Delivery device for a therapeutic substance

Abstract

In some embodiments, the delivery device includes a device actuator and a cannula portion through which the therapeutic substance is expelled. The cannula portion includes an outer shaft, a needle configured to move through the outer shaft, and a plunger configured to move through the needle, forming a positive displacement arrangement.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 009,572, filed on April 14, 2020. The entire disclosure of U.S. Provisional Application No. 63 / 009,572 is incorporated herein by reference.

[0002] The disclosed embodiments relate to delivery devices and related methods of use.

Background Art

[0003] Therapeutic substances are administered to patients through various methods. Various routes of administration are possible, including oral route, inhalation route, topical route, intravascular route, intramuscular route, subcutaneous route, intraperitoneal route, rectal / vaginal route, transluminal route, and more tissue - specific routes (e.g., intrathecal route, intraventricular route, and intra - articular route).

[0004] Cell - based therapeutic agents are generally administered using conventional delivery devices such as needles and syringes, or balloon - dilatation catheters. Injection of cell - based therapeutic agents through the skin or mucosa can help bypass part of the body's defense barriers and enable delivery of cell - based therapeutic agents to specific sites.

Summary of the Invention

Means for Solving the Problems

[0005] In some embodiments, a delivery device is provided. The delivery device can include a device actuator, a needle having a needle lumen, and a plunger configured to move through the needle lumen. Actuation of the device actuator can cause the needle to move in a retraction direction through a shuttle lumen and can cause the plunger to move in a deployment direction through the needle lumen, where the retraction direction is opposite the deployment direction.

[0006] In some embodiments, a delivery device is provided. The delivery device can include a device actuator, an outer shaft having a shuttle lumen, and a needle having a needle lumen. The needle can be configured to move through the outer shaft lumen. The delivery device can also include a plunger configured to move through the needle lumen. Actuation of the device actuator can cause the needle to move a first distance relative to the outer shaft and can cause the plunger to move a second distance relative to the outer shaft, where the first distance is different from the second distance.

[0007] In some embodiments, a delivery device is provided. The delivery device can include a device housing, a device actuator rotatably mounted relative to the device housing, a needle having a needle lumen, and a plunger configured to move through the needle lumen. Rotation of the device actuator can cause the plunger to move through the needle lumen.

[0008] In some embodiments, a method of delivering a substance through a delivery device is provided. The method can include rotating a device actuator by at least 10 complete rotations, resulting in the delivery of a volume of the substance through an outlet of the needle, the volume being greater than or equal to 1 microliter and less than or equal to 50 microliters.

[0009] In some embodiments, a method of loading cells into a delivery device is provided. The method can include moving cells into a needle lumen through a delivery end of the needle, venting air out of the needle lumen through a vent in the needle as the cells are moved into the needle lumen, and closing fluid communication through the vent after the cells have been moved into the needle lumen.

[0010] In some embodiments, a delivery device is provided. The delivery device can include a device housing and a needle. The needle can include a delivery end, a shaft, and a needle lumen extending through the shaft. The delivery device can also include a plunger configured to move through the needle lumen. The needle can also include a vent in the shaft, the vent being spaced from the delivery end.

[0011] In some embodiments, a delivery device is provided. The delivery device can include a device actuator, an outer shaft having a shaft lumen, and a needle having a needle lumen. The needle lumen can have a diameter between 0.1 mm and 0.7 mm (including 0.1 mm and 0.7 mm), and the needle can be configured to move through the shaft lumen. The delivery device can also include a plunger configured to move through the needle lumen, the plunger having a travel distance of at least 100 mm relative to the outer shaft.

[0012] In some embodiments, a method of delivering cells through a delivery device is provided. The method can include moving a needle of the delivery device to a target site and occupying a volume of space at the target site with the needle. The method can also include actuating a device actuator to cause the needle to retract from the volume of space and cause a plunger to move through the needle lumen of the needle toward the volume of space, and delivering cells into the volume of space simultaneously as the needle retracts from the volume of space.

[0013] In some embodiments, a delivery device is provided. The delivery device can include a device actuator, a needle having a needle lumen, a plunger configured to move through the needle lumen, and an indicator having an indicator indicative of a dosage to be delivered. The indicator can be mechanically coupled to the device actuator such that actuation of the device actuator causes the indicator of the indicator to physically move without an electrical input.

[0014] In some embodiments, a delivery device is provided. The delivery device can include a device housing and a needle having a needle lumen. The needle lumen can have a constant diameter over its entire length. The delivery device can also include a plunger configured to move through the needle lumen and a therapeutic agent fully contained within the needle lumen.

[0015] Since the present disclosure is not limited in this regard, it should be recognized that the foregoing concepts, as well as the additional concepts discussed below, may be arranged in any suitable combination. Further, other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments when considered in conjunction with the accompanying drawings.

[0016] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by like numerals. For the sake of clarity, it is possible that not all components are labeled in all of the drawings.

Brief Description of the Drawings

[0017]

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DETAILED DESCRIPTION OF THE INVENTION

[0018] In some conventional delivery devices, the delivery device is inserted into tissue, reaches a target site, a therapeutic agent is ejected from the delivery device and into the target site, and then the delivery device is withdrawn from the target site. As discussed in more detail below, some of these conventional delivery devices experience an unwanted backflow of the therapeutic agent out of the target site when the therapeutic agent is injected into the target site, as recognized by the inventors. Also, in some conventional cell delivery devices, cells provided in a fluid solution held within the device experience a "cell sedimentation" effect, in which the cells may aggregate within the device, for example, due to gravity, as recognized by the inventors. Cell sedimentation can result in a non-uniform concentration of cells being delivered, and it can cause variations in cell seeding density. Also, some conventional delivery devices do not limit a user's ability to rapidly eject a therapeutic agent, as recognized by the inventors. The inventors have recognized that a fast ejection rate can have a detrimental effect on the therapeutic agent. For example, in cell delivery, a fast ejection rate can reduce cell viability, for example, due to damage to the cells through shear stress. Also, the inventors have recognized that a fast ejection rate can cause unnecessary tissue trauma. In some conventional delivery devices, the therapeutic agent is backloaded into the device. Also, the inventors have recognized that backloading may require the therapeutic agent to traverse a long path through the device before reaching the delivery end of the device. Due to the long travel distance, some of the therapeutic agent may remain trapped within the path of the delivery device instead of being delivered, resulting in waste of the therapeutic agent. Moreover, in some conventional devices, the path can include diameter changes and / or non-smooth transitions, any of which can expose the therapeutic agent to detrimental effects.

[0019] The inventors recognized a need for a delivery device that addresses some or all of the problems described above with conventional delivery devices.

[0020] Some embodiments described herein include a delivery device that delivers a therapeutic substance via a volume displacement configuration, in which a plunger moves through a needle lumen and ejects the therapeutic substance out of the needle. In some embodiments, the therapeutic substance to be delivered is a cell or other particle having a particular diameter. However, it should be recognized that the therapeutic substance is not limited to cells or particles. Anywhere the term "cell" is discussed hereinafter, it may be replaced, as appropriate, with any other therapeutic substance.

[0021] According to one aspect, the delivery device can be configured to reduce backflow of the therapeutic substance out of the target site during injection of the therapeutic substance into the target site. In some embodiments, the needle can be arranged to retract while the plunger is advancing. The needle can be capable of creating a cavity in the tissue for the therapeutic substance. When the therapeutic substance is ejected from the needle, the needle is retracted, thereby providing a volume of space for the therapeutic substance to be present within the created cavity.

[0022] FIG. 1 illustrates this backflow concept via a delivery device 400 having an outer cannula 410 and a needle 500. The outer cannula 410 and needle 500 of the delivery device are inserted into tissue 210, and the needle 500 forms a cavity 211 in the tissue 210. A therapeutic substance 180 is being delivered to a target site 215. Since the target site 215 is occupied by the needle 500, the therapeutic substance 180 can be pushed upward 183 between the tissue cavity 211 and the delivery device 400 (instead of occupying the target site 215).

[0023] In contrast, FIG. 2 is a schematic diagram of one embodiment of a delivery device according to the aspects described herein, where the potential backflow issues described above can be reduced. The delivery device includes an outer shaft 40, a needle 50 movable within the outer shaft 40, and a plunger 60 movable within the needle 50. When the plunger 60 advances distally 201 and expels the therapeutic substance 180 from the needle 50 outwardly toward the target site 215, the needle 50 can simultaneously retract proximally 202 outwardly from the cavity 211. Without wishing to be bound by theory, the withdrawal of the needle while expelling the therapeutic substance from the needle can create a volume of space for the therapeutic substance to occupy and help reduce the backflow of the therapeutic substance from the target site 215 outwardly.

[0024] According to one aspect, the delivery device can be configured to help reduce cell sedimentation or particle sedimentation within the needle lumen. In some embodiments, the diameter of the needle lumen is less than 1 mm. In some embodiments, the ratio of the needle lumen diameter to the diameter of the cell or particle is less than 100:1.

[0025] According to one aspect, the delivery device can be configured to help a user control the ejection rate of the therapeutic substance. For some therapeutic substances (e.g., certain types of cells, etc.), a slower ejection rate can help reduce shear or other harmful effects on the cells, which can result in a higher survival rate of the delivered cells. Also, a slower ejection rate can reduce the risk of brain tissue trauma. In some embodiments, the device actuator is a rotary actuator. In some embodiments, a plurality of complete turns of the rotary actuator are required to deliver the total target volume.

[0026] According to one aspect, the delivery device can be configured to improve dose assurance. In some embodiments, the therapeutic substance is contained within the needle lumen, which is relatively small and has a constant diameter. In the case of cells, such an arrangement can help the cells move in conjunction with their fluid solution, which can help ensure delivery of a larger portion of the cells. In some embodiments, such an arrangement can help reduce cell sedimentation.

[0027] According to one aspect, the delivery device can be configured to help reduce waste of the therapeutic substance that may occur during loading of the substance into the delivery device. The inventors have recognized that in some delivery devices into which the substance is backloaded, a portion of the substance may be lost due to the long travel distance required from the loading end of the device to the ejection end of the device. Instead, the inventors have recognized that front-loading the delivery device can help reduce waste of the therapeutic substance. Thus, in some embodiments, the delivery device is configured to be front-loaded with the therapeutic substance. In some embodiments, the delivery device can include an air vent configuration to enable front-loading. In some embodiments, the delivery device can include an arrangement for removing air from the delivery device before use, for preventing injection of air into the target site, and for priming the system after the therapeutic substance has been loaded.

[0028] According to one aspect, the delivery device can include an indicator that includes only mechanical components. Such an arrangement can enable the delivery device to be more portable and easier to sterilize due to the absence of electrical components.

[0029] According to one aspect, the delivery device is used with a stereotactic frame (e.g., for neurosurgical applications). In some embodiments, the delivery device can be sized and shaped to be compatible with an existing stereotactic frame.

[0030] Looking at the exemplary embodiments in the figures, FIG. 3A is a perspective view of one embodiment of the delivery device 1, and a partial cutaway view of the internal components of the delivery device is shown in FIG. 3B. The delivery device has a cannula portion 9 (through which the substance is ejected), a housing 10, a handle 20, and a device actuator 30. As can be seen in the detailed view of FIG. 3B, the cannula portion 9 can include a plurality of components housed within one another. Moving from the outermost component to the innermost component of the cannula portion 9, the cannula portion 9 can include an outer shaft 40, a needle 50 within the outer shaft 40, and a plunger 60 within the needle 50.

[0031] The outer shaft 40 has a shaft lumen 41, and the needle 50 is movable through the shaft lumen 41. The needle 50 has a needle lumen 51, and the plunger 60 is movable through the needle lumen 51. Actuation of the device actuator 30 can cause the plunger 60 to move in the distal direction 8 through the shaft lumen 41. When a therapeutic substance is loaded into the needle lumen 51, movement of the plunger 60 through the needle lumen 51 in the distal direction 8 actively displaces the therapeutic substance out of the needle lumen 51, and thus delivers the therapeutic substance.

[0032] As can be seen in FIG. 3A, the outer shaft 40 can include a plurality of segments having a stepped outer diameter that are sequentially arranged along the longitudinal axis 4 of the device. The stepped outer diameter of the plurality of segments increases along the longitudinal axis 4 of the device from the distal end of the outer shaft 40 toward the proximal end of the outer shaft 40. In one embodiment, one of the plurality of segments can have a first outer diameter or a first range of outer diameters. Further, another of the plurality of segments that is adjacent to and disposed proximal to one of the plurality of segments can have a second outer diameter or a second range of outer diameters, the second outer diameter being larger than the first outer diameter and the second range of outer diameters being larger than the first range of outer diameters and not overlapping the first range of outer diameters. Further, the outer shaft 40 can include an end face that defines a step between one of the plurality of segments and another of the plurality of segments. The end face can project radially outward from the longitudinal axis 4 of the device. Alternatively, the end face can be formed as a chamfered surface that projects at an angle of less than 90 degrees from the longitudinal axis 4 of the device in the proximal direction of the device.

[0033] The outer shaft 40 can be formed from a material such as stainless steel. Other materials can be used to form the outer shaft 40. For example, the outer shaft 40 can be formed from an MRI-compatible material (such as ceramic, glass, or rigid polymer). Also, the outer shaft 40 can be formed from a non-MRI-compatible material if such compatibility is not required during use of the device and / or if other factors such as cost and reusability are prioritized.

[0034] As can be seen in FIG. 4A (FIG. 4A shows the distal portion of the needle 50 and the plunger 60), the needle 50 includes a needle tip 55 that defines a needle opening 58 through which a therapeutic substance is discharged. The needle tip 55 can be formed to have a chamfered outer surface that connects the plane containing the needle opening 58 and a portion of the needle 50 proximal to the needle tip 55 along the longitudinal axis 4 of the device. The needle 50 can be formed from a material such as stainless steel, glass, ceramic, or a rigid polymer.

[0035] FIG. 4C is a perspective view of the needle 50 according to another embodiment. FIG. 4D is a cutaway view of the needle 50. The needle tip 55 of the needle 50 can be formed to have a flat end face that defines the needle opening 58. The flat end face can be disposed on a plane orthogonal to the longitudinal axis 4 of the device. Although not shown in FIGS. 4C and 4D, the end face may be disposed on a plane that forms an angle non-orthogonal to the longitudinal axis 4 of the device. Alternatively, the needle tip 55 can be formed to have a chamfered outer surface as shown in FIG. 4A.

[0036] As can be seen in FIG. 4D, the needle 50 can include a needle tube 53 that defines a needle lumen 51. The needle tube 53 can be formed from a material such as stainless steel, glass, ceramic, or a rigid polymer. More specifically, the needle tube 53 can be formed from a material such as glass coated with polyimide. The needle 50 can further include a ferrule 54 attached to a portion of the needle tube 53. The ferrule 54 can be attached to a portion of the needle tube 53 by an adhesive or other means. The ferrule 54 can be formed from a material selected to reinforce the portion of the needle tube 53 to which the ferrule 54 is attached. By way of example, the ferrule 54 can be formed from a material such as stainless steel. FIG. 4D shows that the ferrule 54 is attached to a portion of the needle tube 53 that extends along the longitudinal axis 4 from the most distal end of the needle tube 53 to the proximal portion of the needle tube 53. Also, the ferrule 54 can be attached to a portion of the needle tube 53 that extends along the longitudinal axis 4 from a first part of the needle tube 53 proximal to the distal end of the needle tube 53 to a second part of the needle tube 53 proximal to the first part. The length of the ferrule 54 along the longitudinal axis 4 is selected to be longer than the maximum length of a portion of the needle tube 53 that can extend distally along the longitudinal axis 4 beyond the opening of the outer shaft 40 out of the shuttle lumen 41, and it is possible to reinforce that portion of the needle tube 53.

[0037] As seen in FIGS. 4A and 4B, the plunger 60 includes a plunger seal 68 that provides a seal against the needle lumen 51 while allowing movement of the plunger 60 through the needle lumen 51. In some embodiments, the plunger seal 68 has an outer diameter that is larger than the outer diameter of the remainder of the plunger body 61. The length of the plunger seal 68 can be selected such that a therapeutic substance loaded in a portion of the needle lumen 51 between the needle opening 58 and the distal end of the plunger seal 68 is prevented from advancing proximally beyond the plunger seal 68 into another portion of the needle lumen 51 proximal to the plunger seal 68. Further, the length of the plunger seal 68 can be selected such that when the plunger 60 is advanced to its most distal position in the needle lumen 51, the plunger seal 68 acts to close a vent 59 provided in the wall 57 of the needle 50. When the distal end of the plunger 60 is advanced beyond the vent 59, the vent 59 remains closed by the plunger seal 68, preventing liquid from entering the needle lumen 51 through the vent 59 and preventing the liquid from advancing beyond the plunger seal 68 into a portion of the needle lumen 51 distal to the plunger seal 68, as well as preventing liquid in a portion of the needle lumen 51 distal to the plunger seal 68 from advancing beyond the plunger seal 68 and entering a portion of the needle lumen 51 proximal to the plunger seal 68. Such a length of the plunger seal 68 is selected to ensure this.

[0038] In some embodiments, the distal portion of the plunger body 61 can be received within the plunger seal 68. The plunger seal 68 can be formed as a heat shrink seal over the plunger body 61. Also, the plunger seal 68 can be formed as a polymer coating through a deposition or coating technique. In other embodiments, rather than the plunger body 61 being received within the plunger seal 68, the two components are connected together. In still other embodiments, the plunger body 61 and the plunger seal 68 can be formed as a single unit.

[0039] According to one aspect, the needle can be arranged to retract while a therapeutic substance is being ejected from the needle. In some embodiments, during use, the needle is inserted into the tissue and reaches the desired target location. Insertion of the needle can create a cavity within the tissue. When the therapeutic substance is ejected from the needle, the needle is simultaneously retracted, thereby providing a volume of space for the therapeutic substance to be present. The inventors have recognized that such an arrangement can help reduce backflow of the therapeutic substance from the target site back through the channel formed within the tissue by the delivery device.

[0040] In embodiments where the delivery device uses a volume displacement delivery configuration (e.g., a plunger that moves distally through the needle lumen to expel the therapeutic substance from the needle), in response to actuation of the device actuator, the needle and the plunger can move simultaneously in opposite directions. That is, actuation of the device actuator can cause the needle to retract in the proximal direction while the plunger advances in the distal direction.

[0041] As used herein, the distal end of the delivery device is the end through which the therapeutic substance is delivered. The proximal end of the delivery device is the end of the device that is opposite the distal end. As an example for illustrative purposes, FIG. 3A shows the proximal end 2 and the distal end 3 of the delivery device 1.

[0042] As used herein, the proximal direction is the direction pointing from the distal end of the delivery device towards the proximal end. The distal direction is the direction pointing from the proximal end of the delivery device towards the distal end. As an example for illustrative purposes, FIG. 3A shows the proximal direction 6 and the distal direction 8.

[0043] In some embodiments, the actuation of the device actuator 30 causes the plunger 60 to advance in the distal direction 8 and the needle 50 to simultaneously retract in the proximal direction 6. In some embodiments, the simultaneous movement of the plunger and the needle in opposite directions is achieved via the arrangement of a translation screw mounted in a threaded passage having screw threads in opposite directions.

[0044] As shown in FIG. 3B, the delivery device 1 can include a needle translation screw 52 attached to the needle 50 and a plunger translation screw 62 attached to the plunger 60. The needle translation screw 52 is mounted in a first threaded passage 56, and the plunger translation screw 62 is mounted in a second threaded passage 66. The threads of the first threaded passage 56 are oriented in a direction opposite to the direction of the threads of the second threaded passage 66. For example, the first threaded passage 56 can have right-handed threads, while the second threaded passage 66 can have left-handed threads, or vice versa. The actuation of the device actuator 30 can impart rotation to each of the first threaded passage 56 and the second threaded passage 66.

[0045] As shown in FIG. 3B, the needle translation screw 52 and the plunger translation screw 62 can be mounted on the guide rails 151, 153. The guide rails can extend through the delivery device 1 in a direction parallel to the longitudinal axis 4 of the device and can be fixed to the housing 10. As shown in FIG. 5, the needle translation screw 52 can include a guide rail lumen 152, and the guide rails 151, 153 pass through the guide rail lumen 152. The needle translation screw 52 can freely linearly translate along the guide rails 151, 153. As shown in FIG. 6, the plunger translation screw 62 can include a guide rail lumen 162, and the guide rails 151, 153 pass through the guide rail lumen 162. The plunger translation screw 62 can freely linearly translate along the guide rails 151, 153.

[0046] The guide rails 151, 153 prevent the needle translation screw 52 from rotating with the first threaded passage when the first threaded passage rotates. As a result, due to the direction of the threads in the first threaded passage 56 and the presence of the guide rails passing through the needle translation screw 52, the rotation of the first threaded passage 56 causes the needle translation screw 52 to translate through the first threaded passage 56. In the exemplary embodiment of FIG. 3B, the needle translation screw 52 moves in the proximal direction 6 when the device actuator 30 is actuated. With the needle 50 attached to the needle translation screw 52, the proximal movement of the needle translation screw 52 moves the needle 50 in the proximal direction 6, thus causing the needle to retract.

[0047] Similarly, the guide rails 151, 153 prevent the plunger translation screw 62 from rotating with the second threaded passage when the second threaded passage rotates. As a result, due to the direction of the threads in the second threaded passage 66 and the presence of the guide rails through which the plunger translation screw 62 passes, the rotation of the second threaded passage 66 causes the plunger translation screw 62 to translate through the second threaded passage 66. In the exemplary embodiment of FIG. 3B, the plunger translation screw 62 moves in the distal direction 8 when the device actuator 30 is actuated. With the plunger 60 attached to the plunger translation screw 62, the distal movement of the plunger translation screw 62 actuates the plunger in the distal direction 8, thereby discharging the therapeutic substance out of the needle opening.

[0048] As shown in more detail in FIG. 5, the needle 50 is connected to the needle translation screw 52. The needle 50 can extend at least partially into the screw lumen 53. The needle 50 can be attached to the needle translation screw 52 via any suitable arrangement (e.g., an adhesive (e.g., epoxy or UV adhesive), a mechanical interlock, an interference fit, welding the components together, etc.), or the needle 50 and the needle translation screw 52 can be integrally formed with each other.

[0049] As used herein, parts that are "integrally formed" with each other are formed as one component, such that they are formed from a single monolithic component (e.g., cast simultaneously as a single piece, such as by die casting or injection molding, or cut from a single material, such as by stamping or die cutting).

[0050] As shown in more detail in FIG. 6, the plunger 60 is connected to the plunger translation screw 62. The plunger 60 can extend at least partially into the screw lumen 63. The plunger 60 can be attached to the plunger translation screw 62 via any suitable arrangement as discussed above with respect to the needle 50 and the needle translation screw 52.

[0051] In some embodiments, the needle 50, and the needle translation screw 52 attached to the needle 50, and / or the plunger 60, and the plunger translation screw 62 attached to the plunger 60 can be removed from the housing 10 and replaced by another needle, and another needle translation screw attached to the another needle, and / or another plunger, and another plunger translation screw attached to the another plunger. The another needle and the another needle translation screw can be disposed in the housing 10 so as to be translated through the first threaded passage 56, and the another plunger and the another plunger translation screw can be disposed in the housing 10 so as to be translated through the second threaded passage 66. The another needle can be a replacement for the needle 50 and have physical dimensions similar to the needle 50 (e.g., the same size needle lumen) and similar functions (e.g., the same amount of travel is allowed). Alternatively, the another needle can have physical dimensions different from the needle 50 (e.g., a different size needle lumen) and different functions (e.g., a different amount of travel is allowed).

[0052] FIG. 7A shows the delivery device in the pre-delivery configuration, and FIG. 7B shows the delivery device in the post-delivery configuration. At the end of delivery, the needle translation screw 52 has translated proximally 6 through the first threaded passage 56, thereby retracting the needle, and the plunger translation screw 62 has translated distally 8 through the second threaded passage 66, thereby advancing the plunger in the deployment direction.

[0053] In some embodiments, after delivery into the volume of space in the tissue created by the needle, the therapeutic substance occupies a portion of the volume of space. In some embodiments, the therapeutic substance occupies a therapeutic substance volume that is within at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, or 60% of the volume of space. In some embodiments, the therapeutic substance occupies a therapeutic substance volume that is about 70%, 60%, 50%, 40%, 30%, 25%, 20%, 15%, 10%, or 5% or less of the volume of space. Combinations of the ranges referenced above are also possible. In some embodiments, the therapeutic substance occupies a therapeutic substance volume that is from about 5% to about 60%, from about 5% to about 50%, from about 5% to about 40%, from about 5% to about 30%, or from about 5% to about 25% of the volume of space.

[0054] According to one aspect, the diameter of the needle lumen is sized for compatibility with the properties of the therapeutic substance. In some embodiments, the therapeutic substance includes cells or other particles having a particular diameter. According to one aspect, the diameter of the needle lumen is sized to be close to the diameter of the cells or particles of the therapeutic substance. For example, in some embodiments, the ratio of the needle lumen diameter to the cell or particle diameter is less than 100:1. In some embodiments, such an arrangement can help reduce cell sedimentation or particle sedimentation within the needle lumen. In some embodiments, such an arrangement can help the cells move in conjunction with their fluid solution, which can help ensure delivery of a larger portion of the cells. Such an arrangement can help improve dose assurance.

[0055] In some embodiments, the delivery device is configured to deliver cells that are nerve cells. In some embodiments, the cells are dopaminergic neuron cells, and in some embodiments, can be iPSC-derived dopaminergic neuron cells. However, the delivery device can be recognized as being used to deliver other types of cells (e.g., mesenchymal stem cells, hematopoietic stem cells, embryonic stem cells or induced pluripotent stem cells, red blood cells, platelets, chondrocytes, skin cells, immune cells (e.g., tumor infiltrating lymphocytes, virus-reconstituted T cells, dendritic cells, regulatory T cells, macrophages), neural crest stem cells, neurons, glia, smooth muscle, heart tissue, chondrocytes, osteocytes, glial-restricted progenitor cells, astrocytes, oligodendrocytes, neuroblasts, megakaryoblasts, megakaryocytes, monoblasts, monocytes, macrophages, myeloid dendritic cells, proerythroblasts, erythroblasts, normoblasts, reticulocytes, platelets, myeloblasts, promyelocytes, neutrophilic myeloblasts, neutrophilic band cells, neutrophils, eosinophilic myeloblasts, eosinophilic band cells, eosinophils, basophilic myeloblasts, basophilic band cells, basophils, committed lymphoid projenitor, pre-NK cells, NK lymphoblasts, NK cells, thymocytes, T-lymphoblasts, T-cells, plasmacytoid dendritic cells, pre-B cells, B-lymphoblasts, B cells, plasma cells, osteoblasts, chondrocytes, myoblasts, myotubes, fibroblasts, adipocytes, mesoderm, ectoderm, primordial germ cells, sperm, eggs, embryonic endoderm, or any other suitable type of cell, etc.).

[0056] In some embodiments, the therapeutic substance contains a cell concentration of at least about 50,000 cells / μL, at least about 100,000 cells / μL, at least about 200,000 cells / μL, at least about 300,000 cells / μL, at least about 400,000 cells / μL, or at least about 500,000 cells / μL. In some embodiments, the therapeutic substance contains a cell concentration of about 500,000 cells / μL or less, about 400,000 cells / μL or less, about 300,000 cells / μL or less, about 200,000 cells / μL or less, about 100,000 cells / μL or less, or about 50,000 cells / μL or less. Combinations of the ranges referenced above are also possible. For example, in some embodiments, the therapeutic substance contains a cell concentration of from about 50,000 cells / μL to about 500,000 cells / μL, or from about 100,000 cells / μL to about 400,000 cells / μL, or from about 200,000 cells / μL to about 300,000 cells / μL.

[0057] In some embodiments, the needle lumen can have a diameter of at least about 0.05 mm, at least about 0.1 mm, at least about 0.15 mm, at least about 0.2 mm, at least about 0.25 mm, at least about 0.3 mm, at least about 0.35 mm, at least about 0.4 mm, at least about 0.45 mm, or at least about 0.5 mm. In some embodiments, the needle lumen can have a diameter of about 1 mm or less, about 0.95 mm or less, about 0.9 mm or less, about 0.85 mm or less, about 0.8 mm or less, about 0.75 mm or less, about 0.7 mm or less, about 0.65 mm or less, about 0.6 mm or less, about 0.55 mm or less, about 0.5 mm or less, about 0.45 mm or less, about 0.4 mm or less, about 0.35 mm or less, about 0.3 mm or less, about 0.25 mm or less, about 0.2 mm or less, about 0.15 mm or less, or about 0.1 mm or less. Combinations of the ranges referenced above are also possible. For example, in some embodiments, the needle lumen can have a diameter of from about 0.1 mm to about 1 mm, or from about 0.15 mm to about 0.9 mm, or from about 0.2 mm to about 0.8 mm, or from about 0.2 mm to about 0.7 mm, or from about 0.2 mm to about 0.6 mm, or from about 0.2 mm to about 0.5 mm, or from about 0.2 mm to about 0.4 mm, or from about 0.25 mm to about 0.3 mm.

[0058] In some embodiments, the cells or particles of the therapeutic substance can have a diameter of at least about 400 nm, at least about 1 micron, at least about 2 microns, at least about 4 microns, at least about 6 microns, at least about 8 microns, at least about 9 microns, at least about 10 microns, at least about 11 microns, at least about 12 microns, at least about 13 microns, at least about 14 microns, at least about 15 microns, at least about 16 microns, at least about 17 microns, at least about 18 microns, at least about 19 microns, at least about 20 microns, at least about 25 microns, at least about 30 microns, at least about 40 microns, at least about 50 microns, at least about 70 microns, at least about 100 microns, at least about 200 microns, or at least about 500 microns. In some embodiments, the cells or particles can have a diameter of about 500 microns or less, about 300 microns or less, about 200 microns or less, about 150 microns or less, about 100 microns or less, about 90 microns or less, about 80 microns or less, about 70 microns or less, about 60 microns or less, about 50 microns or less, about 40 microns or less, about 30 microns or less, about 20 microns or less, about 19 microns or less, about 18 microns or less, about 17 microns or less, about 16 microns or less, about 15 microns or less, about 14 microns or less, about 13 microns or less, about 12 microns or less, about 11 microns or less, about 10 microns or less, about 9 microns or less, about 8 microns or less, about 7 microns or less, about 6 microns or less, about 5 microns or less, about 4 microns or less, about 2 microns or less, or about 1 micron or less. Combinations of the ranges referred to above are also possible.For example, in some embodiments, the cells or particles can have a diameter of from about 400 nm to about 500 microns, or from about 1 micron to about 200 microns, or from about 5 microns to about 150 microns, or from about 8 microns to about 120 microns, or from about 8 microns to about 100 microns, or from about 8 microns to about 50 microns, or from about 8 microns to about 40 microns, or from about 8 microns to about 30 microns, or from about 8 microns to about 20 microns, or from about 10 microns to about 15 microns.

[0059] In some embodiments, the ratio of the needle lumen diameter to the diameter of the cells or particles is at least about 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 150:1, 200:1, 300:1, 400:1, or 500:1. In some embodiments, the ratio of the needle lumen diameter to the diameter of the cells or particles is about 500:1, 400:1, 300:1, 200:1, 100:1, 90:1, 80:1, 70:1, 60:1, 50:1, 40:1, 30:1, 20:1, or 10:1 or less. Combinations of the ranges referred to above are also possible. For example, in some embodiments, the ratio of the needle lumen diameter to the diameter of the cells or particles is from about 10:1 to about 500:1, or from about 50:1 to about 300:1, or from about 60:1 to about 200:1, or from about 70:1 to about 150:1, or from about 80:1 to about 120:1, or from about 90:1 to about 110:1.

[0060] In some embodiments, the entire volume of the therapeutic substance loaded into the delivery device is contained only within the needle lumen of the delivery device. In some embodiments, the needle lumen has a constant diameter along the entire length of the needle. In the case of cells, such an arrangement can help the cells move in conjunction with their fluid solution, which can help ensure delivery of a larger portion of the cells. Such an arrangement can help improve dose assurance. In some embodiments, such an arrangement can help reduce cell sedimentation.

[0061] In some embodiments, the density of the fluid solution in which the cells and / or particles are provided is selected to increase the buoyant force exerted on the cells and / or particles. For example, the density of the fluid solution is selected to be close to the known density of the cells and / or particles to be delivered, taking into account the known density, increasing the buoyant force exerted on the cells and / or particles, and making it possible to achieve or approach neutral buoyancy. Further, the density of the fluid solution is selected to be close to the known density, taking into account the known density of the cells and / or particles to be delivered, thereby making it possible to increase the buoyant force exerted on the cells and / or particles, and thereby bringing the concentration of the cells and / or particles in the fluid solution ejected by the delivery device closer to a predetermined concentration. In other embodiments, the viscosity of the fluid solution can be selected to reduce cell sedimentation, thereby bringing the concentration of the cells and / or particles in the fluid solution ejected by the delivery device closer to a predetermined concentration. In still other embodiments, both the density of the fluid solution and the viscosity of the fluid solution can be selected in the manner described above. Such an arrangement can further help reduce cell sedimentation.

[0062] According to one aspect, the volume of the space through which the plunger moves in response to device operation (and / or the volume of the therapeutic substance ejected by the delivery device) is close to or substantially the same as the volume of the space through which the needle moves during needle retraction. In some embodiments, the volume of the space through which the plunger moves (and / or the volume of the therapeutic substance ejected by the delivery device) is within at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, or 50 percent of the volume of the space through which the needle moves. In some embodiments, the volume of the space through which the plunger moves (and / or the volume of the therapeutic substance ejected by the delivery device) is within 50, 40, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 percent or less of the volume of the space through which the needle moves. Combinations of the ranges referred to above are also possible. In some embodiments, the volume of the space through which the plunger moves (and / or the volume of the therapeutic substance ejected by the delivery device) is from 1 percent to 50 percent, from 1 percent to 40 percent, from 1 percent to 30 percent, from 1 percent to 25 percent, from 1 percent to 20 percent, from 1 percent to 15 percent, from 1 percent to 10 percent, or from 1 percent to 5 percent of the volume of the space through which the needle moves.

[0063] In the volume transfer configuration, the inventors recognized that the plunger travel distance can determine the delivery volume. However, in embodiments where the needle retracts as the plunger advances, the inventors recognized that the needle travel distance may not necessarily match the plunger travel distance in all embodiments. In some embodiments, the needle travel distance can be determined by the anatomical structure of the target site.

[0064] According to one aspect, the needle and the plunger can experience different travel distances during delivery. Such an arrangement can enable the plunger to travel a specific distance to deliver a desired volume of therapeutic substance, while allowing a travel distance of the needle appropriate for the target anatomical structure.

[0065] In some embodiments, the different travel distances of the plunger and the needle are achieved via a difference in the number of threads (e.g., threads per inch) of a threaded passage associated with a translation screw, or via a gear system, or in some embodiments, via a combination of both.

[0066] In the exemplary embodiment shown in FIG. 3B, the first threaded passage 56 (which is the passage along which the needle translation screw 52 translates) has a first number of threads. The second threaded passage 66 (which is the passage along which the plunger translation screw 62 translates) has a second number of threads different from the first number of threads. In some embodiments, such as the embodiment shown in FIG. 3B, the needle travel distance is shorter than the plunger travel distance. To achieve this difference in travel distances, the first threaded passage 56 has a greater number of threads (e.g., a higher number of threads per inch) than the number of threads of the second threaded passage 66. Thus, upon actuation of the device actuator 30, the plunger translation screw 62 translates a greater distance than the needle translation screw. As a result, the plunger moves a greater distance than the needle.

[0067] In some embodiments, the ratio of the first thread count to the second thread count can be at least about 1.5:1, at least about 1.6:1, at least about 1.7:1, at least about 1.8:1, at least about 1.9:1, at least about 2:1, at least about 2.1:1, at least about 2.2:1, at least about 2.3:1, at least about 2.4:1, at least about 2.5:1, at least about 2.6:1, at least about 2.7:1, at least about 2.8:1, at least about 2.9:1, at least about 3:1, at least about 3.1:1, at least about 3.2:1, at least about 3.3:1, at least about 3.4:1, at least about 3.5:1, at least about 3.6:1, at least about 3.7:1, at least about 3.8:1, at least about 3.9:1, at least about 4:1, at least about 4.2:1, at least about 4.4:1, at least about 4.6:1, at least about 4.8:1, at least about 5:1, at least about 6:1, at least about 7:1, at least about 8:1, at least about 9:1, at least about 10:1, at least about 11:1, at least about 12:1, at least about 13:1, at least about 14:1, at least about 15:1, at least about 16:1, at least about 18:1, or at least about 20:1. In some embodiments, the ratio of the first thread count to the second thread count can be about 20:1 or less, about 18:1 or less, about 16:1 or less, about 14:1 or less, about 12:1 or less, about 10:1 or less, about 9:1 or less, about 8:1 or less, about 7:1 or less, about 6:1 or less, about 5:1 or less, about 4.5:1 or less, about 4:1 or less, about 3.9:1 or less, about 3.8:1 or less, about 3.7:1 or less, about 3.6:1 or less, about 3.5:1 or less, about 3.4:1 or less, about 3.3:1 or less, about 3.2:1 or less, about 3.1:1 or less, about 3:1 or less, about 2.9:1 or less, about 2.8:1 or less, about 2.7:1 or less, about 2.6:1 or less, about 2.5:1 or less, about 2.4:1 or less, about 2.3:1 or less, about 2.2:1 or less, about 2.1:1 or less, about 2:1 or less, about 1.9:1 or less, about 1.8:1 or less, about 1.7:1 or less, about 1.6:1 or less, or about 1.5:1 or less. Combinations of the ranges referred to above are also possible.For example, in some embodiments, the ratio of the first thread count to the second thread count may be from about 1.5:1 to about 20:1, or from about 1.6:1 to about 14:1, or from about 1.7:1 to about 10:1, or from about 1.8:1 to about 9:1, or from about 1.9:1 to about 8:1, or from about 2:1 to about 7:1, or from about 2.1:1 to about 6:1, or from about 2.2:1 to about 5:1, or from about 2.3:1 to about 4:1, or from about 2.4:1 to about 3:1 or from about 2.5:1 to about 2.7:1.

[0068] In an exemplary embodiment of FIG. 3B, a gear system is additionally used to further reduce the travel distance of the needle relative to the travel distance of the plunger. As shown in FIGS. 8 and 9, the gear system is a planetary gear system 100 (also known as an epicyclic gear system). The planetary gear system 100 includes a sun gear 160, planetary gears 114, and a ring gear 110.

[0069] The sun gear 160 is connected to the device actuator 30 and the second threaded passage 66, which is associated with the plunger translation screw. As shown in Figure 3B, the sun gear 160, the device actuator 30, and the second threaded passage 66 are integrally formed together as a single component. Also, one complete rotation of the device actuator 30 results in one complete rotation of the sun gear 160 and one complete rotation of the second threaded passage 66. The planet gear 114 rotates around the sun gear 160 and rotates within the ring gear 110. As shown in Figure 9, the planet gear 114 is rotatably mounted on the carrier 150, and the carrier 150 is connected to the first threaded passage 56, which is associated with the needle translation screw. One complete rotation of the carrier 150 results in one complete rotation of the first threaded passage. The relationship between the sun gear 160 and the planet gear 114 produces a gear ratio, where multiple rotations of the sun gear are required to achieve a single complete rotation of the carrier. As a result, the operation of the device actuator 30 results in more rotations of the second threaded passage 66 than the first threaded passage 56, and it results in a greater travel distance of the plunger translation screw 62 and the plunger 60 than the travel distance of the needle translation screw 52 and the needle 50.

[0070] In some embodiments, the gear ratio between the sun gear 160 and the carrier 150 can be at least about 2 to 1, at least about 2.5 to 1, at least about 3 to 1, at least about 3.2 to 1, at least about 3.4 to 1, at least about 3.6 to 1, at least about 3.8 to 1, at least about 4 to 1, at least about 4.1 to 1, at least about 4.2 to 1, at least about 4.3 to 1, at least about 4.4 to 1, at least about 4.5 to 1, at least about 4.6 to 1, at least about 4.7 to 1, at least about 4.8 to 1, at least about 4.9 to 1, at least about 5 to 1, at least about 6 to 1, at least about 7 to 1, at least about 8 to 1, at least about 9 to 1, or at least about 10 to 1. In some embodiments, the gear ratio between the sun gear and the carrier can be about 10 to 1 or less, about 9 to 1 or less, about 8 to 1 or less, about 7 to 1 or less, about 6 to 1 or less, about 5 to 1 or less, about 4.9 to 1 or less, about 4.8 to 1 or less, about 4.7 to 1 or less, about 4.6 to 1 or less, about 4.5 to 1 or less, about 4.4 to 1 or less, about 4.3 to 1 or less, about 4.2 to 1 or less, about 4.1 to 1 or less, about 4 to 1 or less, about 3.8 to 1 or less, about 3.6 to 1 or less, about 3.4 to 1 or less, about 3.2 to 1 or less, about 3 to 1 or less, about 2.5 to 1 or less, about 2 to 1 or less. Combinations of the ranges referenced above are also possible. For example, in some embodiments, the ratio between the sun gear and the carrier is from about 2 to 1 to about 10 to 1, or from about 2.5 to 1 to about 9 to 1, or from about 3 to 1 to about 8 to 1, or from about 3.2 to 1 to about 7 to 1, or from about 3.4 to 1 to about 6 to 1, or from about 3.6 to 1 to about 5 to 1, or from about 3.8 to 1 to about 4.8 to 1, or from about 3.9 to 1 to about 4.6 to 1, or from about 4 to 1 to about 4.5 to 1, or from about 4.1 to 1 to about 4.4 to 1, or from about 4.2 to 1 to about 4.3 to 1.

[0071] In the delivery device shown in the figures, a planetary gear is used, but this aspect is not so limited, so spur gears, helical gears, racks and pinions, bevel gears, mitre gears, worm gears, screw gears, helical gears, hypoid gears, mountain gears, internal gears, sawtooth gears, clock and pin gears, mutilated gears, hypocycloid gear systems, Geneva gears, or any other suitable gear system, etc., other types of gear systems can also be recognized as being used.

[0072] In the exemplary embodiment of FIG. 3B, the delivery device 1 utilizes a combination with a pair of threaded passages having different thread counts from the gear system, allowing the plunger and the needle to experience different travel distances in response to the actuation of the device actuator 30. The combined arrangement results in a travel distance ratio between the plunger and the needle. In other embodiments, the delivery device can utilize a pair of threaded passages (or a gear system) without combining the two.

[0073] In some embodiments, the travel distance ratio between the plunger and the needle can be at least about 2 to 1, at least about 2.5 to 1, at least about 3 to 1, at least about 3.5 to 1, at least about 4 to 1, at least about 4.5 to 1, at least about 5 to 1, at least about 5.5 to 1, at least about 6 to 1, at least about 6.5 to 1, at least about 7 to 1, at least about 7.5 to 1, at least about 8 to 1, at least about 8.5 to 1, at least about 8.7 to 1, at least about 9 to 1, at least about 9.2 to 1, at least about 9.4 to 1, at least about 9.6 to 1, at least about 9.8 to 1, at least about 10 to 1, at least about 11 to 1, at least about 12 to 1, at least about 13 to 1, at least about 14 to 1, at least about 15 to 1, at least about 16 to 1, at least about 17 to 1, at least about 18 to 1, at least about 19 to 1, or at least about 20 to 1. In some embodiments, the travel distance ratio between the plunger and the needle can be about 20 to 1 or less, about 18 to 1 or less, about 16 to 1 or less, about 14 to 1 or less, about 12 to 1 or less, about 11.8 to 1 or less, about 11.6 to 1 or less, about 11.4 to 1 or less, about 11.2 to 1 or less, about 11 to 1 or less, about 10.9 to 1 or less, about 10.8 to 1 or less, about 10.7 to 1 or less, about 10.6 to 1 or less, about 10.5 to 1 or less, about 10.4 to 1 or less, about 10.3 to 1 or less, about 10.2 to 1, 10.1 to 1 or less, about 10 to 1 or less, about 9.9 to 1 or less, about 9.8 to 1 or less, about 9.7 to 1 or less, about 9.6 to 1 or less, about 9.5 to 1 or less, about 9.4 to 1 or less, about 9.3 to 1 or less, about 9.2 to 1 or less, about 9.1 to 1 or less, about 9 to 1 or less, about 8.7 to 1 or less, about 8 to 1 or less, about 7 to 1 or less, about 6 to 1 or less, about 5 to 1 or less, about 4 to 1 or less, about 3 to 1 or less, or about 2 to 1 or less. Combinations of the ranges referred to above are also possible.For example, in some embodiments, the travel distance ratio between the plunger and the needle is from about 2:1 to about 20:1, or from about 3:1 to about 18:1, or from about 4:1 to about 16:1, or from about 5:1 to about 14:1, or from about 6:1 to about 13:1, or from about 7:1 to about 12:1, or from about 8:1 to about 11:1, or from about 9:1 to about 10:1, or from about 9.1:1 to about 10.9:1, or from about 9.2:1 to about 10.8:1, or from about 9.3:1 to about 10.7:1, or from about 9.4:1 to about 10.6:1, or from about 9.5:1 to about 10.5:1, or from about 9.6:1 to about 10.4:1, or from about 9.7:1 to about 10.3:1, or from about 9.8:1 to about 10.2:1, or from about 9.9:1 to about 10.1:1, or from about 10:1 to about 10.1:1, or from about 7:1 to about 10:1, or from about 8:1 to about 9:1.

[0074] In some embodiments, the travel distance of the plunger can be at least about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 180, 200, 250, or 300 mm. In some embodiments, the travel distance of the plunger can be about 300, 250, 200, 180, 160, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30, 20, or 10 mm or less. Combinations of the ranges referred to above are also possible. For example, in some embodiments, the travel distance of the plunger can be from about 10 mm to 300 mm, from 20 mm to 250 mm, from 30 mm to 200 mm, from 40 mm to 180 mm, from 50 mm to 160 mm, from 60 mm to 140 mm, from 70 mm to 140 mm, from 100 mm to 140 mm, or from 120 mm to 140 mm.

[0075] According to one aspect, the device actuator of the delivery device can be a rotatable actuator. In some embodiments, the rotatable device actuator can help slow the ejection rate of the therapeutic substance.

[0076] In some embodiments, as seen in FIG. 3A, the device actuator 30 is rotatably mounted with respect to the housing 10. In some embodiments, such as the exemplary embodiment of FIG. 3A, the axis of rotation of the device actuator is parallel to the longitudinal axis 4 of the delivery device 1. However, in other embodiments, the axis of rotation of the device actuator can be perpendicular to the longitudinal axis of the delivery device. In some embodiments, the longitudinal axis of the delivery device is parallel to the outer shaft of the cannula portion, the needle, and / or the plunger.

[0077] In some embodiments, a plurality of complete turns of the device actuator are required to deliver the total target volume. For example, in an embodiment of a delivery device that utilizes a volume transfer configuration having a plunger that moves through a needle, a plurality of complete turns of the device actuator may be required to move the plunger from its pre-delivery position to its post-delivery position for the maximum volume to be delivered. In some embodiments, for delivering the maximum volume, the post-delivery position of the distal end 65 of the plunger 60 (see FIG. 3B) is at or near the needle opening 58 (see FIG. 4A).

[0078] In the exemplary embodiment shown in FIG. 3B, the number of threads of the second threaded passage 66 can determine how far the plunger translation screw 62 (and thus the plunger 60) moves with each rotation of the device actuator 30.

[0079] In some embodiments, the number of threads of the second threaded passage may be at least about 1 thread per inch (TPI), at least about 4 TPI, at least about 4.4 TPI, at least about 4.6 TPI, at least about 4.8 TPI, at least about 5 TPI, at least about 5.1 TPI, at least about 5.2 TPI, at least about 5.3 TPI, at least about 5.4 TPI, at least about 5.5 TPI, at least about 5.6 TPI, at least about 5.7 TPI, at least about 5.8 TPI, at least about 5.9 TPI, at least about 6 TPI, at least about 6.1 TPI, at least about 6.2 TPI, at least about 6.3 TPI, at least about 6.4 TPI, at least about 6.5 TPI, at least about 7 TPI, at least about 8 TPI, at least about 9 TPI, at least about 10 TPI, at least about 12 TPI, at least about 14 TPI, at least about 20 TPI, at least about 40 TPI, at least about 60 TPI, or at least about 80 TPI. In some embodiments, the number of threads of the second threaded passage may be about 80 TPI or less, about 60 TPI or less, about 40 TPI or less, about 20 TPI or less, about 14 TPI or less, about 12 TPI or less, about 10 TPI or less, about 8 TPI or less, about 7 TPI or less, about 6.9 TPI or less, about 6.8 TPI or less, about 6.7 TPI or less, about 6.6 TPI or less, about 6.5 TPI or less, about 6.4 TPI or less, about 6.3 TPI or less, about 6.2 TPI or less, about 6.1 TPI or less, about 6 TPI or less, about 5.9 TPI or less, about 5.8 TPI or less, about 5.7 TPI or less, about 5.6 TPI or less, about 5.5 TPI or less, about 5.4 TPI or less, about 5.3 TPI or less, about 5.2 TPI or less, about 5.1 TPI or less, about 5 TPI or less, or about 4 TPI or less. Combinations of the ranges referenced above are also possible.For example, in some embodiments, the thread count of the second threaded passage can be from about 1 TPI to about 80 TPI, or from about 4 TPI to about 14 TPI, or from about 4.2 TPI to about 12 TPI, or from about 4.4 TPI to about 10 TPI, or from about 4.6 TPI to about 9 TPI, or from about 4.8 TPI to about 8.6 TPI, or from about 5 TPI to about 7 TPI, or from about 5.2 TPI to about 6.8 TPI, or from about 5.4 TPI to about 6.6 TPI, or from about 5.6 TPI to about 6.4 TPI, or from about 5.8 TPI to about 6.2 TPI, or from about 5.9 TPI to about 6.1 TPI, or from about 6 TPI to about 6.1 TPI.

[0080] In some embodiments, to achieve the maximum delivery volume, the device actuator is rotated by at least 5, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 44, 46, 48, 50, 55, or 60 full rotations. In some embodiments, to deliver the maximum volume, the device actuator is rotated by 60, 50, 48, 46, 44, 42, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 22.5, 21, 20, 18, 16, 14, 12, 10, or 5 or fewer full rotations. Combinations of the ranges referred to above are also possible. For example, in some embodiments, to deliver the maximum volume, the device actuator is rotated by 5 to 60, or 10 to 50, or 20 to 40, or 22 to 38, or 24 to 36, or 25 to 35, or 26 to 34, or 27 to 33, or 28 to 32, or 29 to 31, or 30 to 31, or 15 to 30 full rotations.

[0081] In other embodiments, the device actuator can be rotated only one full rotation, or less than one full rotation, to deliver the maximum delivery volume. In some embodiments, to deliver the maximum delivery volume, the device actuator is rotated at least about 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, or 360 degrees. In some embodiments, to achieve the maximum delivery volume, the device actuator is rotated about 360, 340, 320, 300, 280, 260, 240, 220, 200, 180, 160, 140, 120, or 100 degrees or less. Combinations of the ranges referred to above are also possible. For example, in some embodiments, to deliver the maximum delivery volume, the device actuator is rotated from about 100 degrees to about 360 degrees, or from about 120 degrees to about 340 degrees, or from about 160 degrees to about 300 degrees, or from about 200 degrees to about 260 degrees.

[0082] In some embodiments, the maximum delivery volume can be at least about 1 microliter, at least about 2 microliters, at least about 3 microliters, at least about 4 microliters, at least about 5 microliters, at least about 6 microliters, at least about 7 microliters, at least about 7.2 microliters, at least about 7.4 microliters, at least about 7.6 microliters, at least about 7.8 microliters, at least about 8 microliters, at least about 8.1 microliters, at least about 8.2 microliters, at least about 8.3 microliters, at least about 8.4 microliters, at least about 8.5 microliters, at least about 8.6 microliters, at least about 8.7 microliters, at least about 8.8 microliters, at least about 8.9 microliters, at least about 9 microliters, at least about 9.5 microliters, at least about 10 microliters, at least about 11 microliters, at least about 12 microliters, at least about 13 microliters, at least about 14 microliters, at least about 15 microliters, at least about 20 microliters, at least about 30 microliters, at least about 100 microliters, at least about 1 mL, at least about 10 mL, at least about 100 mL, at least about 500 mL, or at least about 800 mL.In some embodiments, the maximum delivery volume can be about 1000 mL or less, about 800 mL or less, about 500 mL or less, about 100 mL or less, about 10 mL or less, about 1 mL or less, about 100 microliters or less, or about 100 microliters or less, or about 90 microliters or less, or about 80 microliters or less, or about 70 microliters or less, or about 60 microliters or less, or about 50 microliters or less, or about 40 microliters or less, or about 30 microliters or less, or about 20 microliters or less, or about 15 microliters or less, or about 12 microliters or less, or about 10 microliters or less, or about 9.9 microliters or less, or about 9.8 microliters or less, or about 9.7 microliters or less, or about 9.6 microliters or less, or about 9.5 microliters or less, or about 9.4 microliters or less, or about 9.3 microliters or less, or about 9.2 microliters or less, or about 9.1 microliters or less, or about 9 microliters or less, or about 8.8 microliters or less, or about 8.2 microliters or less, or about 8 microliters or less, or about 7 microliters or less, or about 6 microliters or less, or about 5 microliters or less. Combinations of the ranges referenced above are also possible.For example, in some embodiments, the maximum delivery volume can be from 1 mL to about 1000 mL, or from about 10 mL to about 800 mL, or from about 100 mL to about 500 mL, or from about 1 microliter to about 100 microliters, or from about 2 microliters to about 60 microliters, or from about 3 microliters to about 30 microliters, or from about 4 microliters to about 20 microliters, or from about 5 microliters to about 18 microliters, or from about 6 microliters to about 16 microliters, or from about 7 microliters to about 14 microliters, or from about 8 microliters to about 10 microliters, or from about 8.5 microliters to about 9.5 microliters, or from about 8.9 microliters to about 9.1 microliters, or from about 9 microliters to about 9.1 microliters.

[0083] It should be recognized that at least some of the exemplary embodiments discussed herein can be purely mechanical, but in other embodiments, the delivery device can be electrified. For example, in some embodiments, the delivery device can include a motor, and the motor can be actuated by a user to advance a plunger and / or retract a needle. In some embodiments, the delivery device can be controlled remotely using wireless communication. The delivery device can have a portable power source and / or be adapted to receive power from an electrical outlet. In some embodiments, the delivery device can be connected to a motor external to the device via a flexible torque cable.

[0084] According to one aspect, the therapeutic substance is front-loaded into the delivery device through the dispensing end of the device. Such an arrangement can help reduce waste or loss of the therapeutic substance (e.g., by avoiding transfer of the substance through multiple components).

[0085] In some embodiments, the delivery device can include an air vent configuration to enable front loading. In some embodiments, drawing the therapeutic substance into the needle lumen during loading of the delivery device displaces air from the needle lumen. In some embodiments, a vent is provided to allow the displaced air to vent out of the needle lumen. In some embodiments, this vent configuration can help avoid or reduce pressurization of the therapeutic substance and / or the needle lumen. In some embodiments, this vent configuration can help avoid competition between air and the therapeutic substance for volume space. In some embodiments, this vent configuration can help reduce introduction of air bubbles into the therapeutic substance.

[0086] In the exemplary embodiment shown in FIG. 3B, the needle 50 includes a vent 59 in the form of a through-hole opening extending through the wall portion 57 of the needle 50. The vent 59 is opened or closed based on the position of the plunger 60. As shown in FIG. 3B, the vent 59 is closed when the distal end 65 of the plunger 60 is distal to the vent 59. The vent 59 is open when the distal end 65 of the plunger 60 is proximal to the vent 59.

[0087] A front loading sequence according to some embodiments is shown in FIGS. 10A - 10C. As shown in FIG. 10A, with the vent 59 in the open state, the therapeutic substance 180 is moved into the needle lumen 51 through the needle opening 58 in the proximal loading direction 181. As the therapeutic substance 180 is moved into the needle lumen 51, the air that previously occupied the needle lumen 51 vents into the shaft lumen 41 through the open vent 59.

[0088] In some embodiments, the delivery device is passively loaded with a therapeutic substance; for example, the delivery device itself is not actuated during loading. An active loading device (e.g., a pump, etc.) can be used to move the therapeutic substance into the needle lumen. The pump can be a syringe pump or any other suitable pump. In some embodiments, the therapeutic substance is transferred from a holder into the needle lumen.

[0089] Next, as shown in FIG. 10B, vent 59 is closed. In some embodiments, the user closes vent 59 by actuating device actuator 30 to advance plunger 60 distally until the distal end 65 of the plunger is distal to vent 59.

[0090] In some embodiments, a flushing step is performed to remove air from the space between the outer shaft and the needle in the outer lumen. As shown in FIG. 10B, the delivery device includes a flushing port 90. A flushing fluid 184 (e.g., a transplant medium, etc.) is injected through flushing port 90 in a flushing direction 185 and can also be injected through valve 92, channel 93, and an opening 49 in outer shaft 40. The transplant medium can travel through the space between outer shaft 40 and needle 50 as indicated by arrow 182. The user can observe the flushing fluid exiting from the distal end 45 of outer shaft 40, which indicates to the user that the device is primed and ready for delivery into tissue. FIG. 10C shows a primed device ready for delivery with a therapeutic substance 180 loaded into the needle lumen, plunger 60 covering vent 59, and air flushed out of cannula portion 9.

[0091] The inventors have recognized that when the cannula portion 9 is withdrawn from the tissue (with the cannula portion 9 inserted into the tissue) after the therapeutic substance has been discharged from the needle into the volume of the space at the target site 215 created by the withdrawal of the needle, a suction effect is generated. The suction effect can pull a portion of the therapeutic substance out of the target site 215, thereby reducing the dosage of the therapeutic substance delivered to the target site 215.

[0092] The delivery device can be configured to mitigate the suction effect experienced during withdrawal of the cannula portion 9 from the tissue. For example, the valve 92 of the flushing port 90 is configured to be set to an open position, exposing the space inside the cannula portion 9 and, in particular, the space between the outer shaft 40 and the needle 50 to atmospheric pressure, and enabling the flushing fluid 184 to be drained into the tissue when the cannula portion 9 is withdrawn from the tissue. The valve 92 can be configured, for example, to receive a device (such as an open needle, etc.) and expose the space between the outer shaft 40 and the needle 50 to atmospheric pressure, and enable the flushing fluid 184 to be drained into the tissue when the cannula portion 9 is withdrawn from the tissue. Draining the flushing fluid 184 towards the target site 215 counteracts the suction effect, thereby making it possible to mitigate the reduction in the dosage of the therapeutic substance delivered to the target site 215 when the cannula portion 9 is withdrawn from the tissue.

[0093] According to one aspect, the delivery device can include an indicator that includes only mechanical components. Such an arrangement can enable the delivery device to be more portable and / or easier to sterilize due to the absence of electrical components.

[0094] In some embodiments, the gearing system can be used to transmit the actuation force applied to the device actuator to the movement of a component having an indicator reflecting the delivered volume and / or an indicator reflecting the state of the device (e.g., ready to be loaded with a therapeutic substance). An exemplary purpose embodiment of a mechanical indicator is shown in FIG. 11. The indicator configuration of FIG. 11 uses a Geneva gear system 200. The Geneva gear system 200 includes a first drive wheel 230, and the first drive wheel 230 can rotate at a 1:1 ratio with the device actuator 30. The first drive wheel 230 interacts with and drives the driven wheel portion 242 of the gear assembly 240. The gear assembly 240 also includes a drive wheel portion 244, and the drive wheel portion 244 interacts with and drives the driven wheel portion 252 of the indicator gear 250. The indicator gear 250 also includes an indicator portion 254. As shown in FIGS. 3A and 3B, the indicator of the indicator portion 254 can be viewed through the indicator window 255 of the delivery device. When the device actuator 30 is actuated, the indicator portion 254 rotates, reflecting the delivered volume.

[0095] For the purpose of linking the device actuator 30 to the indicator portion 254, it should be recognized that in the exemplary purpose embodiment of FIG. 11, a Geneva gear system is used, but any other suitable gear system or force transmission system can be used. In some embodiments, the delivery device uses a digital display to indicate the delivered volume and / or convey any other suitable information.

[0096] In some embodiments, any one of the delivery devices described herein can be used with a stereotactic frame (e.g., for neurosurgical applications). An example for illustrative purposes of a stereotactic frame is shown in FIG. 12. The stereotactic frame 300 includes an arm 302 for receiving the delivery device. In some embodiments, the delivery device can be sized to physically conform to the stereotactic frame. In the embodiment shown in FIG. 3A for illustrative purposes, the delivery device 1 includes a seating connector 80 that is sized to fit with the arm of the stereotactic frame. The seating connector of the delivery device can be held by the stereotactic frame. In some embodiments, the delivery device is compatible with a stereotactic frame from LEKSELL. However, it should be recognized that since this aspect is not so limited, the delivery device can also be compatible with other stereotactic frames.

[0097] In some embodiments, the delivery device is compatible with a frameless stereotactic system. By way of example, the subject's head (including the targeted tissue) can be fixed by a clamp (such as a standard Mayfield clamp). Further, the delivery device can include a portion of a tracking system for tracking the position and angle of the delivery device. The tracking system can include one or more of an optically based tracking system and an electromagnetic tracking system. The optically based tracking system can include one or more optical cameras, and the one or more optical cameras are configured to track one or more recognizable structures incorporated or provided on the delivery device, or to track one or more unique optical wavelengths emitted from an emitter incorporated or provided on the delivery device. The optically based tracking system can utilize techniques such as distance measurement using the principle of parallax, object recognition, and other image processing techniques to calculate the position and angle of the delivery device relative to the subject's head. The electromagnetic tracking system can include one or more electromagnetic field emitters and one or more electromagnetic field detectors. One of the one or more electromagnetic field emitters and one or more electromagnetic field detectors can be incorporated or provided on the delivery device, while the other of the one or more electromagnetic field emitters and one or more electromagnetic field detectors can be disposed near the delivery device. The electromagnetic tracking system can calculate the position and angle of the delivery device relative to the subject's head based on the known values of the electromagnetic fields emitted by the one or more electromagnetic field emitters and detected by the one or more electromagnetic field detectors. The position and angle of the delivery device calculated by the tracking system can be output as a visual guide for guiding the insertion of the delivery device.Also, the position and orientation of the delivery device calculated by the tracking system can be output to the robotic system, which controls one or more actuators to guide the insertion of the delivery device. Also, the position and orientation of the delivery device calculated by the tracking system can be superimposed on images acquired through an imaging system (e.g., computed tomography, magnetic resonance imaging, and positron emission tomography, etc.) to assist in the insertion of the delivery device. Since this aspect is not so limited, it should be recognized that the delivery device can be compatible with other frameless localization systems.

[0098] In use, in some embodiments, the needle is deployed into the tissue by advancing the entire delivery device distally. If the delivery device is attached to a positioning frame, the frame can assist in guiding the distal movement of the delivery device. Then, to deliver the therapeutic substance, the operator can activate the device actuator.

[0099] It should be recognized that in some embodiments, the needle can be actuated to move in the deployment direction relative to the outer shaft and / or relative to the housing of the delivery device. In some embodiments, a single device actuator can be used for both moving the needle in the deployment direction and ejecting the therapeutic substance. In other embodiments, a first actuator is used to move the needle in the deployment direction and a second actuator is used to eject the therapeutic substance.

[0100] Next, a method for preparing and priming a delivery device for use will be described with reference to FIG. 13. The method can include step S1302. Step S1302 can include placing one or more of needle 50, needle translation screw 52 attached to needle 50, plunger 60, and plunger translation screw 62 attached to plunger 60 into housing 10 and outer shaft 40 of the delivery device. For example, needle translation screw 52 can be arranged to engage a first threaded passage 56, and plunger translation screw 62 can be arranged to engage a second threaded passage 66 in housing 10. Further, plunger 60 can be placed into needle lumen 51 of needle 50, and needle 50 (having plunger 60 disposed therein) can be placed into shaft lumen 41 of outer shaft 40. Step S1302 can enable needle 50 and plunger 60 to be exchanged for needles and plungers of the same type. Further, step S1302 can enable different types of needles 50 (e.g., needles 50 having different volume needle lumens 51) and corresponding plungers 60 to be selected and placed into housing 10 of the delivery device.

[0101] After step S1302, step S1304 can be performed. Step S1304 can include operating device actuator 30 to cause relative movement of needle 50 and plunger 60, and placing needle opening 58 distal to opening 45 of outer shaft 40 along longitudinal axis 4 and placing distal end 65 of plunger 60 proximal to vent 59 of needle 50, as illustrated in FIG. 10A.

[0102] After step S1304, step S1306 may be performed. Step S1306 can include passively front-loading the therapeutic substance 180 into the needle lumen 51 of the needle 50, as illustrated in FIG. 10A. For example, an active loading device (e.g., a pump, etc.) may be used to move the therapeutic substance 180 into the needle lumen 51 in the proximal loading direction 181 through the needle opening 58. Since the distal end 65 of the plunger 60 is moved proximal to the vent 59 of the needle 50 in step S1304, when the therapeutic substance 180 is moved into the needle lumen 51, the air that previously occupied the needle lumen 51 is vented into the shuttle lumen 41 through the opened vent 59.

[0103] After step S1306, step S1308 may be performed. Step S1308 can include operating the device actuator 30 to advance the distal end of the plunger 60 to a position distal to the vent 59 to close the vent 59 of the needle 50, as illustrated in FIG. 10B. Also, step S1308 can include operating the device actuator 30 to move one or more of the needle 50 and the plunger 60 and simultaneously driving the indicator configuration to a position where an indicator reflects that the total dose (of the target volume) of the therapeutic substance 180 is loaded into the needle lumen 51.

[0104] After step S1308, step S1310 may be performed. As illustrated in FIG. 10B, step S1310 includes injecting a flushing fluid 184 into the space between the outer shaft 40 and the needle 50 in a flushing direction 185 through a flushing port 90 of the delivery device and through an opening 49 of the outer shaft 40 to remove air from the space between the outer shaft 40 and the needle 50. The injection of the flushing fluid 184 may be performed until it is observed that the flushing fluid 184 exits from the distal end 45 of the outer shaft 40. At this point, the delivery device may be considered to be in a primed state as illustrated in FIG. 10C.

[0105] It is noted that a method for preparing and priming the delivery device may include a portion of the steps described above while omitting one or more of the steps described above. In situations where the delivery device is intended for single use, step S1302 of placing the needle 50, the needle translation screw 52, the plunger 60, and the plunger translation screw 62 into the housing 10 may be omitted. Alternatively, in situations where the housing 10 is configured to accommodate different types of needles and plungers, step S1302 may be included in the method.

[0106] Next, a method for using the delivery device will be described with reference to FIG. 14. This method can include step S1402. Step 1402 can include the step of deploying the needle 50 and the outer shaft 40 into the tissue. The step of deploying the needle 50 and the outer shaft 40 into the tissue can include the step of advancing the entire delivery device distally and positioning the needle tip 55 at the target site 215. The step of advancing the entire delivery device can be performed manually. Alternatively, the step of advancing the entire delivery device can include guiding the delivery device by a positioning frame or a frameless positioning system for guiding the delivery device and positioning the needle tip 55 at the target site 215.

[0107] After step S1402, step 1404 can be performed. Step S1404 can include the step of operating the device actuator 30 and ejecting the therapeutic substance 180 at the target site 215. The step of ejecting the therapeutic substance 180 can include moving the plunger 60 relative to the needle 50 by moving one or both of the plunger 60 and the needle 50 to eject the therapeutic substance 180. Specifically, the step of ejecting the therapeutic substance 180 can include retracting the needle 50 to create a volume of space for the therapeutic substance 180 ejected from the delivery device, thereby reducing the backflow of the therapeutic substance 180 out of the target site 215.

[0108] After step S1404, step S1406 may be performed. Step S1406 can include draining a flushing fluid 184 that occupies the space between the outer shaft 40 and the needle 50 toward the target site 215. The step of draining the flushing fluid 184 can include setting the valve 92 of the flushing port 90 to the open position, exposing the space between the outer shaft 40 and the needle 50 to atmospheric pressure, and draining the flushing fluid 184 into the tissue. For example, a device (e.g., an open needle, etc.) can be inserted into the valve 92 to set the valve 92 to the open position.

[0109] After step S1406, step S1408 may be performed. Also, step 1408 can be performed together with step S1406. Step S1408 can include withdrawing the needle 50 and the outer shaft 40 from the tissue. The step of withdrawing the needle 50 and the outer shaft 40 from the tissue can include retracting the entire delivery device proximally and separating the needle tip 55 and the outer shaft 40 from the tissue. The step of retracting the entire delivery device can be performed manually. Alternatively, the step of retracting the entire delivery device can include guiding the delivery device by a positioning frame or a frameless positioning system and separating the needle tip 55 and the outer shaft 40 from the tissue.

[0110] It is noted that a method for using the delivery device can include a portion of the steps described above while omitting one or more of the steps described above. For example, if the risk of the suction effect caused by withdrawing the needle 50 from the tissue is considered low, the step S1406 of draining the flushing fluid 184 can be omitted.

[0111] Although the present teachings have been described in connection with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. Instead, the present teachings include various alternatives, modifications, and equivalents, as will be recognized by those of ordinary skill in the art. Accordingly, the foregoing description and drawings are for illustrative purposes only.

Explanation of Signs

[0112] 1 Delivery device 2 Proximal end 3 Distal end 4 Longitudinal axis 6 Proximal direction 8 Distal direction 9 Cannula portion 10 Housing 20 Handle 30 Device actuator 40 Outer shaft 41 Shaft lumen 45 Opening 49 Opening 50 Needle 51 Needle lumen 52 Needle translation screw 53 Needle tube 54 Ferrule 55 Needle tip 56 First threaded passage 57 Wall portion 58 Needle opening 59 Vent 60 Plunger 61 Plunger body portion 62 Plunger translation screw 63 Screw lumen 65 Distal end 66 Second threaded passage 68 Plunger seal 80 Seating connector 90 Flushing port 92 Valve 93 Channel 100 Planet gear system 110 Ring gear 114 Planet gear 150 Carrier 151 Guide rail 152 Guide rail lumen 153 Guide rail 160 Sun gear 162 Guide rail lumen 180 Therapeutic substance 181 Proximal loading direction 182 Arrow 183 Upward 184 Flushing fluid 185 Flushing direction 200 Geneva gear system 201 Forward 202 Reverse 210 Tissue 211 Tissue cavity 215 Target site 230 First drive wheel 240 Gear assembly 242 Driven wheel part 244 Drive wheel part 250 Indicator gear 252 Driven wheel part 254 Indicator part 255 Indicator window 300 Alignment frame 302 Arm 400 Delivery device 410 Outer cannula 500 Needle

Claims

1. A delivery device for delivering a therapeutic substance, a needle having a needle lumen, a plunger configured to move through the needle lumen, and comprising an operation of a device actuator causes the needle to move in a retraction direction and simultaneously causes the plunger to move in a deployment direction through the needle lumen, the retraction direction being opposite to the deployment direction.

2. The delivery device further comprises an outer shaft having a shaft lumen, and the needle is configured to move through the shaft lumen. The delivery device according to claim 1.

3. The operation of the device actuator causes the needle to move a first distance relative to the outer shaft and causes the plunger to move a second distance relative to the outer shaft, the first distance being different from the second distance. The delivery device according to claim 2.

4. The first distance is smaller than the second distance. The delivery device according to claim 3.

5. The delivery device a first threaded passage, a second threaded passage, a first translation screw attached to the needle and positioned in the first threaded passage, a second translation screw attached to the plunger and positioned in the second threaded passage, and further comprising The operation of the device actuator causes rotation of the first threaded passage and rotation of the second threaded passage, which causes the first translation screw to translate through the first threaded passage and the second translation screw to translate through the second threaded passage, the delivery device according to any one of claims 1 to 4.

6. The rotation of the first threaded passage occurs in a first rotation direction, and the rotation of the second threaded passage occurs in a second rotation direction opposite to the first rotation direction, the delivery device according to claim 5.

7. The first threaded passage has a first thread having a first number of threads, the second threaded passage has a second thread having a second number of threads, and the first number of threads is different from the second number of threads, the delivery device according to claim 6.

8. The first threaded passage has a first thread having a first thread direction, the second threaded passage has a second thread having a second thread direction, and the first thread direction and the second thread direction are opposite to each other, the delivery device according to claim 5.

9. The delivery device according to claim 5 further comprises a gear system coupling the device actuator to the first threaded passage and optionally to the second threaded passage.

10. The gear system includes a planetary gear system including a sun gear and a plurality of planetary gears, the planetary gears being rotatably mounted on a carrier, The sun gear is coupled to the device actuator and the second threaded passage, and the carrier is coupled to the first threaded passage, the delivery device according to claim 9.

11. The delivery device according to claim 1, further comprising a gear system connecting the device actuator to the plunger and the needle.

12. The gear system includes a planetary gear system having a sun gear and a plurality of planetary gears, the planetary gears being rotatably mounted on a carrier, the sun gear being attached to the device actuator and coupled to the plunger, and the carrier being coupled to the needle, the delivery device according to claim 11.

13. The delivery device according to claim 12, wherein the needle lumen has a constant diameter throughout its length.

14. The delivery device according to claim 1, wherein the device actuator is rotatably mounted with respect to a device housing, and rotation of the device actuator causes the plunger to move through the needle lumen.

15. The delivery device according to claim 14, wherein the device actuator has a rotation axis parallel to the extending direction of the plunger.

16. The delivery device according to claim 14, wherein a plurality of complete rotations of the device actuator are required to achieve a maximum delivery volume.

17. The delivery device according to claim 10, wherein the sun gear and the device actuator are integrally formed as a single part.

18. The needle has a delivery end and a shaft, the needle lumen extends through the shaft, and the plunger is configured to move through the needle lumen, the needle further including a vent in the shaft, the vent being spaced from the delivery end, the delivery device according to claim 1.

19. The plunger has a first position in which fluid communication through the vent is open, and the plunger has a second position in which fluid communication through the vent is closed, the delivery device according to claim 18.

20. Actuation of the device actuator moves the plunger in the deployment direction and closes fluid communication through the vent, the delivery device according to claim 18.

21. The vent is a through hole extending through the wall of the shaft, the delivery device according to claim 18.

22. A flushing port, An outer shaft surrounding the needle, the outer shaft having an opening, the outer shaft, and A valve for controlling fluid communication between the flushing port and the opening of the outer shaft further comprising, the delivery device according to claim 18.

23. Further comprising a therapeutic substance loaded into the delivery device, the therapeutic substance being completely contained within the needle lumen, the delivery device according to claim 18.

24. An indicator having an indicator indicating the dose to be delivered, the indicator being mechanically coupled to the device actuator, whereby actuation of the device actuator causes the indicator of the indicator to physically move without an electrical input, further comprising an indicator, the delivery device according to claim 1.

25. Further comprising a gear system for mechanically coupling the indicator to the device actuator, the delivery device according to claim 24.

26. A method of loading a therapeutic substance into a delivery device, the delivery device comprising a needle having a needle lumen and a plunger configured to move through the needle lumen, wherein actuation of a device actuator in a first direction causes the needle to move in a retraction direction and simultaneously causes the plunger to move through the needle lumen in a deployment direction opposite to the retraction direction, The method comprising: Moving the therapeutic substance into the needle lumen through the delivery end of the needle; Ventilating air out of the needle lumen through a vent in the needle when the therapeutic substance is moved into the needle lumen; Closing fluid communication through the vent after the therapeutic substance has been moved into the needle lumen. A method comprising the steps of: **Claim 27** The method of claim 26, further comprising activating a pump to move the therapeutic substance into the needle lumen. **Claim 28** The method of claim 26, further comprising connecting the delivery end of the needle to a holder holding the therapeutic substance. **Claim 29** The step of closing fluid communication through the vent comprises moving a plunger in the needle lumen to cover the vent, the vent including an opening in the wall of the needle, the method of claim 26. **Claim 30** The method of claim 26, further comprising priming the delivery device by flushing an outer shaft surrounding the needle with a flushing fluid.

Images