Syringe and syringe system for manipulating fluids

Abstract

Apparatus, method, and system including a syringe for delivering a fluid. The syringe includes a syringe body, a piston, an insert, and a removable plunger. The piston is positioned within the lumen of the syringe body such that the bottom of the piston cooperates with the inner wall of the syringe to define an operating volume. The piston includes a cavity. The insert is positioned at a desired location within the lumen. The insert constricts the lumen and is configured to prevent the piston from retreating beyond the desired location. The removable plunger is configured to removably couple to the piston. The removable plunger includes a tip configured to couple with the cavity of the piston to move the piston when a force is applied to the plunger and to decouple from the piston when the piston engages the insert at the desired location.

Description

Technical Field

[0001] The present disclosure generally relates to fluid delivery, and more specifically, to improvements to syringes, as well as methods of using syringes, aspiration syringes, and systems employing syringes for the manipulation of biological samples.

Background Art

[0002] Syringes are widely used for the manipulation of samples in research, medical, and diagnostic settings. A syringe typically consists of a needle attached to one end of a hollow cylinder and a plunger connected to a sliding piston. Fluid is drawn into the hollow cylinder from the needle by pulling the plunger. The fluid can be injected or dispensed from the hollow cylinder by pushing the plunger to force the fluid out of the needle through the piston. A syringe can be filled with a desired sample immediately before use, or the syringe can be pre-filled with a desired sample.

[0003] In some applications, pre-filled syringes transport samples from one location to another (e.g., within a laboratory or from one geographical location to another). Such pre-filled syringes typically have a plunger attached to a piston that extends well above the upper portion of the hollow cylinder. If the plunger is inadvertently pushed or bumped, fluid can be dispensed at an undesirable time and / or location. Thus, there is a need for an improved syringe that allows for the transport of syringes without the risk of unintentional discharge.

Summary of the Invention

[0004] One aspect of the present disclosure relates to a syringe. The syringe includes a syringe body having an inlet and an inner wall defining a lumen having a longitudinal axis and a diameter, a piston positioned within the lumen of the syringe body, an insert positioned at a desired location within the lumen, and a removable pull rod, also referred to herein as a removable plunger and used interchangeably. The piston has a top and a bottom, and the bottom of the piston together with the inner wall defines a working volume. The piston includes a cavity. The piston is movable along the longitudinal axis to change the working volume. The insert constricts the lumen and prevents the piston from retreating beyond the desired position. The removable pull rod is configured to removably couple to the piston. The removable pull rod includes a tip that couples to the cavity of the piston and moves the piston within the syringe body when a force is applied to the removable pull rod. The removable pull rod decouples from the piston when the piston engages the insert at the desired position.

[0005] In some embodiments, the tip has a conical shape with a narrow end configured to enter a cavity within the piston and a base end configured to couple the piston to the tip. The base end of the tip has a chamfered, spherical, or filleted edge configured to facilitate withdrawal of the tip from the cavity of the piston. The base end includes a base portion configured to taper away from the narrow end. The piston is made of a flexible material.

[0006] In some embodiments, the cavity is cylindrical in shape and sized to provide a friction fit between the tip of the removable pull rod and the piston. The cavity is sized to receive the tip and fit tightly around the tip such that the piston is retractable by the removable pull rod. The cavity of the piston is configured to cover the base portion of the tip.

[0007] In some embodiments, the piston is made of a flexible material. The cavity of the piston is sized smaller than the tip so as to create a friction fit with the tip of the removable pull rod. When the piston receives the removable pull rod, the cavity of the piston expands around the tip, thereby coupling the removable pull rod and the piston. The piston is disposed at the proximal end of a syringe configured to receive fluid, and the desired position is the distal end of the syringe indicating the desired amount of fluid to be filled in the syringe. The cavity extends partially towards the bottom of the piston but does not extend through the bottom of the piston. The piston is axially disposed within the syringe body, and the cavity is formed at the center of the piston and extends axially.

[0008] In some embodiments, the insert may include a hollow cylinder optionally including flanges, barbs, recesses, or grooves defining an internal channel, or may be in a ring shape formed from the plastic of the syringe. The internal channel is larger than the outer diameter of the removable pull rod, and the removable pull rod extends movably through the internal channel, enabling movement along the longitudinal axis and configured to remove the removable pull rod from the syringe when decoupled from the piston. The insert is removably inserted at the distal end of the syringe opposite the inlet. In another example, the insert is fixedly attached to the distal end of the syringe at a desired position within the lumen.

[0009] Furthermore, one aspect of the present disclosure relates to a method for aspirating a syringe, the syringe comprising a piston and a removable pull rod. The method includes inserting the removable pull rod from the distal end of the syringe into the lumen defined by the inner wall of the syringe to couple with the piston, retracting the removable pull rod to retract the piston from the proximal end to the distal end of the lumen to draw fluid into the syringe through the inlet at the proximal end, preventing further retraction of the piston by an insert positioned within the lumen, and removing the removable pull rod from the piston.

[0010] In some embodiments, inserting the removable pull rod involves aligning the tip of the removable pull rod with the cavity of the piston and pushing the tip into the cavity until the removable pull rod is coupled with the piston. The tip is configured to engage with the cavity of the piston and move within the syringe body when a force is applied to the removable pull rod, and to disengage from the piston when the piston engages with the insert.

[0011] In some embodiments, removing the removable pull rod involves further retracting the removable pull rod while the piston is engaged with the insert, thereby removing the tip of the removable pull rod from the cavity of the piston such that the piston remains inserted within the syringe while the removable pull rod is completely removed from the piston.

[0012] Furthermore, the method involves securing the insert at a desired position within the lumen, the desired position corresponding to the amount of fluid to be filled within the syringe.

[0013] Furthermore, one aspect of the present disclosure relates to a system employing one or more syringes for administering and delivering a desired amount of fluid. The system includes a syringe, a supply line for delivering the contents of the syringe, and a syringe receptacle. The syringe includes a syringe body having an inner wall defining a lumen with a longitudinal axis, a removable pull rod with a tip, and a piston positioned within the lumen of the syringe body, the piston together with the inner wall defining an operating volume configured to hold fluid, the piston comprising a cavity configured to engage the tip of the removable pull rod, and an insert narrowing the lumen to prevent the piston from retreating beyond a desired position. The supply line delivers droplets from the syringe into the sterile fluid system. The syringe receptacle receives the syringe and fluidly couples the syringe to the supply line. The system forms a sterile and functionally closed system that can be utilized, for example, in a workflow for generating a cell therapy product.

[0014] In some embodiments, the receptacle and the syringe are coupled together by a fastening mechanism such as a snap, latch, or screw engagement disposed at the distal end of the syringe. For example, in some embodiments, the receptacle and the syringe are coupled by a screw engagement, the syringe including a thread formed at the proximal end on the outer surface of the syringe, and the receptacle including a corresponding thread in an inner portion of the receptacle. The receptacle includes a pierceable septum penetrated by a needle attached to the proximal end of the syringe such that the tip of the needle enters the supply line to supply droplets into the supply line. The receptacle includes a plurality of hollow chambers, each chamber configured to receive one syringe. One or more of the hollow chambers of the receptacle are configured to receive one or more syringes of different sizes. The supply line has an inlet and an outlet, the receptacle being connected between the inlet and the outlet, the inlet receiving a fluid such as a sterile gas, air, or liquid (e.g., a liquid buffer) from a pump, and the outlet delivering fluid from a plurality of syringes within the receptacle.

[0015] In some embodiments, the system further includes a delivery mechanism configured to inject fluid from one or more syringes within a receptacle at a specified time and in a specified amount.

[0016] Furthermore, one aspect of the present disclosure relates to a method of dispensing the contents of a syringe. The method involves filling the syringe by retracting a removable plunger coupled to a piston located within the lumen of the syringe body, separating the removable plunger from the piston after filling the syringe, coupling a syringe receptacle and a supply line, inserting the syringe into the syringe receptacle to fluidly couple the syringe to the supply line, coupling the plunger to the piston, and advancing the plunger by a specified amount to move the piston within the lumen of the syringe body, thereby delivering a desired amount of fluid into the supply line. Fluidly coupling the syringe to the supply line forms a sterile and functionally closed system.

[0017] The above general description of exemplary implementations and the following detailed description thereof are merely exemplary aspects of the teachings of the present disclosure and are not limiting.

[0018] The accompanying drawings, which are incorporated herein and constitute a part of this specification, illustrate one or more embodiments and, together with the description, explain these embodiments. The accompanying drawings are not necessarily drawn to scale. The dimensions of any values illustrated in the accompanying graphs and figures are for illustrative purposes only and may or may not represent actual or preferred values or dimensions. Where applicable, some or all features may not be illustrated to assist in the description of the underlying features. In the drawings,

Brief Description of the Drawings

[0019]

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DETAILED DESCRIPTION OF THE INVENTION

[0020] The following description, which relates to the accompanying drawings, is intended as a description of various embodiments of the disclosed subject matter and is not necessarily intended to represent the only embodiment. In certain instances, the description includes specific details for the purpose of providing an understanding of the disclosed embodiments. However, it will be apparent to one skilled in the art that the disclosed embodiments may be practiced without those specific details. In some instances, well-known structures and components may be shown in block diagram form to avoid obscuring the concepts of the disclosed subject matter.

[0021] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the disclosed subject matter. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Additionally, embodiments of the disclosed subject matter are intended to include modifications and variations thereof.

[0022] Terms such as "distal", "proximal", "upper", "lower", "front", "side", "length", "inferior", "inner", "inner side", "outer side", etc. that can be used in this specification are merely for explaining the reference points, and it should be understood that they do not necessarily limit the embodiments of the present disclosure to any specific orientation or configuration. Further, terms such as "first", "second", "third", etc. only identify one of several parts, components, steps, operations, functions, and / or reference points as disclosed in this specification, and similarly, they do not necessarily limit the embodiments of the present disclosure to any specific configuration or orientation.

[0023] The terms "longitudinal direction", "axial direction", or "axially" when used in this specification are generally in the longitudinal direction for explaining the relative positions of the syringe, the delivery mechanism, and the components of the system of this specification. The term "radial direction" generally refers to a direction perpendicular to the "axial direction". For example, the term "radial direction" generally refers to a direction perpendicular to axis "A".

[0024] The term "fluid" mainly refers to a liquid, but also includes a solid suspension diffused in the liquid, a solid suspension dissolved in the liquid, or a gas coexisting in the liquid in the fluid-containing part of the syringe. In this disclosure, for the purpose of explaining the concept, a fluid is used as an exemplary substance aspirated into the syringe. In many embodiments, a sample can be aspirated without departing from the scope of this disclosure.

[0025] As used in this specification, the term "sample" refers to a liquid that can be used in an assay such as a chemical or biological assay, and may contain one or more reagents such as biological molecules.

[0026] The term "biological molecule" or "biomolecule" is generally intended to refer to any organic or biochemical molecule that occurs in a biological system including whole cells, cell components, substrates, or any part thereof.

[0027] As used herein, "cellular component" is intended to include any component of a cell that can be at least partially isolated upon lysis of the cell. Cellular components include recombinant or synthetically produced components that can be functionally and / or structurally modified to include synthetically (e.g., chemically synthesized) derived components. Cellular components can be organelles such as the nucleus, perinuclear compartment, nuclear membrane, mitochondria, chloroplasts, or cell membrane, or polymers or molecular complexes such as lipids, polysaccharides, proteins (membrane, transmembrane, or cytoplasmic), nucleic acids, virus particles, or ribosomes, or other molecules such as hormones, ions, cofactors, or drugs.

[0028] In various embodiments, a sample includes cells (e.g., mammalian or non-mammalian cells), cellular components, biomolecules, or other reagents (e.g., reagents used in the development or manufacture of cell and gene therapies). In some embodiments, the sample can be a fluid and can be filled into a syringe through a tube, vial, or other container. In some embodiments, the tube, vial, or other container is disposable and is composed of a material suitable for preparing, mixing, centrifuging, transporting, and / or storing solid and liquid samples and reagents such as quartz, glass, metal, or polymers (e.g., polypropylene, polyvinyl, polyurethane, polycarbonate, etc.).

[0029] Systems used in cell-based or gene-based therapies (e.g., CAR T cell therapy) involve a number of instruments that perform multiple processes and often involve the addition of a number of reagent / cell culture components in a specified order to various instruments.

[0030] In the field of cell and gene therapies, a functionally closed sterile system is highly desirable. "Open" steps (e.g., those involving manual intervention) should be minimized to reduce the risk of biological contamination.

[0031] Currently, when electroporation, a common technique used in gene editing, is used to deliver a payload (e.g., a biomolecule such as a nucleic acid or protein, or other reagent), the cells are concentrated and resuspended in an electroporation buffer (e.g., a conductive fluid) within a bag or a rigid container. Once resuspended, additional reagents can be added to the cells in a specific order. Currently, this is achieved within a biosafety cabinet and is considered an open step, having a certain risk of contamination. Ideally, this step is performed outside of the biosafety cabinet within an automated closed system, but current solutions for the automated injection of different fluids are inadequate, especially for low-volume fluids (e.g., <1 ml). Following the addition of the payload and any necessary additional reagents, the bag or other storage medium containing the cells is then coupled to an electroporation platform to electroporate the cells.

[0032] The placement of the syringe and the automated injection of the fluid can be associated with problems including, for example, dead volume, priming issues, or unintended injection of the liquid, such as when the plunger hits or is inadvertently depressed.

[0033] The present disclosure solves some of the problems outlined above and provides new systems, methods, and devices for the injection of samples (including, for example, fluids, suspensions, etc.). In some embodiments, multiple syringes are disposed within a casing (e.g., a consumable) to inject different samples into a tube connecting two devices in order to automate the injection of different samples. The plunger of one or more syringes can be operated to dispense a desired amount of sample from the syringe into a desired location at a desired time.

[0034] Figures 1A - 1C illustrate one embodiment of the syringe 100. The syringe 100 may be a standard syringe which may be an off - the - shelf product or a custom syringe. The syringe 100 includes a syringe body 101 and a pull rod 105 having a plunger fixedly coupled to a piston 103 disposed within the syringe body 101, specifically, within a lumen defined by the inner wall of the syringe body 101.

[0035] In some embodiments, the pull rod 105 may be configured to engage non - removably with the piston 103. Specifically, the pull rod 105 may be configured to be permanently coupled to the piston 103. This permanent coupling may be achieved, for example, via the geometry of the tip of the pull rod 105 and / or a receiving cavity within the piston 103. In some embodiments, for example, as in the embodiment shown in Figure 1C, the tip 120 of the pull rod 105 has a distal end 122 and a proximal end 124. The proximal end 124 of the tip 120 connects to the distal end 126 of a shaft 128. The shaft 128 and the tip 120 together form the pull rod 105.

[0036] In some embodiments, the distal end 122 of the tip 120 may be shaped to facilitate insertion into a cavity of the piston 103 so as to be fixedly coupled to the piston 103. This may include, for example, the distal end 122 of the tip 120 including a taper 123, a fillet, etc. The proximal end 124 of the tip 120 may include one or several features to assist in maintaining the connection between the pull rod 105 and the piston 103. In some embodiments, this may include a shoulder 130 forming an edge 132 that extends partially or entirely around the proximal end 124 of the tip 120. In some embodiments, the shoulder 132 may extend radially from the pull rod 105 and in some embodiments may be perpendicular to the pull rod 105 or form an angle of up to 90 degrees with respect to the pull rod 105 at the proximal end 124 of the tip 120.

[0037] The tip 120 is inserted into the piston 103 and fixedly couples the piston 103 to the pull rod 105. This pull rod 105 cannot be separated from the piston 103 when the pull rod 105 engages with the piston 103.

[0038] Typically, the piston 103 is disposed at the proximal end 110 of a standard syringe 100 when there is no fluid within the syringe 100. The piston 103 moves within the lumen defined by the syringe 100 to vary the working volume of that syringe 100, thereby being able to draw fluid into the syringe 100, expel fluid from the syringe 100, or hold fluid within the syringe 100.

[0039] As shown in FIG. 1B, the syringe 100 can aspirate the fluid LQ1 when the pull rod 105 is retracted, or in other words, when pulled rearward to move the piston 103 toward the distal end 112 of the syringe. When the piston 103 moves toward the distal end 112 of the syringe 100, a vacuum is created within the lumen of the syringe 100 between the piston 103 and the proximal end 110 of the syringe 100. This vacuum causes the fluid LQ1 to be aspirated into the syringe 100. In the example shown, the fluid LQ1 is drawn through a needle N1 coupled to the proximal end 110. In another example, a needle may not be used. When the fluid LQ1 is aspirated into the syringe 100, a portion 105p of the pull rod 105 projects distally from the distal end 112 of the syringe 100.

[0040] Syringe 100 is not very suitable for some applications because part 105p of pull rod 105 extends out of syringe 100 and is exposed. Thus, a small amount of force on pull rod 105 undesirably causes the syringe contents to be discharged from syringe 100 in an undesired manner, which can lead to loss of contents into the system at an undesired time and / or in an undesired amount. For example, the protruding rod portion 105p may accidentally bump, resulting in an unintended dispensing of contents (e.g., fluid LQ1, e.g., a liquid sample) at an unspecified time and / or in an unspecified amount.

[0041] The present disclosure describes a syringe that advantageously eliminates such unintended dispensing by separating the piston from the pull rod. Specifically, a syringe is described herein that includes features that allow separation of the piston from the pull rod or plunger. For example, separation / disengagement of the plunger can be achieved when the piston is retracted. After separating the plunger, the piston remains within the syringe body, thereby holding any contents (e.g., fluid, sample, etc.) within the syringe. Thereafter, the plunger can be re-engaged to dispense the contents, if desired. Those skilled in the art will understand that re-engagement of the plunger is not the only means by which the contents can be dispensed, rather any means of depressing the piston can be used.

[0042] In one embodiment, for example, the pull rod can be configured to be removable from the piston. In one embodiment, an insert that contacts the piston is provided such that the piston remains within the syringe body while the pull rod is disengaged from the piston and removed from the syringe.

[0043] In some embodiments, the pull rod or plunger may include a tip shaped and sized to allow for easy removal of the piston from the plunger. For example, the pull rod may include a tip having a smooth or rounded proximal end, as opposed to a proximal end 124 having a shoulder 130 with a sharp edge 132 as shown in FIG. 1C. Further, in some embodiments, the tip may be sized to create an interference fit with the piston. The interference fit allows the piston to be easily removed after it has been retracted and, if desired, for example, after the piston has reached a desired position within the syringe. In some embodiments, the tip of the plunger may have a curved (e.g., spherical) geometry so that it can be easily removed from the piston.

[0044] In some embodiments, an insert may be provided to further enable stopping the piston at a desired position and allowing the plunger to be removed from the syringe. For example, the insert may be a hollow insert or barb designed to be inserted into the syringe body at a desired location. In some embodiments, the insert may be made from a variety of materials, including polymers such as stainless steel or plastic. The insert may have various shapes and sizes and, in some embodiments, may comprise a cylindrical insert defining an axially extending channel therethrough. The channel through the insert may be sized to allow the plunger to pass through the insert and engage the piston, and in some embodiments, the diameter of the channel through the insert is larger than the diameter of the plunger. In some embodiments, the insert may project into the lumen of the syringe. Thereby, the insert may partially occlude the lumen. The insert engages the piston when the piston is retracted, thereby holding the piston within the lumen and facilitating separation of the plunger from the piston.

[0045] FIG. 2A illustrates one embodiment of an exemplary syringe 200 having a plunger 205 removed from the piston 203. FIG. 2B illustrates a cross-sectional view of one embodiment of a plunger tip 250 engaged with the piston 203 of the syringe 200. The piston 203 can move within the lumen 215 of the syringe 200 to aspirate contents (e.g., fluid, sample, etc.) into the syringe 200 or dispense contents (e.g., fluid, sample, etc.) from the syringe 200. The piston 203 can be moved by the plunger 205 when the plunger 205 is coupled to the piston 203. When the piston 203 is decoupled from the plunger 205, the syringe 200 can be emptied or hold a desired amount of contents (e.g., fluid, sample, etc.). Advantageously, when the plunger 205 is removed from the syringe 200, the syringe 200 does not have any portion of the plunger 205 that protrudes distally from the syringe 200. Accordingly, any unintentional release of contents (e.g., fluid, sample, etc.) from the syringe 200 upon hitting the plunger 205 can be prevented. The plunger 205 or another rod can be re-coupled to the piston 203 to release contents (e.g., fluid, sample, etc.) from the syringe 200, if desired. Alternatively, the piston can be engaged by other means (e.g., an actuator or pressurized gas, pneumatic or otherwise) to facilitate the release of the contents within the syringe.

[0046] As shown in FIG. 2A, the syringe 200 includes a syringe body 201 configured to hold contents (e.g., fluid, sample, etc.). The syringe body 200 includes an inner wall 213 that defines a lumen 215. The piston 203 is movably disposed within the lumen 215 of the syringe body 201. In some embodiments, the piston 203 may be sized and configured to sealingly engage the inner wall 213 such that a desired content, such as a fluid, can be drawn into the lumen 215 when the piston 203 is retracted distally and the content can be dispensed from the lumen 215 when the piston is advanced proximally. The syringe 200 may include a removable plunger 205 (also referred to as a removable pull rod 205) that can be removably coupled to the piston 203. In some embodiments, the syringe 200 may include a stopper surface 209 for stopping the piston 203 and preventing the piston 203 from being removed from the syringe 200.

[0047] The syringe body 201 has an orifice, which can be a luer 211 fluidly connected to the lumen 215. As seen in FIG. 2A, the lumen 215 has a central longitudinal axis A that can extend axially through the luer 211 in some embodiments. The lumen 215 may further have a diameter D1 (see FIG. 4B).

[0048] Optionally, the luer 211 of the syringe 200 can be coupled to a needle N1, whereby a content (e.g., fluid, sample, etc.) can be drawn into or dispensed from the lumen 215. If present, the needle N1 can be integrated with or removable from the syringe 200.

[0049] In some embodiments, the syringe body 201 is made of a material that enables visual detection of the contents within the lumen, such as transparent plastic, transparent glass, etc. The syringe body may be marked with a measurement scale to enable visualization of the amount of contents aspirated within the lumen 215. For example, the measurement scale (similar to that shown in FIG. 1A) may be configured to measure the volume of the contents aspirated within the lumen 215 in milliliters (ml), microliters (μl), ounces (oz), or other units of measurement. In some embodiments, the syringe body 201 is composed of any known material typically used for syringes, such as non-bioreactive plastic, glass, or other materials that do not react with the contents aspirated within the syringe. In some embodiments, the syringe body 201 is composed of or includes a bioreactive material that preserves or otherwise stabilizes the contents of the syringe to maintain a long lifespan.

[0050] In some embodiments, the piston 203 is located within the lumen 215 of the syringe body 201. The piston 203 may be disposed axially within the lumen 215. The piston 203 has a top and a bottom and engages the inner wall 213 of the syringe body 201 in a sealed manner. The bottom of the piston 203, together with the inner wall 213 of the syringe body 201, defines an operating volume configured to hold the contents. The piston 203 is movable along the longitudinal axis A to change the operating volume within the lumen 215. The piston 203 may be disposed at the proximal end 204 of the syringe 200 before receiving the fluid, and the piston 203 may be retracted by being pulled to a desired position within the lumen 215 by the plunger 205, and the desired position may be the distal end 202 of the syringe 200. The piston 203 may be retracted to fill the lumen 215 of the syringe 200 with the contents.

[0051] The piston 203 and the plunger 205 are configured to be removably coupled to each other. For example, in the embodiment shown in FIG. 2A, a cavity is provided on the upper side of the piston 203. The cavity can be configured to engage or disengage with the plunger 205. In some embodiments, the cavity (see, e.g., cavity 252 in FIGS. 2B and 4C) can extend partially towards the bottom of the piston 203. In some embodiments, the cavity does not extend through the bottom of the piston 203. The cavity is formed at the center of the piston 203 and can be configured to fit with an extension from the distal end of the plunger 205. The cavity extends axially through the piston 203 partially.

[0052] The removable plunger 205 is configured to be removably coupled to the piston 203. In some embodiments, a portion of the plunger 205 that engages the piston 203 can be configured to be easily coupled and decoupled from the piston 203. The portion of the plunger 205 is configured such that when the piston 203 is retracted, the plunger 205 remains coupled to the piston 203, but when retracted to a desired position (e.g., when the piston contacts the stopper surface 209), a portion of the plunger 205 can be easily decoupled (e.g., simply by pulling the plunger 205 axially away).

[0053] In some embodiments, the tip portion 250 of the removable plunger 205 can be configured to engage and disengage with the cavity of the piston 203. In some embodiments, the tip can advance into the cavity 252 of the piston 203. The tip 250 can be sized to engage deformably with the wall of the cavity 252 of the piston 203. This deformation and the resulting force can couple the piston 203 to the tip 250 of the plunger 205. When coupled, a force is applied to the plunger 205 to displace the plunger longitudinally and move the piston 203 within the lumen 215. When the piston 203 reaches the desired position indicating that the desired amount of fluid has been filled into the syringe, further distal movement of the piston 203 can be blocked by the insert 210, and the plunger 205 can be separated from the piston 203. Specifically, the tip 250 of the plunger 205 can retract from the cavity 252 of the piston 203. The tip portion 250 engages tightly with the cavity 252 of the piston 203 such that the force applied to displace the piston 203 is greater than the frictional force between the piston 203 and the lumen 215, but less than the force required to disengage the plunger 205 from the piston 203.

[0054] In some embodiments, as illustrated in FIGS. 2B and 4C, the cavity 252 of the piston 203 has a hollow cylindrical shape and is sized to receive the tip 250 deformably and provide a friction fit between the tip 250 of the removable plunger 205 and the piston 203. The cavity 252 can have an inner diameter D3 configured to receive the tip 250 of the plunger 205, and the tip 250 has a diameter larger than the diameter D3 of the cavity 252. The cavity 252 can be sized to receive the tip 250 and fit tightly around the tip 250 such that the piston 203 can be retracted by the removable plunger 205.

[0055] In some embodiments, the cavity 252 of the piston 203 can be sized smaller than the size of the tip 250 of the plunger 205. The shape of the cavity 252 can conform to or match the shape of the tip 250 of the removable plunger 205 such that when the piston 203 receives the removable plunger 205, the cavity 252 of the piston 203 expands around the tip 250 to couple the removable plunger 205 and the piston 203. It can be understood that the shapes and sizes of the cavity 252 and the tip 250 are exemplary and do not limit the scope of the present disclosure. In some embodiments, the cavity 252 can have different shapes, such as a conical shape, a rectangular shape, a spherical shape, or other standard or custom geometric shapes, including combinations thereof, that allow for a fit between the cavity and the tip 250 of the plunger 205 such that the plunger 205 can be easily coupled and decoupled from the piston 203.

[0056] Figure 3 illustrates an exemplary geometric shape of a plunger tip 250 that engages a cavity 252 (shown in FIG. 2B) of a piston 203. Either end of the tip 250 has a sufficient taper or curvature such that the plunger 205 can engage the piston 203 and move it, but will disengage when sufficient force in the opposite direction is applied between the plunger 205 and the piston 203. For example, as shown in FIG. 2B, the diameter of the tip 250 is greater than the diameter D3 of the cavity 252 (shown in FIG. 2B). In some embodiments, the tip 250 can be conical or spherical. For example, the tip 250 can be configured to enter the cavity 252 within the piston 203 (shown in FIG. 2B), also referred to herein as the narrow proximal end 260 or the proximal end 260, and a distal end 262, also referred to herein as the base end 262, configured to couple the piston 203 to the tip 250, and can be conical. For example, the proximal end 260 can have a diameter DT1, and the tip 250 can have a maximum diameter DT2 that is greater than the diameter DT1. The diameter DT1 of the narrow end 260 is less than the diameter D3 of the cavity 252 to allow at least partial insertion of the tip 250 without any resistance from the piston's cavity 252. The diameter DT2 is greater than the diameter D3 of the cavity 252 such that force is required to push the tip 250 into the cavity 252 of the piston 203 to tightly engage the piston 203 and the plunger 205. Thus, the tip 250 facilitates the coupling of the plunger 205 to the piston 203 such that the plunger 205 does not disengage from the piston 203 when the piston is retracting.

[0057] In some embodiments, the distal end 262 of the tip 250 has a diameter that is reduced compared to the diameter DT2. This reduced diameter may facilitate the retraction of the tip 250 from the cavity 252 of the piston 203, thereby facilitating the easy decoupling of the plunger 205 from the piston 203. In some embodiments, the reduced diameter may include a chamfered, spherical, or filleted edge that extends around the distal end 262 of the tip 250 to create a smooth edge. The smooth edge, along with the shape and size of the tip 250 that cooperate with the cavity 252, enable the plunger 205 to be pushed into and pulled out of the piston with a small force. In some embodiments, the distal end 262 of the tip 250 does not include a shoulder having a sharp edge as shown in FIG. 1C, which is typically found on a typical plunger used within a typical syringe. Such a sharp edge on a typical plunger digs into the piston when the piston is pulled out, inhibiting the removal of the plunger from the piston without damaging the piston. Instead, the distal end 262 includes a reduced diameter that tapers towards the maximum diameter DT2. In some embodiments, the cavity 252 of the piston 203 may be shaped to conform or match the base portion of the tip 250 (e.g., the portion at the distal end 262), creating a fit that supports the retraction of the piston 203 from the plunger 205 without decoupling from the plunger 205. For example, the cavity 252 may be cylindrical in shape and may have a diameter smaller than the reduced diameter of the distal end 262. In such embodiments, the cavity may deform around the shape of the tip 250 and conform or match it, specifically around the shape of the distal end 262 of the tip 250 and conform or match it.

[0058] In some embodiments, the removable plunger 205 can be a cylindrical rod having a shaft diameter DS1, with a tip 250 extending from the shaft portion 205T. The shaft portion 205T has a smaller diameter DS2 compared to the shaft diameter DS1 of the plunger 205. In some embodiments, the plunger 205 can have a shaft portion 205T with a diameter DS2 that is smaller than the size (e.g., diameter D3) of the cavity 252, while the shaft diameter DS1 can be approximately equal to or larger than the size (e.g., diameter D3) of the cavity 252. The smaller diameter DS2 ensures that only the tip 250 engages the cavity 252 of the piston 203, while the shaft portion 205T does not engage the cavity 252. In some embodiments, the shaft diameter DS1 of the plunger 205 allows insertion of the tip 250 to the maximum depth of the cavity 252, such that any forceful insertion into the cavity 252 does not damage the piston 203, e.g., the tip 250 does not tear the bottom end of the piston 203.

[0059] In some embodiments, the piston 203 can be made of an elastic material, such as a flexible material, e.g., a rubber material or silicone or other elastically deformable material. The terms "elastic" and "elastic material" mainly refer to crosslinked thermosetting polymers such as silicone or rubber-like polymers that are more easily deformable than plastics. Such materials are, for example, biologically and chemically inert / non-reactive and are thus suitable for use with reactive or biological fluids and are not easily affected by leaching or gas migration under ambient temperature and pressure. In some embodiments, the plunger 205 can be made of a metal (e.g., steel, etc.), plastic, or other material harder than the piston 203. In some embodiments, the plunger 205 can have a surface roughness such that a friction fit with the material of the piston 203 occurs, but is smooth enough to allow easy removal of the plunger 205 from the piston 203.

[0060] In some embodiments, the stopper surface 209 is positioned at a desired location within the lumen 215 to prevent the piston 203 from retracting from the syringe body 201. The stopper surface 209 may, in some embodiments, constrict the lumen 215 and may be configured to prevent the piston 203 from retracting beyond the desired location. As an example, the stopper surface 209 may be a portion of an insert (e.g., 210 of FIG. 2A) fixedly attached at a desired location within the lumen 215 of the syringe 200. In some embodiments, the insert 210 is press-fit, adhered, crimped, or welded in place within the lumen 215. In some embodiments, the distal end 202 of the syringe 200 may be shaped to include one or more structural features, such as protrusions, recesses, grooves, or slots, to prevent movement of the stopper surface 209 beyond a desired point within the syringe 200. FIG. 4A shows a perspective view of one embodiment of the insert 210 (including the stopper surface 209 as shown in FIG. 2B) within the syringe 200, and FIG. 4B shows a cross-sectional view of one embodiment of the insert 210 within the syringe 200. FIG. 4C is a cross-sectional view of one embodiment of the insert 210 engaged with the piston 203 of the syringe 200 such that the plunger 205 may be disengaged from the piston 203.

[0061] As shown in FIGS. 4A - 4C, the insert 210 may comprise a hollow cylinder that defines an internal channel 221. The internal channel 221 has a diameter larger than the outer diameter (e.g., D1) of the removable plunger 205. In some embodiments, the internal channel 221 is configured such that the removable plunger 205 is movably extendable through the internal channel 221 and moves along the longitudinal axis A, and is able to remove the removable plunger 205 from the syringe 200 when decoupled from the piston 203. In some embodiments, the insert 210 may be inserted (e.g., removably inserted or permanently inserted) into the distal end 202 of the syringe 200 on the opposite side of the luer 211. In some embodiments, the insert 210 may be fixedly attached to the distal end of the syringe at a desired position within the lumen 215. In some embodiments, the insert 210 may be a ring integrally formed inside the syringe 200 or a protrusion extending radially inwardly. For example, a hot metal bar, an ultrasonic welder, or electromagnetic radiation, such as a laser, may be used to melt a portion (e.g., internal and / or external portions) of the syringe body 201 to form a ring, flange, ledge, or other structure that acts as an insert having a stopper surface. Thus, instead of adding components within the syringe 200, the existing syringe plastic may be melted or otherwise modified to form the insert 210 having the stopper surface 209.

[0062] As shown in FIG. 4C, the internal channel 221 of the insert 210 may have a diameter D2 that is larger than the diameter D3 of the cavity 252 and smaller than the outer diameter of the piston 203. The insert 210 has a length H1 such that the bottom end extends to a desired position where the piston 203 can retreat, and the upper end can be substantially coplanar with the distal end 202 of the syringe 200 in some embodiments. Since the internal channel 221 is smaller in size than the outer diameter of the piston 203, the insert 210 blocks the piston 203 and prevents the piston 203 from being completely removed from the distal end 202 of the syringe 200 when the contents are aspirated into the syringe. Also, while the insert 210 is restraining the piston 203, the removable plunger 205 can be withdrawn from the cavity 252 by applying a small amount of tensile force to decouple it from the piston 203. Once decoupled, the plunger 205 can freely pass through the internal channel 221 and can be completely removed from the distal end 202 of the syringe 200.

[0063] Figures 5A-5D illustrate one embodiment of a method of aspirating fluid into a syringe and removing a plunger from the syringe. In some embodiments, as shown in FIG. 5A, a syringe 200 comprising a piston 203, a removable plunger 205, and an insert 210 may be received. In some embodiments, the syringe 200 may optionally be coupled to a needle N1. The removable plunger 205 may be inserted into a lumen 215 defined by an inner wall 213 of the syringe 200 from a distal end 202 of the syringe 200, as shown in FIG. 5B, and coupled to the piston 203. In some embodiments, inserting the removable plunger 205 involves aligning a tip 250 of the removable plunger 205 with a cavity 252 of the piston 203 and pushing the tip 250 into the cavity 252 until the removable plunger 205 is coupled to the piston 203. As discussed herein, the tip 250 is configured to engage the cavity 252 of the piston 203 and move the piston within the syringe body 201 when a force is applied to the removable plunger 205 causing the plunger 205 to be displaced longitudinally. The tip of the plunger 250 is further configured to disengage from the piston 203 when the piston 203 engages the insert 210.

[0064] The removable plunger 205 may be retracted distally to retract the piston 203 from the proximal end 204 of the syringe 200 toward the distal end, thereby allowing fluid LQ1 to enter the syringe 200 via a luer 211 that is operably connected to the needle N1, as shown in FIG. 5C. Also, as shown in FIG. 5C, further distal retraction of the piston may be prevented via an insert 210 positioned within the lumen 215 of the syringe body 201. Since the piston 203 is blocked by the insert 210, further retraction of the plunger 205 may disengage the plunger 205 from the piston 203, and thus, as shown in FIG. 5D, the removable plunger 205 may be removed from the piston 203.

[0065] In some embodiments, removing the removable plunger 205 involves further retracting the removable plunger 205 while the piston 203 is engaged with the insert 210, such that the tip 250 of the removable plunger is removed from the cavity 252 of the piston 203 while the removable plunger 205 is completely removed from the piston 203 and the piston 203 remains inserted within the syringe.

[0066] As discussed herein, the insert 210 can be fixed within the syringe body 201 or removably inserted from the distal end 202 of the syringe 200. Thus, the method can further include securing the insert 210 at a desired position within the lumen of the syringe body 201, the desired position corresponding to the amount of contents (e.g., fluid, sample, etc.) to be filled within the syringe.

[0067] Once a desired amount of contents (e.g., fluid, sample, etc.) is aspirated into the syringe 200, the loaded syringe 200 can be used in different applications such as for preparation of the gene editing step of CAR T cell therapy. Thus, it will be appreciated that depending on the particular application, multiple syringes 200 can be filled with different types of contents such as biomolecules (e.g., Cas9 protein, guide RNA, and donor DNA respectively for gene editing applications). The syringe 200 can then be loaded into a receptacle configured to deliver the contents to the system. Advantageously, since the syringe 200 does not have a plunger 205 portion protruding from the syringe body 201, the syringe 200 can be easily transported and handled without unintentional release or mixing of the fluid.

[0068] FIG. 6A illustrates an exemplary system 300 employing a plurality of syringes 200 (discussed with respect to FIGS. 2-5) within a receptacle 301 according to some embodiments. The receptacle 301 is configured to receive one or several syringes 200, and specifically, the embodiments shown in FIGS. 6A and 6D are configured to receive a plurality of syringes such as 200A, 200B, 200C, and 200D that carry the same or different types of contents (e.g., LQ1, LQ2, LQ3, LQ4, or other samples) in the same or different amounts. In some embodiments, the receptacle 301, together with other components, can be configured to inject fluid from one or more of the syringes 200A-200D at a desired time and in a desired amount.

[0069] FIG. 6B is a front view of one embodiment of the receptacle 301, and FIG. 6C is a cross-sectional view of one embodiment of the receptacle 301. In some embodiments, the receptacle 301 (see also FIG. 6D) can be coupled to a supply line 303 (see also FIG. 6E) between an inlet 304 and an outlet 306. During operation, the inlet 304 can receive sterile gas or air (e.g., filtered or sterilized) or a liquid carrier (e.g., buffer, water, etc.) from a pump. The contents (e.g., fluids LQ1-LQ4) can be injected into the receptacle 301 via the syringes 200A, 200B, 200C, 200D, and the contents of the syringes are replaced by the fluid delivered through the outlet 306. For example, in some embodiments, the outlet 306 is connected (e.g., in a closed sterile manner) to a system such as an electroporation or other transfection system (e.g., as described in International Patent Application No. PCT / US2020 / 05713, which is hereby incorporated by reference in its entirety) or a culture system. Thus, the systems described herein can be used to generate cell therapies or treatments using genetically modified cells, CAR T cells, NK cells, stem cells, etc.

[0070] Referring to FIGS. 6A - 6C, system 300 includes a syringe such as syringe 200A, a supply line 303, and a syringe receptacle 301 configured to receive the syringe and fluidly couple the syringe to supply line 303. Supply line 303 may be configured to deliver droplets from a syringe (e.g., 200A, 200B, 200C, and / or 200D) to deploy a solution for inspection or treatment. Supply line 303 may include a channel 313 for carrying fluid between an inlet 304 and an outlet 306.

[0071] As discussed herein, syringe 200A (or 200B - 200D) includes a syringe body 201 having an inner wall that defines a lumen 215 with a longitudinal axis, a removable plunger 205 including a tip 250, a piston 203 positioned within lumen 215 of syringe body 201, and an insert 210 that constricts lumen 215. Piston 203, together with inner wall 213, defines an operating volume configured to hold contents. Piston 203 includes a cavity 252 configured to engage the tip 250 of removable pull rod 205. Piston 203 is movable along the longitudinal axis to vary the operating volume. Insert 210 constricts the lumen to prevent the piston 203 from retracting beyond a desired position.

[0072] In some embodiments, the receptacle 301 and the syringe 200A are coupled. In some embodiments, a portion of the syringe 200 can engage a portion of the receptacle 301 to couple the syringe 200 and the receptacle 301. In some embodiments, the receptacle 301 and the syringe 200A are coupled by a fastening mechanism such as a snap, latch, or screw engagement. For example, in one embodiment, the fastening mechanism is a screw engagement configured as a screw type mechanism that includes threads formed on the proximal end on the outer surface of the syringe 200A that are received by threads formed on the receptacle 301 within an internal portion of the receptacle 301. Additional syringes (e.g., 200B, 200C, and 200D) can be coupled to the receptacle in the same manner as syringe 200A. In other embodiments, as shown in FIG. 6C, one or more syringes (e.g., 200A-200D) can be coupled to the receptacle 401 additionally or alternatively via a needle (e.g., N1) that penetrates a septum 315 (e.g., made of a pierceable material such as an elastomeric material, rubber, silicone, cork, etc.).

[0073] In some embodiments, the receptacle 301 can be further sealed to the supply line 303 by one or several O-rings, gaskets, or other sealing means. For example, as shown in FIG. 6C, the receptacle 301 can be inserted into the supply line 303, and the O-ring 316 can be positioned proximate the insertion portion of the receptacle and proximate the mating surfaces of both the receptacle 301 and the supply line 303. In some embodiments, these O-rings 316 also prevent the entry of any material from the outside around the O-ring portion. This also creates a secondary seal at the bottom of the receptacle 301.

[0074] In some embodiments, supply line 303 and receptacle 301 may be coupled together. In some embodiments, receptacle 301 and supply line 303 may be coupled together via one or several fastening members such as one or several screws, bolts, nuts, etc., or may be adhered together. In some embodiments, receptacle 301 and supply line 303 may be coupled together via one or several mating features that may snap and / or fit together to fixedly mount and / or releasably fixedly mount receptacle 301 to supply line 303.

[0075] As illustrated in FIGS. 6C and 6D, receptacle 301 includes a plurality of hollow chambers 321-324 (marked in FIG. 6D), and each chamber may be configured to receive one syringe. For example, the first hollow chamber 321 receives syringe 200A, the second hollow chamber 322 receives syringe 200B, the third hollow chamber 323 receives syringe 200C, and the fourth hollow chamber 324 receives syringe 200D. In some embodiments, one or more of the hollow chambers of the receptacle are configured to receive one or more syringes of different sizes. The plurality of chambers 321-324 are isolated from each other. In some embodiments, receptacle 301 may be made of plastic or other materials.

[0076] In some embodiments, as shown in FIG. 6C, receptacle 301 includes a septum 315 that is penetrated by a needle N1, which is attached to the proximal end of the syringe such that the tip of the needle enters the supply line and supplies droplets into the supply line. Septum 315 can be rubber or other material that can be punctured while maintaining a closed sterile fluid path. Syringe 200A is axially aligned with septum 315. In some embodiments, septum 315 is installed near the top of supply line 303 (e.g., above channel 313) to prevent leakage of fluid or gas from the supply line and create a closed sterile fluid connection 303 into receptacle 301. In some embodiments, septum 315 may enter supply line 303 to ensure a tight seal.

[0077] In some embodiments, as shown in FIGS. 6B, 6C, and 6E, supply line 303 has an inlet 304 and an outlet 306. Receptacle 301 is connected between inlet 304 and outlet 306 of supply line 303. In some embodiments, inlet 304 can receive sterile gas or air from a pump, and outlet 306 can deliver a mixture of contents from a plurality of syringes 200A-200D within receptacle 301.

[0078] In some embodiments, a drive mechanism (see FIG. 6B) can be configured to inject the contents from one or more of syringes 200A-200D into supply line 303 at a specified time and in a specified amount. When the system 300 determines that the contents should be injected, the individual pistons 203 will be driven downward until the desired amount of contents has been injected into supply line 303 or until the pistons 203 reach the bottom. The contents from a syringe, e.g., 200A, will enter supply line 303 and be driven to its destination by sterile air or buffer supplied at inlet 304 or by a vacuum applied at outlet 306.

[0079] In some embodiments, when syringe, e.g., piston 203 of 200A, is driven downward, all other syringes 200B, 200C, and 200D will be held in the downward position until they are dispensed. This prevents subsequent contents from exiting supply line 303 and entering the empty syringes.

[0080] Figures 7A - 7H illustrate an exemplary system 400 employing a plurality of syringes 200 (discussed with respect to FIGS. 2 - 5) within receptacle 401, according to some embodiments. Receptacle 401 is configured to receive some syringes 200, such as 200A, 200B, 200C, and 200D, which carry the same or different types of contents (e.g., LQ1, LQ2, LQ3, LQ4, or other samples) in the same or different amounts. In some embodiments, receptacle 401, together with other components, can be configured to inject fluid from one or more of syringes 200A - 200D at a desired time and in a desired amount.

[0081] Figures 7A - 7H illustrate embodiments of the present disclosure that include four syringes, but it will be understood that system 400 can be configured to include more or fewer than four syringes. For example, in various embodiments, system 400 can be configured to include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more syringes by expanding or contracting the configuration illustrated in FIGS. 7A - 7I, such as by increasing or decreasing the number of syringes and associated components.

[0082] Figures 7B and 7C are front views of one embodiment of system 400, and FIG. 7D is a cross-sectional view of one embodiment of system 400. In some embodiments, receptacle 401 may be coupled to supply line 403 between inlet 404 and outlet 406. During operation, inlet 404 receives sterile gas or air (e.g., filtered or sterile air), and / or a liquid carrier (e.g., buffer, water, etc.) from a pump. Contents (e.g., fluids LQ1-LQ4) may be injected into receptacle 401 via syringes 200A, 200B, 200C, 200D, and the contents of the syringes are replaced by the air or carrier being delivered via outlet 406. For example, in some embodiments, outlet 406 is connected to a system such as an electroporation or other transfection system (e.g., as described in International Patent Application No. PCT / US2020 / 05713, which is hereby incorporated by reference in its entirety), or a culture system (e.g., in a closed sterile manner). Thus, the systems described herein are for generating therapies or treatments such as CAR T cell therapy.

[0083] Referring to FIGS. 7A-7H, system 400 includes a syringe such as syringe 200A, a supply line 403, and a syringe receptacle 401 configured to receive the syringe and fluidly couple the syringe to supply line 403. Supply line 403 may be configured to deliver droplets from a syringe (e.g., 200A, 200B, 200C, and / or 200D) to develop a solution used in performing an assay. Supply line 403 may include a channel 413 for carrying fluid between inlet 404 and outlet 406.

[0084] As discussed herein, the syringe 200A (or 200B - 200D) includes a syringe body 201 having an inner wall that defines a lumen 215 with a longitudinal axis, a removable plunger 205 including a tip 250, a piston 203 positioned within the lumen 215 of the syringe body 201, and an insert 210 that constricts the lumen 215. The piston 203, together with the inner wall 213, defines a working volume configured to hold the contents. The piston 203 includes a cavity 252 configured to engage the tip 250 of the removable pull rod 205. The piston 203 is movable along the longitudinal axis to vary the working volume. The insert 210 constricts the lumen to prevent the piston 203 from retracting beyond a desired position.

[0085] In some embodiments, the receptacle 401 and the syringe 200A are coupled. In some embodiments, a portion of the syringe 200 can engage a portion of the receptacle 401 to couple the syringe 200 and the receptacle 401. In some embodiments, the receptacle 401 and the syringe 200A are coupled by a fastening mechanism. For example, in one embodiment, one or more hollow chambers 421 - 424 (marked in FIG. 7F) engage a structure formed on the syringe body 201 and include a latch structure 455 configured to hold the syringe 200A within the receptacle 401. Alternatively, the fastening mechanism can be configured as a screw - type mechanism that includes threads formed on the proximal end of the outer surface of the syringe 200A that are received by threads formed on the receptacle 401 within an inner portion of the receptacle 401. Additional syringes (e.g., 200B, 200C, and 200D) can be coupled to the receptacle in the same manner as the syringe 200A. In other embodiments, as shown in FIGS. 7C and 7D, one or more syringes (e.g., 200A - 200D) can be coupled to the receptacle 401 additionally or alternatively via a needle (e.g., N1) that penetrates a septum 415 (e.g., made of a pierceable material such as an elastomeric material, rubber, silicone, cork, etc.).

[0086] In some embodiments, the receptacle 401 may be further sealed to the supply line 403 by one or several O-rings, gaskets, or other sealing means. For example, as shown in FIGS. 7C and 7D, the receptacle 401 may be inserted into the supply line 403, and the O-ring 416 may be positioned proximate to the insertion portion of the receptacle and proximate to the mating surfaces of both the receptacle 401 and the supply line 403. In some embodiments, these O-rings 416 also prevent the ingress of any material from the outside around the O-ring portion. This also creates a secondary seal at the bottom of the receptacle 401.

[0087] In some embodiments, the receptacle 401 is formed as a single structure configured to couple with the supply line 403. In some embodiments, the receptacle 401 is formed as a single structure configured to couple with the supply line 403, and the receptacle 401 includes a front portion 401A and a rear portion 401B connected by a hinge region 401C, and the front portion 401A and the rear portion 401B are joined to form the receptacle 401. In the embodiment shown in FIG. 7A, the receptacle 401 includes a front portion 401A and a rear portion 401B that are mechanically joined together by one or more screw connections 450 including screws. As further illustrated in FIG. 7A, the front portion 401A and the rear portion 401B are connected by a hinge portion 401C, and the front portion 401A and the rear portion 401B are brought into contact about the longitudinal axis A-A' of the hinge portion 401C, and the receptacle 401 is formed by joining the front portion 401A and the rear portion 401B together to have a clam shell configuration.

[0088] In some embodiments, the receptacle 401 is formed from separate components and is configured to couple with the supply line 403. For example, in one embodiment, the receptacle 401 is formed by joining a front portion 401A and a rear portion 401B, and the front portion 401A and the rear portion 401B are formed as separate components prior to assembly of the receptacle 401.

[0089] The front and rear portions of the receptacle 401 illustrated in FIG. 7A are joined using one or more screw connections including screws, while on the other hand, any suitable type of fastening connection such as, for example, one or more press-fit connections, latches, snaps, chemical or thermal bonding or welding, adhesives, etc. may be utilized.

[0090] In various embodiments, the supply line 403 and the receptacle 401 are configured to be joined together. In some embodiments, the receptacle 401 and the supply line 403 may be joined via one or more fastening connections such as one or several screws, bolts, nuts, press-fit connections, latches, snaps, chemical or thermal bonding or welding, adhesives. In some embodiments, the receptacle 401 and the supply line 403 may be joined together via one or several mating features that can snap and / or fit together to fixedly mount and / or removably fixedly mount the receptacle 401 to the supply line 403. In some embodiments, the supply line 403 and the receptacle 401 are joined together before the receptacle 401 is fully formed by bringing the front portion 401A and the rear portion 401B into contact around the longitudinal axis of the hinge portion 401C and joining the front portion 401A to the rear portion 401B.

[0091] As illustrated in FIGS. 7C and 7D, in some embodiments, the receptacle 401 includes a plurality of hollow chambers 421 - 424 (marked in FIG. 7F), each chamber being configured to receive one syringe. For example, the first hollow chamber 421 receives the syringe 200A, the second hollow chamber 422 receives the syringe 200B, the third hollow chamber 423 receives the syringe 200C, and the fourth hollow chamber 424 receives the syringe 200D. In some embodiments, one or more of the hollow chambers of the receptacle 401 are configured to receive one or more syringes of different sizes. In some embodiments, the plurality of chambers 421 - 424 are isolated from each other. In some embodiments, the receptacle 401 is composed of a polymeric material such as plastic.

[0092] In some embodiments, as shown in FIGS. 7C - 7E, receptacle 401 includes a septum 415 that is penetrated by a needle N1, which is attached to the proximal end of a syringe such that the tip of the needle enters a supply line and supplies droplets into the supply line. In an embodiment, septum 415 can be composed of silicone, an elastomeric material, rubber, or other materials that can be pierced while maintaining a closed sterile fluid path. Syringe 200A is axially aligned with septum 415. In some embodiments, septum 415 is placed near the top of supply line 403 (e.g., above channel 413) to prevent leakage of fluid or gas from the supply line and to create a closed sterile fluid connection 403 into receptacle 401. In some embodiments, septum 415 may enter supply line 403 to ensure a tight seal.

[0093] In some embodiments, as shown in FIGS. 7C - 7H, supply line 403 has an inlet 404 and an outlet 406. Receptacle 401 is connected between inlet 404 and outlet 406 of supply line 403. In some embodiments, inlet 404 can receive sterile gas or air from a pump, and outlet 406 can deliver a mixture of contents from a plurality of syringes 200A - 200D into receptacle 401.

[0094] In an embodiment, the drive mechanism can be configured to inject the contents from one or more of syringes 200A - 200D into supply line 403 at a specified time and in a specified amount. When the system 400 determines that the contents should be injected, the individual pistons 203 will be driven downward until the desired amount of contents has been injected into supply line 403 or until the piston 203 reaches the bottom. The contents from a syringe, e.g., 200A, will enter supply line 403 and be driven to its destination by the fluid supplied at inlet 404.

[0095] In some embodiments, when the syringe, e.g., piston 203 of 200A, is driven downward, all other syringes 200B, 200C, and 200D will be held in the downward position until they are dispensed. This prevents subsequent contents from exiting supply line 403 and entering the empty syringes.

[0096] In various embodiments, the drive mechanism for advancing piston 203 downward can be a pneumatic mechanism, a lead screw mechanism, a load spring mechanism, or other drive mechanism. For example, the pneumatic mechanism can include creating a face seal with the top of each syringe 200A - 200D and pressurizing the interior of the syringe to drive the piston downward. In some embodiments, a vision system or Hall effect sensor may be required to determine the location of piston 203 and generate feedback indicating the amount of contents dispensed into supply line 303 or 403.

[0097] In various embodiments, the lead screw mechanism used in the system of the present disclosure includes a linear actuator, such as a lead screw and a stepper motor, configured to drive each piston downward. Limit switches and encoders can be incorporated to determine whether the piston is in the upper / lower position.

[0098] In various embodiments, the load spring mechanism used within the stem of the present disclosure includes one or several compression springs configured to compress when the syringe is removed, thereby storing energy for the next execution. When the syringe is received, each spring can be individually released to drive the piston. Release of the spring can be achieved by a mechanical actuator, including, for example, one or more solenoids and / or cam mechanisms. In some embodiments, damping springs can be used to deploy the springs more slowly and gently. A mechanical limit switch can be used to determine the upper / lower position of the piston.

[0099] Although certain embodiments have been described, these embodiments are presented by way of example only and are not intended to limit the scope of the disclosure. In fact, the novel methods, apparatuses, and systems described herein may be embodied in various other forms, and furthermore, various omissions, substitutions, and changes in the forms of the methods, apparatuses, and systems described herein may be made without departing from the concept of the disclosure. The appended claims and their equivalents are intended to cover such forms or modifications as fall within the scope and concept of the disclosure.

Claims

1. A syringe comprising: a syringe body having an inlet and an inner wall defining a lumen having a longitudinal axis and a diameter; a piston positioned within the lumen of the syringe body, the piston having an upper portion and a bottom portion, the bottom portion of the piston together with the inner wall defining a working volume, the piston comprising a cavity, the piston being movable along the longitudinal axis to change the working volume; an insert positioned at a desired position within the lumen, the insert narrowing the lumen and configured to prevent retraction of the piston beyond the desired position; a removable pull rod configured to be removably coupled to the piston, the removable pull rod having a tip configured to couple to the cavity of the piston to move the piston within the syringe body when a force is applied to the removable pull rod and to allow decoupling from the piston when the piston engages the insert at the desired position.

2. The syringe according to claim 1, wherein the tip has a conical shape having a narrow end configured to enter the cavity within the piston and a base end configured to couple the piston to the tip.

3. The syringe according to claim 2, wherein the base end of the tip has a chamfered edge, a spherical edge, or a filleted edge configured to facilitate withdrawal of the tip from the cavity of the piston.

4. The syringe according to claim 2, wherein the base end of the tip does not include a sharp edge having a 90-degree angle between adjacent surfaces.

5. The syringe according to claim 2, wherein the piston is made of a flexible material.

6. The syringe according to claim 5, wherein the cavity is cylindrical and sized to provide a friction fit between the tip of the removable pull rod and the piston.

7. The syringe according to claim 5, wherein the cavity is sized to receive the tip and fit tightly around the tip so that the piston is retractable by the removable pull rod.

8. The syringe according to claim 2, wherein the proximal end includes a base portion configured to taper away from the narrow end.

9. The syringe according to claim 8, wherein the cavity of the piston is configured to cover the base portion of the tip.

10. The piston is made of a flexible material, the cavity of the piston is sized smaller than the size of the tip, and is configured to match the shape of the tip of the removable pull rod. When the piston receives the removable pull rod, the cavity of the piston expands around the tip, thereby coupling the removable pull rod and the piston. The syringe according to claim 9.

11. The insert includes a hollow cylinder defining an internal channel, the internal channel is larger than the outer diameter of the removable pull rod, and the removable pull rod extends movably through the internal channel, allowing movement along the longitudinal axis and configured to remove the removable pull rod from the syringe when decoupled from the piston. The syringe according to claim 1.

12. The syringe according to claim 1, wherein the insert is removably inserted into the distal end of the syringe opposite the inlet.

13. The syringe according to claim 1, wherein the insert is fixedly attached to the distal end of the syringe at the desired position within the lumen.

14. The piston is disposed at the proximal end of the syringe configured to receive fluid, and the desired position is the distal end of the syringe indicating the desired amount of the fluid filled in the syringe, the syringe according to claim 1.

15. The syringe according to claim 14, wherein the cavity extends partially towards the bottom of the piston but does not extend through the bottom of the piston.

16. The syringe according to claim 1, wherein the piston is axially disposed within the syringe body, and the cavity is formed at the center of the piston and extends axially.

17. A method of aspirating a syringe, the syringe comprising a piston and a removable pull rod, the method comprising: Inserting the removable pull rod from the distal end of the syringe into the lumen defined by the inner wall of the syringe and coupling it to the piston; Retracting the removable pull rod to retract the piston from the proximal end of the lumen towards the distal end, thereby introducing fluid into the syringe through the inlet at the proximal end; Preventing further retraction of the piston by an insert positioned within the lumen; Removing the removable pull rod from the piston.

18. Inserting the removable pull rod comprises Aligning the tip of the removable pull rod with the cavity of the piston; Pushing the tip into the cavity until the removable pull rod is coupled to the piston. When a force is applied to the removable pull rod, the tip is configured to engage with the cavity of the piston and move within the syringe body, and is configured to be disengaged from the piston when the piston engages with the insert. The method according to claim 17.

19. Removing the removable pull rod includes further retracting the removable pull rod while the piston is engaged with the insert, whereby the removable pull rod is completely removed from the piston, but the piston remains inserted within the syringe, removing the tip of the removable pull rod from the cavity of the piston. The method according to claim 18.

20. The method according to claim 17, further comprising fixing the insert at a desired position within the lumen, the desired position corresponding to the amount of fluid to be filled within the syringe.

21. A system, A syringe, A syringe body having an inner wall defining a lumen having a longitudinal axis, A removable pull rod having a tip, A piston located within the lumen of the syringe body, the piston together with the inner wall defining an operating volume configured to hold fluid, the piston comprising a cavity configured to engage the tip of the removable pull rod, the piston being movable along the longitudinal axis to change the operating volume. A piston, A syringe comprising an insert that narrows the lumen to prevent the piston from retreating beyond a desired position, and A supply line configured to deliver droplets from the syringe to deploy a solution for inspection or treatment, A system comprising a syringe receptacle configured to receive the syringe and fluidly couple the syringe to the supply line. **Claim 22** The system according to claim 21, wherein the receptacle and the syringe are coupled by a snap mechanism disposed at a distal end of the syringe. **Claim 23** The system according to claim 21, wherein the receptacle and the syringe are coupled by a screw-type mechanism, the syringe includes a thread formed at a proximal end on an outer surface of the syringe, and the receptacle includes corresponding threads in an inner portion of the receptacle. **Claim 24** The system according to claim 21, wherein the receptacle includes a rubber septum penetrated by a needle, and the needle is attached to a proximal end of the syringe such that a tip of the needle enters the supply line to supply droplets into the supply line. **Claim 25** The system according to claim 21, wherein the receptacle includes a plurality of hollow chambers, and each chamber is configured to receive one syringe. **Claim 26** The system according to claim 25, wherein one or more of the hollow chambers of the receptacle are configured to receive one or more syringes of different sizes. **Claim 27** The system according to claim 26, wherein the supply line has an inlet and an outlet, the receptacle is connected between the inlet and the outlet, the inlet receives sterile air, vacuum, or a buffer from a pump, and the outlet delivers fluid from the plurality of syringes within the receptacle. **Claim 28** The system according to claim 27, further comprising a delivery mechanism configured to inject fluid from one or more syringes within the receptacle at a specified time and a specified amount. **Claim 29** The system according to claim 21, wherein the tip has a conical or spherical shape with a narrow end configured to enter the cavity within the piston and a base end configured to couple the piston to the tip.

30. The system according to claim 29, wherein the base end of the tip has a chamfered edge or a filleted edge configured to facilitate the retraction of the tip from the cavity of the piston.

31. The system according to claim 29, wherein the piston is made of a flexible material.

32. The system according to claim 31, wherein the cavity is cylindrical or spherical in shape and sized to provide a friction fit between the tip of the removable pull rod and the piston.

33. The system according to claim 29, wherein the base end includes a base portion configured to taper away from the narrow end.

34. The system according to claim 33, wherein the cavity of the piston is configured to cover the base portion of the tip.

35. The system according to claim 34, wherein the piston is made of a flexible material, the cavity of the piston is sized smaller than the size of the tip, is configured to conform to the shape of the tip of the removable pull rod, and when the piston receives the removable pull rod, the cavity of the piston expands around the tip, thereby coupling the removable pull rod and the piston.

36. The system according to claim 21, wherein the insert comprises a hollow cylinder defining an internal channel, the internal channel being larger than the outer diameter of the removable pull rod, the removable pull rod being movably extended through the internal channel and being capable of moving along the longitudinal axis, and being configured to remove the removable pull rod from the syringe when decoupled from the piston.

37. A method of dispensing the contents of a syringe, the method comprising: filling the syringe by retracting a removable pull rod coupled to a piston located within the lumen of the syringe body; after filling the syringe, separating the removable pull rod from the piston; inserting the syringe into a syringe receptacle to fluidly couple the syringe to a supply line; coupling the removable pull rod to the piston; advancing the removable pull rod by a specified amount to move the piston within the lumen of the syringe body, thereby delivering a desired amount of fluid into the supply line.

38. The method according to claim 37, further comprising coupling the syringe receptacle and the supply line.

39. The method according to claim 37, wherein fluidly coupling the syringe to the supply line forms a sterile and functionally closed system.

40. A method of performing an assay, comprising: delivering a sample into a fluid stream contained within a functionally closed system from a syringe according to any one of claims 1 to 39; performing an assay.

41. The method according to claim 40, wherein the sample contains a gene editing reagent and the flow of the fluid contains cells.

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