 432. In some embodiments, the thickness and / or diameter of one or more of syringe body 260, syringe body spring 264, syringe body shaft 268, syringe rod shaft 520, or cartridge 432 can be minimized to reduce the overall diameter of fluid injection system 100 or to reduce the number or angle of bends in fluid delivery member 320. In some cases, the radius at which the proximal end of fluid delivery member 320 is derived from the longitudinal axis of fluid injection system 100 depends on the path of fluid delivery channel 270 (e.g., the path of fluid delivery channel 270 through syringe body 260).

[0093] In some cases, one or more fluid delivery members 320 are coupled to the syringe body 260, for example, at a proximal end 327 of the fluid delivery member 320. In some cases, the one or more fluid delivery members 320 are in fluid communication with one or more fluid delivery channels 270. For example, the proximal end 327 of the fluid delivery member 320 can be in fluid communication with the fluid delivery channel 270, for example, at a delivery channel interface 290.

[0094] The fluid delivery channel 270 may be a fluid pathway connecting a fluid source (e.g., cartridge 432) and the fluid delivery member 320. The fluid delivery channel 270 may comprise a portion of one or more of the syringe body 260, the cartridge abutment 410, or the cartridge interface 420. The low-profile fluid injection system 100 may comprise multiple fluid delivery channels 270. For example, the low-profile fluid injection system may comprise a number of fluid delivery channels 270 equal to the number of fluid delivery members 320 and / or cartridge chambers 400. In some cases, the low-profile fluid injection system may comprise multiple fluidically independent pathways connecting a fluid source (e.g., cartridge 432) to a target tissue. For example, a fluidically independent pathway may comprise a fluid source, a fluid delivery channel 270, and a fluid delivery member 320, where the fluidically independent pathway is not in fluid communication with another fluid source (e.g., via the fluid delivery channel 270 and / or the fluid delivery member 320 in fluid communication with another fluid source). In some embodiments, fluid injection system 100 comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-50, or more than 50 independent fluid pathways. In some cases, the inclusion of multiple fluidically independent pathways within fluid injection system 100 allows for independent treatments and / or subsequent independent analysis of multiple diagnostic and / or multiple therapeutic agents.

[0095] In some cases, fluid delivery channel 270, or a portion thereof, can serve as a fluid reservoir. For example, at least a portion of fluid delivery channel 270 can contain a fluid to be delivered to a target tissue, or a portion thereof, using fluid injection system 100. In some cases, fluid delivery channel 270 is primed with fluid before fluid injection system 100 is used to inject fluid into a target tissue, or a portion thereof. As further disclosed herein, fluid 480 in a fluid source (e.g., cartridge 432) can be pressurized while in fluid communication with fluid delivery channel 270, which can cause fluid 480 to flow from the fluid source into fluid delivery channel 270.

[0096] 4A and 4B show a representative example of loading a cartridge 432 into the fluid injection system 100. One or more fluids contained within the cartridge 432 can be fluidly connected to the fluid delivery channel 270 by engaging a cartridge plunger 440 with a cartridge interface 420. In some cases, the one or more fluids in the cartridge 432 can be pressurized when the cartridge 432 is loaded into the cartridge retainer 430 (e.g., as a result of the cartridge 432 being biased against the lip of the cartridge retainer 430 by the cartridge abutment 410). In some cases, pressurization of the fluid in the cartridge 432 during loading of the cartridge 432 into the fluid injection system 100 can cause the fluid to fill or partially fill the fluid delivery channel 270.

[0097] In many cases, a fluid delivery mechanism 280 (e.g., a fluid delivery rod 280) is used to drive fluid from at least a portion of the fluid delivery channel 270 toward the distal end 114 of the fluid delivery member 320. The fluid delivery mechanism 280 can comprise one or more fluid delivery rods. The fluid delivery rod 280 can be slidably disposed within at least a portion of the fluid delivery channel 270. In some cases, the fluid delivery rod 280 is sized such that translation of the fluid delivery rod 280 along at least a portion of the fluid delivery channel 270 (e.g., translation distally relative to the fluid injection system 100) can increase pressure inside at least a portion of the fluid delivery channel 270, causing squeezing of fluid from the distal end of the fluid delivery member 320, for example, after the actuator 250 is actuated. As shown in FIG. 3 , the fluid delivery rod 280 can be introduced into the fluid delivery channel 270 at a bend in the fluid delivery channel 270. For example, the distal end 284 of the extension member can be positioned at or adjacent to a bend in the fluid delivery channel 270. It is also contemplated that the fluid delivery channel 270 may include a three-way junction (e.g., a T-junction) where the fluid delivery rod resides within an arm of the three-way junction in alignment with a portion of the fluid delivery channel 270 adjacent to and downstream (e.g., distal) of the three-way junction.

[0098] Fluid delivery channel 270 can be in fluid communication with purge channel 271. Purge channel 271 can be in fluid communication with air outside of fluid injection system 100. In some cases, purge channel 271 comprises a channel and / or gap through a component of system 100 (e.g., syringe body 260) and / or between two or more components of system 100 (e.g., between syringe body 260 and the housing of system 100). In some cases, air (or another gas) present within a channel, reservoir, or cartridge of fluid injection system 100 can be vented through purge channel 271. Purge channel 271 can be useful, for example, during loading or injection, as excess gas or pressure can be released via purge channel 271.

[0099] Fluid injection system 100 can include lockout assembly 500. Lockout assembly 500 can be coupled (e.g., slidably coupled) to syringe rod 257. In some cases, syringe rod 257 is rigidly coupled to syringe rod 257. In some cases, syringe rod 257 can pass through a hole or channel in lockout assembly 500 (e.g., a hole or channel in lockout assembly 500).

[0100] The lockout assembly 500 can include one or more lockout pins 501. The lockout assembly 500 can include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10 lockout pins 501. The one or more lockout pins 501 of the lockout assembly can be located on a circumferential side of the lockout assembly 500. For example, the one or more lockout pins 501 can protrude from a circumferential side of the lockout assembly 500. The lockout assembly 500 can include one or more springs. In some cases, the one or more lockout pins 501 of the lockout assembly 500 can be coupled to one or more springs of the lockout assembly 500. In some cases, one or more springs of lockout assembly 500 can be configured to bias one or more lockout pins 501 of lockout assembly 500 outward (e.g., radially outward) from lockout assembly 500. Lockout pins 501 can be configured to anchor lockout assembly 500 in a longitudinal location along syringe rod shaft 520. In some cases, one or more lockout pins 501 of lockout assembly 500 can be biased outward against an inner surface of syringe rod shaft 520. In some cases, one or more lockout pins 501 can extend into one or more lockout stops 560 of syringe rod shaft 520 (e.g., as a result of being biased against an inner surface of syringe rod shaft 520 by a spring of lockout assembly 500) to anchor the lockout assembly in a longitudinal location on syringe rod shaft 520.In some cases, one or more lockout pins 501 are biased against an inner surface of syringe rod shaft 520 before actuator 250 is engaged, and when actuator 250 is engaged, one or more lockout pins of 501 slide longitudinally along one or more inner surfaces of syringe rod shaft 520. In cases where syringe rod shaft 520 includes one or more lockout stops 560 (e.g., along the inner surface of syringe rod shaft 520), one or more lockout pins 501 can be configured to extend at least partially into one or more lockout stops 560 (e.g., as a result of engaging actuator 250 and / or biasing lockout pin 501 against syringe rod shaft 520 using one or more springs of lockout assembly 500). In some cases, the lockout assembly 500 is prevented from translating longitudinally (e.g., distally, proximally, or both distally and proximally) when one or more lockout pins 501 are at least partially extended into one or more lockout stops 560.

[0101] In some cases, such as in embodiments where the fluid injection system 100 is a multi-use system, the one or more lockout pins 501 are configured to releasably engage with a side of the syringe rod shaft 520 (e.g., one or more lockout stops 560). In some cases, the one or more lockout pins may be wedge-shaped. For example, the lockout pins may have an angled or beveled surface facing the distal end of the fluid injection system 100. In some cases, one or more members, such as rods or sticks, may be introduced into the fluid injection system 100 (e.g., via one or more holes, ports, or channels in the proximal end of the fluid injection system 100) to disengage the one or more lockout pins 501 from the one or more lockout stops 560. The members configured to disengage the one or more lockout pins 501 from the one or more lockout stops 560 may have a pointed or wedge-shaped distal end. In some cases, urging one or more members against one or more engaged lockout pins 501 (e.g., via one or more access holes, ports, or channels in the proximal end of system 100) can urge one or more lockout pins 501 back into the body of lockout assembly 500 (e.g., by compressing one or more springs of lockout assembly 500). Disengaging one or more lockout pins 501 from one or more lockout stops 560 can allow one or more components of system 100, such as lockout assembly 500, to advance longitudinally in the proximal direction when actuator 250 is released (e.g., as a result of a force being applied directly or indirectly to lockout assembly 500 by syringe rod spring 510). FIG. 7 shows an image of the internal workings of fluid injection system 100, including lockout assembly 500, lockout pin 501, and syringe rod spring 510.

[0102] The fluid injection system 100 can include a syringe rod retainer 258 (e.g., a syringe rod pin). The syringe rod retainer 258 may be coupled (e.g., rigidly coupled) to the syringe rod 257. Often, the syringe rod retainer 258 is coupled to the syringe rod 257 at a longitudinal location of the syringe rod 257 that is proximal to the lockout assembly 500 (e.g., relative to the longitudinal axis of the fluid injection system 100). In some aspects, the syringe rod retainer 258 prevents the lockout assembly from sliding off the proximal end of the syringe rod 257 (e.g., due to the force exerted by the syringe rod spring 510). In some aspects, the syringe rod retainer 258 does not prevent the syringe rod 257 from sliding through the lockout assembly 500 (e.g., in a proximal direction relative to the longitudinal axis of the fluid injection system 100).

[0103] Fluid injection system 100 can include one or more lockout stops 560. Lockout stop 560 can be fixedly attached to syringe rod shaft 520. Often, lockout stop 560 is attached (e.g., fixedly attached) to syringe rod shaft 520 at different locations along the longitudinal axis of fluid injection system 100. Often, multiple lockout stops 560 are attached to syringe rod shaft 520 at multiple locations around the inner circumference of syringe rod shaft 520. In some cases, one or more lockout stops can comprise a continuous spiral shape around syringe rod shaft 520.

[0104] In some cases, the lockout assembly translates forward (e.g., distally relative to the longitudinal axis of the fluid injection system 100) when the syringe rod 257 is translated distally relative to the longitudinal axis of the fluid injection system (e.g., when the actuator 250 is engaged). In some cases, the lockout assembly 500 can pass the lockout stops 560 when the lockout assembly translates distally relative to the longitudinal axis of the fluid injection system 100. In many cases, the lockout assembly 500 cannot pass one or more lockout stops 560 when the lockout assembly translates proximally relative to the longitudinal axis of the fluid injection system 100 (e.g., when the actuator 250 is engaged and then disengaged).

[0105] In some cases, actuation of the volume selector 530 (e.g., rotation of the volume selector dial 530) can rotate the syringe rod shaft 520 and attached lockout stop 560 within the housing of the fluid injection system 100. In some cases, the injection volume is selected by rotating the lockout stop 560 into a home position such that the lockout assembly 500 cannot pass the lockout stop when translated proximally relative to the longitudinal axis of the fluid injection system 100.

[0106] Fluid delivery mechanism 280 (e.g., one or more fluid delivery rods 280) can be coupled to lockout assembly 500. In some cases, one or more fluid delivery rods 280 are rigidly attached to lockout assembly 500. Often, one or more fluid delivery rods 280 are coupled to lockout assembly 500 at the proximal ends 282 of the one or more fluid delivery rods 280. Often, when the lockout assembly is prevented from translating proximally within the housing of fluid injection system 100 (e.g., relative to the longitudinal axis of fluid injection system 100), the fluid delivery rods are also prevented from further translating proximally relative to the longitudinal axis of fluid injection system 100 (e.g., when actuator 250 is engaged and then disengaged).

[0107] Fluid injection system 100 can include syringe rod spring 510. In some cases, syringe rod spring 510 (e.g., a proximal end of syringe rod spring 510) can be biased against syringe rod retainer 258 (e.g., a syringe rod pin). In some cases, syringe rod spring 510 can be biased against a proximal portion of syringe body 260 and / or strut coupling 256. In some cases, syringe rod spring 510 is disposed in compression between syringe rod retainer 258 and one or both of syringe body 260 and strut coupling 256.

[0108] In some cases, the spring constant of syringe rod spring 510 is less than that of syringe body spring 264. In some cases, a proximally directed force acting on syringe body 260 (e.g., as provided by syringe body spring 264) that exceeds a distally directed force acting on syringe body 260 (e.g., as provided by syringe rod spring 510) will allow syringe body 260 to translate proximally relative to the longitudinal axis of fluid injection system 100, for example, as a result of an unbalanced force acting on syringe body 260. In some cases, such as various instances where lockout assembly 500 or a portion thereof (e.g., one or more lockout pins 501) contacts (e.g., engages) lockout stop 560, syringe body spring 264, with a spring constant greater than that of syringe rod spring 510, will translate syringe body 260 and syringe rod 257 proximally while fluid delivery rod 280 and lockout assembly 500 remain in place. In some cases, this can push fluid delivery channel 270 over the fluid delivery rod, resulting in the propulsion of fluid from at least a portion of fluid delivery channel 270, through fluid delivery member 320, and into the target tissue.

[0109] The amount of fluid delivered to the tissue may be related to the distance the one or more fluid delivery members 320 are extended from the distal end 114 of the elongated member 110 and / or the extent to which the actuator 250 is engaged (e.g., depressed). In many cases, the amount of fluid delivered to the tissue may be directly related to the distance the one or more fluid delivery members 320 are extended from the distal end 114 of the elongated member 110, which may depend directly on the extent to which the actuator 250 is engaged. For example, in some cases, the actuator 250 can be further depressed to engage the lockout pin 501 with a lockout stop 560 located closer to the distal end of the syringe rod shaft 520. In many cases, the act of depressing the actuator 250 also further extends the fluid delivery member 320 a greater distance from the distal end 114 of the elongated member 110. Releasing the actuator 250 that has been depressed to a further extent can also cause the fluid delivery mechanism 280 (e.g., the fluid delivery rod 280) to push a large amount of fluid out of the fluid delivery channel 270 as the syringe body 260 moves proximally within the housing of the system 100 (e.g., due to the force exerted by the syringe body spring 264 against the syringe body 260 and the interior of the distal end of the housing of the system 100).

[0110] (extension member) The system 100 may include an elongate member 110 having a lumen 112 defined by its inner wall. The lumen 112 may extend the entire length of the elongate member 110 from a proximal end 113 to a distal end 114 along or parallel to the longitudinal axis of the elongate member 110. The elongate member 110 may comprise a hollow tube. For example, the elongate member 110 may comprise a sheath, a hypotube shaft, a needle, or the like. Alternatively, the lumen 112 may extend along any length desired by one skilled in the art, with any configuration relative to the longitudinal axis of the elongate member 110 desired by one skilled in the art. The distal end of the lumen 112 may correspond to the distal end 114 of the elongate member 110 as shown.

[0111] The elongate member 110 may comprise a metal, stainless steel, nitinol, a conventional thermoplastic used in interventional introducers (e.g., HDPE, Pebax, etc.), or the like, or any combination thereof.

[0112] The elongated member 110 may comprise a rigid material. Alternatively, or in combination, the elongated member 110 may comprise a flexible material.

[0113] FIG. 8 shows a schematic diagram of a handheld, low-profile fluid injection system 100. The system 100 may include multiple fluid delivery members 320 disposed within an elongate member 110 as described herein. Each of the multiple fluid delivery members 320 may include a fluid delivery lumen therethrough and at least one exit port 322 at its distal end as described herein. Each of the fluid delivery lumens may be fluidically independent from all other fluid delivery lumens as described herein. The multiple fluid delivery members 320 may have a retracted configuration and an extended configuration as described herein. The system 100 may include one or more fluid delivery channels 270 fluidly coupled to the fluid delivery lumens as described herein. In some embodiments, each fluid delivery channel 270 may be fluidly coupled to a single fluid delivery lumen of the multiple fluid delivery members 320. For example, system 100 including three fluid delivery members 320 as shown may have three fluid delivery channels 270 fluidly coupled to fluid delivery member 320 such that each fluid delivery member 320 and fluid delivery channel 270 is fluidically independent from all other fluid delivery members 320 and fluid delivery channels 270. System 100 may also include one or more fluid delivery channels 280 as described herein. For example, system 100 may include three fluid delivery rods 280 as shown, each operably coupled to a single fluid delivery channel (e.g., fluid reservoir) of the three fluid delivery channels (e.g., fluid reservoirs). The three fluid delivery rods 280 may be configured to be operated simultaneously or independently of one another as described herein. Actuation of fluid delivery rod 280 may cause fluid to be delivered from the multiple fluid delivery channels 270 to the multiple fluid delivery members 320 and out the exit port 322 into the tissue of interest. The system 100 may include an actuator 250 adjacent the proximal end of the elongate member 110 and operably coupled to the plurality of fluid delivery members 320 and / or the movable body 160 for extending or retracting the plurality of fluid delivery members 320 as described herein.Fluid delivery rod 280 may be actuated by actuator 250 to allow simultaneous fluid delivery and retraction of fluid delivery member 320 as described herein.

[0114] The housing of system 100 may include a handle 170 (e.g., a grip) adjacent the proximal end of elongated member 110. In some embodiments, fluid delivery channel 270 may be located within handle 170 as shown. In some embodiments, fluid delivery channel 270 may be located within or coupled to a syringe body 260 that is slidably disposed within handle 170 or elongated member 110.

[0115] Alternatively, or in combination, the fluid delivery channel 270 may be located outside the handle 170, for example, in an external fluid bag that is fluidly coupled to the proximal end of the handle 170 and / or the fluid delivery member 320 via tubing.

[0116] FIG. 9 shows a cross-sectional view of the elongate member 110 of the low-profile fluid injection system 100. Multiple fluid delivery members 320 may be disposed within the lumen 112 of the elongate member 110, as described herein. The elongate member 110 may have an outer diameter 116 sized for use as a minimally or non-invasive injection system, as described herein. The inner diameter 118 of the elongate member 110, which defines the lumen 112, may determine the size and / or number of fluid delivery members 320 that may be disposed therein. For example, the elongate member 110 may be an 18G tubing having an outer diameter 116 of 1.27 mm and an inner diameter 118 of 0.84 mm. As many as seven 31G needles, each having an outer diameter 324 of 0.26 mm, may fit within the lumen 112 of the 18G tubing. The multiple fluid delivery members 320 may have an inner diameter 326 sized to provide fluid delivery, as described herein. The size of the elongate member 110 and / or the size of the fluid delivery members 320 may be adjusted as desired to provide a desired geometry and / or number of fluid delivery members 320 in the system.

[0117] In some embodiments, the elongate member 110 may comprise a needle, sheath, or tube with a gauge number of about 10 to about 20. The elongate member 110 may have an outer diameter 116 within a range bounded by any two of the following gauge numbers: 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. The elongate member 110 may have a gauge number of, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0118] The elongated member 110 may have an outer diameter 116 of about 0.9 mm to about 3.5 mm. The elongated member 110 may have an outer diameter 116 of about 2 mm to about 4 mm. The elongated member 110 may have an outer diameter 116 within a range bounded by any two of the following values: 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, or 4 mm.

[0119] The elongated member 110 may have an outer diameter 116 of about 3 French to about 10 French. The elongated member 110 may have an outer diameter 116 within a range bounded by any two of the following values: 3 French, 4 French, 5 French, 6 French, 7 French, 8 French, 9 French, or 10 French. The elongated member 110 may have an outer diameter 116 of about 3 French, about 4 French, about 5 French, about 6 French, about 7 French, about 8 French, about 9 French, or about 10 French, for example.

[0120] The elongate member 110 may have an outer diameter 116 sized to fit within the working channel of a conventional biopsy access needle, a conventional endoscope, a conventional laparoscopic system, a conventional vascular access sheath, or the like, as described herein.

[0121] The elongated member 110 may have a longitudinal length of about 4 cm to about 250 cm. For example, the elongated member 110 may have a length of 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 1 cm to 20 cm, 4 cm to 20 cm, 5 cm to 15 cm, 7 cm to 13 cm, or 9 cm to 11 cm. Alternatively, the elongated member 110 may have a length of about 100 cm to about 250 cm. The extension member 110 may have a length within a range bounded by any two of the following values, for example: 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 25 cm, 30 cm, 35 cm, 40 cm, 45 cm, 50 cm, 75 cm, 100 cm, 125 cm, 150 cm, 175 cm, 200 cm, 225 cm, 250 cm, 275 cm, or 300 cm.

[0122] System 100 may be configured for fluid delivery from about 1 cm to about 300 cm away from a patient access point (e.g., mouth, skin surface, rectum, etc.). In some embodiments, the system may be configured for fluid delivery from about 1 cm to about 30 cm below the skin surface. For example, the system may be configured for fluid delivery from about 1 cm to about 4 cm below the skin surface or from about 4 cm to about 20 cm below the skin surface. Alternatively, the system may be configured for fluid delivery from about 20 cm to about 40 cm below the skin surface. Alternatively, the system may be configured for fluid delivery from about 100 cm to about 250 cm below the skin surface or from an entry point into the body (e.g., mouth).

[0123] The length of the elongated member 110 used for a particular application may depend on the location of the tissue site of interest. For example, a system 100 with a longer elongated member 110 can be used to deliver one or more agents to target tissue located deeper inside a subject or tissue.

[0124] (Fluid Delivery Member) One or more fluid delivery members 320 may be disposed within the lumen 112 of the elongate member 110. For example, four fluid delivery members 320 may be covered by the elongate member 110 as shown. Any desired number of fluid delivery members 320 may be housed within the lumen 112 of the elongate member 110, as described herein. Each fluid delivery member 320 may comprise a distal end, a proximal end, an inner wall defining a fluid delivery lumen therein, and an exit port 322 at its distal end fluidly coupled to the lumen. Each fluid delivery lumen may be fluidically independent from all other fluid delivery lumens. One or more fluid delivery members 320 may comprise multiple needles or tubes. For example, one or more of the fluid delivery members 320 may comprise multiple pencil-tip needles, blunt-tip needles, or bevel-tip needles.

[0125] In some embodiments, each fluid delivery member 320 may include a single outlet port 322 at its distal end, as described herein. In some embodiments, some or all of the multiple fluid delivery members 320 may include at least one additional outlet port 322 along their exposed length that is fluidly coupled to a fluid delivery lumen, as described, for example, in PCT / US2008 / 073212 (the entire contents of which are incorporated herein by reference).

[0126] The fluid delivery member 320 may have a retracted configuration and an extended configuration. The fluid delivery member 320 may remain in the retracted configuration while the system 100 is inserted into the patient's body (e.g., through the skin or mouth 701) and positioned in close proximity to the tumor site 702. The fluid delivery member 320 may be extended into the tumor 702, as shown, out the distal end 114 of the elongate member 110 to the extended configuration, to deliver a therapeutic agent to the tumor tissue 702. The fluid delivery member 120 may be returned to the retracted configuration for removal of the system 100 from the patient.

[0127] The plurality of fluid delivery members 320 may comprise one or more of a metal or a plastic. The plurality of fluid delivery members 320 may comprise a shape memory alloy. The plurality of fluid delivery members 320 may comprise stainless steel, nitinol, a conventional thermoplastic used in interventional introducers (e.g., HDPE, Pebax, etc.), or the like, or any combination thereof.

[0128] The plurality of fluid delivery members 320 may comprise a flexible material. Alternatively, or in combination, the plurality of fluid delivery members 320 comprise a rigid material.

[0129] In some embodiments, the fluid delivery member 320 may comprise a needle, sheath, or tube with a gauge in the range of about 28 to about 33. One or more of the fluid delivery members 320 may be a 25-gauge needle. In some cases, the fluid delivery member 120 may comprise a 20-gauge, 21-gauge, 22-gauge, 23-gauge, 24-gauge, 26-gauge, 27-gauge, 28-gauge, 29-gauge, 30-gauge, 31-gauge, 32-gauge, or 33-gauge needle. The fluid delivery member 320 may have an outer diameter 124 within a range bounded by any two of the following gauges: 28, 29, 30, 31, 32, or 33. One or more of the fluid delivery members may have a gauge of, for example, 28, 29, 30, 31, 32, or 33.

[0130] The fluid delivery member 320 may have an outer diameter 324 in the range of about 0.05 mm to about 0.5 mm. The fluid delivery member 320 may have an outer diameter 324 in the range bounded by any two of the following values: 0.05 mm, 0.06 mm, 0.07 mm, 0.08 mm, 0.09 mm, 0.1 mm, 0.15 mm, 0.2 mm, 0.25 mm, 0.3 mm, 0.35 mm, 0.4 mm, 0.45 mm, or 0.5 mm. One or more of the fluid delivery members 120 may have an outer diameter 324 of about 0.05 mm, about 0.06 mm, about 0.07 mm, about 0.08 mm, about 0.09 mm, about 0.1 mm, about 0.15 mm, about 0.2 mm, about 0.25 mm, about 0.3 mm, about 0.35 mm, about 0.4 mm, about 0.45 mm, or about 0.5 mm.

[0131] The system 100 may include one or more fluid delivery members 320 disposed within the lumen 112 of the elongate member 110. The system 100 may include, for example, a plurality of fluid delivery members 320. The plurality of fluid delivery members 320 may include at least two fluid delivery members 320. The plurality of fluid delivery members 320 may include between 2 and 20 fluid delivery members 320. The plurality of fluid delivery members 320 may include a number of fluid delivery members 320 within a range bounded by any two of the following values: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0132] 10A shows a schematic diagram of a low-profile fluid injection system 100 with a fluid delivery member 320 in a retracted configuration. FIG. 10B shows the system 100 with a fluid delivery member 320 in an extended configuration. The system 100 may include multiple fluid delivery members 320 disposed within the elongate member 110, as described herein. Each of the multiple fluid delivery members 320 may include a fluid delivery lumen and at least one exit port 322 at its distal end, as described herein. Each of the fluid delivery lumens may be fluidically independent from all other fluid delivery lumens, as described herein. The multiple fluid delivery members 320 may have a retracted configuration and an extended configuration, as described herein.

[0133] The fluid delivery member 320 may be configured to be completely enclosed within the lumen 112 of the elongate member 110 in the retracted configuration. In some cases, each of the multiple fluid delivery members 320 may extend from the distal end 114 of the elongate member 110 to the proximal end of the elongate member 110. For example, the length of each of the multiple fluid delivery members 320 may be substantially similar to the length of the elongate member 110.

[0134] Each of the plurality of fluid delivery members 320 may have a length within a range of about 4 cm to about 250 cm. For example, each of the plurality of fluid delivery members 320 may have a length within a range of about 4 cm to about 20 cm. Alternatively, each of the plurality of fluid delivery members 320 may have a length within a range of about 100 cm to about 250 cm. Each of the plurality of fluid delivery members 320 may have a length within a range bounded by any two of the following values, for example: 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 25 cm, 30 cm, 35 cm, 40 cm, 45 cm, 50 cm, 75 cm, 100 cm, 125 cm, 150 cm, 175 cm, 200 cm, 225 cm, 250 cm, 275 cm, or 300 cm.

[0135] The length of the fluid delivery member 320 may be adjusted depending on the length of the elongate member 110 and / or the location of the tissue site of interest.

[0136] The fluid delivery members 320 may extend out from the distal end 114 of the elongate member 110 to an extended configuration, as described herein. In the extended configuration, each of the multiple fluid delivery members 320 may be angled away from the longitudinal axis 111 of the elongate member 110.

[0137] In some embodiments, the distal end 114 of the elongate member 110 may comprise one or more angle elements 115 (e.g., expansion mechanisms) positioned to guide the plurality of fluid delivery members 320 and angle them away from the longitudinal axis 111 of the elongate member 110 in the extended configuration. The angle elements or expansion mechanisms may comprise, for example, one or more channels or guides in the elongate member 110 that preferentially guide the plurality of fluid delivery members 320 into a desired expanded configuration.

[0138] Alternatively, or in combination, at least the distal end of each of the plurality of fluid delivery members 320 may comprise a shape memory material or a compressible material such that extension of the plurality of fluid delivery members 320 from the distal end 114 of the elongate member 110 enables the distal exposed end of each of the plurality of fluid delivery members 320 to self-expand in a discrete pattern.

[0139] In the extended configuration, each of the plurality of fluid delivery members 320 may be angled away from the longitudinal axis 111 of the elongated member 110 at an oblique angle. Each of the plurality of fluid delivery members 320 may be angled away from the longitudinal axis 111 of the elongated member 110 at an angle (e.g., a flared angle) within a range of about 10° to about 90°. One or more of the plurality of fluid delivery members 320 may be angled away from the longitudinal axis 111 of the elongated member 110 at an angle 329 within a range bounded by any two of the following values: 10°, 15°, 20°, 25°, 30°, 35°, 40°, 45°, 50°, 55°, 60°, 65°, 70°, 75°, 80°, 85°, or 90°. For example, one or more of the multiple fluid delivery members 120 may be angled away from the longitudinal axis 111 of the elongated member 110 at an angle 329 of 10° to 45°, 15° to 30°, or 20° to 25° (e.g., when extended from the distal end 114 of the elongated member 110 outside the biological tissue or when extended inside the biological tissue).

[0140] In the extended configuration, each of the plurality of fluid delivery members 320 may be angled away from the longitudinal axis 111 of the elongate member 110 such that the distance 321 between the distal ends of each of the plurality of fluid delivery members 320 is within a range of about 1 mm to about 10 mm. Each of the plurality of fluid delivery members 320 may be angled away from the longitudinal axis 111 of the elongate member 110 such that the distance 321 between the distal ends of each of the plurality of fluid delivery members 320 is within a range bounded by any two of the following values: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, or 10 mm.

[0141] In the extended configuration, each of the plurality of fluid delivery members 320 may have a length 323 extending out from the distal end 114 of the elongate member 110. The length 323 of each of the plurality of fluid delivery members 320 extending out from the distal end 114 of the elongate member 110 in the extended configuration may be in a range of about 1 mm to about 50 mm, such as in a range of about 5 mm to about 40 mm. The length 323 of each of the plurality of fluid delivery members 320 extending out from the distal end 114 of the elongate member 110 in the extended configuration may be within a range bounded by any two of the following values: 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm, 45 mm, or 50 mm.

[0142] (Fluid Delivery Channel) System 100 may include one or more fluid delivery channels 270 (e.g., fluid reservoirs) fluidly coupled to a fluid delivery lumen. In some embodiments, each fluid delivery channel 270 is fluidly coupled to a single fluid delivery lumen of multiple fluid delivery members 320. For example, a system 100 including three fluid delivery members 320 as shown may have three fluid delivery channels 270 fluidly coupled to the fluid delivery members 320 such that each fluid delivery member 320 and fluid delivery channel 270 is fluidly independent from all other fluid delivery members 320 and fluid delivery channels 270. Alternatively, one or more fluid channels 270 or portions thereof may each be fluidly coupled to more than one fluid delivery member 320. For example, one fluid delivery channel 270 may be fluidly coupled to two fluid delivery members 320. Alternatively, or in combination, one or more fluid delivery members 320 may be fluidly coupled to more than one fluid delivery channel 270, for example, in cases where mixing of fluids is desired within the fluid delivery member 320. For example, one fluid delivery member 320 may be fluidly coupled to two fluid delivery channels 270 to mix two different fluids together within the fluid delivery member 320 during injection.

[0143] In some embodiments, the fluid delivery channel 270 may be loaded with fluid prior to inserting the distal end 114 of the elongate member 110 into the body. Alternatively, or in combination, the fluid delivery channel 270 may be loaded with fluid during or after inserting the distal end 114 of the elongate member 110 into the body.

[0144] In some embodiments, the fluid delivery channel 270 may be coupled directly to the proximal end of the fluid delivery member 320 .

[0145] In some embodiments, the fluid delivery channel 270 is not directly coupled to the proximal end of the fluid delivery member 320, but may be fluidly coupled thereto.

[0146] In some embodiments, the plurality of fluid delivery channels 270 may comprise the fluid delivery lumens of the plurality of fluid delivery members 320. For example, the plurality of fluid delivery channels 270 may be directly and openly coupled to the fluid delivery lumens of the plurality of fluid delivery members 320 such that loading fluid into the plurality of fluid delivery channels 270 also loads (or primes) the fluid into the fluid delivery lumens. In some embodiments, the fluid delivery lumens of the plurality of fluid delivery members 320 may be the plurality of fluid delivery channels 270. That is, the plurality of fluid delivery channels 270 may consist of the fluid delivery lumens of the plurality of fluid delivery members 320, and fluid may be loaded directly into the fluid delivery lumens.

[0147] In some embodiments, the multiple fluid delivery channels 270 may comprise multiple cartridges as described herein.

[0148] Each of the plurality of fluid delivery channels 270 may have a volume (i.e., hold a volume of fluid therein) within a range of about 10 μl to about 500 μl. Each of the plurality of fluid delivery channels 270 may have a volume within a range bounded by any two of the following values: 10 μl, 20 μl, 30 μl, 40 μl, 50 μl, 60 μl, 70 μl, 80 μl, 90 μl, 100 μl, 125 μl, 150 μl, 175 μl, 200 μl, 225 μl, 250 μl, 275 μl, 300 μl, 325 μl, 350 μl, 375 μl, 400 μl, 425 μl, 450 μl, 475 μl, or 500 μl.

[0149] The volume of each fluid delivery channel 270 may comprise the volume of each fluid delivery member lumen fluidly coupled thereto, which may vary depending on the length of the elongated member 110 when fluid is "primed" within the entire fluid pathway prior to use.

[0150] In some embodiments, system 100 may include one or more labeling reservoirs (e.g., one or more cartridges 432) fluidly coupled to one or more of the fluid delivery lumens or one or more of the plurality of fluid delivery channels 270. For example, each fluid delivery member 320 (e.g., each fluid delivery lumen of each fluid delivery member 320) or fluid delivery channel 270 may be fluidly coupled to a labeling reservoir (e.g., cartridge 432) that holds a labeling agent therein. In some cases, each cartridge 432 (e.g., each labeling reservoir) may be fluidly independent from all other cartridges 432 (e.g., labeling reservoirs). System 100 may be configured to mix the labeling agent and therapeutic agent within fluid delivery channel 270 or one or more of the connected fluid delivery lumens such that the fluid infused into the tissue contains both the labeling agent and the therapeutic agent within the same infusion column. In some cases, mixing may occur prior to infusion of the therapeutic agent. In some cases, mixing may occur during the infusion of the therapeutic agent.

[0151] FIG. 11A shows three exemplary prototype low-profile fluid injection systems 100 with three fluid delivery members 320 in a retracted configuration. FIG. 11B shows a system 100 with a fluid delivery member 320 in an extended configuration. The fluid injection systems 100 are shown next to a dime for scale comparison. Three systems 100 were formed using low-profile elongated members 110 having gauge numbers of 18, 16, and 14 (from left to right in FIGS. 12A and 12B , respectively). In the retracted configuration, the three fluid delivery members 320 were fully enclosed within the elongated member 110 of each system 100. In the extended configuration, the three fluid delivery members 320 flared out from the distal end 114 of the elongated member 110 at an angle away from the longitudinal axis 111 of the elongated member 110 of each system 100, as described herein.

[0152] FIG. 12A shows a prototype of an exemplary low-profile fluid injection system 100 with three fluid delivery members 320 in a retracted configuration. FIG. 12B shows the system 100 with the fluid delivery members 320 in an extended configuration. The fluid injection system 100 is shown next to a dime for scale comparison. In the retracted configuration, the three fluid delivery members 320 were fully enclosed within the elongated member 110. In the extended configuration, the three fluid delivery members 320 flared out from the distal end 114 of the elongated member 110 at an angle away from the longitudinal axis 111 of the elongated member 110, as described herein.

[0153] FIG. 13A shows a schematic diagram of a top view of subcutaneous tumor tissue 702 following injection using low-profile fluid injection system 100. FIG. 13B shows a perspective view of an injection column 704 created following injection using low-profile fluid injection system 100. System 100 may be configured to inject one or more agents (e.g., drugs) into the tissue at discrete, mapped locations (i.e., injection sites) 703 to allow a user to observe a spatially defined tumor response to the drugs at the injection sites 703. The agents may be injected into the tissue in uniform, column-like trajectories 704 through the z-axis of the tissue, as shown in FIG. 13B. In some cases, the agents can be injected into the tissue in columns that are parallel to one another. In some cases, the agents can be injected into the tissue in columns that are not parallel to one another (e.g., as shown in FIG. 13C). For example, one or more agents can be injected into the tissue in a column oriented in line with one or more fluid delivery members (e.g., when the fluid delivery members are in an extended (e.g., flared) configuration). The one or more agents may be injected into the tumor with a label as described herein to aid in the identification of drug candidates and / or to confirm successful drug delivery.

[0154] System 100 may be configured to inject multiple fluids at multiple injection sites 703, forming multiple injection columns 704 within the tissue. In some embodiments, each fluid delivery member 320 may inject a different fluid / agent such that the number of distinct agents / fluids injected into the tumor is the same as the number of fluid delivery members 320 / injection sites 703. In other embodiments, one or more fluid delivery members 320 may inject the same fluid / agent such that the number of distinct agents / fluids injected into the tumor is less than the number of fluid delivery members 320 / injection sites 703. Alternatively, or in combination, one or more of the fluid delivery members 320 may inject fluids / agents having the same active ingredient but at different concentrations.

[0155] The drug may be left in the tumor 702 for a predetermined period of time, for example, about 24 to about 72 hours, before excision and analysis. During that time, the drug may diffuse into the tissue immediately surrounding the injection column 704. The injection columns 704 produced by the system 100 may be spaced in a manner to prevent cross-contamination or to allow the drugs to mix within the tissue, as desired by one skilled in the art.

[0156] The tissue 702 may be excised for analysis of the therapeutic effectiveness and / or toxicity of the drug. Assessing the therapeutic effectiveness of the drug may include analyzing the tissue 702 for known markers of, for example, cytotoxicity, hypoxia, angiogenesis, immune response, dysregulation of target biochemical or genetic pathways, or the like, or any combination thereof.

[0157] Tissue 702 may be sampled at multiple tumor depths to assess the consistency of tumor response to drugs, which may be particularly useful for heterogeneous tumor types with spatially varying microenvironments. The excised tissue may be cut into multiple serial sections, for example, at predetermined intervals along the injection column, and analyzed by any known histology, histochemistry, immunohistology, immunohistochemistry, histopathology, microscopy, cytology, biochemistry, pharmacology, molecular biology, immunochemistry, imaging, or other analytical technique, or combinations thereof, known to those skilled in the art.

[0158] 14 shows a schematic diagram of a low-profile fluid injection system 100. System 100 may be used to deliver one or more agents, such as therapeutic agents or drugs, through the skin 701 or other access point (e.g., the mouth) to an internal target tissue 702, for example, in a subcutaneous tumor.

[0159] FIG. 15A shows the distal end of an exemplary low-profile fluid injection system 100 comprising an angled element and three fluid delivery members 320 in an unextended (e.g., retracted) configuration adjacent to simulated tumor tissue 702a. The simulated tumor tissue 702a comprised a 0.55% agarose gel stained with red food coloring inside a test tube. The distal end 114 of the elongated member 110 was positioned adjacent to the simulated tumor tissue 702a. The three fluid delivery members 320 were then extended into the simulated tumor tissue 702a. As shown in FIG. 15B, the fluid delivery members 320 were successfully extended into the simulated tumor tissue at an oblique angle. As disclosed herein, an actuator 250 can be engaged to cause the fluid delivery members 320 to assume the extended configuration, as shown in FIG. 15B. 15C shows the system 100 during fluid injection into the simulated tumor tissue 702a and simultaneous retraction of the fluid delivery member 320. The fluid delivery member 320 was retracted at a rate of 0.75 mm / sec while one microliter of each fluid containing 50% green food coloring was injected into the simulated tumor tissue 702a. The simultaneous injection and retraction resulted in a clear injection column 702 within the simulated tumor tissue 702a.

[0160] (Fluid delivery mechanism) The system 100 may include one or more fluid delivery mechanisms 280. In many cases, the fluid delivery mechanism may include a fluid delivery rod 280. The fluid delivery mechanism may include multiple fluid delivery rods 280. Actuation of the fluid delivery rod 280 may cause fluid to be delivered from the multiple fluid delivery channels 270 to the multiple fluid delivery members 320, out the exit port 322, and into the tissue of interest.

[0161] In some embodiments, the fluid delivery mechanism 280 may comprise a single fluid delivery rod 280 operably coupled to each of the multiple fluid delivery channels 270 such that actuation of the fluid delivery rod 280 causes fluid to be delivered from each of the multiple fluid delivery members 320 simultaneously.

[0162] Alternatively, the fluid delivery mechanism 280 may comprise multiple fluid delivery rods. In some embodiments, each of the multiple fluid delivery rods 280 may be operably coupled to a single fluid delivery channel 270 (e.g., fluid reservoir) of the multiple fluid delivery channels 270 (e.g., fluid reservoirs). In some embodiments, the multiple fluid delivery rods 280 may function independently of one another such that each of the multiple fluid delivery members 320 may deliver fluid independently of all other fluid delivery members 320. In some embodiments, each of the multiple fluid delivery rods 280 may be operably coupled to more than one fluid delivery channel 270 (e.g., one fluid reservoir) of the multiple fluid delivery channels (e.g., fluid reservoirs).

[0163] Fluid delivery mechanism 280 may comprise a mechanical actuator or an electromechanical actuator. In some embodiments, fluid delivery rod 280 may comprise one or more of a plunger or a pump. In some embodiments, fluid delivery rod 280 comprises a gasket (e.g., a rubber gasket or a plastic gasket). For example, fluid delivery rod 280 can comprise a gasket at its distal end, which can be configured to form a watertight junction with the inner side (e.g., inner wall surface) of the fluid delivery channel. In some cases, fluid delivery rod 280 does not comprise a gasket. In many embodiments, fluid delivery rod 280 is configured to slide through a fluid channel (e.g., a fluid delivery channel) or reservoir. Moving fluid delivery rod 280 within a fluid channel or reservoir (e.g., sliding fluid delivery rod 280 through a fluid delivery channel or reservoir) can move fluid within the fluid delivery channel or reservoir. For example, moving fluid delivery rod 280 distally relative to a fluid delivery channel or reservoir can move fluid within the fluid delivery channel or reservoir distally within the fluid delivery channel or reservoir. In some cases, moving the fluid delivery channel or reservoir proximally relative to fluid delivery rod 280 can move fluid within the fluid delivery channel or reservoir distally relative to the fluid delivery channel or reservoir. The diameter of fluid delivery rod 280 can be sized relative to the inner diameter of fluid delivery channel 270 or reservoir such that fluid within fluid delivery channel 270 or reservoir is moved when fluid delivery rod 280 is moved relative to fluid delivery channel 270 or reservoir.

[0164] Fluid delivery rod 280 may be operated manually. Alternatively, or in combination, fluid delivery rod 280 may be operated automatically, for example, by a computer program as described herein.

[0165] FIG. 16A shows a schematic diagram of low-profile fluid injection system 100 prior to fluid injection with fluid delivery member 320 in an unextended configuration. In some cases, actuator 250 can be engaged to extend one or more fluid delivery members 320 into tissue 702 (e.g., as shown in FIG. 16B). In some cases, the degree to which actuator 250 is engaged determines the distance the fluid delivery member 320 is extended into tissue 702. Fluid delivery member 320 can be retracted into the fluid injection system (e.g., into elongated member 110), as shown in FIG. 16C. In some cases, retraction of fluid delivery member 320 is passive (e.g., due to the action of a spring internal to system 100) or active (e.g., as a result of pulling actuator 250 back to its initial position).

[0166] FIG. 16D shows a schematic diagram of the low-profile fluid injection system 100 prior to fluid injection with the fluid delivery member 320 in the extended configuration. FIG. 16E shows the system 100 after simultaneous fluid injection and retraction of the fluid delivery member 320. The system 100 may include multiple fluid delivery members 320 disposed within the elongate member 110, as described herein. Each of the multiple fluid delivery members 320 may include a fluid delivery lumen therethrough and at least one exit port 322 at its distal end, as described herein. Each of the fluid delivery lumens may be fluidically independent from all other fluid delivery lumens, as described herein. The multiple fluid delivery members 320 may have a retracted configuration and an extended configuration, as described herein. The system 100 may include one or more fluid delivery channels 270 fluidly coupled to the fluid delivery lumens, as described herein. In some embodiments, each fluid delivery channel 270 may be fluidly coupled to a single fluid delivery lumen of multiple fluid delivery members 120. For example, a system 100 comprising three fluid delivery members 320 as shown may have three fluid delivery channels 270 fluidly coupled to the fluid delivery members 320 such that each fluid delivery member 320 and fluid delivery channel 270 is fluidly independent from all other fluid delivery members 320 and fluid delivery channels 270. The system 100 may comprise one or more fluid delivery channels 280 as described herein. For example, the system 100 may comprise three fluid delivery rods 280 as shown, each operably coupled to a single fluid delivery channel 270 (e.g., fluid reservoir 130) of the three fluid delivery channels (e.g., fluid reservoirs). The three fluid delivery rods 280 may be configured to operate simultaneously or independently of one another as described herein. Actuation of the fluid delivery rod 280 may cause fluid to be delivered from the plurality of fluid delivery channels 270 to the plurality of fluid delivery members 320, out the exit port 322 and into the tissue of interest.

[0167] (actuator) The system 100 may include an actuator 250 (e.g., an extension actuator 250) adjacent the proximal end of the extension member 110 and operably coupled to the plurality of fluid delivery members 320 and / or syringe bodies 260 operably coupled thereto, as described herein. The actuator 250 can reside at an angle 259 relative to the longitudinal axis 101 of the fluid injection system 100 when the actuator is not engaged. In some embodiments, the actuator angle 259 can be between 10 degrees and 180 degrees, between 10 degrees and 90 degrees, between 30 degrees and 90 degrees, between 30 degrees and 60 degrees, or between 30 degrees and 45 degrees. In some cases, the actuator angle 259 can be an angle about the actuator hinge 251. In some cases, the actuator angle 259 can be measured relative to a plane parallel to the longitudinal axis 101 of the fluid injection system 100. For example, the actuator angle 259 can be measured relative to a plane parallel to the longitudinal axis 101 extending through the actuator hinge 251 .

[0168] Actuation of the actuator 250 may transition the plurality of fluid delivery members 320 from a retracted configuration to an extended configuration or from an extended configuration to a retracted configuration. The actuator 250 may comprise a mechanical actuator or an electromechanical actuator.

[0169] Actuator 250 may be operated manually. Alternatively, or in combination, actuator 250 may be operated automatically, for example, by a computer program as described herein.

[0170] In some embodiments, fluid delivery rod 280 may be actuated by actuator 250 to enable simultaneous fluid delivery and retraction of fluid delivery member 320, as described herein. Alternatively, or in combination, fluid delivery rod 280 may be independently actuated by actuator 250.

[0171] Actuation of the fluid delivery rod 280 may be operably coupled to the multiple fluid delivery members 320 and / or the syringe body 260 of the system 100 such that fluid delivery occurs simultaneously with retraction of the fluid delivery members 320 from the extended configuration to the retracted configuration. The multiple fluid delivery members 320 may be configured to retract from the extended configuration to the retracted configuration simultaneously with fluid delivery from the fluid delivery members 320. The simultaneous fluid delivery and retraction of the fluid delivery members 320 may assist in the formation of a clean injection column 704 within the tissue of interest (as shown in FIG. 9 ).

[0172] Simultaneous fluid delivery and retraction of fluid delivery member 320 may be achieved by “pulling” fluid delivery channel 270 and fluid delivery member 320 toward stationary fluid delivery rod 280 within the body of system 100. Fluid delivery channel 270 may be operatively coupled to or located within syringe body 260 of system 100, for example, slidably disposed within extension member 110 or a handle or the like. Retraction of fluid delivery member 320 from the extended configuration (shown in FIG. 16D ) to the retracted configuration (shown in FIG. 9 ) may include retracting syringe body 260 and fluid delivery channel 270 located therein from a distal position to a proximal position to engage stationary fluid delivery rod 280 and allow fluid to flow from fluid delivery channel 270 to the distal end of fluid delivery member 320 and out exit port 322. This mechanism of action can be contrasted with conventional plunger-syringe-like mechanisms in which a fluid delivery rod is "pushed" into a stationary fluid delivery reservoir (eg, fluid delivery channel 270) located within the body of the system.

[0173] Simultaneous fluid delivery or retraction of the fluid delivery member 320 may be achieved by electromechanical means. For example, a cooperating gear may retract the fluid delivery member 320 while a micropump may pump fluid from the fluid delivery member 320.

[0174] The actuator 250 may be configured to retract the multiple fluid delivery members 320 from the extended configuration to the retracted configuration at the same rate. Alternatively, the actuator 250 may be configured to retract one or more of the multiple fluid delivery members 320 at different rates, for example, to maintain the same fluid delivery volume per area for fluids of different viscosities or flow rates.

[0175] The fluid delivery member 320 may be retracted at a rate sufficient to generate the injection column 704 as described herein.

[0176] The fluid delivery member 320 may be retracted at a speed within a range of about 0.1 mm / sec to about 10 mm / sec. For example, the speed may be within a range bounded by any two of the following values: about 0.1 mm / sec, about 0.2 mm / sec, about 0.3 mm / sec, about 0.5 mm / sec, about 1 mm / sec, about 2 mm / sec, about 3 mm / sec, about 4 mm / sec, about 5 mm / sec, about 6 mm / sec, about 7 mm / sec, about 8 mm / sec, about 9 mm / sec, or about 10 mm / sec.

[0177] Each of the fluid delivery channels 270 may hold the same volume of fluid. Alternatively, one or more of the fluid delivery channels 270 may hold different volumes of fluid.

[0178] Each of the plurality of fluid channels 270 may have a volume within a range of about 10 μl to about 500 μl. For example, the volume of a fluid channel 270 may be within a range bounded by any two of the following values: about 10 μl, about 20 μl, about 30 μl, about 40 μl, about 50 μl, about 75 μl, about 100 μl, about 150 μl, about 200 μl, about 250 μl, about 300 μl, about 350 μl, about 400 μl, about 450 μl, or about 500 μl.

[0179] The fluid delivery lumens of the multiple fluid delivery members 320 may each hold the same volume of fluid. Alternatively, one or more of the fluid delivery lumens of the multiple fluid delivery members 320 may hold different volumes of fluid.

[0180] Each of the fluid delivery lumens of the plurality of fluid delivery members 320 may have a volume within a range of about 0.1 μl to about 10 μl. For example, the volume of a fluid delivery member lumen may be within a range bounded by any two of the following values: about 0.1 μl, about 0.2 μl, about 0.3 μl, about 0.5 μl, about 1 μl, about 2 μl, about 3 μl, about 4 μl, about 5 μl, about 6 μl, about 7 μl, about 8 μl, about 9 μl, or about 10 μl.

[0181] The volume of each of the fluid delivery lumens may depend on the length of its corresponding fluid delivery member 320, which may vary depending on the length of the elongated tube 110 and the location of the tissue site of interest.

[0182] The fluid delivery rod 280 may be configured to deliver fluid out of the outlet port 322 at a flow rate sufficient to generate an injection column 704 as described herein, with minimal shear forces and induction of mechanical-chemical damage to the tissue 702.

[0183] Fluid delivery rod 280 may be configured to deliver fluid out of outlet port 322 at a flow rate within a range of about 0.1 μl / sec to about 10 μl / sec. For example, the flow rate may be within a range bounded by any two of the following values: about 0.1 μl / sec, about 0.2 μl / sec, about 0.3 μl / sec, about 0.5 μl / sec, about 1 μl / sec, about 2 μl / sec, about 3 μl / sec, about 4 μl / sec, about 5 μl / sec, about 6 μl / sec, about 7 μl / sec, about 8 μl / sec, about 9 μl / sec, or about 10 μl / sec.

[0184] (Volume Selector) 18A and 18B show a fluid injection system 100 including a volume selector 530. In many cases, the volume selector 530 is used to control the volume of fluid injected into the target tissue. The volume selector 530 can be disposed at the proximal end of the fluid injection system 100. The volume selector 530 can be coupled (e.g., rigidly coupled) to a volume adjustment screw 540. The volume adjustment screw 540 can be coupled to a syringe rod shaft 520. In some cases, actuating (e.g., rotating) the volume selector 530 can actuate the syringe rod shaft 520 (e.g., rotate the syringe rod shaft 520 about the longitudinal axis 101 of the fluid injection system 100). In some cases, the volume selector 530 includes a dial. In some cases, the volume selector 530 can be used to set the volume to be injected into the target tissue by rotating the dial to a selected volume position. In some cases, the volume selector 530 can be used to select the volume to be injected from a plurality of discrete volumes. In some cases, a volume selector can be used to select a volume from a continuous range of volumes.In some embodiments, the volume selector 530 is selected from the group consisting of 1 microliter to 1.5 microliters, 1.5 microliters to 2.0 microliters, 2.0 microliters to 2.5 microliters, 2.5 microliters to 3.0 microliters, 3.0 microliters to 3.5 microliters, 3.5 microliters to 4.0 microliters, 4.0 microliters to 4.5 microliters, 4.5 microliters to 5.0 microliters, 5.0 microliters to 5.5 microliters, 5.5 microliters to 6.0 microliters, 6.0 microliters to 6.5 microliters, 6.5 ... The volume selector 530 can be used to set the volume for injection from 10.0 microliters to 7.0 microliters, 7.0 microliters to 7.5 microliters, 7.5 microliters to 8.0 microliters, 8.0 microliters to 8.5 microliters, 8.5 microliters to 9.0 microliters, 9.0 microliters to 9.5 microliters, 9.5 microliters to 10.0 microliters, 10.0 microliters to 50.0 microliters, 50.0 microliters to 100.0 microliters, 100.0 microliters to 500.0 microliters, or greater than 500.0 microliters. In some cases, activating the volume selector 530 may activate one or more lockout stops of the fluid injection system 100. In some cases, actuating one or more lockout stops of fluid injection system 100 can include rotating syringe rod shaft 520 (e.g., rotating syringe rod shaft 520 can include rotating one or more lockout stops 560 to a position for engaging lockout assembly 500). As disclosed herein, the selected volume can relate to the distance one or more fluid delivery members 320 extend from distal end 114 of elongated member 110 when actuator 250 is engaged.For example, selecting a larger volume for delivery using the volume selector 530 can increase the distance that the one or more fluid delivery members 320 extend from the distal end 114 of the elongate member 110 when the actuator 250 is engaged. The volume selector 530 can include one or more volume setting indicators 550. The volume setting indicators 550 can include one or more visual and / or tactile features. In some cases, the one or more visual and / or tactile features can include information regarding possible injection volume settings.

[0185] (distal cap) 19A and 19B, the fluid injection system 100 may include a distal cap 600. The distal cap may be useful for preventing accidental leakage of fluids (e.g., agents) included by the fluid injection system 100. One or more fluids to be delivered to a target tissue may be harmful if allowed to contact non-target tissue (e.g., the skin of a subject or the skin of a bystander). In some cases, the distal cap 600 may prevent accidental contact of one or more fluids of the fluid injection system 100 with non-target tissue. The distal cap 600 may include one or more cap reservoirs 620. In some cases, the cap reservoirs 620 of the distal cap 600 may be useful for collecting fluids from the distal ends 328 of the one or more fluid delivery members 320. The distal cap 600 may also be useful in determining whether one or more channels, openings (e.g., apertures), or reservoirs of the system 100 are clogged and would impede fluid flow, and in ensuring that one or more channels and / or reservoirs of the fluid injection system 100 are completely filled (e.g., to prevent incomplete filling). For example, one or more fluid delivery members 320 of the fluid injection system 100 can be immersed in a fluid containing one or more agents contained within one or more insert reservoirs 630 of the distal cap 600 to fill one or more channels and / or reservoirs of the fluid injection system 100. Loading the fluid injection system 100 from the distal cap 600 may also be useful in reducing the volume of liquid and / or solid agents to be delivered to (e.g., injected into) tissue.

[0186] The distal cap 600 can include a cap insert 610. The cap insert 610 can include one or more cap reservoirs 620. In some cases, the cap insert 610 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30, 30-40, 40-50, or more than 50 cap reservoirs 620. The cap reservoirs 620 of the cap insert 610 can have a fluid capacity of 0.1 microliters to 10 microliters, 10 microliters to 20 microliters, 20 microliters to 50 microliters, 50 microliters to 100 microliters, 100 microliters to 200 microliters, 200 microliters to 500 microliters, 500 microliters to 1,000 microliters, or more than 1,000 microliters.

[0187] The distal cap 600 can include an insert receiver 630. In various embodiments, the cap insert 610 and the insert receiver 630 are configured such that the cap insert can be fitted inside the insert receiver 630, for example, while the cap insert 610 and the insert receiver 630 are each seated on the distal end 114 of the elongate member 110. In some cases, the inner diameter of the distal portion of the insert receiver 630 is the same as the outer diameter 650 of the distal portion of the cap insert 610. In some cases, the inner diameter of the distal portion of the insert receiver 630 is 0.1 mm to 0.2 mm, 0.2 mm to 0.5 mm, 0.5 mm to 1.0 mm, 1.0 mm to 5.0 mm, or 5.0 mm larger than the outer diameter 650 of the distal portion of the cap insert 610. The distal end of the insert receiver 630 can have an outer diameter 670 between 0.5 mm and 1.0 mm, between 1.0 mm and 2.0 mm, between 2.0 mm and 3.0 mm, between 3.0 mm and 4.0 mm, between 4.0 mm and 5.0 mm, between 5.0 mm and 6.0 mm, between 6.0 mm and 7.0 mm, or greater than 7.0 mm.

[0188] The insert receiver 630 can include one or more receiver cutouts 640. The receiver cutouts 640 can be, for example, cut-out features in the insert receiver 630 located on a distal edge of the insert receiver 630. In some cases, the receiver cutouts 640 can be useful in removing the cap insert 610 from the insert receiver 630. For example, a cap insert 610 with a distal end that is flush with the distal end of the insert receiver 630 can be removed from the insert receiver 630 by contacting the cap insert 610 in a space created by the receiver cutouts 640 and guiding the cap insert 610 out of the insert receiver 630. In some cases, the cap insert 610 can be removed from the distal end 114 of the elongated member 110 without removing the insert receiver 630 from the distal end 114 (e.g., when a used cap insert is being replaced with a different cap insert).

[0189] The distal cap can include a proximal end 602 and a distal end 604. In some cases, the proximal end 602 of the distal cap 600 is shaped to receive the distal end 114 of the elongate member 100. The proximal end 602 of the distal cap 600 can have an inner diameter 660 that is equal to or slightly larger than the outer diameter of the distal end 114 of the elongate member 110. In some cases, the distal end 114 of the elongate member 110 has structural features configured to retain the distal cap on the distal end of the elongate member 110. For example, the distal end 114 of the elongate member 110 can include an indentation shaped to mate with a lip or fastening mechanism on the proximal end 602 of the distal cap 600.

[0190] The distal cap 600 can be used to fill (e.g., prime) at least a portion of the fluid injection system 100 with one or more fluids, including one or more active substances.

[0191] (cartridge) 20A and 20B, the low-profile fluid injection system 100 may include a cartridge 432. The cartridge 132 may be removable from the fluid injection system 100. The cartridge 432 may include a cartridge shell 470. In some cases, the cartridge 132 is disposable. In some cases, the cartridge 432 is reusable. The cartridge 432, or one or more portions thereof, may be autoclavable. A fluid injection system 100 including a removable and / or reusable cartridge 432 can have improved versatility. For example, one or more cartridges 432 to be used with the fluid injection system 100 can be prepared in advance. In some cases, one or more cartridges 432 can be prepared remotely and transported or shipped to the location where they will be used. The low-profile fluid injection system 100, which includes one or more cartridges 432, can also be easily reconfigured from a first injection configuration to a second injection configuration (e.g., by substituting and / or rearranging one or more cartridges 432 used in the fluid injection system).

[0192] Cartridge 432 may be fully or partially filled with fluid prior to being inserted or loaded into chamber 400. Cartridge 432 may be pre-filled by a technician or pharmacist before cartridge 432 is loaded into a chamber of device 100. In some cases, pre-filled cartridge 432 can be stored, shipped, or frozen. Alternatively, or in combination, cartridge 432 may be loaded with fluid after being inserted or loaded into chamber 400. For example, cartridge 432 may be loaded with a fluorescent label prior to being inserted into chamber 400, and subsequently loaded with a drug compound after being inserted into chamber 400.

[0193] The cartridge may be preloaded with one or more agents (e.g., one or more therapeutic agents, one or more indicators, and / or one or more buffers or excipients). In some embodiments, the cartridge 432 may be preloaded with one or more indicators (e.g., labels). Alternatively, or in combination, the cartridge 432 may be preloaded with one or more therapeutic compounds.

[0194] Cartridge 432 can include a cartridge stopper 450. Cartridge stopper 450 can include one or more of a variety of materials useful for capping vials. Cartridge stopper 450 can include a polymer or copolymer. Cartridge stopper 450 can include natural or synthetic rubber (e.g., butyl rubber). In some cases, cartridge stopper 450 includes a self-healing material (e.g., a material capable of maintaining a watertight seal after being punctured). In some cases, cartridge 432 can be loaded by injecting one or more fluids (e.g., one or more agents) through cartridge stopper 450.

[0195] In some cases, cartridge 432 further includes a stopper seal 460. In some cases, stopper seal 460 is configured to hold cartridge stopper 450 in place at an end (e.g., proximal end 432b) of cartridge 432 and / or to assist in maintaining a watertight seal at the end of cartridge 432 (e.g., by exerting a compressive force on the cartridge stopper within the end of cartridge 432). Stopper seal 460 can include a metal, polymer, copolymer, or ceramic material. In some cases, stopper seal 460 is a crimp seal.

[0196] The cartridge 432 can include a cartridge plunger 440. In some cases, the cartridge plunger 440 is slidably inserted into or positioned at a longitudinal position inside the cartridge 432. For example, the cartridge plunger can be positioned at a longitudinal position inside the cartridge 432 closer to the distal end 432a of the cartridge 432 than to the proximal end 432b of the cartridge 432. In some cases, the cartridge plunger 440 is translated distally along the longitudinal axis of the cartridge 432 when the cartridge 432 is loaded with one or more fluids (e.g., one or more active substances), for example, by injecting one or more fluids through a cartridge stopper 450. The cartridge plunger 440 can include a plunger interface 442. In some cases, the plunger interface 442 can include a material (e.g., a self-healing material) that can be pierced by a needle. In some cases, the plunger interface 442 can include a feature configured to place the contents of the cartridge 432 in fluid communication with the fluid delivery channel 270 , such as a port configured to engage with the delivery channel interface 290 .

[0197] The cartridge 432 can include one or more cartridge reservoirs configured to hold a volume of fluid 480. In some cases, the cartridge 432 includes multiple cartridge reservoirs. In some cases, two or more of the multiple cartridge reservoirs of the cartridge 432 can be in fluid communication with one another. For example, pressure applied to the cartridge plunger 440 (e.g., when the cartridge 432 is loaded into the chamber 400 of the fluid injection system 100) can mix the contents of the two or more cartridge reservoirs of the cartridge 432.

[0198] The various cartridges 432 disclosed herein may be configured to hold a volume of fluid 480 (e.g., by slidably inserting a cartridge plunger 440). The cartridge 432 can be configured to hold a specific volume of fluid by changing the position of the cartridge plunger 440. In some cases, cartridge 432 is configured to hold a volume between 1 microliter and 500 microliters, between 10 microliters and 500 microliters, between 100 microliters and 500 microliters, between 200 microliters and 500 microliters, between 300 microliters and 500 microliters, between 1 microliter and 250 microliters, between 1 microliter and 100 microliters, between 1 microliter and 50 microliters, between 1 microliter and 40 microliters, between 1 microliter and 30 microliters, between 1 microliter and 20 microliters, between 1 microliter and 10 microliters, between 1 microliter and 9 microliters, between 1.25 microliters and 9 microliters, between 2 microliters and 8 microliters, between 3 microliters and 7 microliters, between 3.75 microliters and 6.5 microliters, between 4 microliters and 6 microliters, or between 0.1 microliters and 1 microliter. The volume of the cartridge 432 may be within a range bounded by any two of the following values: about 1 μl, about 2 μl, about 3 μl, about 4 μl, about 5 μl, about 6 μl, about 7 μl, about 8 μl, about 9 μl, or about 10 μl. Each of the multiple cartridges 432 of the fluid injection system 100 may hold the same volume of fluid. Alternatively, one or more of the multiple cartridges 432 may hold different volumes of fluid.

[0199] The cartridge 432 can have an outer diameter of 2.0 mm to 3.0 mm, 3.0 mm to 4.0 mm, 4.0 mm to 5.0 mm, 5.0 mm to 6.0 mm, 6.0 mm to 7.0 mm, 7.0 mm to 8.0 mm, 8.0 mm to 9.0 mm, 9.0 mm to 10.0 mm, or greater than 10.0 mm. The cartridge 432 can have an inner diameter of less than 1.0 mm, 1.0 mm to 2.0 mm, 2.0 mm to 3.0 mm, 3.0 mm to 4.0 mm, 4.0 mm to 5.0 mm, 5.0 mm to 6.0 mm, 6.0 mm to 7.0 mm, 7.0 mm to 8.0 mm, 8.0 mm to 9.0 mm, 9.0 mm to 10.0 mm, or greater than 10.0 mm.

[0200] The cartridge 432 may be configured to be inserted into a correspondingly shaped recess or chamber 400 in the housing of the fluid injection system 100. In some cases, the cartridge 432 can be held in place by the cartridge retainer 430 after being loaded into the chamber 400 of the fluid injection system 100. The cartridge retainer 430 can include various structural elements for holding the cartridge 432 in place (e.g., during use of the fluid injection system 100). For example, the cartridge retainer 430 can include a spring mechanism for biasing the cartridge 432 against the chamber 400 and / or against the cartridge abutment 410. In many cases, the cartridge retainer 430 includes a clip for holding the cartridge 432 in place within the chamber 400. The cartridge retainer 430 can include a lip shaped to fit over the proximal end 432b of the cartridge 432 when the cartridge 432 is pressed against the cartridge abutment 410. An exemplary embodiment of cartridge retainer 430 comprises a lip shown in FIG. 4B.

[0201] In some cases, positioning the cartridge 432 within the chamber 400 (e.g., by engaging the cartridge 432 with the cartridge retainer 430) can cause the cartridge abutment 410 to apply a compressive force to the cartridge plunger 440. In some cases, the force applied to the cartridge plunger 440 (e.g., by the cartridge abutment 410) can cause pressurization of the fluid 480 inside the cartridge 432. In some cases, pressurization of the fluid 480 inside the cartridge 432 can cause the fluid 480 to flow from the cartridge 432 into the fluid delivery channel 270 (e.g., via the cartridge interface 420). In some embodiments, the cartridge 432 can be directly coupled to the proximal end of the fluid delivery member 320 (e.g., when the cartridge 432 is engaged with the cartridge retainer 430).

[0202] In some embodiments, the cartridge 432 may be loaded with fluid prior to inserting the distal end 114 of the elongate member 110 into the body. Alternatively, or in combination, the cartridge 432 may be loaded with fluid during or after inserting the distal end 114 of the elongate member 110 into the body.

[0203] In some embodiments, the cartridge 432 may be loaded into the system 100 prior to inserting the distal end 114 of the elongate member 110 into the body. Alternatively, or in combination, the cartridge 432 may be loaded into the system 100 during or after inserting the distal end 114 of the elongate member 110 into the body.

[0204] In some embodiments, one or more of the cartridges 432 may include a labeling reservoir as described herein. One or more cartridges 432 may, for example, hold a labeling agent therein. One or more cartridges 432 may be configured to mix the labeling agent and the therapeutic agent therein, such that the fluid injected into the tissue includes both the labeling agent and the therapeutic agent within the same injection column. In some cases, mixing may occur prior to injection of the therapeutic agent. In some cases, mixing may occur during injection of the therapeutic agent.

[0205] (Agent) The fluid 480 of the cartridge 432 can include one or more agents. The one or more agents of the fluid 480 can be therapeutic agents. For example, the fluid 480 can include one or more drugs, such as an anti-tumor drug. In some cases, the fluid 480 includes multiple agents. In some cases, the fluid 480 includes multiple therapeutic agents. Often, the two cartridges 432 of the fluid injection system 100 include different agents or different combinations of agents.

[0206] In some cases, one or more agents of fluid 480 may be a diagnostic agent. For example, fluid 480 may include an indicator agent. The indicator agent may include a fluorescent dye, a chromogenic dye, or a fibrinogen marker.

[0207] One or more agents of fluid 480 can include fluorescent tracking molecules, which can be useful for tracking regions of a target tissue that are contacted by fluid 480 injected into the target tissue (e.g., using fluid injection system 100). Importantly, the use of fluorescent tracking molecules in fluid injection system 100 can aid in determining the relative location and / or orientation of the target tissue, for example, during a second time point or after explantation of the target tissue.

[0208] The fluorescent tracer molecule can be a microparticle. The fluorescent tracer molecule can be a fluorescent tracer microsphere (FTM). For example, the fluorescent tracer molecule can be a polymer microsphere. The fluorescent tracer molecule can include polystyrene. In some cases, polystyrene can provide performance advantages during data acquisition and analysis steps. For example, polystyrene is commonly used in histology processes and is resistant to harsh chemicals that may be used during imaging and analysis of injected tissue, such as xylene, which can adversely affect certain polymers and / or leach dyes from indicator molecules containing various other materials. In some cases, tissue processing may involve the use of an aliphatic hydrocarbon (e.g., Clear-Rite) to improve dye retention of the FTM particles. TM 3) can be used. Crosslinking agents can be used to improve the chemical and heat resistance properties of FTM particles. For example, FTM particles can include DVB-crosslinked polystyrene. DVB crosslinking agents can be used at concentrations of 0.1% to 5% during FTM particle formation. In some cases, fluorescent tracking microspheres (FTM) can include benzoguanamine formaldehyde resin. In some cases, fluorescent tracking microspheres can offer the advantage of allowing the microspheres to be sectioned using common sectioning practices. In such situations, it may be less likely that the microspheres will be dragged across the tissue into which they are injected during the sectioning process, which can cause tissue tearing and / or particle displacement relative to each other or the tissue.

[0209] Advantages of fluid injection system 100 with fluorescent tracking microspheres (FTMs) include the ability to precisely track one or more agents and / or fluids delivered to tissue, and to process tissue containing one or more FTMs without damaging the tissue or causing significant adverse effects on the brightness of the FTMs. In addition, the FTMs retain excellent brightness and visibility within tissue, even when the FTMs are formulated with relatively small amounts of dye.

[0210] FTMs can be delivered to multiple sites 703 within tissue 702 using a fluid injection system such as system 100 disclosed herein, and one or more FTMs are detected within tissue 702 prior to tissue ablation (e.g., as shown in FIGS. 21A-21D). By using a radiation source 800, such as a visible or ultraviolet light source (e.g., in the form of a handheld device), it is possible to determine the location, orientation, and / or one or more boundaries of one or more injection sites 703 within the tissue, even if the injected tissue has moved or the injection site has healed. In many cases, the use of FTMs in such situations is superior to both the use of metal fiducial implants and the use of tattoos in conjunction with imaging methods (e.g., fluoroscopy, ultrasound, or computed tomography) at least because FTMs can be easily imaged using handheld radiation sources, they do not require specialized detectors (e.g., they can often be visually identified when imaged), and they are compatible with assays (e.g., immunohistochemistry, fluorescence imaging with or without antibodies, and in situ hybridization) performed on tissue after delivery of the tracking particles (e.g., after tissue excision). Thus, the use of FTM particles can reduce or eliminate the need for large, expensive equipment, for example, because FTM particles can be quickly and intuitively imaged and evaluated using smaller (e.g., handheld) radiation sources such as handheld ultraviolet lights. The lights and filters used to illuminate and detect the injection site are compact and handheld, and may allow for rapid and economical detection compared to the large fluoroscopic instruments used in surgical settings to detect metal fiducial markers placed within tumors during the biopsy and resection process.

[0211] Other examples of infusion devices, systems, and methods that can be used in conjunction with FTM include those disclosed in U.S. Patent Nos. US8,349,554, US8,657,786, US8,834,428, US8,475,412, US8,672,887, US8,926,567, US9,205,201, and US9,205,202 (incorporated herein in their entirety for all purposes). The methods of using FTMs disclosed herein can also be applied to other devices, systems, and methods, such as those disclosed in U.S. Patent Nos. 8,349,554, 8,657,786, 8,834,428, 8,475,412, 8,672,887, 8,926,567, 9,205,201, and 9,205,202 (which are incorporated herein in their entireties for all purposes).

[0212] It may be advantageous to control the size of fluorescent tracking microspheres (FTMs) to be delivered to tissue. For example, particles with diameters greater than 100 nanometers resist migration after injection, which may be due to changes in local fluid pressure, diffusion, and / or tissue deformation. Particles with diameters of 5 micrometers or smaller may be less likely to be phagocytosed by cells within the injected tissue. Fluorescent tracking molecules may be 0.1 micrometer to 1.0 micrometer, 1.0 micrometer to 5.0 micrometer, 5.0 micrometer to 10.0 micrometer, 4.0 micrometer to 11.0 micrometer, 4.0 micrometer to 12.0 micrometer, or 1.0 micrometer to 20.0 micrometer. In many cases, the plurality of FTM particles to be delivered to tissue (e.g., loaded into a cartridge or distal cap, or located within a fluid delivery channel or reservoir of system 100) can have diameters within a CV range of 0.1% to 1.0%, 1.0% to 2.0%, 2.0% to 3.0%, 3.0% to 4.0%, 4.0% to 5.0%, or 5.0% to 10.0%. In some cases, a first cartridge 432 or fluid delivery channel 270 can comprise a population of FTMs having a first diameter, and a second cartridge or fluid delivery channel 270 can comprise a second population of FTMs having a second diameter. In some cases, a first set of one or more agents to be delivered to a tissue with a first population of FTMs can be differentiated from a second set of one or more agents to be delivered to a tissue with a second population of FTMs by the relative or absolute size (e.g., diameter) and / or signal (e.g., emitted fluorescent wavelength) of the first and second FTM populations. Thus, it is possible to generate many clearly distinguishable FTM populations using a relatively small number of fluorescent dyes, which may require fewer fluorescent imaging channels of a detector to distinguish. For example, using two diameters of FTM particles and two different dyes, it is possible to generate six uniquely distinguishable FTM particle populations (e.g., using either a single dye or two dyes together).Fluorescent tracking microspheres (e.g., sized 5.0 micrometers to 10.0 micrometers) are small enough to travel with the fluid injected into the target tissue, small enough that they are unlikely to be phagocytosed, and large enough that they are likely to remain localized during tissue analysis and processing, if applicable.

[0213] Fluorescent tracking microspheres (FTM) can include dyes. For example, FTM particles can include polymer microspheres dyed with one or more dyes. Fluorescent tracking molecules can include organic dyes. The organic dyes of fluorescent tracking molecules can be fluorescent organic dyes. In some cases, aqueous dyes, such as aqueous ultraviolet dyes, can be used with FTM particles; however, organic dyes are superior in many applications due to their reduced tendency for leaching of particles in aqueous environments. FTM can be formulated to include dyes (e.g., fluorescent dyes) within the range of 0.1% to 0.4%, 0.01% to 1%, or 0.1% to 5% (wt. to wt.) weight content per bead. In some cases, the fluorescent tracking molecules can have an excitation wavelength of 450 nm to 495 nm or 300 nm to 600 nm. Dyes that can be used in conjunction with FTM (e.g., incorporated into FTM particles) include Nile Red, Yellow 160, BODIPY dyes, Lucifer Yellow, xanthene derivatives (e.g., fluorescein, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine (TRITC), Oregon Green, eosin, Texas Red), cyanine derivatives (e.g., Cy2, Cy3, Cy3B, Cy3.5, Cy5, Cy5.5, Cy7, cyanine indocarbocyanine, oxacarbocyanine, thiazolinone ... The dyes may include, for example, acarbocyanine, merocyanine), squaraine derivatives, squaraine rotaxane derivatives, naphthalene derivatives, coumarin derivatives, oxadiazole derivatives (e.g., pyridyloxazole, nitrobenzoxadiazole, benzoxadiazole), anthracene derivatives, pyrene derivatives (e.g., Cascade Blue), oxazine derivatives (Nile Red, Nile Blue, cresyl violet, oxazine 170, etc.), acridine derivatives, arylmethine derivatives, or tetrapyrrole derivatives. In some cases, each cartridge 432 comprising the fluid injection system 100 can have a different detection wavelength or range of detection wavelengths. The dye of the FTM particles can generate a detectable signal (e.g., upon excitation by a radiation source such as a visible light lamp or ultraviolet light). In some cases, the signal from the FTM particles can be detected using one or more detectors.In some cases, the signal from the FTM particles is visually assessed (e.g., by a surgeon, technician, nurse, histologist, researcher, or other scientist). The signal from the FTM particles (e.g., from the dye of the FTM particles) can be between 350 nm and 750 nm, between 400 nm and 600 nm, between 450 nm and 550 nm, between 400 nm and 500 nm, between 500 nm and 600 nm, above 750 nm, or below 350 nm.

[0214] In many cases, fluid injection system 100 can be loaded with FTM particles that include different dyes or combinations of dyes. For example, a first fluid delivery member can be loaded with and / or used to deliver a first population of FTMs that includes one or more different sets of dyes than a second population of FTM particles that is loaded into or delivered using a second fluid delivery member. Thus, a first set of one or more agents to be delivered to tissue from the first fluid delivery member can be differentiated from a second set of one or more agents to be delivered to tissue from the second delivery member.

[0215] Due to the strong activation of fluorescent tracking microspheres, FTM can be added to drugs for delivery to tissues at concentrations of 0.1% to 5%, 5% to 10%, 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, or greater than 50%. In some cases, FTM (e.g., polystyrene FTM) can be formulated (e.g., with one or more agents) into fluids to be delivered to tissues at 35 milligrams per milliliter (mg / ml) to 45 mg / ml, 25 mg / ml to 50 mg / ml, 15 mg / ml to 60 mg / ml, 10 mg / ml to 65 mg / ml, 0.01 mg / ml to 1 mg / ml, 1 mg / ml to 10 mg / ml, or greater than 60 mg / ml. In some cases, formulation of FTM in a fluid for delivery in the range of 10 mg / ml to 50 mg / ml provides the best brightness and density of FTM particles.

[0216] One or more agents of fluid injection system 100 may be implantable agents. For example, one or more agents comprising system 100 or delivered to tissue using system 100 may be implantable agents, such as implants configured for controlled release of a substance. The implantable agent may include a pellet, powder, slurry, or microdevice. In some cases, the implantable agent may include an injectable micropump. In some cases, the implantable agent may include a degradable matrix, such as a degradable polymer matrix. The implantable agent may be configured to deliver (e.g., release) one or more agents (e.g., drugs) into tissue during and / or after injection. In some cases, one agent may be delivered to tissue by the implantable agent. In some cases, multiple agents may be delivered to tissue by the implantable agent. The implantable agent delivered by system 100 may include a bioabsorbable material.

[0217] An implantable agent (e.g., a degradable polymer particle or a micropump) can be configured to release one or more agents into tissue at a constant rate or at a variable rate. In some cases, the rate of release of one or more agents into tissue by the implantable agent can increase over time. In some cases, the rate of release of one or more agents into tissue by the implantable agent can decrease over time. In some cases, the rate of release of one or more agents into tissue by the implantable agent can both increase and decrease over time. In some cases, control of the rate of release of an agent into tissue by the implantable agent can be achieved by engineering the degradable particle to have greater or lesser amounts of agent at different locations within the implantable agent, and / or by selecting the composition of the implantable agent (e.g., by selecting the type or ratio of one or more polymers or copolymers comprising various portions of the implantable agent) and / or by varying the distribution of the agent to be delivered through the implantable agent. The use of implanted agents can be advantageous to control the exposure of tissue to one or more agents.

[0218] In some cases, the implantable agent may be, for example, a fiducial marker for marking a location within tissue. For example, the implantable agent may include one or more pellet- or tablet-shaped implants that may be delivered to tissue through one or more fluid delivery members 320 to mark an injection site. In some cases, the implantable agent including the fiducial marker may include a metal or metal alloy. In some cases, the implantable agent including the fiducial marker may be detectable using an electromagnetic field and / or using a radioactive source or visual inspection.

[0219] (Application) The devices, systems, and methods described herein may be used for the delivery of any agent to solid tissue for therapeutic or non-therapeutic purposes.

[0220] The devices, systems, and methods described herein may be used for preclinical drug development and testing, and / or clinical drug development and testing.

[0221] The devices, systems, and methods described herein may be used for personalized medicine applications, such as to determine the most effective therapeutic drug or agent combination for tumor treatment of an individual patient.

[0222] The devices, systems, and methods described herein may be used to access and deliver one or more fluids to a target site within the body. The target site may be, for example, about 1 cm to about 300 cm away from a patient access point (e.g., mouth, skin surface, rectum, etc.). The target site may be, for example, about 1 cm to about 30 cm below the skin surface. The target site may be, for example, 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 1 cm to 20 cm, 5 cm to 15 cm, 7 cm to 13 cm, or 9 cm to 11 cm below the skin surface. The target site may be, for example, about 4 cm to about 20 cm below the skin surface. The target site may be, for example, about 100 cm to about 250 cm away from the patient access site.

[0223] The target site may be a superficial target site that can be accessed, for example, percutaneously, for example, at a depth of about 0.2 cm to about 4 cm within a human patient.

[0224] The target site may be an intermediate target site that can be accessed, for example, percutaneously, for example, at a depth of about 4 cm to about 20 cm within a human patient.

[0225] The target site may also be a deeper target site that can be accessed, for example, endoscopically or interventionally, for example, at a depth of about 100 cm to about 250 cm from an entry point within a human patient (e.g., from the mouth to the stomach).

[0226] In some cases, the target site may be a tumor. The tumor may be located anywhere within the patient's body. For example, the tumor may be located within the patient's skin, breast, brain, prostate, colon, rectum, kidney, pancreas, lung, liver, heart, stomach, intestine, ovary, testicle, cervix, lymph node, thyroid, esophagus, head or neck, eye, bone, or bladder. The tumor may be located anywhere within the body where solid tumors are found.

[0227] Tumors that may be treated using the devices, systems, and methods described herein include, but are not limited to, gastric cancer, esophageal cancer, liver metastasis from colon cancer, papillary renal cell carcinoma, head and neck cancer, thyroid cancer, ovarian cancer, cervical cancer, lymphoma, skin cancer (e.g., melanoma, etc.), pancreatic cancer, prostate cancer, testicular cancer, renal cell carcinoma, breast cancer, colon cancer, brain cancer (e.g., medulloblastoma, glioblastoma, etc.), lung cancer (e.g., mesothelioma, small cell lung cancer, non-small cell lung cancer, etc.), liver cancer (e.g., hepatocellular carcinoma, etc.), bladder cancer, rhabdomyosarcoma, and osteosarcoma.

[0228] The devices, systems, and methods described herein may be used to deliver one or more therapeutic agents to a tissue of interest. The therapeutic agent may be delivered in liquid form. Exemplary therapeutic agents for cancer treatment include, but are not limited to, general chemotherapy drugs, bisphosphonates, hormone therapy, antibodies, immunotherapy (e.g., CAR T cells, NK cells, etc.), steroids, angiogenesis inhibitors, proteasome / protease inhibitors, tyrosine kinase inhibitors, interferons, interleukins, and the like, and any combination thereof.

[0229] The devices, systems, and methods described herein may be used to deliver one or more labels (also referred to herein as tags or probes). The label may be delivered with another agent, e.g., a therapeutic agent, or as a single agent. The label may be conjugated to another agent, e.g., a therapeutic agent, or delivered with another agent in solution (unbound). The label may aid in the detection of the injection site or column using conventional imaging techniques, such as those described herein and known to those skilled in the art. Exemplary labels include, but are not limited to, fluorescent labels, radioactive labels, gas chromatography / mass spectrometry (GCMS) tags, chemically inert visible infusion tracking dyes (ITDs), and the like, as well as combinations thereof.

[0230] (method) 17 shows a method 1700 of injecting fluid into a tumor in a patient's body using a fluid injection system 100 as described herein. The method may use one or more of the systems and devices described herein.

[0231] In step 1701, a fluid injection system may be provided. The fluid injection system may be any of the fluid injection systems 100 described herein. The fluid injection system may include, for example, an elongate member, multiple fluid delivery members disposed therein, and multiple fluid reservoirs (e.g., fluid delivery channels) fluidly coupled to the multiple fluid delivery members. Each of the multiple fluid reservoirs (e.g., fluid delivery channels) may be coupled to a single fluid delivery member, and each fluid delivery member is fluidically independent from all other fluid delivery members.

[0232] Providing a fluid injection system 100 (e.g., as in step 1701) can include providing a cartridge 432 such as those disclosed herein. The cartridge 432 can be loaded into the fluid injection system 100. For example, the cartridge 432 can be loaded into the fluid injection system 100. Often, the cartridge 432 is loaded into the chamber 400 of the fluid injection system 100. Loading the cartridge 432 into the fluid injection system 100 can include sliding the cartridge 432 through the chamber 400 with the distal end 432a of the cartridge 432 oriented closer to the distal end 114 of the elongated member 110 than the proximal end 432b of the cartridge 432. Loading the cartridge 432 can include contacting the cartridge abutment 410 with the cartridge plunger 440. In some cases, loading the cartridge 432 into the fluid injection system 100 includes engaging the cartridge 432, or a portion thereof (e.g., the cartridge plunger 440 or the plunger interface 442), with the cartridge interface 420. Engaging the cartridge 432, or a portion thereof, with the cartridge interface 420 may include releasably engaging the cartridge 432 with the cartridge interface 420. For example, the cartridge 432, or a portion thereof (e.g., the cartridge plunger 440 or the plunger interface 442) may be pierced by the cartridge interface 420 (e.g., the cartridge interface 420 comprises a needle or a pointed channel) or threaded onto the threads of the cartridge interface 420. Engaging the cartridge 432, or a portion thereof, with the cartridge interface 420 (e.g., via a delivery channel 270, which may extend through the cartridge interface 420 and / or the cartridge abutment 410) may include achieving a fluid connection between the fluid 480 contained within the cartridge 432 and one or more fluid delivery members 320.An exemplary embodiment of loading cartridge 432 into system 100 is shown in Figures 4A and 4B.

[0233] In step 1702, at least a portion of fluid injection system 100 (e.g., elongate member 110 or a portion thereof) may be inserted into tissue (which may include, e.g., a portion of a subject's body). The dimensions of elongate member 100 (e.g., as disclosed herein) enable use of fluid injection system 100 in applications where minimally invasive intervention would be contraindicated (e.g., where the tumor is inoperable and / or systemic intervention may lead to adverse effects such as an acute immune response). Insertion may occur with one or more fluid delivery members 320 in an unexpanded configuration (e.g., retracted within elongate member 110 of system 100). In some cases, a disposable or autoclavable coaxial sheath may be positioned around elongate member 110 prior to inserting at least a portion of fluid injection system 100 into tissue, for example, to enable multiple uses of system 100 (e.g., at different insertion points in the subject's body). In some cases, the coaxial sheath can be anchored to the fluid injection system 100 by connecting at least a portion of the coaxial sheath to the distal coupling 190 .

[0234] In step 1703, the distal end of the fluid injection system may be positioned at or near a target tissue (e.g., a tumor or portion within a patient's body). The system may be positioned, for example, so that the elongated member 110 is in close proximity to, e.g., touching, the target tissue. Positioning the system may include, for example, positioning the system under the guidance of an imaging system, for example, using an ultrasound or fluoroscopic imaging system.

[0235] In step 1704, one or more fluid delivery members 320 may be extended from the distal end 114 of the elongated member 110 into the target tissue (e.g., tumor tissue). The extension of the fluid delivery members 320 may be actuated by an actuator 250, which may comprise a mechanical actuator and / or an electromechanical actuator. The actuator may comprise, for example, a thumbwheel, a level, an electric actuator, or the like. Actuation of the actuator may be automatic or manual. The multiple fluid delivery members may be configured to extend out from the distal end of the elongated member with a predetermined pattern or curvature. The fluid delivery members may be configured to angle away from the longitudinal axis 111 of the elongated member 110. The fluid delivery members may be configured to angle away from the longitudinal axis 111 of the elongated member 110, for example, at one or more oblique angles relative to the longitudinal axis.

[0236] In step 1705, fluid may be injected into the tumor via the fluid delivery member. As disclosed herein, injection of fluid into the targeted tumor tissue via the fluid delivery member can include disengaging the actuator 250. In some cases, injecting fluid into the tumor tissue (e.g., step 1705) can also include retracting the fluid delivery member back into the elongated member (e.g., step 1706). For example, some embodiments of the fluid injection system 100 can allow for simultaneous injection of fluid and withdrawal of the fluid delivery member.

[0237] In step 1706, the fluid delivery member may be retracted from the tumor into the elongated member. As disclosed herein, the fluid delivery member can be retracted (e.g., to an unextended configuration) when the actuator 250 is disengaged.

[0238] In step 1707, the fluid injection system may be removed from the patient's body.

[0239] In step 1708, the tumor may be excised for analysis. The tumor may be excised immediately after fluid injection. The tumor may be excised within 4 hours of fluid injection, e.g., 4 to 24 hours, 4 to 48 hours, 6 to 24 hours, or 4 to 8 hours. The tumor may be excised within several days of fluid injection, e.g., about 1 to about 7 days. The tumor tissue may be analyzed as described herein. For example, the tumor tissue may be analyzed to determine the effectiveness of one or more therapeutic drugs or combinations of agents on the tumor.

[0240] Although the above steps illustrate a method 1700 for injecting fluid into a tumor in a patient's body using a fluid injection system according to an embodiment, many variations based on the present teachings are described herein. Steps may be completed in a different order. Steps may be added or deleted. Some of the steps may include sub-steps. Many of the steps may be repeated as often as is beneficial or necessary for the desired procedure.

[0241] For example, in some embodiments, steps 1705 and 1706 may optionally occur simultaneously, such that fluid is injected into the tumor while the fluid delivery member is slowly retracted back into the elongate member. Simultaneous injection and retraction may aid in the formation of an injection column, for example, as shown in Figures 15A-15C and described herein.

[0242] In some embodiments, one or more of the steps of method 1700 may be used for fluid injection into ex vivo or in vitro tissue, in such embodiments, steps 1702, 1707, and 1708 may be optional in certain embodiments of the methods disclosed herein.

[0243] 21A-21D, methods disclosed herein can include detecting and / or evaluating one or more agents delivered to (e.g., injected into) tissue prior to any resection or explantation of the injected tissue. Methods disclosed herein can include a step including inserting at least one fluid delivery member 320 into tissue 702, which can be a tissue of interest such as a target tissue containing a tumor (e.g., as shown in FIG. 21A). Methods disclosed herein can include a step including delivering (e.g., injecting) one or more agents into tissue 702 (e.g., as shown in FIG. 21B). Optionally, methods disclosed herein can include a step of allowing time to pass, e.g., allowing the one or more agents delivered to tissue 702 to diffuse or flow through the tissue and / or allowing the one or more agents to affect tissue 702 (e.g., as shown in FIG. 21C). A radiation source 800 can be used to detect (e.g., via illumination) one or more agents delivered to tissue 702 (e.g., as shown in FIG. 21D ). For example, the precise location 703 of one or more sites where one or more agents have been delivered to tissue can be rapidly and precisely determined by using radiation device 800. In some cases, the ability to detect one or more agents delivered to tissue 702 can be useful in determining the tissue or portion of tissue to be ablated (e.g., for analysis) based on, for example, the distribution of the one or more agents determined by imaging tissue 702. While a magnetic detector can be used in addition to or instead of radiation source 702 to detect and / or evaluate one or more agents (e.g., agents comprising magnetic tags) delivered to tissue 702, it will be understood by those skilled in the art that a radiation source allows for more precise determination of the spatial distribution of the agents and can be used in conjunction with agents that are not magnetic (e.g., pigmented agents and / or fluorescent agents).

[0244] Radiation source 800 can comprise an ultraviolet (UV) light source, a visible light source, an infrared illuminator, or a coherent light source. Radiation source 800 can be a handheld radiation source or a handheld emitter of a larger radiation source, which can enable detection and / or evaluation of an agent (e.g., FTM particles) prior to or during an ablation or explantation procedure. In some cases, a detector such as a camera or a fluorescence detector can be used to detect the signal of one or more agents delivered to tissue 702. In many cases, the one or more agents delivered to the tissue (optionally, radiation source 800) will be selected such that the signal from the one or more agents is visible to the naked eye. For example, FTM particles can be detected using radiation source 800 prior to ablation or explantation of tissue from a subject (e.g., as disclosed herein).

[0245] 21A-21D are representative examples of steps that may be included in the methods disclosed herein. Some methods disclosed herein may not include all of the steps shown in FIGS. 21A-21D, and some methods disclosed herein may include additional steps not shown in the figures. For example, methods disclosed herein may include detecting one or more agents (e.g., one or more fluorescent particles) in tissue 702.

[0246] (system) In some embodiments, system 100 is a handheld system. Alternatively, or in combination, system 100 may be configured for robotic control and operation, for example, using instructions from a computer-readable program as described herein.

[0247] In some embodiments, system 100 may be configured as a stand-alone access device for use in accessing a tissue site of interest, such as tumor tissue or a portion thereof. Fluid injection system 100 including elongated member 110 configured to puncture a subject's skin and / or penetrate internal tissue (e.g., target tissue such as cancerous tissue) is one of various embodiments of fluid injection system 100 disclosed herein that may be configured as a stand-alone access device. In some cases, a system configured to be a stand-alone access device may include a rounded or pointed end that may be useful for puncturing or separating biological tissue. In some cases, a system configured to be a stand-alone access device may include a rigid elongated member that may be useful for manipulating or directing a needle (e.g., one or more fluid delivery members 320) for injection into, through, or around tissue.

[0248] In some embodiments, system 100 may be configured for use with conventional non- or minimally invasive surgical access devices and introducers known to those skilled in the art. For example, elongate member 110 may have an outer diameter sized to fit within the working channel of a conventional biopsy access needle, a conventional endoscope, a conventional laparoscopic system, a conventional vascular access sheath, or the like. System 100 may be inserted into the working lumen of a conventional access device to reach the tissue of interest. The versatility of fluid injection system 100 disclosed herein for use with existing access devices and needles limits the training a practitioner would need to master the use of fluid injection system 100 when performing the techniques and assays described herein.

[0249] Alternatively, or in combination, system 100 may further include its own introducer for providing access to a tumor site of interest. For example, system 100 can include an introducer sheath for puncturing or penetrating tissue. The introducer of system 100 can be coaxial with the axis (e.g., longitudinal axis) of system 100 or with the axis (e.g., longitudinal axis) of a component of system 100, such as elongated member 110. In some cases, the introducer of system 100 is separate from the housing of system 100 and / or another component of system 100, such as elongated member 110 of system 100. The introducer can be used to create a pathway to the target tissue (e.g., by inserting the introducer into the tissue of interest). In some cases, the introducer is used to create a pathway to the target tissue before another component of system 100, such as elongated member 110, is inserted into the target tissue and / or any intervening tissue. In some cases, the introducer can be coupled to a distal coupling 190 of the system 100 (eg, the distal coupling 190 comprises a luer lock coupling component).

[0250] The devices, systems, and methods described herein may be used in conjunction with an imaging system for perioperative imaging of the fluid injection system during use. Perioperative imaging may include imaging of the tumor prior to insertion of the system 100 into the patient, during insertion and positioning of the system 100 adjacent to the tumor, during fluid delivery, during retraction and removal of the injection system 100 from the patient, and / or after removal of the system 100. The imaging system may be any imaging system known to those skilled in the art. For example, the imaging system may be an ultrasound imaging system, an ultrasound biomicroscopy (UBM) system, an X-ray imaging system, a fluorescence imaging system, an optical coherence tomography (OCT) imaging system, a magnetic resonance (MR) imaging system, or any other imaging system known to those skilled in the art.

[0251] The systems or methods disclosed herein may comprise a computer or the use thereof. For example, one or more steps of method 1700 (or other method steps disclosed or inherently implied herein) may be performed by a fully or partially automated system comprising a computer. In some cases, fluid injection system 100 comprises a computer. In some cases, fluid injection system 100 comprises an imaging system (e.g., to assist in the insertion, installation, and / or operation of the system). The computer can comprise a processor (e.g., a controller). The computer can comprise a non-transitory computer-readable memory that may comprise instructions that, when executed, may cause one or more components of the system to perform one or more steps of the methods disclosed herein. In some cases, the operation of the system depends fully or partially on one or more user inputs.

[0252] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It is understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

[Claim 1] A method, system, device, etc. as shown in the drawings.

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