Medication infusion devices, systems and methods

Abstract

[0003] Devices, systems, and methods for medication infusion are described herein. In some embodiments, the system includes a patient access subassembly, a first fluid reservoir, a second fluid reservoir, and an assembly. The assembly can have a first configuration in which the patient access subassembly is in fluid communication with the first fluid reservoir via a first tube, a second configuration in which the first fluid reservoir is in fluid communication with the second fluid reservoir, and a third configuration in which the first fluid reservoir is in fluid communication with the patient access subassembly via the second tube, and in the third configuration, the first fluid reservoir is fluidly isolated from the first tube.

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims priority to co-pending U.S. Provisional Patent Application No. 62 / 946,856, entitled "Medication Infusion Devices, Systems, and Methods," filed December 11, 2019, and U.S. Provisional Patent Application No. 62 / 946,858, entitled "Medication Infusion Devices, Systems, and Methods," filed December 11, 2019, the disclosures of both of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION Embodiments described herein relate to devices, systems, and methods for combining a medication with a patient's biological fluids ex vivo (i.e., outside the patient's body) and for reinfusing the combination back into the patient. In particular, embodiments described herein relate to medication infusion devices, systems, and methods for combining a medication with a patient's blood ex vivo and for reinfusing the combined medication and blood back into the patient. [Background technology]

[0003] background Some types of medications, such as those used in chemotherapy, cause pain and other side effects when delivered intravenously to patients. For example, some medications can release nitric oxide during infusion, causing a severe burning sensation in patients. These medications may be necessary to treat patients suffering from various medical problems, such as cancer. Therefore, the infusion rate is often reduced to alleviate infusion-related pain, resulting in long infusion durations (e.g., greater than 8 hours). However, long infusion durations reduce the number of treatable patients in clinical settings, whether in private practice during routine work hours, group practice, or hospital-based clinics. Long infusion durations are not only time-consuming and uncomfortable for individual patients, but also increase the risk of infection.

[0004] Thus, there is a need for devices, systems and methods that can reduce or eliminate pain and other side effects associated with the delivery of pharmaceutical agents to a patient's vasculature while allowing for a reduced duration of administration. Summary of the Invention

[0005] overview Systems, devices, and methods for extracorporeal medication infusion are described herein. In some embodiments, the extracorporeal blood device can include a venous or arterial blood line for removing blood from a patient, treating the blood with medication, and returning the treated blood to the patient through a filter. For example, in some embodiments, the method includes connecting a patient access subassembly to a patient. The patient access subassembly can be fluidly connected via the assembly to a first fluid reservoir containing a first substance and a second fluid reservoir containing a second substance. Cells can be drawn through the patient access subassembly and into the first fluid reservoir, with the cells and the first substance forming a third substance. The assembly can be operated so that the first fluid reservoir is fluidly isolated from the patient access subassembly and the first fluid reservoir is in fluid communication with the second fluid reservoir. A portion of the third substance can then be transferred from the first fluid reservoir through the assembly to the second fluid reservoir, with a portion of the third substance and the second substance forming a fourth substance. A fourth substance can be transferred from the second fluid reservoir through the assembly to the first fluid reservoir, with a remainder of the third substance and the fourth substance forming a fifth substance. The assembly can be operated so that the first fluid reservoir is in fluid communication with the patient access subassembly. The fifth substance can be transferred from the first fluid reservoir through the assembly, through the patient access subassembly, and to the patient. A third fluid reservoir containing saline solution can be fluidly coupled to the assembly. The assembly can be operated so that the third fluid reservoir is in fluid communication with the patient access subassembly through the assembly. At least a portion of the saline solution can be transferred from the assembly to the patient access subassembly. [Brief explanation of the drawings]

[0006] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] FIG. 1 is a schematic illustration of a system according to one embodiment. [Figure 2] FIG. 2 is a schematic illustration of a system according to another embodiment. [Figure 3]FIG. 3 is a flowchart of a method according to one embodiment. [Figure 4] FIG. 4 is a flowchart of a method according to another embodiment. [Figure 5] FIG. 5 is an illustration of a system according to another embodiment. [Figure 6] FIG. 6 is a top view of a mixing assembly of an exemplary system according to one embodiment. [Figure 7] FIG. 7 is a top view of a filter subassembly of the system of FIG. 6 according to one embodiment. [Figure 8] FIG. 8 is a top view of a patient access subassembly of the system of FIG. 6 according to one embodiment. [Figure 9] FIG. 9 is a top view of the mixing assembly of FIG. 6 in a partially assembled configuration according to one embodiment. [Figure 10] 10 is a top view of a portion of the mixing assembly of FIG. 6 and a portion of the patient access subassembly of FIG. 8 shown prior to assembly. [Figure 11] 11 is a top view of a portion of the mixing assembly of FIG. 6 and a portion of the patient access subassembly of FIG. 8 shown in an assembled configuration. [Figure 12] 12 is a top view of a portion of the mixing assembly of FIG. 6 and a portion of the patient access subassembly of FIG. 8 shown in a blood withdrawal configuration. [Figure 13] 13 is a top view of a portion of the mixing assembly of FIG. 6 and a portion of the patient access subassembly of FIG. 8 shown in a disconnected configuration. [Figure 14] FIG. 14 is a top view of a portion of the mixing assembly of FIG. 6 shown in the first stage of the mixing procedure. [Figure 15] FIG. 15 is a top view of a portion of the mixing assembly of FIG. 6 shown in a second stage of the mixing procedure. [Figure 16] 16 is a top view of a portion of the mixing assembly of FIG. 6 with the syringe of the mixing assembly separated. [Figure 17]FIG. 17 is a top view of a portion of the mixing assembly of FIG. 6 with the selective fluid flow preventer in an open configuration. [Figure 18] FIG. 18 is a top view of a portion of the mixing assembly of FIG. 6 with the selective fluid flow preventer in a closed configuration. [Figure 19] FIG. 19 is a top view of the system of FIG. 6 before injection. [Figure 20] FIG. 20 is a top view of an exemplary system according to one embodiment. [Figure 21] FIG. 21 is a top view of the mixing assembly of the system of FIG. 20 in a partially assembled configuration. [Figure 22] 22 is a top view of the patient access subassembly of the system of FIG. 20. FIG. [Figure 23] 23 is a perspective view of a subassembly connector of the system of FIG. 20. FIG. [Figure 24] 24 is a top view of the patient access subassembly of the system of FIG. 22 coupled to the subassembly connector of FIG. 23. FIG. [Figure 25] FIG. 25 is a top view of the system of FIG. 20 with the patient access subassembly connected to the mixing assembly. [Figure 26] FIG. 26 is a top view of the system of FIG. 20 during the blood withdrawal stage of the administration procedure. [Figure 27] FIG. 27 is a top view of a portion of the mixing assembly of FIG. 21 in a mixing configuration. [Figure 28] FIG. 28 is a top view of a portion of the mixing assembly of FIG. 21 during the mixing stage of the administration procedure. [Figure 29] FIG. 29 is a top view of a portion of the mixing assembly of FIG. 21 in a well-mixed, pre-injection configuration. [Figure 30] FIG. 30 is a top view of a portion of the mixing assembly of FIG. 21 in an injection configuration. [Figure 31] FIG. 31 is a top view of the system of FIG. 20 during the injection stage of the administration procedure. [Figure 32] FIG. 32 is a top view of a portion of the mixing assembly of FIG. 21 in a pre-flush configuration. [Figure 33] FIG. 33 is a top view of the system of FIG. 20 with a syringe containing saline solution connected to the mixing assembly. [Figure 34] FIG. 34 is a top view of the system of FIG. 20 after being flushed with saline solution. [Figure 35] FIG. 35 is a top view of an exemplary system according to one embodiment. [Figure 36] FIG. 36 is a top view of an exemplary system according to another embodiment. [Figure 37] FIG. 37 is a perspective view of a light assembly according to one embodiment. [Figure 38] FIG. 38 is a top view of an exemplary system according to one embodiment. [Figure 39] 39 is a top view of the patient access subassembly of the system of FIG. 38. FIG. [Figure 40] FIG. 40 is a flowchart of a method according to one embodiment. [Figure 41] FIG. 41 is a schematic illustration of an exemplary system according to one embodiment. [Figure 42] FIG. 42 is a perspective view of an exemplary system according to one embodiment. [Figure 43] FIG. 43 is a perspective view of an exemplary system according to one embodiment. [Figure 44] FIG. 44 is a schematic illustration of the exemplary system of FIGS. 42 and 43 at various stages of operation according to one embodiment. [Figure 45] FIG. 45 is a schematic illustration of the exemplary system of FIGS. 42 and 43 at various stages of operation according to one embodiment. [Figure 46] FIG. 46 is a schematic illustration of the exemplary system of FIGS. 42 and 43 at various stages of operation according to one embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0007] Detailed Description In some embodiments, the devices, systems, and methods described herein can be used for extracorporeal blood treatment (e.g., with medications). For example, a system or device can be used to withdraw blood from a patient's vein or artery, combine the blood with one or more medications to create treated blood, and reintroduce the treated blood into the patient through a filter (e.g., to trap microbubbles and debris). The system or device can be closed or include a closed circuit to prevent infection of the treated blood. In some embodiments, the system or device can include an inlet line, a stopcock, a reservoir, and an outlet line, and blood can be withdrawn through the inlet line and stopcock into the reservoir and returned from the reservoir to the patient through the stopcock and outlet line. The system or device can include one or more filters positioned before and / or after the stopcock in the blood circuit. Optionally, the system or device may also include one or more secondary fluid reservoirs (e.g., fluid containers and / or bags), each containing one or more of a medicinal (e.g., drug), an anticoagulant, an antioxidant, and / or a flush solution. In some embodiments, the system or device may optionally include a partial deoxygenation device for removal of gas from the treated blood and / or a pump device for controlling the flow of blood and / or treated blood through the system or device.

[0008] In some embodiments, the method includes connecting a patient access subassembly to a patient. The patient access subassembly can be fluidly connected via the assembly to a first fluid reservoir containing a first substance and a second fluid reservoir containing a second substance. Cells can be drawn through the patient access subassembly and into the first fluid reservoir, with the cells and the first substance forming a third substance. The assembly can be manipulated so that the first fluid reservoir is fluidly isolated from the patient access subassembly and is in fluid communication with the second fluid reservoir. A portion of the third substance can then be transferred from the first fluid reservoir through the assembly to the second fluid reservoir, with the portion of the third substance and the second substance forming a fourth substance. The fourth substance can be transferred from the second fluid reservoir through the assembly to the first fluid reservoir, with the remainder of the third substance and the fourth substance forming a fifth substance. The assembly can be operated so that the first fluid reservoir is in fluid communication with the patient access subassembly. A fifth substance can be transferred from the first fluid reservoir through the assembly, through the patient access subassembly, and to the patient. A third fluid reservoir containing a saline solution can be fluidly coupled to the assembly. The assembly can be operated so that the third fluid reservoir is in fluid communication with the patient access subassembly through the assembly. At least a portion of the saline solution can be transferred from the assembly to the patient access subassembly. In some embodiments, the kit includes a first assembly including a first fluid reservoir, a second fluid reservoir, a valve assembly, and a first tubing. The first fluid reservoir, the second fluid reservoir, and the first tubing can be fluidly coupled to the valve assembly. The valve assembly can be configured to selectively allow fluid communication between the first fluid reservoir and the second fluid reservoir and between the first fluid reservoir and the first tubing. The kit may also include a second assembly including a patient access port fluidly connected to a second tube.The second tube may be configured to be fluidly coupled to a valve assembly of the first assembly via a first flow path including the third tube and via a second flow path through the first tube, and the valve assembly may be in fluid communication with the patient access port via the first tube and via the second tube. The kit may further include a third fluid reservoir configured to be coupled to the valve assembly, and the valve assembly may selectively allow fluid communication between the third fluid reservoir and the first tube.

[0009] In some embodiments, the method includes fluidly connecting a first connecting member of a first subassembly to a valve assembly of a second subassembly. The second subassembly may include a first fluid reservoir and a second fluid reservoir fluidly connected to the valve subassembly. The first fluid reservoir may be selectively fluidly connected to the second fluid reservoir via the valve assembly. The first subassembly may include a patient access port, a first connecting member, and a second connecting member. The first connecting member and the second connecting member may be in fluid communication with the patient access port. The first connecting member may be connected to the valve assembly, such that the first fluid reservoir of the second subassembly is in selective fluid communication with the patient access port via a first fluid flow path. The second connecting member of the first subassembly may be fluidly connected to the valve assembly, such that the first fluid reservoir is in selective fluid communication with the patient access port via a second flow path different from the first flow path. A third fluid reservoir may be coupled to the valve assembly, the third fluid reservoir being in selective fluid communication with the patient access port via the second fluid path.

[0010] In some embodiments, the device includes a patient access subassembly, a first fluid reservoir, a second fluid reservoir, and an assembly. The first fluid reservoir can be configured to contain a first fluidic substance. The second fluid reservoir can be configured to contain a second fluidic substance. The assembly can have a first configuration in which the patient access subassembly is in fluid communication with the first fluid reservoir via a first tube, a second configuration in which the first fluid reservoir is in fluid communication with the second fluid reservoir, and a third configuration in which the first fluid reservoir is in fluid communication with the patient access subassembly via the second tube. The first fluid reservoir can be fluidly isolated from the first tube in the third configuration.

[0011] In some embodiments, the device includes a patient access subassembly, a first fluid reservoir, a second fluid reservoir, and an assembly. The patient access subassembly can be configured to provide access to a patient's blood vessel. The first fluid reservoir can be configured to contain a first fluidic agent. The second fluid reservoir can be configured to contain a second fluidic agent. The assembly can include a first valve, a second valve, and a third valve. The first fluid reservoir can be in selective fluid communication with the second fluid reservoir via the first and second valves. The patient access subassembly can be in selective fluid communication with the first fluid reservoir via the first valve. The third valve can be configured to be coupled to the third fluid reservoir, and the third fluid reservoir is in selective fluid communication with the patient access subassembly via the first and second valves.

[0012] In some embodiments, the medicament described herein can include any suitable medicament or therapeutic agent, such as those described in U.S. Patent Nos. 7,507,842; 8,299,053; and / or 8,927,527; and / or International Publication WO / 2017 / 123593A1, the contents of each of which are incorporated herein by reference.For example, the medicament can include 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone.In another example, the medicament can include propofol (also known as Diprivan).In another example, the medicament can include ozone.In another example, the medicament can include nitric oxide. For example, the pharmaceutical may include a nitric oxide donor, such as sildenafil (also known as VIAGRA®), tadalafil (also known as CIALIS®), vardenafil (also known as Levitra®), and / or a nitrate ester, such as nitroglycerin, sodium nitrite, and / or sodium nitrate. In another example, the pharmaceutical may include an electrophile capable of binding to a sulfhydryl group (e.g., a sulfhydryl-reactive alkylating agent), such as maleimide, iodoacetate, iodoacetic acid, bromoacetate, bromoacetic acid, iodoacetamide, chloroacetamide, acrylate, and / or bromoacetamide. In another example, the pharmaceutical agent may include a chemotherapeutic agent (e.g., an antitumor platinum coordination complex, an antimetabolite, a mitotic inhibitor, an anticancer antibiotic, a topoisomerase I and / or II inhibitor, a proteasome inhibitor, a histone deacetylase inhibitor, a nitrogen mustard alkylating agent, a nitrosourea alkylating agent, a non-classical alkylating agent, an estrogen antagonist, an androgen antagonist, an mTOR inhibitor, and / or a tyrosine kinase inhibitor).

[0013] 1 is a schematic illustration of system 100. In some embodiments, system 100 is useful for withdrawing cells (e.g., packed red blood cells, white blood cells, and / or platelets) from a patient, combining a medication with the patient's cells ex vivo, and infusing the combined cells and medication into the patient's bloodstream. System 100 includes a patient access subassembly 110, a first fluid reservoir 120, a second fluid reservoir 130, a third fluid reservoir 180, and assembly 140. Assembly 140 can include a first valve 150, a second valve 160, and a third valve 170. First fluid reservoir 120 can be coupled to first valve 150, and second fluid reservoir 130 can be coupled to second valve 160. In some embodiments, third valve 170, first valve 150, and second valve 160 can be arranged in series. In some embodiments, first valve 150 can be mated with third valve 170 and second valve 160. In some embodiments, first valve 150 can be fluidly connected to third valve 170 and second valve 160, for example, via interconnecting tubing. Third fluid reservoir 180 can be connected to third valve 170. In some embodiments, third fluid reservoir 180 can be separated from assembly 140 during a portion of use of system 100 (e.g., during the initial blood withdrawal through first tubing 102 and / or the transfer between first fluid reservoir 120 and second fluid reservoir 130).

[0014] Patient access subassembly 110 may be coupled to third valve 170 via first tubing 102, and patient access subassembly 110 may be in fluid communication with third valve 170 via a first fluid pathway. Patient access subassembly 110 may be coupled to second valve 160 via second tubing 104, and patient access subassembly 110 may be in fluid communication with second valve 160 via a second fluid pathway. Thus, in some embodiments, system 100 may function as a closed-loop system in which fluid may flow away from patient access subassembly 110 via first tubing 102 and return to patient access subassembly 110 via second tubing 104.

[0015] In an exemplary use scenario, second fluid reservoir 130 may contain a pharmaceutical agent, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, dinitroazetidine, propofol, a nitric oxide donor, a sulfhydryl-reactive alkylating agent, and / or ozone. System 100 may be attached to a patient via patient access subassembly 110. A volume of the patient's blood may be drawn through patient access subassembly 110, through first tubing 102, through assembly 140, and into first fluid reservoir 120. A portion of the drawn volume of blood may be transferred via assembly 140 to second fluid reservoir 130, where it combines with the pharmaceutical agent to form a first combined substance. The first combined substance may then be returned to first fluid reservoir 120 via assembly 140, where it combines with the remaining blood to form a second combined substance. The second combined substance may then be pushed through assembly 140, through second tubing 104, and through patient access subassembly 110, where it flows into the patient's bloodstream.

[0016] Each of the first valve 150, the second valve 160, and the third valve 170 can be configured to transition between two or more configurations, each corresponding to a different flow path. Each of the first valve 150, the second valve 160, and the third valve 170 can include any suitable valve mechanism, such as a manual valve mechanism, a solenoid-actuated valve mechanism, a motor-actuated valve mechanism, a hydraulic valve mechanism, and / or a pneumatic valve mechanism. For example, each of the first valve 150, the second valve 160, and the third valve 170 can include a three-way stopcock. Each of the first valve 150, the second valve 160, and the third valve 170 can define or include an interior region such that fluid can travel through the interior region. First fluid reservoir 120 may be coupled to first valve 150, and first fluid reservoir 120 may be in selective fluid communication with patient access subassembly 110 via third valve 170 and first valve 150, with second fluid reservoir 130 via first valve 150 and second valve 160, or with second tubing 104 via first valve 150 and second valve 160. For example, first valve 150 may have a first configuration in which first valve 150 allows fluid communication between an interior region of third valve 170 and first fluid reservoir 120, but fluidly isolates an interior region of second valve 160 from both first fluid reservoir 120 and the interior region of third valve 170. The first valve 150 may have a second configuration in which the first valve 150 allows fluid communication between the interior regions of the first fluid reservoir 120 and the second valve 160, but fluidly isolates the interior region of the third valve 170 from both the interior regions of the first fluid reservoir 120 and the second valve 160. The first valve 150 may have a third configuration in which the first valve 150 allows fluid communication between the interior regions of the third valve 170 and the second valve 160, but fluidly isolates the first fluid reservoir 120 from both the interior regions of the third valve 170 and the second valve 160.

[0017] In some embodiments, second fluid reservoir 130 can be coupled to second valve 160, such that second fluid reservoir 130 can be in selective fluid communication with first fluid reservoir 120 via second valve 160 and first valve 150, and with patient access subassembly 110 via second valve 160. For example, second valve 160 can have a first configuration in which second valve 160 allows fluid communication between an interior region of first valve 150 and second fluid reservoir 130, but fluidly isolates second tube 104 from both second fluid reservoir 130 and an interior region of first valve 150. The second valve 160 may have a second configuration in which the second valve 160 allows fluid communication between the interior region of the first valve 150 and the second tube 104, but fluidly isolates the second fluid reservoir 130 from both the interior region of the first valve 150 and the second tube 104.

[0018] A third valve 170 may be coupled to the first valve 150, and the patient access subassembly 110 and the third fluid reservoir 180 may each be in selective fluid communication with the first fluid reservoir 120 and / or the second tubing 104 via the third valve 170. For example, the third valve 170 may have a first configuration in which the third valve 170 allows fluid communication between the interior region of the first tubing 102 and the first valve 150, but fluidly isolates the third fluid reservoir 180 (or a connector configured to be coupled to the third fluid reservoir 180) from both the interior region of the first tubing 102 and the first valve 150. The third valve 170 may have a second configuration in which the third valve 170 allows fluid communication between the third fluid reservoir 180 and the interior region of the first valve 150, but fluidly isolates the first tube 102 from both the interior region of the first valve 150 and the third fluid reservoir 180.

[0019] Thus, assembly 140 may have a first assembly configuration in which patient access subassembly 110 is in fluid communication with first fluid reservoir 120 via first tube 102, a second assembly configuration in which first fluid reservoir 120 is in fluid communication with second fluid reservoir 130, and a third assembly configuration in which first fluid reservoir 120 is in fluid communication with patient access subassembly 110 via second tube 104. In the first assembly configuration, first valve 150 may be in its first configuration, third valve 170 may be in its first configuration, and first tube 102 and first fluid reservoir 120 may be in fluid communication via third valve 170 and first valve 150. In the first assembly configuration, the second valve 160 is isolated from the flow path from the patient access subassembly 110 through the first tube 102, the third valve 170, and the first valve 150 to the first fluid reservoir 120, so that the second valve 160 can be in either the first or second configuration of the second valve 160.

[0020] In the second assembly configuration, first valve 150 can be in its second configuration, second valve 160 can be in its first configuration, and first reservoir 120 of the first fluid and second fluid reservoir 130 are in fluid communication via first valve 150 and second valve 160. Third valve 170 is isolated from the flow path between first fluid reservoir 120 and second fluid reservoir 130 via first valve 150 and second valve 160, such that third valve 170 can be in either its first or second configuration.

[0021] In the third assembly configuration, first valve 150 can be in its third configuration, second valve 160 can be in its second configuration, and first fluid reservoir 120 can be in fluid communication with second tubing 104. Because third valve 170 is isolated from the flow path between first fluid reservoir 120 and second tubing 104 via first valve 150 and second valve 160, third valve 170 can be in either its first or second configuration.

[0022] In some embodiments, assembly 140 can have a fourth assembly configuration in which third fluid reservoir 180 is in fluid communication with second tube 104. In the fourth assembly configuration, first valve 150 can be in its third configuration, second valve 160 can be in its second configuration, and third valve 170 can be in its second configuration, with third fluid reservoir 180 in fluid communication with second tube 104 (and patient access subassembly 110) via third valve 170, first valve 150, and second valve 160. In the fourth assembly configuration, the flow path from third fluid reservoir 180 to second tube 104 can be fluidly isolated from first tube 102, first fluid reservoir 120, and second fluid reservoir 130.

[0023] First fluid reservoir 120, second fluid reservoir 130, and / or third fluid reservoir 180 can be defined within or included in any suitable fluid-containing component. For example, in some embodiments, system 100 can include several syringes, where first fluid reservoir 120, second fluid reservoir 130, and / or third fluid reservoir 180 are each defined by a syringe having a barrel and a plunger, and fluid can be drawn into and expelled from each of the fluid reservoirs, e.g., via movement of the respective plungers. In some embodiments, system 100 can include one or more gas syringes. For example, second fluid reservoir 130 can be a gas syringe. In some embodiments, system 100 may include several fluid bags, where first fluid reservoir 120, second fluid reservoir 130, and / or third fluid reservoir 180 may each be defined by a fluid bag, and fluid may be drawn into and / or expelled from each of the fluid reservoirs, for example, by squeezing the respective fluid bag, by a pump, and / or by the effect of gravity on the fluid. In some embodiments, system 100 may include a combination of one or more syringes and one or more fluid bags, where one or more of first fluid reservoir 120, second fluid reservoir 130, and / or third fluid reservoir 180 may be defined by a syringe, and one or more others may be defined by a fluid bag.

[0024] In some embodiments, first fluid reservoir 120 may contain (e.g., may be pre-filled with) an anticoagulant, such as ACD-A, ACD-B, EDTA, or heparin. In some embodiments, first fluid reservoir 120 may be pre-filled with both an anticoagulant and an antioxidant (e.g., vitamin C or N-acetylcysteine). In some embodiments, second fluid reservoir 130 may contain (e.g., may be pre-filled with) a pharmaceutical, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, nitric oxide, and / or ozone. In some embodiments, third fluid reservoir 180 may contain (e.g., may be pre-filled with) saline.

[0025] The patient access subassembly 110 may include any suitable element configured to provide access to the patient's vasculature. For example, the patient access subassembly 110 may include a needle, such as a Huber needle. In some embodiments, the patient access subassembly 110 may include a connector configured to couple to a port coupled to the patient's vasculature. The patient access subassembly 110 may also include a connector, such that the patient's vasculature may be in fluid communication with the first tubing 102 and / or the second tubing 104. For example, the patient access subassembly 110 may include connectors configured to couple to the first tubing 102, the second tubing 104, and the patient's vasculature, e.g., via a third tubing coupled to a needle or port. For example, in some embodiments, the connector of the patient access subassembly 110 may be configured to couple to a connector disposed at the end of an intravenous tubing line. The intravenous tubing line may be fluidly connected to the patient's vasculature (e.g., before being connected to the connector of the patient access subassembly 110), and the patient's vasculature is in fluid communication with the first tube 102 and the second tube 104 via the patient access subassembly 110.

[0026] In use, first fluid reservoir 120 may be pre-filled with a volume of anticoagulant. Second fluid reservoir 130 may be pre-filled with a volume of medication. Third fluid reservoir 180 may be pre-filled with a volume of saline solution. In some embodiments, third fluid reservoir 180 may be separated from assembly 140 during an initial stage of use of system 100. In some embodiments, third fluid reservoir 180 may be attached to assembly 140 prior to an initial stage of use of system 100 (e.g., prior to connecting patient access subassembly 110 to the patient's vasculature). In some embodiments, assembly 140 and / or second tubing 104 may be primed (e.g., filled with saline) prior to connecting assembly 140 and / or second tubing 104 to patient access subassembly 110.

[0027] Patient access subassembly 110 may be placed in fluid communication with the patient's vasculature (e.g., by inserting a needle of patient access subassembly 110 through the patient's skin or by connecting patient access subassembly 110 through the patient's skin to an existing port (e.g., a connector connected to an intravascular tubing line)). Assembly 140 may be aligned in a first assembly configuration, with patient access subassembly 110 in fluid communication with first fluid reservoir 120 via first tubing 102, third valve 170, and first valve 150. For example, first valve 150 may be operated or toggled to its first configuration, and third valve 170 may be operated or toggled to its first configuration. Blood may then be drawn from the patient through patient access subassembly 110, first tubing 102, third valve 170, first valve 150, and into first fluid reservoir 120, where the blood combines with the anticoagulant to form a first substance. For example, a plunger of a syringe defining first fluid reservoir 120 may be moved relative to the barrel of the syringe to draw blood into first fluid reservoir 120.

[0028] Assembly 120 can then be transitioned to a second assembly configuration, with first fluid reservoir 120 in fluid communication with second fluid reservoir 130. For example, first valve 150 and second valve 160 can be operated or toggled such that first valve 150 is in its second configuration and second valve 160 is in its first configuration. A portion of the first substance (e.g., a volume equal to or greater than the volume of the medication in second fluid reservoir 130) can then be transferred from first fluid reservoir 120 to second fluid reservoir 130, with the portion of the first substance combining with the medication in second fluid reservoir 130 to form the second substance. For example, the plunger of the syringe defining first fluid reservoir 120 can be moved to expel a portion of the first substance from first fluid reservoir 120 and to push the first substance into second fluid reservoir 130. In some embodiments, the plunger or syringe defining second fluid reservoir 130 can be simultaneously moved relative to the barrel of the syringe to assist in drawing the first substance into second fluid reservoir 130.

[0029] Assembly 140 remains in the second assembly configuration, and a second substance can be transferred from second fluid reservoir 130 to first fluid reservoir 120, where the second substance combines with the remainder of the first substance in first fluid reservoir 120 to form a third substance. For example, the plunger of a syringe defining second fluid reservoir 130 can be moved to expel the second substance from second fluid reservoir 130 and push the second substance into first fluid reservoir 120. In some embodiments, the plunger or syringe defining first fluid reservoir 120 can be simultaneously moved relative to the barrel of the syringe to assist in drawing the second substance into first fluid reservoir 120.

[0030] Assembly 140 may then be transitioned to a third assembly configuration, with first fluid reservoir 120 in fluid communication with patient access subassembly 110 via first valve 150, second valve 160, and second tubing 104. For example, first valve 150 may remain in its second configuration, and second valve 160 may be operated or toggled such that second valve 160 is in its second configuration. A third substance may then be transferred from first fluid reservoir 120 to the patient's vasculature system via first valve 150, second valve 160, second tubing 104, and patient access subassembly 110.

[0031] After transferring the third substance to the patient's vasculature, third fluid reservoir 180 may be coupled to third valve 170. Assembly 140 may then be transitioned to a fourth assembly configuration, with third fluid reservoir 180 in fluid communication with patient access subassembly 110 via third valve 170, first valve 150, second valve 160, and second tubing 104. For example, first valve 150 may be operated or toggled such that first valve 150 is in the first valve 150 third configuration, second valve 160 may remain in the second valve 160 second configuration, and third valve 170 may be operated or toggled such that third valve 170 is in the third valve 170 second configuration. The contents of third fluid reservoir 180 (i.e., saline) can then be transferred to patient access subassembly 110 via third valve 170, first valve 150, second valve 160, and second tubing 104, causing the saline to flow through the fluid flow path of the third substance. System 100 can then be removed from the patient.

[0032] In some embodiments, system 100 may optionally include an actuation subsystem (not shown). The actuation subsystem may include one or more actuators configured to mate with one or more of the components of system 100. For example, rather than manually adjusting the configuration or orientation of the valves of assembly 140, the actuators may engage and adjust the configuration or orientation of the valves of assembly 140. In some embodiments, the actuation subsystem may include a first actuator operably coupled to first valve 150, a second actuator operably coupled to second valve 160, and a third actuator operably coupled to third valve 170. Each of the first actuator, second actuator, and third actuator may be configured to transition (e.g., manipulate or toggle) each of first valve 150, second valve 160, and third valve 170 between their respective actuation configurations. The actuation subsystem may also include a first reservoir actuator configured to control fluid flow into and out of a first fluid reservoir, a second reservoir actuator configured to control fluid flow into and out of a second fluid reservoir, and a third reservoir actuator configured to control fluid flow into and out of a third fluid reservoir.

[0033] In some embodiments, rather than including an actuation subsystem, system 100 may optionally be connectable to a separate actuation system (not shown). For example, the actuation system may include a housing and several actuators, each configured to operably switch and / or control the flow of fluid to a valve arrangement or reservoir of system 100. The actuation system may be configured to receive system 100, and the actuation system may operably switch system 100 and control the operation of system 100 to perform any of the method steps described herein. In some embodiments, system 100 may be disposable and the actuation system may be reusable.

[0034] FIG. 2 is a schematic illustration of system 200. Unless explicitly stated otherwise, similarly named and referenced components may be structurally and / or functionally similar to those described above with respect to FIG. 1. In some embodiments, system 200 is useful for withdrawing cells (e.g., packed red blood cells, white blood cells, and / or platelets) from a patient, combining a medication with the patient's cells ex vivo, and infusing the combined cells and medication into the patient's bloodstream. System 200 includes a patient access subassembly 210, a first fluid reservoir 220, a second fluid reservoir 230, a third fluid reservoir 280, and assembly 240. Assembly 240 may include a first valve 250, a second valve 260, and a third valve 270. In some embodiments, assembly 240 may be a three-gang valve manifold having three levers, each of which controls the configuration of a valve in the valve manifold. First fluid reservoir 220 may be coupled to first valve 250 via first connector 222, and second fluid reservoir 230 may be coupled to second valve 260 via second connector 232. In some embodiments, first valve 250 may be mated with third valve 270 and second valve 260. In some embodiments, first valve 250 may be fluidly coupled to third valve 270 and second valve 260, for example, via interconnecting tubing. Third fluid reservoir 280 may be coupled to third valve 270 via third connector 282. In some embodiments, third fluid reservoir 280 may be separated from assembly 240 during a portion of use of system 200. The first connector 232, the second connector 222, and / or the third connector 282 may be needleless connectors (also referred to as needle-free connectors). The system 200 may also include a first tube 202, a second tube 204A, a third tube 204B, and a filter 290, where the second tube 204A is connected to the second valve 260 and the filter 290, and the third tube 204B is connected to the patient access subassembly 210 and the filter 290.In some embodiments, filter 290 can have a pore size of, for example, 150 microns. In some embodiments, filter 290 can have a pore size of, for example, 170 microns to 260 microns, including all values ​​and subranges therebetween. Filter 290 can be used to filter sediments, which are prevented from flowing through patient access subassembly 210 and into the patient. For example, in some embodiments, filter 290 can prevent embolism (e.g., by filtering platelet and white blood cell clots and / or aggregates, blood bubbles, and / or hemoglobin that may be released, for example, from lysed red blood cells).

[0035] Patient access subassembly 210 may include a patient access port 212, access tubing 216, and a connector 214. Patient access port 212 may include any suitable element configured to provide access to a patient's vasculature. For example, patient access subassembly 210 may include a needle, such as a Huber needle. In some embodiments, patient access subassembly 210 may include a connector configured to be coupled to a port previously coupled to the patient's vasculature. Connector 214 of patient access subassembly 210 may be coupled to third valve 270 via first tubing 202, and patient access subassembly 210 may be in fluid communication with third valve 270 via a first fluid pathway. In some embodiments, patient access subassembly 210 includes first tubing 202. Connector 214 may be coupled to second valve 260 via a second fluid pathway including second tubing 204A, third tubing 204B, and filter 290, and patient access subassembly 210 may be in fluid communication with second valve 260 via the second fluid pathway. In some embodiments, connector 214 may be, for example, a Y-connector. Thus, in some embodiments, system 200 may function as a closed-loop system in which fluid may flow away from patient access subassembly 210 via first tubing 202 and return to patient access subassembly 210 via second tubing 204A, filter 290, and third tubing 204B.

[0036] In an exemplary usage scenario, second fluid reservoir 230 may contain a pharmaceutical agent, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, a nitric oxide donor, a chemotherapeutic agent (e.g., an antitumor platinum coordination complex, an antimetabolite, a mitotic inhibitor, an anticancer antibiotic, a topoisomerase I and / or II inhibitor, a proteasome inhibitor, a histone deacetylase inhibitor, a nitrogen mustard alkylating agent, a nitrosourea alkylating agent, a non-classical alkylating agent, an estrogen antagonist, an androgen antagonist, an mTOR inhibitor, and / or a tyrosine kinase inhibitor), and / or ozone. System 200 may be attached to a patient via patient access subassembly 210. A volume of the patient's blood may be drawn through patient access subassembly 210, through first tubing 202, through assembly 240, and into first fluid reservoir 220. A portion of the withdrawn volume of blood may be transferred via assembly 240 to second fluid reservoir 230, where it combines with the medication to form a first combined substance. The first combined substance may then be returned via assembly 240 to first fluid reservoir 220, where it combines with the remaining blood to form a second combined substance. The second combined substance may then be forced through assembly 240, through second tube 204A, through filter 290, through third tube 204B, and through patient access subassembly 210, where it enters the patient's bloodstream.

[0037] Each of first valve 250, second valve 260, and third valve 270 may be configured to transition between two or more configurations, each configuration corresponding to a different available flow path through assembly 240. Each of first valve 250, second valve 260, and third valve 270 may include any suitable valve mechanism, such as a manual valve mechanism, a solenoid-actuated valve mechanism, a motor-actuated valve mechanism, a drop-pressure valve mechanism, and / or a pneumatic valve mechanism. For example, each of first valve 250, second valve 260, and third valve 270 may include a three-way stopcock. Each of first valve 250, second valve 260, and third valve 270 may define or include an interior region through which fluid may travel. First fluid reservoir 220 may be coupled to first valve 250, and first fluid reservoir 220 may be in selective fluid communication with patient access subassembly 210 via third valve 270 and first valve 250, with second fluid reservoir 230 via first valve 250 and second valve 260, or with second tubing 204 via first valve 250 and second valve 260. For example, first valve 250 may have a first configuration that allows fluid communication between an interior region of third valve 270 and first fluid reservoir 220, but fluidly isolates an interior region of second valve 260 from both first fluid reservoir 220 and the interior region of third valve 270. The first valve 250 may have a second configuration in which the first valve 250 allows fluid communication between the interior regions of the first fluid reservoir 220 and the second valve 260, but fluidly isolates the interior region of the third valve 270 from both the interior regions of the first fluid reservoir 220 and the second valve 260. The first valve 250 may have a third configuration in which the first valve 250 allows fluid communication between the interior regions of the third valve 270 and the second valve 260, but fluidly isolates the first fluid reservoir 220 from both the interior regions of the third valve 270 and the second valve 260.

[0038] In some embodiments, second fluid reservoir 230 can be coupled to second valve 260, such that second fluid reservoir 230 can be in selective fluid communication with first fluid reservoir 220 via second valve 260 and first valve 250, and with patient access subassembly 210 via second valve 260. For example, second valve 260 can have a first configuration in which second valve 260 allows fluid communication between an interior region of first valve 250 and second fluid reservoir 230, but fluidly isolates second tube 204A from both second fluid reservoir 230 and an interior region of first valve 250. The second valve 260 may have a second configuration in which the second valve 260 allows fluid communication between the interior region of the first valve 250 and the second tube 204A, but fluidly isolates the second fluid reservoir 230 from both the interior region of the first valve 250 and the second tube 204A.

[0039] A third valve 270 may be coupled to the first valve 250, and the patient access subassembly 210 and the third fluid reservoir 280 may each be in selective fluid communication with the first fluid reservoir 220 and / or the second tubing 204A via the third valve 270. For example, the third valve 270 may have a first configuration in which the third valve 270 allows fluid communication between the interior region of the first tubing 202 and the first valve 250, but fluidly isolates the third fluid reservoir 280 (or a connector configured to be coupled to the third fluid reservoir 280) from both the interior region of the first tubing 202 and the first valve 250. The third valve 270 may have a second configuration in which the third valve 270 allows fluid communication between the third fluid reservoir 280 and the interior region of the first valve 250, but fluidly isolates the first tube 202 from both the interior region of the first valve 250 and the third fluid reservoir 280.

[0040] Thus, assembly 240 may have a first assembly configuration in which patient access subassembly 210 is in fluid communication with first fluid reservoir 220 via first tube 202, a second assembly configuration in which first fluid reservoir 220 is in fluid communication with second fluid reservoir 230, and a third assembly configuration in which first fluid reservoir 220 is in fluid communication with patient access subassembly 210 via second tube 204A. In the first assembly configuration, first valve 250 may be in its first configuration, third valve 270 may be in its first configuration, and first tube 202 and first fluid reservoir 220 may be in fluid communication via third valve 270 and first valve 250. In the first assembly configuration, the second valve 260 is isolated from the flow path from the patient access subassembly 210, through the first tube 202, the third valve 270, the first valve 250, and to the first fluid reservoir 220, so that the second valve 260 can be in either the first or second configuration of the second valve 260.

[0041] In the second assembly configuration, first valve 250 can be in its second configuration, second valve 260 can be in its first configuration, and first reservoir 220 of a first fluid and second fluid reservoir 230 are in fluid communication via first valve 250 and second valve 260. Third valve 270 is isolated from the flow path between first fluid reservoir 220 and second fluid reservoir 230 via first valve 250 and second valve 260, such that third valve 270 can be in either its first or second configuration.

[0042] In the third assembly configuration, first valve 250 can be in its third configuration, second valve 260 can be in its second configuration, and first fluid reservoir 220 can be in fluid communication with second tubing 204A. Because third valve 270 is isolated from the flow path between first fluid reservoir 220 and second tubing 204A via first valve 250 and second valve 260, third valve 270 can be in either its first or second configuration.

[0043] In some embodiments, assembly 240 can have a fourth assembly configuration in which third fluid reservoir 280 is in fluid communication with second tube 204A. In the fourth assembly configuration, first valve 250 can be in its third configuration, second valve 260 can be in its second configuration, and third valve 270 can be in its second configuration, with third fluid reservoir 280 in fluid communication with second tube 204A (and patient access subassembly 210) via third valve 270, first valve 250, and second valve 260. In the fourth assembly configuration, the flow path from third fluid reservoir 280 to second tube 204A can be fluidly isolated from first tube 202, first fluid reservoir 220, and second fluid reservoir 230.

[0044] First fluid reservoir 220, second fluid reservoir 230, and / or third fluid reservoir 280 can be defined in or contained in any suitable fluid-containing component. For example, in some embodiments, system 200 can include several syringes, where first fluid reservoir 220, second fluid reservoir 230, and / or third fluid reservoir 280 are each defined by a syringe having a barrel and a plunger, and fluid can be drawn into and expelled from each of the fluid reservoirs, e.g., via movement of the respective plungers. In some embodiments, system 200 may include several fluid bags, where first fluid reservoir 220, second fluid reservoir 230, and / or third fluid reservoir 280 may each be defined by a fluid bag, and fluid may be drawn into and / or expelled from each of the fluid reservoirs, for example, by squeezing the respective fluid bag, by a pump, and / or by the effect of gravity on the fluid. In some embodiments, system 200 may include a combination of one or more syringes and one or more fluid bags, where one or more of first fluid reservoir 220, second fluid reservoir 230, and / or third fluid reservoir 280 may be defined by a syringe, and one or more others may be defined by a fluid bag.

[0045] In some embodiments, first fluid reservoir 220 may contain (e.g., may be pre-filled with) an anticoagulant, such as ACD-A, ACD-B, EDTA, or heparin. In some embodiments, first fluid reservoir 220 may be pre-filled with both an anticoagulant and an antioxidant (e.g., vitamin C or N-acetylcysteine). In some embodiments, second fluid reservoir 230 may contain (e.g., may be pre-filled with) a medication, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, a nitric oxide donor, a chemotherapy drug, and / or ozone. In some embodiments, third fluid reservoir 280 may contain (e.g., may be pre-filled with) saline.

[0046] 2, system 200 may include several selective flow preventers coupled to the tubing of system 200 and configured to transition between open and closed configurations, such that flow through the tubing may be temporarily prevented. For example, first selective flow preventer 218 may be disposed on access tube 216, second selective flow preventer 206 may be disposed on first tube 202, and third selective flow preventer 208 may be disposed on third tube 204B. Each of first selective flow preventer 218, second selective flow preventer 206, and third selective flow preventer 208 may be, for example, a tubing clamp or a roller clamp.

[0047] In use, first fluid reservoir 220 may be pre-filled with a volume of anticoagulant. Second fluid reservoir 230 may be pre-filled with a volume of medication. Third fluid reservoir 280 may be pre-filled with a volume of saline. In some embodiments, third fluid reservoir 280 may be separated from assembly 240 during the initial stages of use of system 200.

[0048] With first tubing 202 connected to third valve 270 and third tubing 204B connected to connector 214, each of first selective flow preventer 218, second selective flow preventer 206, and third selective flow preventer 208 in a closed configuration. Patient access subassembly 210 may be placed in fluid communication with the patient's vasculature via patient access port 212 (e.g., by inserting a needle of patient access port 212 through the patient's skin or by connecting patient access port 212 to an existing port through the patient's skin or a connector connected to an intravascular tubing line). Assembly 240 may be aligned in a first assembly configuration, with patient access subassembly 210 in fluid communication with first fluid reservoir 220 via first tubing 202, third valve 270, and first valve 250. For example, first valve 250 may be operated or toggled to its first configuration, and third valve 270 may be operated or toggled to its first configuration. First selective flow preventer 218 and second selective flow preventer 206 may then be transitioned to their open configurations. Blood may then be drawn from the patient through patient access subassembly 210, first tubing 202, third valve 270, first valve 250, and into first fluid reservoir 220, where the blood combines with an anticoagulant to form a first substance. For example, a plunger of a syringe defining first fluid reservoir 220 may be moved relative to the barrel of the syringe to draw blood into first fluid reservoir 220.

[0049] First selective flow preventer 218 and second selective flow preventer 206 may then be transitioned to a closed configuration. Assembly 220 may then be transitioned to a second assembly configuration, with first fluid reservoir 220 in fluid communication with second fluid reservoir 230. For example, first valve 250 and second valve 260 may be operated or toggled such that first valve 250 is in its second configuration and second valve 260 is in its first configuration. A portion of the first substance (e.g., a volume greater than or equal to twice the volume of the medication in second fluid reservoir 230) may then be transferred from first fluid reservoir 220 to second fluid reservoir 230, where the portion of the first substance combines with the medication in second fluid reservoir 230 to form the second substance. For example, the plunger of the syringe defining first fluid reservoir 220 can be moved to expel a portion of the first substance from first fluid reservoir 220 and push the first substance into second fluid reservoir 230. In some embodiments, the plunger or syringe defining second fluid reservoir 230 can be simultaneously moved relative to the barrel of the syringe to assist in drawing the first substance into second fluid reservoir 230.

[0050] While assembly 240 remains in the second assembly configuration, a second substance can be transferred from second fluid reservoir 230 to first fluid reservoir 220, and the second substance can combine with the remainder of the first substance in first fluid reservoir 220 to form a third substance. For example, the plunger of a syringe defining second fluid reservoir 230 can be moved to expel the second substance from second fluid reservoir 230 and push the second substance into first fluid reservoir 220. In some embodiments, the plunger or syringe defining first fluid reservoir 220 can be simultaneously moved relative to the barrel of the syringe to assist in drawing the second substance into first fluid reservoir 220.

[0051] Assembly 240 may then be transitioned to a third assembly configuration, with first fluid reservoir 220 in fluid communication with patient access subassembly 210 via first valve 250, second valve 260, second tubing 204, filter 290, and third tubing 204B. For example, first valve 250 may remain in the first valve 250 second configuration, and second valve 260 may be operated or toggled such that second valve 260 is in the second valve 260 second configuration. Third selective flow preventer 208 and first selective flow preventer 218 may be transitioned to an open configuration. A third substance may then be transferred from first fluid reservoir 220 to the patient's vasculature system via first valve 250, second valve 260, second tubing 204A, filter 290, third tubing 204B, and patient access subassembly 210.

[0052] After transferring the third substance to the patient's vasculature, third fluid reservoir 280 may be coupled to third valve 270. Assembly 240 may then be transitioned to a fourth assembly configuration, with third fluid reservoir 280 in fluid communication with patient access subassembly 210 via third valve 270, first valve 250, second valve 260, and second tubing 204. For example, first valve 250 may be operated or toggled such that first valve 250 is in the first valve 250 third configuration, second valve 260 may remain in the second valve 260 second configuration, and third valve 270 may be operated or toggled such that third valve 270 is in the third valve 270 second configuration. The contents of third fluid reservoir 280 (i.e., saline) may then be transferred to patient access subassembly 210 via third valve 270, first valve 250, second valve 260, second tubing 204A, filter 290, and third tubing 204B, flushing the saline out to the end of the fluid flow path of the third substance. Third selective flow preventer 208 and first selective flow preventer 218 may then be transitioned to a closed configuration, and third tubing 204B may be detached from connector 214. First tubing 202 may be detached from third valve 270. Patient access subassembly 210 may then be removed from the patient.

[0053] In some embodiments, system 200 may optionally include an actuation subsystem (not shown). The actuation subsystem may include one or more actuators configured to mate with one or more of the components of system 200. For example, rather than manually adjusting the configuration or orientation of the valves of assembly 240, the actuators may switch and adjust the configuration or orientation of the valves of assembly 240. In some embodiments, the actuation subsystem may include a first actuator operably coupled to first valve 250, a second actuator operably coupled to second valve 260, and a third actuator operably coupled to third valve 270. Each of the first actuator, second actuator, and third actuator may be configured to transition (e.g., operate or toggle) each of first valve 250, second valve 260, and third valve 270 between their respective operational configurations. The actuation subsystem may also include a first reservoir actuator configured to control the flow of fluid into and out of the first fluid reservoir 220, a second reservoir actuator configured to control the flow of fluid into and out of the second fluid reservoir 230, and a third reservoir actuator configured to control the flow of fluid into and out of the third fluid reservoir 280. The first reservoir actuator may be configured to operably switch and control the position of a plunger associated with the first fluid reservoir 220 to control the flow of fluid into and out of the first fluid reservoir 220, the second reservoir actuator may be configured to operably switch and control the position of a plunger associated with the second fluid reservoir 230 to control the flow of fluid into and out of the second fluid reservoir 230, and the third reservoir actuator may be configured to operably switch and control the position of a plunger associated with the third fluid reservoir 280 to control the flow of fluid into and out of the third fluid reservoir 280.

[0054] In some embodiments, rather than including an actuation subsystem, system 200 may optionally be connectable to a separate actuation system (not shown). For example, the actuation system may include a housing and several actuators, each configured to operably switch and / or control the flow of fluid to a valve arrangement or reservoir of system 200. The actuation system may be configured to receive system 200, and the actuation system may operably switch system 200 and control the operation of system 200 to perform any of the method steps described herein. In some embodiments, system 200 may be disposable and the actuation system may be reusable.

[0055] FIG. 3 is a flowchart illustrating method 300. In some embodiments, method 300 can be used in conjunction with any of the systems described herein to withdraw cells (e.g., packed red blood cells, white blood cells, and / or platelets) from a patient, combine a pharmaceutical agent with the patient's cells ex vivo, and infuse the combined cells and pharmaceutical agent into the patient's bloodstream. Unless explicitly noted otherwise, similarly named components may be structurally and / or functionally similar to those in FIG. 1 and / or FIG. 2. As shown in FIG. 3, method 300 includes, in step 302, connecting a patient access subassembly to a patient, the patient access subassembly being fluidly connected via the assembly to a first fluid reservoir containing a first substance (e.g., an anticoagulant and / or antioxidant) and a second fluid reservoir containing a second substance (e.g., a pharmaceutical agent such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, nitric oxide, and / or ozone). Cells (e.g., packed red blood cells, white blood cells, and / or platelets) may be drawn through the patient access subassembly, step 304, through the assembly, and into a first fluid reservoir, with the cells and the first substance forming a third substance. The assembly may be operated, step 306, so that the first fluid reservoir is fluidly isolated from the patient access subassembly and the first fluid reservoir is in fluid communication with a second fluid reservoir. A portion of the third substance may be transferred from the first fluid reservoir through the assembly to the second fluid reservoir, step 308, with a portion of the third substance and the second substance forming a fourth substance. The fourth substance may be transferred from the second fluid reservoir through the assembly to the first fluid reservoir, step 310, with the remainder of the third substance and the fourth substance forming a fifth substance. The assembly may be operated, step 312, so that the first fluid reservoir is in fluid communication with the patient access subassembly. A fifth substance may be transferred from the first fluid reservoir through the assembly, through the patient access subassembly, and to the patient in step 314. A third fluid reservoir containing a saline solution may be fluidly coupled to the assembly in step 316.The assembly may be manipulated so that the third fluid reservoir is in fluid communication with the patient access subassembly through the assembly, step 318. At least a portion of the saline solution may be transferred from the assembly to the patient access subassembly, step 320.

[0056] FIG. 4 is a flowchart illustrating method 400. In some embodiments, method 400 can be used with any of the systems described herein to assemble a system for withdrawing cells (e.g., packed red blood cells, white blood cells, and / or platelets) from a patient, combining a medicament with the patient's cells ex vivo, and infusing the combined cells and medicament into the patient's bloodstream. Unless expressly indicated otherwise, similarly named components may be structurally and / or functionally similar to those in FIG. 1 and / or FIG. 2. As shown in FIG. 4, method 400 includes, in step 402, fluidly coupling a first connecting member of a first subassembly to a valve assembly of a second subassembly. The second subassembly may include a first fluid reservoir and a second fluid reservoir fluidly coupled to the valve subassembly. The first fluid reservoir may optionally be fluidly coupled to the second fluid reservoir via the valve assembly. The first subassembly may include a patient access port, a first connecting member, and a second connecting member. The first connecting member and the second connecting member may be in fluid communication with the patient access port. The first connecting member may be connected to the valve assembly, with a first fluid reservoir of the second subassembly in selective fluid communication with the patient access port via a first flow path. The second connecting member of the first subassembly may be fluidly connected to the valve assembly in step 404, with the first fluid reservoir in selective fluid communication with the patient access port via a second flow path different from the first flow path. The third fluid reservoir may be connected to the valve assembly in step 406, with the third fluid reservoir in selective fluid communication with the patient access port via the second flow path.

[0057] FIG. 5 is an illustration of a system 500 useful for withdrawing cells (e.g., packed red blood cells, white blood cells, and / or platelets) from a patient, combining a medication with the patient's cells ex vivo, and infusing the combined cells and medication into the patient's bloodstream. System 500 is a non-limiting example and may be the same or similar in structure and / or function to any of the systems described herein, e.g., system 100 and / or system 200. Unless expressly noted otherwise, similarly named and referenced components may be structurally and / or functionally similar to those described above, e.g., with respect to FIG. 1 and / or FIG. 2. System 500 includes a syringe 520, a valve 550, a first fluid bag 530, a second fluid bag 542, and a filter 590. Syringe 520 includes a barrel 523 and a plunger 525 that together define a fluid reservoir. Syringe 520 may be pre-filled with an anticoagulant, such as ACD-A, ACD-B, EDTA, or heparin. System 500 may also include a first tube 502 fluidly connected to a patient's blood vessel, through which cells may be withdrawn from the patient. First tube 502 may include a first connector 521, which may be, for example, a needleless connector (also referred to as a needle-free connector), and first tube 502 may be connected to valve 550 via needleless connector 521. System 500 may also include a second connector 523, which may be, for example, a double male luer lock, and a needle 531. Valve 550 may be connected to first fluid bag 530 via second connector 523 and needle 531.

[0058] Syringe 520 can be coupled to valve 550, which can control the flow of fluid into and out of syringe 520. Valve 550 can have a first configuration in which the reservoir of syringe 520 is in fluid communication with first tubing 502, and movement of plunger 525 relative to barrel 523 draws cells from the patient into the reservoir of syringe 520, but the reservoir of syringe 520 is fluidly isolated from second connector 523. Valve 550 can have a second configuration in which the reservoir of syringe 520 is in fluid communication with first fluid bag 530 via second connector 523 and needle 531, but the reservoir of syringe 520 is fluidly isolated from first tubing 502. Valve 550 can include any suitable valve mechanism, such as a manual valve mechanism, a solenoid-actuated valve mechanism, a motor-actuated valve mechanism, a drop-pressure valve mechanism, and / or a pneumatic valve mechanism, etc. In some embodiments, valve 550 can be a stopcock, and a portion of valve 550 can rotate between a first configuration and a second configuration.

[0059] First fluid bag 530 includes first reservoir 536, second reservoir 534, and dividing strip 538. Second reservoir 534 may be pre-filled with a medication, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, a nitric oxide donor, a chemotherapy drug, and / or ozone. Dividing strip 538 may be removable, and the medication in second reservoir 534 may migrate to first reservoir 536 (e.g., due to gravitational effects).

[0060] The second fluid bag 542 may be pre-filled with saline (e.g., 0.9% sodium chloride). The first fluid bag 530 may be fluidly connected to a filter 590 via a second tube 504A, and the second fluid bag 542 may be fluidly connected to the filter 590 via a saline tube 505. A first selective flow preventer 506 may be disposed on the second tube 504A, and the first selective flow preventer 506 may selectively apply pressure to the second tube 504A to prevent fluid flow therethrough. A second selective flow preventer 508 may be disposed on the saline tube 505, and the first selective flow preventer 508 may selectively apply pressure to the saline tube 505 to prevent fluid flow therethrough.

[0061] Filter 590 may be the same or similar in structure and / or function as filter 290 described above with respect to FIG. 2 . For example, filter 590 may have any suitable pore size depending on the substance intended to be filtered from the fluid passing through filter 590. Filter 590 may be connected to third tube 504B, and fluid exiting filter 590 may be infused into a patient via third tube 504B. Third selective flow preventer 518 may be disposed on third tube 504B, and first selective flow preventer 506 may selectively apply pressure to third tube 504B to prevent fluid flow therethrough. First selective flow preventer 506, second selective flow preventer 508, and third selective flow preventer 518 may each be, for example, a roller clamp or any other suitable type of tubing clamp.

[0062] In use, valve 550 can be arranged in a first configuration, first selective flow preventer 506, second selective flow preventer 508, and third selective flow preventer 518 can each be closed, and fluid flow through second tube 504A, third tube 504B, and saline tube 505 can be blocked. Plunger 525 can then be moved (e.g., pulled), and cells can be drawn from the patient, through first tube 502, and into barrel 523 of syringe 523. In some embodiments, the cells can be combined with a clotting agent in syringe 523 to form a first substance. Valve 550 can then be transitioned to a second configuration. Plunger 525 can then be moved (e.g., pushed), and the first substance can be expelled from syringe 520, through second connector 523 and needle 531, and into first reservoir 536, first fluid bag 530. Dividing strip 538 may then be removed, and the medication in second reservoir 534 may be released and combined with the first substance in reservoir 536 to form a second substance. First selective flow preventer 506 and third selective flow preventer 518 may then be transitioned to an open position, allowing the second substance to flow through second tube 504A, filter 590, third tube 504B, and into the patient's blood vessel. Second selective flow preventer 508 may then be transitioned to an open position, allowing the contents of second fluid bag 542 (e.g., saline) to flow through saline tube 505, filter 590, third tube 504B, and into the patient's blood vessel.

[0063] FIG. 6 is a top view of mixing assembly 601 of system 600 prior to assembly of system 600. System 600 may be the same or similar in structure and / or function to any of the systems described herein. Unless expressly noted otherwise, similarly named and referenced components may be structurally and / or functionally similar to those described above, e.g., with respect to FIGS. 1, 2, and / or 5. In some embodiments, system 600 is useful for withdrawing cells (e.g., packed red blood cells, white blood cells, and / or platelets) from a patient, combining a medicament with a patient's cells ex vivo, and infusing the combined cells and medicament into the patient's bloodstream. Mixing assembly 601 includes a first syringe 620 defining a first fluid reservoir, a second syringe 630 defining a second fluid reservoir, a first fluid bag 642, and assembly 640. First syringe 620 includes a barrel 623 and a plunger 625. The second syringe 630 includes a barrel 633 and a plunger 635. The assembly 640 includes a first valve 650 and a second valve 660. In some embodiments, the assembly 640 may include two sets of valve manifolds. Each of the first valve 650 and the second valve 660 may include a valve lever for controlling fluid flow through the valve. The direction of extension of the valve lever may indicate the direction of the fluid line to be disconnected or "off." In some embodiments, the first valve 650 may be connected to the second fluid valve 660 by a user (e.g., a clinician, doctor, or nurse) during assembly of the mixing assembly 601. The first valve 650 may include a needleless connection port for connection to a needleless connector, such as the third connector 614 described below. The first syringe 620 may be coupled to a first valve 650 via a first connector 622, and the second syringe 630 may be coupled to a second valve 660 via a second connector 632. The first valve 650 may be coupled to the second valve 660. The first fluid bag 642 may be coupled to the second valve 660 via a first tube 604.The first selective flow preventer 606 may be disposed on the first tube 604, and the first selective flow preventer 606 may selectively prevent fluid flow through the first tube 604. For example, the first selective flow preventer 606 may have an open configuration and a closed configuration, and the first selective flow preventer 606 is configured to squeeze the first tube 604 closed in the closed configuration. For example, the first selective flow preventer 606 may be a roller clamp or a tubing clamp. The first connector 632 and / or the second connector 622 may be a needleless connector (also referred to as a needle-free connector). For example, the first connector 632 and / or the second connector 622 may be an ICU Medical MCIOO MicroClave Neutral Connector. The first syringe 620 may be pre-filled with an anticoagulant, such as ACD-A, ACD-B, EDTA, or heparin. Second syringe 630 may be pre-filled with a medication, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, a nitric oxide donor, a chemotherapeutic agent (e.g., a tyrosine kinase inhibitor), and / or ozone. In some embodiments, first syringe 620 may have a volume of 20 mL. In some embodiments, second syringe 630 may have a volume of 10 mL. In some embodiments, second syringe 630 may be pre-filled with 1 mL to 5 mL of medication.

[0064] In an exemplary usage scenario, second fluid reservoir 630 may contain a medication, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, a nitric oxide donor, a chemotherapeutic agent (e.g., a tyrosine kinase inhibitor), and / or ozone. System 600 may be attached to a patient via patient access subassembly 610 (described below). A volume of the patient's blood may be drawn through patient access subassembly 610 and through assembly 640 into first fluid reservoir 620. A portion of the drawn blood volume may be transferred via assembly 640 to second fluid reservoir 630, where it combines with the medication in second fluid reservoir 630 to form a first combined substance. The first combined substance may then be returned via assembly 640 to first fluid reservoir 620, where it combines with the remaining blood to form a second combined substance. The second combined substance may then be extruded through assembly 640, through first tube 604, and into first fluid bag 642. The second combined substance may then be delivered from first fluid bag 642 to the patient's bloodstream via patient access subassembly 610, as described below with reference to FIG.

[0065] Each of first valve 650 and second valve 660 may be configured to transition between two or more configurations, each configuration corresponding to a different available flow path through assembly 640. Each of first valve 650 and second valve 660 may include any suitable valve mechanism, such as a manual valve mechanism, a solenoid-actuated valve mechanism, a motor-actuated valve mechanism, a drop-pressure valve mechanism, and / or a pneumatic valve mechanism. For example, each of first valve 650 and second valve 660 may include a three-way stopcock. Each of first valve 650 and second valve 660 may define or include an interior region through which fluid may travel. The first syringe 620 may be coupled to a first valve 650, such that the first syringe 620 may be in selective fluid communication with the patient access subassembly 610 (described below) via the first valve 650, with the second syringe 630 via the first valve 650 and a second valve 660, or with the first tubing 604 via the first valve 650 and a second valve 660. For example, the first valve 650 may comprise a junction of three fluid lines and may fluidly isolate one of the three fluid lines while allowing fluid to flow between the other two lines. The first valve 650 may include a lever 651 that may rotate to transition the first valve 650 between various valve configurations. The lever 651 may be configured to extend in the direction of the fluid line to be isolated. So, for example, first valve 650 may have a first configuration in which first valve 650 allows fluid communication between patient access subassembly 610 and first syringe 620, but fluidly isolates an interior region of second valve 660 from both first syringe 620 and patient access subassembly 610. First valve 650 may have a second configuration in which first valve 650 allows fluid communication between an interior region of first syringe 620 and second valve 660, but fluidly isolates patient access subassembly 610 from both first syringe 620 and internal regions of second valve 660.The first valve 650 may have a third configuration in which the first valve 650 allows fluid communication between the interior regions of the patient access subassembly 610 and the second valve 660, but fluidly isolates the first syringe 620 from both the patient access subassembly 610 and the interior regions of the second valve 660.

[0066] In some embodiments, second syringe 630 can be coupled to second valve 660, such that second syringe 630 can be in selective fluid communication with first syringe 620 via second valve 660 and first valve 650, and with first tubing 604 via second valve 760. For example, second valve 660 can comprise a junction of three fluid lines and can fluidly isolate one of the three fluid lines while allowing fluid flow between the other two lines. Second valve 660 can include a lever 661 that can be rotated to transition second valve 660 between various valve configurations. Lever 661 can be configured to extend in the direction of the fluid line to be isolated. Thus, for example, the second valve 660 may have a first configuration in which the second valve 660 allows fluid communication between the interior region of the first valve 650 and the second syringe 630, but fluidly isolates the first tube 604 from both the second syringe 630 and the interior region of the first valve 650. The second valve 660 may have a second configuration in which the second valve 660 allows fluid communication between the interior region of the first valve 650 and the first tube 604, but fluidly isolates the second syringe 630 from both the interior region of the first valve 650 and the first tube 604.

[0067] As shown in FIG. 7, system 600 can also include a filter subassembly 690 including second tube 605A, third tube 605B, fourth tube 605C, and filter 691, which are shown and described in more detail with respect to FIG. 19. In some embodiments, filter 691 can be a drip chamber. System 600 can also include a second fluid bag 640. Second fluid bag 640 can contain, for example, saline (e.g., 0.9% sodium chloride). In some embodiments, second fluid bag 640 can be, for example, a 100 mL bag.

[0068] As shown in FIG. 8 , system 600 may also include a patient access subassembly 610. Patient access subassembly 610 may include a patient access port 612, access tubing 616, and a third connector 614. Patient access port 612 may include any suitable element configured to provide access to a patient's vasculature. For example, patient access subassembly 610 may include a needle, such as a Huber needle. In some embodiments, patient access subassembly 610 may include a connector configured to couple to a port previously connected to the patient's vasculature. Third connector 614 of patient access subassembly 610 may be coupled to first valve 650 (as shown in FIG. 6 ), and patient access subassembly 610 may be in fluid communication with first valve 650. In some embodiments, patient access subassembly 610 may be a 19G x 1.5 inch or larger needle.

[0069] 9 shows a top view of the mixing assembly 601 in a partially assembled configuration prior to attachment to the patient access subassembly 610. As shown, both the first valve 650 and the second valve 660 can be arranged such that the first connector 622 and the second connector 632 are fluidly isolated. The lever 651 of the first valve 650 and the lever 651 of the second valve 660 are both oriented toward the first connector 622 and the second connector 632, respectively, indicating that fluid flow is isolated along these flow lines. Additionally, the first selective flow preventer 606 can be slid close to or adjacent to the first fluid bag 642 and transitioned to a closed position, where flow is prevented within the first tube 604.

[0070] 10 , when the third selective flow preventer 618 is in a closed configuration to prevent fluid flow through the access tubing 616, the needleless connection port of the first valve 650 can be coupled to the third connector 614. In some embodiments, the third connector 614 can be swapped with alcohol prior to coupling the third connector 614 to the first valve 650.

[0071] 11 , first syringe 620 can be coupled to first connector 622, and second syringe 630 can be coupled to second connector 632. In some embodiments, an isopropyl alcohol pad can be used to wipe first connector 622 and second connector 632 before coupling first connector 622 and second connector 632 to first syringe 620 and second syringe 630, respectively. Lever 651 of first valve 650 and lever 661 of second valve 660 can then be rotated so that first lever 651 is oriented toward second valve 660 and second lever 661 is oriented toward first tubing 604. Thus, the first valve 650 can fluidly isolate the first syringe 620 and the patient access subassembly 610 from the second valve 660, and the second valve 660 can fluidly isolate the second syringe 630 and the first valve 650 from the first tube 604.

[0072] 12, when patient access port 612 is connected to a patient's blood vessel, third selective flow preventer 618 can be opened to allow blood to flow through access tubing 616. Blood can then be drawn from the patient, through patient access subassembly 610, through first valve 650, and into syringe barrel 623. For example, plunger 625 can be pulled as shown in FIG. 12 to draw blood into syringe barrel 623. The blood can be combined with an anticoagulant in syringe barrel 623 to form a first substance.

[0073] 13 , the patient access subassembly 610 may then be disconnected from the first valve 650. First, the lever 651 of the first valve 650 may be rotated to orient it toward the third connector 614, fluidly isolating the third connector 614 and the access tubing 616 from the first syringe 620 and the second valve 660. The third selective flow preventer 618 may be closed to prevent fluid flow through the access tubing 616. The third connector 614 may then be disconnected from the first valve 650.

[0074] 14 , a first substance in syringe barrel 623 of first syringe 620 can be transferred to syringe barrel 633 of second syringe 630 by moving (e.g., pushing) plunger 625 relative to syringe barrel 623, and the first substance is transferred through first valve 650 and through second valve 660 to second syringe 630. In some embodiments, plunger 635 of second syringe 630 can be simultaneously moved (e.g., pulled) while pushing plunger 625 of first syringe 620 to assist in the transfer of the first substance. In some embodiments, the first substance can be transferred to second syringe 630 at a flow rate low enough to avoid stress (e.g., shear stress and hemolysis) on red blood cells within the first substance (e.g., stress caused by pushing plunger 625 too forcefully). For example, the first substance may be transferred to the second syringe 630 at a flow rate ranging from about 0.2 mL per second to about 1 mL per second. In some embodiments, the first substance may be transferred to the second syringe 630 at a flow rate of about 0.5 mL per second. When the first substance is in the second syringe 630, the first substance may be combined with the pharmaceutical agent to form the second substance.

[0075] 15 , a second substance in syringe barrel 633 of second syringe 630 can be transferred to syringe barrel 623 of first syringe 620 by moving (e.g., pushing) plunger 635 relative to syringe barrel 633, and the second substance is transferred through second valve 660 and through first valve 650 to first syringe 620. In some embodiments, plunger 625 of first syringe 620 can be simultaneously moved (e.g., pulled) while pushing plunger 635 of second syringe 630 to assist in the transfer of the second substance. In some embodiments, the second substance can be transferred to first syringe 620 at a flow rate low enough to avoid stress on red blood cells within the second substance (e.g., stress caused by pushing plunger 635 too forcefully). For example, the second substance may be transferred to the first syringe 620 at a flow rate ranging from about 0.2 mL per second to about 1 mL per second. In some embodiments, the second substance may be transferred to the first syringe 620 at a flow rate of about 0.5 mL per second.

[0076] 16 , lever 661 of second valve 660 can be rotated to extend toward second syringe 630, fluidly isolating second syringe 630 from second valve 660. Second syringe 630 can then be disconnected from second connector 632.

[0077] 17 , first selective flow preventer 606 can be transitioned to an open configuration, and fluid can flow through first tube 604 and into first fluid bag 642. A second substance in first syringe 620 can then be transferred through first tube 604 and into first fluid bag 642 by moving (e.g., pushing) plunger 625 of first syringe 620, forcing the second substance from within first syringe 620 through first valve 650, second valve 660, and first fluid tube 604 into first fluid bag 642.

[0078] As shown in FIG. 18, the first selective flow preventer 606 can be transitioned to a closed configuration, preventing the third substance in the first fluid bag 642 from flowing out of the first fluid bag 642 through the first tube 604.

[0079] 19 shows a portion of system 600 in a configuration ready for infusion. As shown, third tubing 605B of filter subassembly 690 can be fluidly connected to second fluid bag 642 via a needle on a first end of third tubing 605B. When second selective flow preventer 608A disposed on second tubing 605C is closed to prevent fluid flow through second tubing 605A, filter subassembly 690 can be filled with saline from second fluid bag 640. Fourth selective flow preventer 608B on third tubing 605B can then be closed. When first selective flow preventer 618 is in a closed configuration on access tubing 616 and patient access subassembly 610 still fluidly connected to the patient's blood vessel, fourth tubing 605C of filter subassembly 690 can then be connected to third connector 614 of patient access subassembly 610. The first selective flow preventer 618 may then be opened to allow the patient access subassembly 610 to be filled.

[0080] The second tube 605A of the filter subassembly 690 may then be fluidly connected to the first fluid bag 642 via a needle on a first end of the second tube 605A. The third selective flow preventer 608A may then be opened to allow the second substance to move through the second tube 605A, through the filter 691, through the fourth tube 605C, and through the patient access subassembly 610 to the patient. In some embodiments, a pump may be used to transfer the second substance from the first fluid bag 642 to the patient through the patient access subassembly 610. In some embodiments, the second substance may be transferred at a rate of 3 mL / min for the first 15 minutes of the infusion, then increasing by 1 mL / min every 10 minutes for the remainder of the infusion.

[0081] When first fluid bag 642 is empty (i.e., when most or all of the second substance has been transferred through second tubing 608A), the first fluid bag may be moved to a position below filter 691. Fourth selective flow preventer 618 may then be opened to allow a volume of saline (e.g., approximately 25 mL) to transfer from second fluid bag 640, through third tubing 605B, through second tubing 605A, and into first fluid bag 642 to combine with any remaining second substance in first fluid bag 642. Fourth selective flow preventer 618 may then be closed on third tubing 605B. First fluid bag 642 may then be raised above filter 691, and the combination of second substance and saline in first fluid bag 642 may be transferred to the patient (e.g., at the highest fluid rate used during the initial transfer of the second substance). Once the first fluid bag 642 is emptied, the third selective flow preventer 608A can be closed to clamp off the second tube 605A, and the fourth selective flow preventer 608B can be opened to allow saline to flow from the second fluid bag 640 through the filter subassembly 690 and the patient access subassembly 610 until the tubing of the filter subassembly 690 and the patient access subassembly 610 is clear (i.e., until the saline pushes the second substance and saline combination through the tubing of the filter subassembly 690 and the patient access subassembly 610).

[0082] Thus, system 600 can function as a closed loop system in which fluid can flow away from patient access subassembly 610 through assembly 640 and return to patient access subassembly 610 via second tube 605A, filter 691 and fourth tube 605C.

[0083] FIG. 20 is a top view of system 700 in an assembled configuration. System 700 can be the same or similar in structure and / or function to any of the systems described herein, such as system 100 or system 200. Unless explicitly noted otherwise, similarly named and referenced components can be structurally and / or functionally similar to those described above, e.g., with respect to FIGS. 1 and 2 . In some embodiments, system 700 is useful for withdrawing cells (e.g., packed red blood cells, white blood cells, and / or platelets) from a patient, combining a medicament with the patient's cells ex vivo, and infusing the combined cells and medicament into the patient's bloodstream. System 700 includes a patient access subassembly 710, a first syringe 720 defining a first fluid reservoir, a second syringe 730 defining a second fluid reservoir, a third syringe 780 defining a third fluid reservoir, and assembly 740. Assembly 740 includes a first valve 750, a second valve 760, and a third valve 770. In some embodiments, assembly 740 may include a triple valve manifold. Each of first valve 750, second valve 760, and third valve 770 includes a valve lever for controlling the flow of fluid through the valve. The direction of extension of the valve lever may indicate the direction of the separated or "disconnected" fluid lines. First syringe 720 may be connected to first valve 750 via first connector 722, and second syringe 730 may be connected to second valve 760 via second connector 732. First valve 750 may be mated with third valve 770 and second valve 760, and first valve 750 may be in fluid communication with third valve 770 and second valve 760. Third syringe 780 may be coupled to third valve 770 via third connector 782. In some embodiments, third syringe 780 may be separated from assembly 740 during a portion of use of system 700. First connector 732, second connector 722 and / or third connector 782 may be needleless connectors (also referred to as needle-free connectors).For example, first connector 732, second connector 722, and / or third connector 782 can be an ICU Medical MCIOO MicroClave Neutral Connector. System 700 also includes first tubing 702, second tubing 704A, third tubing 704B, and filter 790, second valve 760, second tubing 704A connected to filter 790, and third tubing 704B connected to patient access subassembly 710 and filter 790. In some embodiments, filter 790 can be, for example, a 150 micron filter. In some embodiments, filter 790 can be a 170 micron filter to a 260 micron filter.

[0084] In an exemplary use scenario, second fluid reservoir 730 may contain a medication, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, nitric oxide, and / or ozone. System 700 may be attached to a patient via patient access subassembly 710. A volume of the patient's blood may be drawn through patient access subassembly 710, through first tubing 702, and through assembly 740 into first fluid reservoir 720. A portion of the drawn volume of blood may be transferred via assembly 740 to second fluid reservoir 730, where it combines with the medication to form a first combined substance. The first combined substance may then be returned via assembly 740 to first fluid reservoir 720, where it combines with the remaining blood to form a second combined substance. The second combined substance can then be pushed through assembly 740, through second tube 704A, through filter 790, through third tube 704B and through patient access subassembly 710, and the second combined substance flows into the patient's bloodstream.

[0085] The patient access subassembly 710 may include a patient access port 712, access tubing 716, and a connector 714. The patient access port 712 may include any suitable element configured to provide access to the patient's vasculature. For example, the patient access subassembly 710 may include a needle, such as a Huber needle. In some embodiments, the patient access subassembly 710 may include a connector configured to couple to a port previously connected to the patient's vasculature. The connector 714 of the patient access subassembly 710 may be coupled to a third valve 770 via the first tubing 702, and the patient access subassembly 710 may be in fluid communication with the third valve 770 via the first fluid pathway. In some embodiments, the patient access subassembly 710 includes the first tubing 702. The connector 714 may be coupled to a second valve 760 via a second fluid pathway including a second tube 704A, a third tube 704B, and a filter 790, and the patient access subassembly 710 may be in fluid communication with the second valve 760 via the second fluid pathway. Thus, the system 700 may function as a closed-loop system in which fluid may flow away from the patient access subassembly 710 via the first tube 702 and return to the patient access subassembly 710 via the second tube 704A, the filter 790, and the third tube 704B. In some embodiments, the patient access subassembly 710 may be a 19G x 0.75 inch or a 19G x 1 inch. In some embodiments, the patient access subassembly 710 may be a BARD EZ Huber SHQ19-75YS or 100YS. In some embodiments, the patient access subassembly 710 may include a needle having a needle length depending on the patient size (e.g., a 1 inch, 1.25 inch, or 1.5 inch needle length).

[0086] Each of the first valve 750, the second valve 760, and the third valve 770 may be configured to transition between two or more configurations, each configuration corresponding to a different available flow path through the assembly 740. Each of the first valve 750, the second valve 760, and the third valve 770 may include any suitable valve mechanism, such as a manual valve mechanism, a solenoid-actuated valve mechanism, a motor-actuated valve mechanism, a drop-pressure valve mechanism, and / or a pneumatic valve mechanism. For example, each of the first valve 750, the second valve 760, and the third valve 770 may include a three-way stopcock. Each of the first valve 750, the second valve 760, and the third valve 770 may define or include an interior region through which fluid may travel. A first syringe 720 may be coupled to a first valve 750, and the first syringe 720 may be in selective fluid communication with the patient access subassembly 710 via a third valve 770 and the first valve 750, with the second syringe 730 via the first valve 750 and the second valve 760, or with the second tubing 704 via the first valve 750 and the second valve 760. For example, the first valve 750 may have a first configuration in which the first valve 750 allows fluid communication between an interior region of the third valve 770 and the first syringe 720, but fluidly isolates the second valve 760 from both the first syringe 720 and the interior region of the third valve 770. The first valve 750 may have a second configuration in which the first valve 750 allows fluid communication between the interior regions of the first syringe 720 and the second valve 760, but fluidly isolates the third valve 770 from both the interior regions of the first syringe 720 and the second valve 760. The first valve 750 may have a third configuration in which the first valve 750 allows fluid communication between the interior regions of the third valve 770 and the second valve 760, but fluidly isolates the first syringe 720 from both the interior regions of the third valve 770 and the second valve 760.

[0087] In some embodiments, second syringe 730 may be coupled to second valve 760, such that second syringe 730 may be in selective fluid communication with first syringe 720 via second valve 760 and first valve 750, and with patient access subassembly 710 via second valve 760. For example, second valve 760 may have a first configuration in which second valve 760 allows fluid communication between an interior region of first valve 750 and second syringe 730, but fluidly isolates second tube 704A from both the interior region of second syringe 730 and first valve 750. The second valve 760 may have a second configuration in which the second valve 760 allows fluid communication between the interior region of the first valve 750 and the second tube 704A, but fluidly isolates the second syringe 730 from both the interior region of the first valve 750 and the second tube 704A.

[0088] A third valve 770 may be coupled to the first valve 750, and the patient access subassembly 710 and the third syringe 780 may each be in selective fluid communication with the first syringe 720 and / or the second tubing 704A via the third valve 770. For example, the third valve 770 may have a first configuration in which the third valve 770 allows fluid communication between the first tubing 702 and the interior region of the first valve 750, but fluidly isolates the third syringe 780 (or a connector configured to be coupled to the third syringe 780) from both the first tubing 702 and the interior region of the first valve 750. The third valve 770 may have a second configuration in which the third valve 770 allows fluid communication between the third syringe 780 and the interior region of the first valve 750, but fluidly isolates the first tube 702 from both the interior region of the first valve 750 and the third syringe 780.

[0089] Thus, assembly 740 may have a first assembly configuration in which patient access subassembly 710 is in fluid communication with first syringe 720 via first tubing 702, a second assembly configuration in which first syringe 720 is in fluid communication with second syringe 730, and a third assembly configuration in which first syringe 720 is in fluid communication with patient access subassembly 710 via second tubing 704A. In the first assembly configuration, first valve 750 may be in its first configuration, third valve 770 may be in its first configuration, and first tubing 702 and first syringe 720 may be in fluid communication between third valve 770 and first valve 750. In the first assembly configuration, the second valve 760 is isolated from the flow path from the patient access subassembly 710 through the first tube 702, the third valve 770, and the first valve 750 to the first syringe 720, so that the second valve 760 can be in either the first or second configuration of the second valve 760.

[0090] In the second assembly configuration, first valve 750 can be in its second configuration, second valve 760 can be in its first configuration, and first reservoir 720 of a first fluid and second syringe 730 are in fluid communication via first valve 750 and second valve 760. Third valve 770 is isolated from the flow path between first syringe 720 and second syringe 730 via first valve 750 and second valve 760, such that third valve 770 can be in either its first or second configuration.

[0091] In the third assembly configuration, the first valve 750 can be in the first valve 750 third configuration, the second valve 760 can be in the second valve 760 second configuration, and the first syringe 720 can be in fluid communication with the second tube 704A. Because the third valve 770 is isolated from the flow path between the first syringe 720 and the second tube 704A via the first valve 750 and the second valve 760, the third valve 770 can be in either the third valve 770 first or second configuration.

[0092] In some embodiments, assembly 740 can have a fourth assembly configuration in which third syringe 780 is in fluid communication with second tube 704A. In the fourth assembly configuration, first valve 750 can be in its third configuration, second valve 760 can be in its second configuration, and third valve 770 can be in its second configuration, with third syringe 780 in fluid communication with second tube 704A (and patient access subassembly 710) via third valve 770, first valve 750, and second valve 760. In the fourth assembly configuration, the flow path from third syringe 780 to second tube 704A can be fluidly isolated from first tube 702, first syringe 720, and second syringe 730.

[0093] In some embodiments, the first syringe 720 may contain (e.g., be pre-filled with) an anticoagulant, such as ACD-A, ACD-B, EDTA, or heparin. For example, the first syringe 720 may contain approximately 1.5 mL of ACD-A anticoagulant. In some embodiments, the first syringe 720 may be pre-filled with both an anticoagulant and an antioxidant (e.g., vitamin C or N-acetylcysteine). In some embodiments, the second syringe 730 may contain (e.g., be pre-filled with) a medication, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, a nitric oxide donor, a chemotherapy drug, and / or ozone. In some embodiments, the third syringe 780 may contain (e.g., be pre-filled with) saline or Ringer's lactate solution. In some embodiments, first syringe 720 may have a volume of 20 mL, and second syringe 730 may have a volume of 10 mL. In some embodiments, second syringe 730 may have a volume less than 10 mL, for example, second syringe 730 may have a volume of 3 mL when used with a smaller amount of medicament (e.g., 0.5-2 mg). In some embodiments, second syringe 730 may be pre-filled with 0.25 mL to 5 mL of medicament, each containing 0.5-4 mg of medicament. In some embodiments, third syringe 780 may have a volume of 60 mL.

[0094] 20 , system 700 may include several selective flow preventers coupled to the tubing of system 700, such that flow through the tubing may be temporarily prevented. For example, a first selective flow preventer 718 may be disposed on access tube 716, a second selective flow preventer 706 may be disposed on first tube 702, and a third selective flow preventer 708 may be disposed on third tube 704B. Each of first selective flow preventer 718, second selective flow preventer 706, and third selective flow preventer 708 may be, for example, a tubing clamp or a roller clamp.

[0095] As shown in FIGS. 21-34, system 700 can be assembled from a kit of separate components. FIGS. 21-23 show various views of the components of system 700 before assembly. Specifically, FIG. 21 shows mixing assembly 707, which is a subassembly of system 700 including assembly 740, first syringe 720, second syringe 730, second tubing 704A, filter 790, and third tubing 704B. As shown, third tubing 704B is coupled to filter 790 at a first end and to coupler 705 at a second end. Additionally, mixing assembly 707 includes connector 782 coupled to third valve 770 of assembly 740. As shown, in the pre-assembly configuration, each valve of assembly 740 can be configured to isolate each valve from its respective connector and / or syringe. Additionally, as described above, each valve of assembly 770 includes a valve lever that extends in the "away" direction of the respective valve, indicating which flow path is closed for that particular valve. Specifically, first valve 750 is configured in the third configuration of first valve 750 (e.g., with the lever of first valve 750 oriented toward first connector 722), whereby first connector 722 and first syringe 720 are fluidically isolated from assembly 740. Second valve 760 is configured in the second configuration of second valve 760 (e.g., with the lever of second valve 760 oriented toward second connector 732), whereby second connector 732 and second syringe 730 are fluidically isolated from assembly 740. The third valve 770 is configured in a first configuration of the third valve 770 (e.g., with the lever of the third valve 770 directed toward the third connector 782), where the third connector 782 is fluidly isolated from the assembly 740. The assembly 740, the second tube 704A, the filter 790, and the third tube 704B can be filled with saline (e.g., 0.9% sodium chloride) prior to delivery to the user (e.g., by a pharmacy). Additionally, the third tube 704B can be pinched closed by a third selective flow preventer 708.In some embodiments, mixing assembly 707 may be packaged (e.g., by a pharmacy) prior to use in a sterile pouch or container separate from the other components of system 700. A user (e.g., a clinician, doctor, or nurse) may unpackage mixing assembly 707 to assemble system 700 for use.

[0096] Additionally, the third syringe 780 may be provided separately from the mixing assembly 707 and may be separate from the connector 782. Additionally, the first fluid reservoir 720 may be pre-filled with a volume of anticoagulant. The second fluid reservoir 730 may be pre-filled with a volume of medication. The third fluid reservoir 780 may be pre-filled with a volume of saline. In some embodiments, the third fluid reservoir 780 may be included in the same sterile pouch or container as the other components of the mixing assembly 707. In some embodiments, the third fluid reservoir 780 may be packaged separately (e.g., in a separate sterile pouch or container).

[0097] As shown in FIG. 22 , the patient access subassembly 710 may also be provided separately from the mixing assembly 707. The patient access subassembly 710 may be provided with an end cap 711 on the end of the first tube 702 opposite the connector 714. Additionally, FIG. 23 shows an access connector 771 that may be provided with other components of the system 700. The access connector 771 may be a needleless connector (also referred to as a needle-free connector) configured to couple to a tubing system or fluid inlet / outlet. The access connector 771 may be the same or similar in structure and / or function to the first connector 732, the second connector 722, and / or the third connector 782. Additionally, the first selective flow preventer 718 and the second selective flow preventer 706 may be in a closed position to prevent flow through the access tube 716 and the first tube 702, respectively. In some embodiments, patient access subassembly 710 may be packaged (e.g., by a pharmacy) in a sterile pouch or container prior to use, separate from other components of system 700. A user (e.g., a clinician, doctor, or nurse) may unpack patient access subassembly 710 to assemble system 700 for use.

[0098] 24, the end cap 711 of the patient access subassembly 710 can be removed and replaced with an access connector 771. The access connector 771 can then be wiped with an alcohol pad, which can be included in a kit with the other components of the system 700.

[0099] 25 , access connector 771 can be coupled to third valve 770 of assembly 740 by, for example, removing the cap on the port of third valve 770 and coupling access connector 771 to the port. Additionally, coupler 705 of third tubing 704B can be coupled to connector 714 by removing the cap on coupler 705, wiping coupler 705 with an alcohol pad, and coupling coupler 705 to connector 714. Patient access subassembly 710 can be positioned in fluid communication with the patient's vasculature via patient access port 712 (e.g., by inserting a needle in patient access port 712 through the patient's skin or by coupling patient access port 712 to an existing port through the patient's skin (e.g., a peripherally inserted central catheter)). In some embodiments, patient access subassembly 710 can be positioned in fluid communication with the patient's vasculature via patient access port 712 prior to coupling patient access subassembly 710 to mixing assembly 707. For example, a user (e.g., a clinician, doctor, or nurse) may connect the patient access port 712 to the patient's vasculature, e.g., via a connector connected to tubing already in place within the patient, and then verify that blood is flowing within the access tubing 716 and the first tubing 702 before connecting the first tubing 702 to the assembly 740 and the connector 714 to the coupler 705 at the end of the third tubing 704B.

[0100] 26 , assembly 740 can be arranged in a first assembly configuration such that patient access subassembly 710 is in fluid communication with first syringe 720 via first tube 702, third valve 770, and first valve 750. For example, first valve 750 can be manipulated or toggled into its first configuration (e.g., a lever of first valve 750 can be rotated such that the interior region of first valve 750 is fluidly isolated from the interior region of second valve 760, and such that syringe 730 is in fluid communication with patient access port 712). First selective flow preventer 718 and second selective flow preventer 706 can then each be transitioned to an open configuration, and fluid can flow through access tube 716 and first tube 702, respectively.

[0101] Blood may then be drawn from the patient through the patient access subassembly 710, the first tubing 702, the third valve 770, the first valve 750, and into the first fluid reservoir 720, where the blood is combined with the anticoagulant in the first syringe 720 to form a first substance. For example, the plunger of the first syringe 720 may be moved relative to the barrel of the first syringe 720, and blood may be drawn into the first syringe 720. In some embodiments, 12 mL of blood may be drawn into the first syringe 720 and combined with the anticoagulant. For example, 12 mL of blood may be combined with 1.5 mL of anticoagulant previously drawn into the first fluid reservoir 720, such that the first fluid reservoir 720 contains 13.5 mL of the first substance. In some embodiments, about 10 mL to about 14 mL of blood can be drawn into the first syringe 720 and combined with an anticoagulant.

[0102] 27, assembly 720 may then be transitioned to a second assembly configuration, with first syringe 720 in fluid communication with second syringe 730. For example, first valve 750 and second valve 760 may be manipulated or toggled such that first valve 750 is in its second configuration and second valve 760 is in its first configuration (e.g., the lever of first valve 750 is oriented toward third valve 730 such that the interior region of the first valve is fluidly isolated from the interior region of third valve 730, and the lever of second valve 720 is oriented toward second tube 704A such that the interior region of second valve 720 is fluidly isolated from second tube 704A). Additionally, first selective flow preventer 718 and second selective flow preventer 706 may each be transitioned to a closed configuration, preventing fluid flow through access tube 716 and first tube 702, respectively.

[0103] 28 , a portion of the first substance may then be transferred from first syringe 720 to second syringe 730, where the portion of the first substance is combined with a medicament in second syringe 730 to form a second substance. For example, the plunger of first syringe 720 may be moved to expel a portion of the first substance from first syringe 720 and push the first substance into second syringe 730. In some embodiments, the plunger of second syringe 730 may be simultaneously moved relative to the barrel of second syringe 730 to assist in drawing the first substance into second syringe 730. In some embodiments, the portion of the transferred first substance may be equal to the volume of medicament in second syringe 730. For example, second syringe 730 may contain 2 mL of a medication (e.g., a 4 mg dose of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, propofol, nitric oxide, and / or ozone) prior to assembly of system 700, and 2 mL of a first substance may be transferred from first syringe 720 to second syringe 730, with second syringe 730 containing 4 mL of a second substance. Further, in some embodiments, the first substance may be transferred from first syringe 720 to second syringe 730 at a flow rate low enough to avoid stress (e.g., shear stress and hemolysis) on red blood cells within the first substance (e.g., stress caused by pushing the plunger of first syringe 720 too forcefully). For example, the first substance may be transferred to the second syringe 730 at a flow rate ranging from about 0.2 mL per second to about 1 mL per second. In some embodiments, the first substance may be transferred to the second syringe 730 at a flow rate of about 0.5 mL per second.

[0104] 29 , while assembly 740 remains in the second assembly configuration, a second substance can be transferred from second syringe 730 to first syringe 720, where the second substance is combined with the remainder of the first substance in first syringe 720 to form a third substance. For example, the plunger of second syringe 730 can be moved to expel the second substance from second syringe 730 and push the second substance through second valve 760 and first valve 750 into first syringe 720. In some embodiments, the plunger of first syringe 720 can be simultaneously moved to assist in drawing the second substance into first syringe 720. Furthermore, in some embodiments, the second substance may be transferred from second syringe 730 to first syringe 720 at a flow rate slow enough to avoid stress on red blood cells within the second substance (e.g., stress caused by pushing the plunger of second syringe 730 too forcefully). For example, the second substance may be transferred to first syringe 720 at a flow rate ranging from about 0.2 mL per second to about 1 mL per second. In some embodiments, the second substance may be transferred to first syringe 720 at a flow rate of about 0.5 mL per second.

[0105] In some embodiments, after transferring the second substance from the second syringe 730 to the first syringe 720 and combining with the remainder of the first substance to form the third substance, the third substance may remain in the first syringe 720 for any suitable waiting period. For example, in some embodiments, the waiting period may be at least about 2 minutes. In some embodiments, the waiting period may be about 2 minutes to about 4 minutes. After the third substance remains in the first syringe 720 for the waiting period, the third substance may be infused into the patient's vasculature, thereby reducing patient discomfort during the infusion (e.g., because nitric oxide in the third substance is absorbed by blood cells during the waiting period). In some embodiments, during the waiting period, the fluid line from the assembly 740 to the patient (e.g., the first tubing 702) may be flushed. For example, a fourth syringe (not shown) containing saline may be fluidly coupled to the third valve 770. The third valve 770 may be transitioned to a third configuration in which the third valve 770 allows fluid communication between the first tube 702 and the fourth syringe, but fluidly isolates the fourth syringe from the interior region of the first valve 750. Saline may then be delivered from the fourth syringe, through the first tube 702, through the access tube 716, and through the patient access port 712 to the patient's vasculature, and blood may be flushed from the flow path. The third valve 770 may then be transitioned to fluidly isolate the fourth syringe and / or the first tube 702 from the first valve 750 (e.g., to a closed position). The fourth syringe may then be removed from the third valve 770.

[0106] 30 , assembly 740 may then be transitioned to a third assembly configuration, with first syringe 720 in fluid communication with patient access subassembly 710 via first valve 750, second valve 760, second tubing 704, filter 790, and third tubing 704B. For example, first valve 750 may remain in the first valve 750 second configuration, and second valve 760 may be manipulated or toggled such that second valve 760 is in the second valve 760 second configuration (e.g., a lever of second valve 760 may be rotated to point toward second syringe 720 such that second syringe 720 is fluidly isolated from the interior region of second valve 760). Additionally, first selective flow preventer 718 and third selective flow preventer 708 may each be transitioned to an open configuration and fluid may flow through access tube 716 and third tube 704B, respectively.

[0107] 31 , the third substance may then be transferred from first syringe 720 to the patient's vasculature via first valve 750, second valve 760, second tubing 704A, filter 790, third tubing 704B, and patient access subassembly 710. In some embodiments, the third substance may be transferred from first syringe 720 to patient access subassembly 710 at a rate slow enough to avoid stress on red blood cells within the third substance. For example, the third substance may be transferred to the patient at a flow rate ranging from about 0.2 mL per second to about 1 mL per second. In some embodiments, the third substance may be transferred to the patient at a flow rate of about 0.5 mL per second.

[0108] As shown in FIG. 32 , after transferring the third substance to the patient's vasculature, the first valve 750 can be rotated so that the lever points toward the first syringe 720, fluidly isolating the first syringe 720 from the interior regions of the second valve 760 and the third valve 770.

[0109] 33, a third syringe 780 may be coupled to a third valve 770 via a third connector 782. The assembly 740 may then be transitioned to a fourth assembly configuration, in which the third syringe 780 is in fluid communication with the patient access subassembly 710 via the third valve 770, the first valve 750, the second valve 760 and the second tubing 704A. For example, when the first valve 750 is in the first valve 750 third configuration and the second valve 760 is in the second valve 760 second configuration, the third valve 770 can be operated or toggled such that the third valve 770 is in the third valve 770 second configuration (e.g., the lever of the third valve 770 is directed toward the first tube 702 such that the first valve 750 and the third syringe 780 are fluidly isolated from the first tube 702).

[0110] 34 , the contents of the third fluid reservoir 780 (i.e., saline) may then be transferred to the patient access subassembly 710 via the third valve 770, the first valve 750, the second valve 760, the second tubing 704A, the filter 790, and the third tubing 704B, causing the saline to flow to the end of the fluid flow path of the third substance. In some embodiments, the contents of the third fluid reservoir 780 may be delivered to the patient access subassembly 710 via the third valve 770, the first valve 750, the second valve 760, the second tubing 704A, the filter 790, and the third tubing 704B at a rate of about 0.5 mL / s. In some embodiments, the first portion of the contents of the third fluid reservoir 780 may be delivered at a rate of 0.5 mL / s, and the remainder of the contents of the third fluid reservoir 780 may be delivered at a rate greater than 0.5 mL / s. For example, the first 10-20 mL of the contents of the third fluid reservoir 780 may be delivered at a rate of 0.5 mL / s, and the remaining contents of the third fluid reservoir 780 may be delivered at a rate greater than 0.5 mL / s. The system 700 may then be removed from the patient.

[0111] In some embodiments, rather than providing portions of system 700 separately, system 700 may be packaged together in an assembled configuration within a sterile pouch or container. Second syringe 730 may be provided separately (e.g., within or separate from the sterile pouch). A practitioner, such as an infusion nurse, may open the sterile pouch at the patient's bedside, fill system 700 with saline, and connect second syringe 730 to assembly 740 (e.g., prior to operation of system 700).

[0112] Although not shown, system 700 (and any of the embodiments described herein) can optionally include a partial deoxygenation device (not shown). For example, in some embodiments, the combination of blood with a pharmaceutical agent, such as 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone or another hemoglobin-binding compound, can promote an increase in autoxidation-generated reactive oxygen species (ROS) that are not completely neutralized by other antioxidants combined with the blood using system 700. Excessively oxidized red cells in the blood can result in premature removal by the reticuloendothelial system (RES) in the body or hemolysis in system 700, both of which are undesirable. Therefore, to avoid these undesirable outcomes, the treated blood (e.g., blood mixed with 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone) can be transferred through a partial deoxygenation device (e.g., into through an inlet of the partial deoxygenation device and out through an outlet of the partial deoxygenation device, which can be the same as or different from the inlet). The partial deoxygenation device may include a bag configured to receive the treated blood. The bag may be coupled to system 700, for example, between valve assembly 740 and connector 714 of patient access subassembly 710, and the blood mixed with the contents of second reservoir 730 may travel through the bag (e.g., pushed into the bag and then squeezed out of the bag and on to the patient) before being infused into the patient. For example, the bag may be coupled between filter 790 and third tubing 704B or between third tubing 704B and patient access subassembly 710. In some embodiments, the bag may be pre-filled with nitrogen.

[0113] In some embodiments, the bag may include an oxygen-impermeable outer layer, an oxygen-permeable inner layer, and an oxygen scrubber. The inner layer may be disposed inside the outer layer and may define a reservoir. The oxygen scrubber may be disposed between the inner and outer layers and may include any suitable material capable of absorbing oxygen (e.g., an oxygen sorbent such as iron powder with or without a catalyst such as palladium). In some embodiments, the bag (e.g., the reservoir defined by the inner layer) may be pre-filled with an analgesic and / or anesthetic prior to use of the system 700 to alleviate patient pain and / or discomfort associated with the injection. Analgesics may include, for example, morphine, oxycodone, fentanyl, sufentanil, pethidine, and / or any other suitable analgesic. Anesthetics may include, for example, ropivacaine, lidocaine, bupivacaine, chloroprocaine, and / or any other suitable anesthetic. In some embodiments, rather than the bag being a partial deoxygenation device, the bag may define a reservoir pre-filled with analgesic and / or anesthetic agents that are mixed with the treated blood prior to reinfusion.

[0114] In some embodiments, each of first valve 750, second valve 760, and third valve 770 may include a visible indicator that shows the intended sequence of actuation of the valves and / or devices associated with the intended operation of system 700. For example, each of first valve 750, second valve 760, and third valve 770 may be formed with or include a different color, or may be labeled with a different number (e.g., 1, 2, 3, etc.) or letter (e.g., A, B, C, etc.).

[0115] In some embodiments, the system can include a leukocyte filter upstream of the valve assembly. For example, Figure 35 is a top view of system 800. System 800 can be similar in structure and / or function to any of the systems described herein, such as system 700. For example, each of the components of system 800 can be the same or similar in structure and / or function to the corresponding component of system 700.

[0116] For example, system 800 includes patient access subassembly 810, first syringe 820, second syringe 830, third syringe 880, and assembly 840. Patient access subassembly 810, first syringe 820, second syringe 830, third syringe 880, and assembly 840 may be the same as or similar in structure and / or function to patient access subassembly 710, first syringe 720, second syringe 730, third syringe 780, and assembly 740. Furthermore, assembly 840 may include first valve 850, second valve 860, and third valve 870. First valve 850, second valve 860, and third valve 870 may be the same as or similar to first valve 750, second valve 760, and third valve 770. The system may also include a first connector 832, a second connector 822, and a third connector 882, which may be the same as and / or similar to first connector 732, second connector 722, and third connector 782. As shown in FIG. 35 , system 800 may also include a first tube 802 having a first tube portion 802A and a second tube portion 802B, a second tube 804A, a third tube 804B, and a filter 890, where second tube 804A is connected to second valve 860 and filter 890, and third tube 804B is connected to patient access subassembly 810 and filter 890.

[0117] As shown in FIG. 35 , leukocyte filter 895 is disposed between first tube portion 802A of first tube 802 and second tube portion 802B of first tube 802. Leukocyte filter 895 can filter white blood cells to prevent damage to red blood cells, which, in some embodiments, serve as carriers for in vivo delivery of medication to a patient after combining the medication with the patient's blood ex vivo. Because white blood cells (also referred to as leukocytes) can synthesize or produce inflammatory molecules, leukocyte filter 895 can be used to remove white blood cells (e.g., leukoreduction) from fluid (e.g., blood) drawn from a patient via patient access subassembly 810 by filtering the white blood cells to reduce potential oxidation and damage to the red blood cells. Leukocyte filter 895 can have any suitable pore size for filtering white blood cells from red blood cells. For example, the pore size of the leukocyte filter 895 may be in the range of 6 to 16 μm. Thus, white blood cells may be filtered from the flow of blood from the patient before being drawn into the first syringe 820, preventing the white blood cells from oxidizing the red blood cells.

[0118] In some embodiments, a fourth valve and a fourth syringe can be included in the mixing assembly. For example, Figure 36 is a top view of system 900. System 900 can be similar in structure and / or function to any of the systems described herein, such as system 700. For example, each of the components of system 900 can be the same or similar in structure and / or function to the corresponding component of system 700.

[0119] For example, system 900 includes a patient access subassembly 910, a first syringe 920, a second syringe 930, a third syringe 980, and assembly 940. Patient access subassembly 910, a first syringe 920, a second syringe 930, a third syringe 980, and assembly 940 may be the same as or similar in structure and / or function to patient access subassembly 710, a first syringe 720, a second syringe 730, a third syringe 780, and assembly 740. Furthermore, assembly 940 may include a first valve 950, a second valve 960, and a third valve 970. The first valve 950, the second valve 960, and the third valve 970 may be the same as or similar to the first valve 750, the second valve 760, and the third valve 770. The system may also include a first connector 932, a second connector 922, and a third connector 982, which may be the same as and / or similar to first connector 732, second connector 722, and third connector 782. As shown in FIG. 35 , the system 900 may also include a first tube 902 having a first tube portion 902A and a second tube portion 902B, a second tube 904A, a third tube 904B, and a filter 990, where the second tube 904A is connected to the patient access subassembly 940 and the filter 990, and the third tube 904B is connected to the patient access subassembly 910 and the filter 990.

[0120] 35, a leukocyte filter 995 may optionally be disposed between the first tube portion 902A of the first tube 902 and the second tube portion 902B of the first tube 902. Thus, white blood cells may be filtered from the flow of blood from the patient before being drawn into the first syringe 920 to prevent the white blood cells from oxidizing the red blood cells.

[0121] Additionally, system 900 may include one or more additional sets of one or more valves, one or more connectors, and / or one or more syringes. As shown in FIG. 36 , assembly 940 includes a fourth valve 998 coupled to a fourth syringe 994 via a fourth connector 996. In some embodiments, fourth syringe 994 may be pre-filled with and / or contain an antioxidant, such as vitamin C or N-acetylcysteine. Although fourth valve 998 is shown coupled between second valve 960 and second tubing 940A, in some embodiments, fourth valve 998 may be positioned in any suitable location relative to the other valves, such as between first valve 950 and second valve 960. The fourth valve 998 and fourth syringe 994 may be configured to draw a portion of the first substance or blood from the first syringe 920 into the fourth syringe 994, combine it with the antioxidant in the fourth syringe 994, and then return the combination to the first syringe 920, similar to that described with respect to the second valve 760 and second syringe 730 above.

[0122] In some embodiments, one or more tubes used in any of the systems described herein may be colored (e.g., green) so that the clot may be more easily visualized by the user. Additionally, in some embodiments, a system such as any of the systems described herein may include a light assembly. In some embodiments, multiple light sources, such as LEDs, may be positioned proximal to or adjacent to the tubes of any of the systems described herein so that the clot may be more easily visualized. For example, multiple light sources may provide green light so that the clot appears black. For example, FIG. 37 is an illustration of a light assembly 1000. The light assembly 1000 may be positioned proximal to a portion of the tubing of any of the systems described herein to aid in visualization of the clot. The light assembly 1000 may project green light from a light source 1028 so that the clot appears black. In some embodiments, the light assembly may include a magnifying glass 1029 to help the user see the contents of a portion of the tubing more closely. Additionally, the light assembly 1000 may include a clip 1027 to allow the light assembly 1000 to be securely attached to an object associated with the infusion system, such as a fluid bag pole.

[0123] In some embodiments, the kit can include a light assembly, such as light assembly 1000 shown and described with respect to Figure 37, and any of the systems disclosed herein. For example, the kit can include light assembly 1000 and system 700 shown and described above.

[0124] In some embodiments, as described above, the system can include a patient access subassembly having a connector configured to couple to a connector of the patient's intravascular tubing. The intravascular tubing can be fluidly connected to the patient's vascular system prior to attachment to the system. For example, the intravascular tubing can be a peripherally inserted central catheter (PICC), and the connector of the intravascular tubing can be any appropriate standard connector. For example, FIG. 38 is a top view of system 1100. System 1100 can be similar in structure and / or function to any of the systems described herein, such as system 700. For example, each of the components of system 1100 can be the same or similar in structure and / or function to the corresponding component of system 700.

[0125] For example, system 1100 includes patient access subassembly 1110, first syringe 1120, second syringe 1130, third syringe (not shown), and assembly 1140. Patient access subassembly 1110, first syringe 1120, second syringe 1130, third syringe, and assembly 1140 may be the same or similar in structure and / or function as patient access subassembly 710, first syringe 720, second syringe 730, third syringe 780, and assembly 740. Additionally, assembly 1140 may include first valve 1150, second valve 1160, and third valve 1170. First valve 1150, second valve 1160, and third valve 1170 can be the same as or similar to first valve 750, second valve 760, and third valve 770. The system can also include a first connector 1132, a second connector 1122, and a third connector 1182, which can be the same as and / or similar to first connector 732, second connector 722, and third connector 782. As shown in FIG. 35 , system 1100 can also include a first tubing 1102, a second tubing 1104A, a third tubing 1104B, and a filter 1190 included in a patient access subassembly 1110, where second tubing 1104A is connected to second valve 1160 and filter 1190 and third tubing 1104B is connected to patient access subassembly 1110 and filter 1190.

[0126] FIG. 38 is a top view of patient access subassembly 1110 of system 1100. As shown, patient access subassembly 1110 may be provided separately from the rest of system 1100. Patient access subassembly 1110 may include a patient access port 1112, access tubing 1116, and a connector 1114. Patient access port 1112 may include a connector configured to connect access tubing 1116 to intravenous tubing (e.g., a PICC line) previously connected to the patient's vasculature. For example, as shown in FIG. 38, patient access port 1112 may be connected to connector 1199 disposed at the end of intravenous tubing 1197, and system 1100 may be in fluid communication with intravenous tubing 1197. The connector 1114 of the patient access subassembly 1110 may be coupled to the third valve 1170 via the first tubing 1102, and the patient access subassembly 1110 may be in fluid communication with the third valve 1170 via a first fluid pathway. The connector 1114 may be coupled to the second valve 1160 via a second fluid pathway including the second tubing 1104A, the third tubing 1104B, and the filter 1190, and the patient access subassembly 1110 may be in fluid communication with the second valve 1160 via the second fluid pathway. Thus, the system 1100 may function as a closed-loop system in which fluid may flow away from the patient access subassembly 1110 via the first tubing 1102 and return to the patient access subassembly 1110 via the second tubing 1104A, the filter 1190, and the third tubing 1104B. The patient access subassembly 1110 may be provided with an end cap 1111 at the end of the first tube 1102 opposite the connector 1114. The system 1100 may include any suitable number of selective flow preventers coupled to the tubing of the system 1100, wherein flow through the tubing may be temporarily prevented. For example, a selective flow preventer 1106 may be disposed on the first tube 1102 as shown in FIG. 39. Each of the selective flow preventers (e.g., selective flow preventer 706) may be, for example, a tubing clamp or a roller clamp.

[0127] In some embodiments, as shown in FIG. 40 , a system such as any of the systems described herein can be prepared for assembly and / or partially assembled at a pharmacy prior to delivery to a user. For example, a user (e.g., a clinician or pharmacist) can open one or more pouches under a laminar flow hood or similar sterile environment. At least some components of a system, such as a mixing assembly, can be distributed among one or more pouches. For example, the mixing assembly can be the same as or similar to mixing assembly 707 described above with respect to FIG. 21 . In some embodiments, a first pouch can include a first tube (e.g., second tube 704A) connected in series to a filter (e.g., filter 790) connected in series to a second tube (e.g., third tube 704B), and a second pouch can include a syringe, a valve manifold assembly (e.g., assembly 740), and / or an injection cap (also referred to as a connector). The components of the mixing assembly can be individually packaged within the second pouch. For example, the second pouch may include a first syringe (e.g., first syringe 720), a second syringe (e.g., second syringe 730), and a third syringe (e.g., third syringe 780). For example, the first syringe may be a 20 mL syringe, the second syringe may be a 10 mL syringe, and the third syringe may be a 60 mL syringe. Each of the syringes may be empty. The connectors may include a first connector (e.g., first connector 722), a second connector (e.g., second connector 732), and a third connector (e.g., third connector 782).

[0128] As shown in 1202, each of the syringes can be prepared by filling them with the appropriate material. The first syringe can be filled with a volume of anticoagulant (e.g., 1.5 mL of ACD-A), such as any of the anticoagulants described herein. The second syringe can be filled with a volume of medication (e.g., 2 mL for a 4 mg dose of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone), such as any of the medications described herein. The third syringe can be filled with saline (e.g., 60 mL of saline). Each of the first, second, and third syringes can then be capped and labeled.

[0129] The first tube may then be coupled to a manifold assembly, as shown at 1204. In some embodiments, one end of the manifold assembly (e.g., the end including a third valve, such as third valve 770) may have a male connector, and the opposite end of the manifold assembly (e.g., the end including a second valve, such as second valve 760) may have a female connector. The free end of the first tube (e.g., the end opposite the end coupled to the filter) may have a male connector, the free end of the first tube being configured to be coupled to the side of the manifold assembly having the female connector.

[0130] Each of the valves of the manifold assembly can be arranged in a configuration that allows fluid to flow through the manifold assembly from a first end to a second end (e.g., a toggle of each of the valves can be oriented away from the syringe port of the valve). The first connector, the second connector, and the third connector can be coupled to each of the first valve, the second valve, and the third valve, respectively.

[0131] As shown at 1206, the mixing assembly can then be primed by flushing the manifold assembly, the first tube, the filter, and the second tube. For example, a saline syringe can be connected to an available end of the manifold assembly (opposite the end of the manifold assembly that is connected to the first tube). In some embodiments, the saline syringe can be a pre-filled fourth syringe. In some embodiments, rather than using a fourth syringe for priming, the first syringe can be primed with saline (e.g., 20 mL of saline) and then used to deliver the saline to the mixing assembly before the anticoagulant is primed. In some embodiments, the syringe used to deliver the primed saline can be connected to the manifold assembly via another appropriate connector.

[0132] After connecting a syringe containing saline to the end of the manifold assembly, the saline can be delivered from the syringe through a fluid line including a chamber of the manifold assembly (e.g., partially defined by the internal chamber of a valve of the manifold assembly), a first tube, a filter, and a second tube, with air being pushed out the open end of the second tube. In some embodiments, a first portion of the saline (e.g., 10 mL) can be pushed through the fluid line, and the filter can then be engaged (e.g., tapped or shaken) to promote the release of any remaining air from the filter. The remainder of the saline (e.g., the remaining 10 mL) can then be delivered through the fluid line (e.g., from the same syringe as the first portion of the saline or from a second saline syringe attached in place of the first saline syringe). Once the filled saline has been delivered, the saline syringe can be separated from the manifold assembly. As shown at 1208, both the open end of the manifold assembly and the open end of the second tube can be sealed (e.g., capped). Additionally, a selective flow preventer (eg, third selective flow preventer 708) may be connected to the second tube and closed.

[0133] The valves of the manifold assembly can be translated (e.g., the lever of each valve can be rotated 180 degrees to point toward the syringe port) so that the syringe ports of the valves are fluidly isolated from each other and from the first tubing. As shown at 1210, a first syringe can be coupled to the first valve and a second syringe can be coupled to the second valve. The syringes can be coupled to the first and second valves, with gradations on the syringes visible to a user during operation of the system (e.g., facing upward toward the patient surface or toward the bottom of the manifold assembly (e.g., the side opposite the side containing the valve levers). As shown at 1212, the mixing assembly (e.g., first syringe, second syringe, manifold assembly, first tubing, filter, and second tubing) can be placed in an assembled configuration within a sterile container (e.g., a bag or pouch). As shown at 1214, the third syringe can be placed in a sterile container separate from the manifold assembly. The mixing assembly can then be delivered as a sterile kit to another user, e.g., a nurse, physician, or clinician, for connection to the patient's vasculature via the patient access subassembly.

[0134] Although not shown, in some embodiments, rather than including a first fluid line from the patient access subassembly to the valve assembly and a separate second fluid line from the valve assembly to the patient access subassembly, the system may include a single fluid line for transport of fluid to and from the valve assembly. In some embodiments, one or more of the syringes may include a filter between the syringe's fluid reservoir and the single fluid line to prevent unwanted particles from the syringe from entering the patient's vasculature. In some embodiments, for example, a system similar to system 700 may be configured such that fluid flows from a patient access subassembly similar to patient access subassembly 710 through a first tube similar to first tube 702. The system may then be configured and used such that after a mixing procedure is performed with a similar mixing assembly (e.g., mixing assembly 740, including first syringe 720 and second syringe 730), the combined blood and medicinal substance may be returned to the patient access subassembly via the first tube. In such systems, filters may be included at the interface of one or more of the syringes with the assembly and / or along the fluid flow path through the first tubing, for example, to filter precipitates from the combined blood and medication material as it is returned to the patient via the patient access subassembly. A syringe containing saline solution may then be coupled to the assembly to flush the flow path, similar to that described for other systems herein.

[0135] In some embodiments, any of the systems described herein can include a timer. For example, the timer can be a standard timer that includes a clip that can grip a portion of the system (e.g., an assembly or tubing line). In some embodiments, the timer can be used to ensure that the process using the system does not exceed a predetermined time threshold (e.g., to reduce the risk of infection). In some embodiments, the predetermined time threshold can be, for example, four hours or less. In some embodiments, the predetermined time threshold can be determined based on standards set by, for example, the American Academy of Blood Banks (AABB). In some embodiments, the timer can be started when blood is drawn from the patient. In some embodiments, the timer can be a countdown timer, where the timer activates an alarm or other indicator at or near the predetermined time threshold. In some embodiments, the timer can be a countup timer, where the user can monitor the time that has elapsed since the mixing and infusion procedure began. In some embodiments, the timer can be integrated into any of the systems described herein, where the timer can control the start or stop of the blood drawing, processing, and infusion process. For example, in some embodiments, a timer may control the opening and / or closing of one or more valves in the system, and after a predetermined time threshold has elapsed since the timer was started (e.g., a valve was opened prior to blood withdrawal or the timer was manually started), the timer will close the one or more valves and stop the infusion.

[0136] In some embodiments, rather than drawing blood from a patient through a patient access subassembly into a first reservoir (e.g., by pulling the plunger of a syringe defining the first reservoir), the patient's blood may be drawn and processed before being drawn into an assembly such as any of the assemblies described herein. For example, the patient's blood may be drawn and processed before being combined with an anticoagulant and / or medication (e.g., before being drawn into the first reservoir in the first syringe). Thus, rather than combining whole blood with an anticoagulant and / or medication, individual cells (e.g., platelets, red blood cells, white blood cells, and / or tumor cells) may be isolated from other components of the patient's blood and combined with an anticoagulant and / or medication. Furthermore, plasmapheresis (i.e., separation of plasma from blood cells) and / or leukapheresis (i.e., separation of white blood cells from other components of a blood sample) may be performed on blood drawn from a patient, and then the resulting plasma or white blood cells, respectively, may be combined with an anticoagulant and / or medication. In some embodiments, the buffy coat (e.g., a concentrated white blood cell suspension) can be separated from the drawn blood and then combined with an anticoagulant and / or medication. For example, a patient's blood can be separated by centrifugation, and only a portion of the patient's blood can be combined with an anticoagulant, combined with medication, and then returned to the patient.

[0137] For example, in some embodiments, blood can be drawn from a patient (e.g., via a syringe and / or via any of the patient access assemblies described herein). The blood can then be separated into component blood portions by any standard technique, such as by centrifugation. One or more components of the blood (e.g., platelets, red blood cells, white blood cells, plasma, and / or tumor cells) can then be drawn into a first syringe of any of the systems described herein (e.g., system 700) and combined with an anticoagulant to form a first substance. For example, the blood components can be transferred from the centrifuge to a fluid bag or syringe and then transferred to the first syringe. The remainder of the mixing and injection procedure can then be performed by any of the methods described herein and / or using any of the systems described herein. For example, a portion of the first substance can then be transferred to a second syringe and combined with a medication in the second syringe to form a second substance. The second substance can then be transferred to the first syringe and combined with the remainder of the first substance to form a third substance. A third substance can then be delivered to the patient. A third syringe can then be used to deliver, for example, saline or Ringer's lactate solution to the patient via the same fluid pathway through which the third substance was delivered.

[0138] In some embodiments, a closed system transfer device (CSTD) can be used in place of any of the connectors described herein. For example, a CSTD can be used in place of any of the needleless connectors described herein. The CSTD can be, for example, a CSTD manufactured by Equashield®, PhaSeal®, Chemoclav®, OnGuard®, or any other suitable CSTD.

[0139] In some embodiments, the system can include a dual-needle syringe. For example, Figure 41 is a schematic illustration of a system 1300. System 1300 includes a syringe 1340 (also referred to herein as a "dual-needle syringe"), a valve 1350, a patient intravenous port 1312 (also referred to herein as a "patient access port"), and a blood filter 1390. Blood filter 1390 can be the same as or similar in structure and / or function to any of the blood filters described herein.

[0140] Syringe 1340 includes a barrel 1341 and a plunger 1343. The barrel 1341 and plunger 1343 define a reservoir. The barrel 1341 may be transparent and may include indicator markings so that the volume of the reservoir can be visually observed by an operator of system 1300. Syringe 1340 also includes a fluid inlet 1345 and a fluid outlet 1346. The fluid inlet 1345 may be connected to a valve 1350 via a first tube 1302. The fluid outlet 1346 may be connected to the valve 1350 via a second tube 1304A, a blood filter 1390, and a third tube 1304B. Fluid inlet 1345 may have any suitable shape and / or may include any suitable connecting component such that first tubing 1302 may be coupled to fluid inlet 1345 and may be in fluid communication with the reservoir of syringe 1340. Fluid outlet 1346 may have any suitable shape and / or may include any suitable connecting component such that second tubing 1304A may be coupled to fluid outlet 1346 and may be in fluid communication with the reservoir of syringe 1340. Valve 1350 may be coupled to patient intravenous port 1312 via fourth tubing 1316. Patient intravenous port 1312 may be coupled to the patient via intravenous tubing 1397. First tube 1302, second tube 1304A, third tube 1304B, fourth tube 1316 and / or intravenous tubing 1397 may be transparent and flexible (eg, standard intravenous tubing).

[0141] Patient intravenous port 1312 may be the same or similar in structure and / or function to any of the patient access ports described herein, such as, for example, patient access port 1112. For example, patient intravenous port 1312 may include a connector configured to fluidly couple fourth tubing 1316 to intravenous tubing 1397. Intravenous tubing 1397 may be coupled to the patient's vasculature system (e.g., the intravenous tubing may be a PICC line) before being coupled to fourth tubing 1316 via patient intravenous port 1312. In some embodiments, intravenous tubing 1397 may include a connector disposed at an end of intravenous tubing 1397, which may be the same or similar in structure and / or function to any of the connectors described herein, such as, for example, connector 1199. Intravenous tubing 1397 may be coupled to patient intravenous port 1312 via a connector.

[0142] The reservoir within barrel 1341 may be pre-filled (e.g., at a pharmacy under sterile conditions). The reservoir may be pre-filled with, for example, a medication and an anticoagulant. The medication may include any of the medications described herein, such as, for example, 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone. The anticoagulant may be any of the anticoagulants described herein, such as, for example, ACD-A. The volume of medication placed within the reservoir of syringe 1340 may be any suitable volume (e.g., 2 mL), such as any of the volumes described herein. The volume of anticoagulant placed within the reservoir of syringe 1340 may be any suitable volume (e.g., 1.5 mL), such as any of the volumes described herein. In some embodiments, the reservoir may additionally or alternatively be pre-filled with any suitable substance described herein.

[0143] Valve 1350 may be, for example, a three-way stopcock. Valve 1350 may be the same or similar in structure and / or function to any of the valves described herein. Valve 1350 may have a first configuration in which first tube 1302 is in fluid communication with fourth tube 1316, and fluid may flow from intravenous tubing 1397, through patient intravenous port 1312, through fourth tube 1316, through valve 1350, through first tube 1302, through fluid inlet 1345, and to the reservoir of syringe 1340. In the first configuration of valve 1350, third tube 1304B may be fluidly isolated from fourth tube 1316 such that fluid flowing from fourth tube 1316, through valve 1350, and into first tube 1302 is not diverted into third tube 1304B. The valve 1350 may have a second configuration in which the third tube 1304B is in fluid communication with the fourth tube 1316 and fluid may flow from the reservoir of the syringe 1340, through the second tube 1304A, through the hemofilter 1390, through the third tube 1304B, through the valve 1350, through the fourth tube 1316, through the patient intravenous port 1312, through the intravenous tubing 1397, and into the patient's vasculature. In the second configuration of the valve 1350, the first tube 1302 may be fluidly isolated from the fourth tube 1316 such that fluid flowing from the third tube 1304B, through the valve 1350, and into the fourth tube 1316 is not diverted back into the first tube 1302. The valve 1350 may have a third configuration in which the first tube 1302 and the third tube 1304B are fluidly isolated from the fourth tube 1316. The valve 1350 may be configured to be transitioned between the first configuration, the second configuration, and the third configuration via manual operation (e.g., via rotation of a lever on the valve 1350).

[0144] To prepare system 1300, the reservoir of syringe 1340 may be filled with a medication and an anticoagulant. Valve 1350 may be positioned in the third configuration such that the medication and anticoagulant are separated from fourth tubing 1316. In use, patient intravenous tubing 1397 may be coupled to the intravenous tubing such that fourth tubing 1316 is in fluid communication with intravenous tubing 1397. Valve 1350 may then be transitioned from the third configuration to the first configuration, with fourth tubing 1316 in fluid communication with first tubing 1302. Plunger 1343 may be withdrawn from fluid inlet 1345 such that blood is withdrawn from the patient's vasculature, through fourth tubing 1316, through valve 1350, through first tubing 1302, through fluid inlet 1345, and into the reservoir of syringe 1340. The blood may combine with the medication and anticoagulant in the reservoir to form a combined substance. The valve 1350 may then be transitioned to a second configuration, and the third tube 1304B may be in fluid communication with the fourth tube 1316. The plunger 1343 may then be pushed into the fluid outlet 1346, and the combined substance may be discharged from the reservoir through the fluid outlet, through the second tube 1304A, through the hemofilter 1390, through the third tube 1304B, through the valve 1350, through the fourth tube 1316, through the patient intravenous port 1312, through the intravenous tubing 1397, and into the patient's vasculature. The fluid flow rate from the reservoir may be the same or similar to the fluid flow rate from any of the reservoirs described herein.

[0145] In some embodiments, rather than including valve 1350, system 1300 may include Y-shaped tubing (e.g., tubing in the shape of a "Y") and any suitable number of clamps. For example, the tubing may include a distal tubing portion, a first proximal tubing portion, and a second proximal tubing portion. The tubing portions may be integrally formed or may be connected via a connector (e.g., a Y-connector). Each of the distal tubing portion, the first proximal tubing portion, and the second proximal tubing portion may be in fluid communication with each other. The first proximal tubing portion may be coupled to a fluid inlet 1345 of syringe 1340, and the second proximal tubing portion may be coupled to a fluid outlet 1346 of syringe 1340. A first clamp may be disposed on the first proximal tubing portion, and a second clamp may be disposed on the second proximal tubing portion. Each of the first clamp and the second clamp may be transitionable between an open and a closed configuration. The first clamp may allow fluid to flow through the first proximal tubing section in an open configuration and may prevent fluid from flowing through the first proximal tubing section in a closed configuration (e.g., by clamping against a sidewall of the closed first proximal tubing section). The second clamp may allow fluid to flow through the second proximal tubing section in an open configuration and may prevent fluid from flowing through the second proximal tubing section in a closed configuration (e.g., by clamping against a sidewall of the closed second proximal tubing section). In some embodiments, the second proximal tubing section may be coupled to fluid outlet 1346 via a blood filter, such as blood filter 1390. In some embodiments, the second proximal tubing section may be coupled to a Y-connector connecting the first proximal tubing section, the distal tubing section, and the second proximal tubing section via a blood filter, such as blood filter 1390. In some embodiments, the blood filter is a 22 micron linear filter.

[0146] In use, a patient's intravenous tubing 1397 may be coupled to the intravenous tubing 1397 with a first clamp closed and a second clamp closed, such that both the fluid inlet 1345 and the fluid outlet 1346 are fluidly isolated from the distal tubing portion and the intravenous tubing 1397. The first clamp may then be opened such that the distal tubing portion is in fluid communication with the fluid inlet 1345 through the first proximal tubing portion. When the second clamp is closed to block the flow path through the second proximal tubing portion, the plunger 1343 may be withdrawn away from the fluid inlet 1345 such that blood is withdrawn from the patient's vasculature, through the intravenous tubing 1397, through the distal tubing portion, through the first proximal tubing portion, and into the reservoir of the syringe 1340. The blood may combine with the medication and anticoagulant in the reservoir to form a combined substance. The first clamp can then be closed and the second clamp can be opened, blocking the flow path through the first proximal tubing section and allowing fluid to flow through the second proximal tubing section. Plunger 1343 can then be pushed into fluid outlet 1346, causing the combined material to be expelled from the reservoir, through fluid outlet 1346, through the second proximal tubing section, through an optional blood filter, through the distal tubing section, through intravenous tubing 1397, and into the patient's vasculature. The fluid flow rate from the reservoir can be the same or similar to the fluid flow rate from any of the reservoirs described herein.

[0147] In some embodiments, rather than using a syringe with an inlet and a separate outlet, the system can include a syringe with openings that can be used as the inlet and outlet. The syringe can be connected to a fluid flow path (e.g., any suitable tubing and connector) configured to be connected to the patient's vasculature via a fluid access port or needle. The fluid flow path can include a filter device having a filter that can be translated (e.g., rotated, slid, shifted, or otherwise moved) in and out of the fluid flow path. In some embodiments, the filter can be a 22-micron linear filter. In some embodiments, the filter can be any of the filters described herein (e.g., a blood filter). The filter device can have a first open end and a second open end. In the first configuration of the filter device, the filter can be positioned so as not to obstruct fluid flow from the first open end to the second open end, and fluid can flow freely through the filter device without migrating through the filter. In the second configuration of the filter device, the filter can be moved to a position where it blocks flow from the first open end to the second open end, and fluid moving through the filter device must pass through the filter. In some embodiments, the filter can be snapped into position in the second configuration (e.g., by applying pressure to the exterior of the filter device to move the filter). The syringe can be pre-filled with an anticoagulant and medication, similar to syringe 1340 described above. In use, with the filter device in the first configuration, the syringe plunger can be pulled to draw blood from the patient, through the filter device, and into the syringe reservoir. Saline can be flushed through the fluid line from the patient to the syringe. After mixing the blood with the anticoagulant and medication to form a combined substance, the filter device can be transitioned to the second configuration. The syringe plunger can then be pushed to force the combined substance back out of the reservoir, through the filter of the filter device, and into the patient's vasculature.

[0148] In some embodiments, rather than being manually operated, the system may be automated or semi-automated. For example, as shown in FIGS. 42 and 43, which are perspective views of system 1400, system 1400 includes a base 1485, a support 1493, and a display screen 1489. Support 1493 extends beyond base 1485. A set of fluid bags may be suspended from support 1493. The set of fluid bags may include a first fluid bag 1420, a second fluid bag 1480, and a third fluid bag 1430. As shown in FIG. 42, in some embodiments, first fluid bag 1420, second fluid bag 1480, and third fluid bag 1430 may be suspended from a set of scales 1493 configured to measure the weight of each of first fluid bag 1420, second fluid bag 1480, and third fluid bag 1430 during operation of system 1400.

[0149] The first fluid bag 1420 may contain an anticoagulant, the second fluid bag 1480 may contain saline, and the third fluid bag 1430 may contain a medication. The anticoagulant may include any suitable anticoagulant, such as any of the anticoagulants described herein (e.g., ACD-A). The medication may include any suitable medication, such as any of the medications described herein.

[0150] The base 1485 may include an air detector 1492A, a clamp 1492B, a cassette / pumping assembly 1487, and a mixing module 1481. Although not shown in FIGS. 42 and 43 , the first fluid bag 1420, the second fluid bag 1480, and the third fluid bag 1430 may each be coupled to the cassette / pumping assembly 1487 via a fluid line (e.g., fluid tubing and connectors). Additionally, the cassette / pumping assembly 1487 may be coupled to the patient's vasculature via a fluid line (e.g., fluid tubing and connectors). The air detector 1492A may be fluidly coupled to a fluid line coupled to the patient's vasculature and configured to monitor the fluid line for air during infusion from the cassette / pumping assembly 1487 through the fluid line. The clamp 1492 may be coupled to the fluid line coupled to the patient's vasculature and configured to transition from an open configuration to a closed configuration. In the open configuration of the clamp 1492, fluid may travel through the fluid line. In the closed configuration of clamp 1492, clamp 1492 can squeeze the fluid line (e.g., the sidewall of the tubing of the fluid line) to prevent flow through the fluid line. In an emergency, for example, clamp 1492 can be transitioned from the open configuration to the closed configuration to fluidly isolate the patient's vasculature from system 1400.

[0151] 44-46 are various schematic illustrations of system 1400 at various stages of operation. As shown in FIG. 44, cassette / pumping assembly 1487 can include first cassette 1487A, second cassette 1487B, and third cassette 1487C. Mixing module 1481 can include fourth fluid bag 1481A. Each of first cassette 1487A, second cassette 1487B, and third cassette 1487C can include a cover (e.g., a clear plastic cover) and a pump tube having a first end and a second end. Each of the first cassette 1487A, the second cassette 1487B, and the third cassette 1487C can be configured to mate with a rotor assembly and a motor, respectively, of the cassette / pumping assembly 1487 to form a peristaltic pump, and fluid flow through the pump tubing of the first cassette 1487A, the second cassette 1487B, and the third cassette 1487C can be controlled by the rotor assembly and motor base, respectively. The system 1400 can include a control assembly including a processor (e.g., a microprocessor) and memory. Each of the motors of the cassette / pumping assembly 1487 can be operated under control of the processor, and the rate of fluid flow through each of the first cassette 1487A, the second cassette 1487B, and the third cassette 1487C can be controlled by operating the respective speeds of the respective motors.

[0152] A first end of the pump tubing of the first cassette 1487A can be configured to be fluidly coupled to the patient's vasculature via a fluid line (e.g., one or more tubing and connectors). For example, the fluid line can include tubing that connects to the patient's existing intravenous port. A second end of the pump tubing of the first cassette 1487A can be configured to be fluidly coupled to the fourth fluid bag 1481A of the mixing module 1481 via one or more tubing and connectors.

[0153] A first end of the pump tubing of the second cassette 1487B can be configured to be fluidly coupled to the first fluid bag 1420 via a fluid line (e.g., a tube having a spike that pierces the first fluid bag 1420). The fluid line can include an antimicrobial filter. A second end of the pump tubing of the second cassette 1487B can be configured to be fluidly coupled to a fluid line from the patient to the first cassette 1487A.

[0154] A first end of the pump tubing of the third cassette 1487C can be configured to be fluidly coupled to the third fluid bag 1430 via a fluid line (e.g., a tube having a spike that pierces the third fluid bag 1430). The fluid line can include an antimicrobial filter. A second end of the pump tubing of the third cassette 1487C can be configured to be fluidly coupled to a flow path from the first cassette 1487A to the fourth fluid bag 1481A.

[0155] As shown in FIG. 44 , after system 1400 is connected to the patient's vasculature (e.g., via connection to an existing port or via a needle connected to the patient's vasculature), cassette / pumping assembly 1487 can actuate first cassette 1487A to withdraw a predetermined volume of whole blood from the patient's vasculature and pump the whole blood into fourth fluid bag 1481A. The whole blood can be withdrawn at a predetermined rate (e.g., a rate selected by the operator). For example, the flow rate of whole blood withdrawn into system 1400 can be from about 20 mL / min to about 100 mL / min. In some embodiments, the flow rate of whole blood during the withdrawal process can be adjusted by the operator of system 1400 during the procedure.

[0156] The cassette / pumping assembly 1487 may actuate the second cassette 1487B to withdraw a predetermined volume of anticoagulant from the first fluid bag 1420 and pump the anticoagulant into a fluid line transporting whole blood by the first cassette 1481A to the fourth fluid bag 1481A. The second cassette 1487B may be actuated by the rotor assembly and motor of the cassette / pumping assembly 1487 to pump the anticoagulant into a fluid line coupled to the first cassette 1487A at a first predetermined flow rate, and the first cassette 1487A may be configured to withdraw a mixture of whole blood and anticoagulant at a second predetermined flow rate, the mixture of whole blood and anticoagulant in the fourth fluid bag 1481A having a predetermined or target ratio of whole blood to anticoagulant (e.g., 10:1). The weight of the first fluid bag 1420 may be monitored by a set of scales on the scale 1493 from which the first fluid bag 1420 is suspended.

[0157] The cassette / pumping assembly 1487 can actuate the third cassette 1487C to withdraw a predetermined volume of medication from the third fluid bag 1430 and add the medication to the whole blood and anticoagulant being transported by the first cassette 1481 A to the fourth fluid bag 1481 A. The weight of the third fluid bag 1480 can be monitored via a scale on a set of scales 1493 from which the third fluid bag 1480 is suspended.

[0158] The mixing module 1481 (shown in FIGS. 42 and 43) can be configured to incubate and / or mix the anticoagulant, whole blood, and medication in the fourth fluid bag 1481A. The mixing module 1481 can be configured to operate for a predetermined amount of time. The mixing can be performed slowly enough so as not to cause hemolysis above a predetermined threshold safety level. As shown in FIG. 45, while mixing the contents of the fourth fluid bag 1481A, the cassette / pumping assembly 1487 can provide saline solution from the second fluid bag 1480 to the patient's vasculature (e.g., to keep the patient's veins open). For example, the line from the second fluid bag 1480 can be loosened so that saline can drip from the second fluid bag 1480 into the patient. The weight of the second fluid bag 1480 can be monitored by a set of scales on a scale 1493 from which the second fluid bag 1480 is suspended.

[0159] 46 , after the contents of the fourth fluid bag 1481A are sufficiently mixed, the cassette / pumping assembly 1487 can actuate the first cassette 1487A to withdraw the contents of the fourth fluid bag 1481A from the fourth fluid bag 1481A and pump the contents at a controlled flow rate into the patient's vasculature. The system 1400 can then be removed from the patient.

[0160] First cassette 1487A, second cassette 1487B, and third cassette 1487C may be disposable and replaceable (e.g., for each patient). Additionally, first fluid bag 1420, second fluid bag 1480, third fluid bag 1430, and fourth fluid bag 1481A may be disposable and replaceable (e.g., for each patient).

[0161] System 1400 (e.g., a control assembly including the processor of system 1400) may be configured to monitor the patient's withdrawal and infusion pressures (also referred to as "return pressures") during the procedure to ensure patient safety and accessibility. If the withdrawal pressure is below a predetermined pressure limit or outside a predetermined pressure range, system 1400 may alert the operator (e.g., via display screen 1489). If the withdrawal pressure is above a predetermined pressure limit or outside a predetermined pressure range, system 1400 may alert the operator (e.g., via display screen 1489). During infusion, air detector 1492A may monitor the infusion line to prevent air from being infused into the patient.

[0162] In some embodiments, display screen 1489 may include a touch screen and / or user input buttons. Display screen 1489 may be configured to allow an operator of system 1400 to control operation (e.g., set or adjust flow rates through first cassette 1487A, second cassette 1487B, and / or third cassette 1487C), gather information on the status and operational state of the system, and address error conditions.

[0163] In some embodiments, system 1400 can be configured to draw approximately 125 mL of whole blood and combine the whole blood with a 50 mg dose of medication (e.g., approximately 25 mL of medication) in fourth fluid bag 1481 A. In some embodiments, system 1400 can be configured to draw a volume of whole blood and combine the whole blood and medication in a 5:1 ratio in fourth fluid bag 1481 A.

[0164] In some embodiments, the method includes withdrawing a fluid (e.g., containing whole blood or cells such as packed red blood cells, white blood cells, or platelets) from a patient's vasculature into a first fluid reservoir. The method can be similar to any of the methods described herein and can be performed, for example, using any of the systems described herein. The fluid can be combined with a first substance in the first fluid reservoir to form a second substance. The first substance can be, for example, an anticoagulant, such as any of the anticoagulants described herein. For example, in some embodiments, the first fluid reservoir can be pre-filled with the first substance. In some embodiments, the first substance can be added to the first fluid reservoir after the fluid has been withdrawn or pumped into the first fluid reservoir. In some embodiments, the second substance can then be combined with a third substance to form a fourth substance. For example, in some embodiments, the second substance can be combined with a third substance in the first fluid reservoir by transferring the third substance to the first fluid reservoir. In some embodiments, rather than transferring the third substance to a first fluid reservoir, the second substance can be transferred to a second fluid reservoir pre-filled with the third substance. For example, the third substance can be a medication, such as any of the medications described herein. The fourth substance can then be transferred to the patient's vasculature (e.g., by injection through a patient access port). In some embodiments, the fourth substance can be retained in a fluid reservoir (e.g., the first fluid reservoir or the second fluid reservoir) for a duration (e.g., at least 2 minutes) before transferring the fourth substance to the patient's vasculature.

[0165] In some embodiments, only a portion of the second substance may be combined with the third substance to form a fourth substance (e.g., by transferring a portion of the second substance to a second fluid reservoir into which the third substance is pre-filled or subsequently introduced). The fourth substance may then be combined with the remainder of the second substance to form a fifth substance (e.g., by combining the fourth substance with the remainder of the second substance in the first, second, or third fluid reservoir). The fifth substance may then be transferred to the patient's vasculature (e.g., by injection through a patient access port). In some embodiments, a portion of the second substance has a first volume, and the fifth substance has a second volume, the second volume being at least about twice the size of the first volume. In some embodiments, the fourth substance may be retained in the fluid reservoir for a duration (e.g., at least 2 minutes) before transferring the fifth substance to the patient's vasculature.

[0166] While various embodiments are described above, it should be understood that the embodiments are presented by way of example only, and not by way of limitation. Where the methods described above depict certain events occurring in a particular order, the order of the certain events may be modified. Furthermore, certain events may be performed simultaneously in a parallel process where possible, or may be performed sequentially as described above.

[0167] While the above-described schematic diagrams and / or embodiments show particular components arranged in a particular orientation or position, the placement of the components may be changed. While the embodiments are specifically shown and described, it will be understood that various changes in form and detail may be made. Any portion of the apparatus and / or methods described herein may be combined in any combination, except mutually exclusive combinations. The embodiments described herein may include various combinations and / or subcombinations of the functions, components, and / or features of the different embodiments described. The present invention includes the following aspects. Item 1 connecting a patient access subassembly to the patient, wherein the patient access subassembly is fluidly connected via the assembly to a first fluid reservoir containing a first substance and a second fluid reservoir containing a second substance; drawing the cells through the patient access subassembly, through the assembly, and into a first fluid reservoir such that the cells and the first substance form a third substance; manipulating the assembly so that the first fluid reservoir is fluidly isolated from the patient access subassembly and so that the first fluid reservoir is in fluid communication with the second fluid reservoir; transferring a portion of the third substance from the first fluid reservoir through the assembly to the second fluid reservoir such that the portion of the third substance and the second substance form a fourth substance; transferring the fourth substance from the second fluid reservoir through the assembly to the first fluid reservoir such that the remainder of the third substance and the fourth substance form a fifth substance; manipulating the assembly so that the first fluid reservoir is in fluid communication with the patient access subassembly; transferring a fifth substance from the first fluid reservoir through the assembly, through the patient access subassembly, and to the patient; fluidly connecting a third fluid reservoir containing a saline solution to the assembly; manipulating the assembly so that the third fluid reservoir is in fluid communication with the patient access subassembly through the assembly; and transferring at least a portion of the saline solution from the assembly to a patient access subassembly; A method comprising: Section 2 Item 10. The method of item 1, wherein the portion of the third material has a first volume, the portion of the fourth material has a second volume, and the second volume is at least about twice the size of the first volume. Section 3 Item 2. The method of item 1, wherein withdrawing the cells from the patient access subassembly withdraws the cells from the patient access subassembly into the assembly via a first flow path, and wherein transferring a fifth substance into the patient access subassembly and into the patient transfers the fifth substance out of the assembly and into the patient access subassembly via a second flow path, wherein the first flow path is different from the second flow path. Section 4 Item 10. The method of item 1, wherein the step of manipulating the assembly includes adjusting the orientation of one or more valves of the assembly. Section 5 Item 1, wherein the first substance comprises an anticoagulant. Section 6 Item 1, wherein the second substance comprises a pharmaceutical agent. Section 7 Item 7. The method of item 6, wherein the pharmaceutical agent comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, or dinitroazetidine. Section 8 Item 7. The method according to item 6, wherein the medicament comprises propofol. Section 9 Item 7. The method of item 6, wherein the medicament comprises a nitric oxide donor. Section 10 Item 7. The method of item 6, wherein the medicament comprises ozone. Section 11 2. The method of paragraph 1, wherein the cells comprise at least one of packed red blood cells, white blood cells, or platelets. Section 12 before transferring the fifth substance from the first fluid reservoir through the assembly and through the patient access subassembly to the patient; Item 14. The method of item 1, further comprising the step of leaving the fifth substance in the first fluid reservoir for a sustained period of time. Section 13 Item 13. The method of item 12, wherein the duration is at least 2 minutes. Item 14 a first assembly including a first fluid reservoir, a second fluid reservoir, a valve assembly, and a first tube, wherein the first fluid reservoir, the second fluid reservoir, and the first tube are fluidly coupled to the valve assembly, and the valve assembly is configured to selectively allow fluid communication between the first fluid reservoir and the second fluid reservoir and between the first fluid reservoir and the first tube; a second assembly including a patient access port fluidly coupled to a second tube, wherein the second tube is configured to be fluidly coupled to the valve assembly of the first assembly via a first flow path including the third tube and via a second flow path through the first tube, and the valve assembly may be in fluid communication with the patient access port via the first tube and via the second tube; and a third fluid reservoir configured to be coupled to the valve assembly, wherein the valve assembly can selectively allow fluid communication between the third fluid reservoir and the first tube; Includes a kit. Section 15 Item 15. The kit of item 14, wherein the valve assembly is connected to the first tube via a filter, the filter configured to filter fluid substances transferred between the first fluid reservoir and the patient access port. Section 16 15. The kit of paragraph 14, wherein the first fluid reservoir comprises an antioxidant. Section 17 Item 17. The kit according to Item 16, wherein the antioxidant comprises at least one of vitamin C or N-acetylcysteine. Section 18 15. The kit of paragraph 14, wherein the first fluid reservoir contains an anticoagulant. Section 19 15. The kit of paragraph 14, wherein the second fluid reservoir contains a medication. Section 20 20. The kit of claim 19, wherein the medicament comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, or dinitroazetidine. Section 21 Item 20. The kit according to Item 19, wherein the medicament comprises propofol. Section 22 20. The kit of paragraph 19, wherein the medicament comprises at least one of nitric oxide or a nitric oxide donor. Section 23 Item 20. The kit according to Item 19, wherein the medicament comprises ozone. Section 24 15. The kit of paragraph 14, wherein the third fluid reservoir contains a saline solution. Section 25 15. The kit of paragraph 14, wherein the third fluid reservoir contains Ringer's lactate solution. Section 26 Item 15. The kit of item 14, further comprising a fourth fluid reservoir configured to be fluidly connected to the valve assembly, wherein the valve assembly can selectively allow fluid communication between the fourth fluid reservoir and the first fluid reservoir. Section 27 Item 15. The kit of paragraph 14, further comprising at least one of a first syringe containing a first fluid reservoir, a second syringe containing a second fluid reservoir, and a third syringe containing a third fluid reservoir. Section 28 Item 15. The kit of item 14, wherein the valve assembly includes a first valve, a second valve, and a third valve, the first fluid reservoir being in selective fluid communication with the second fluid reservoir via the first valve and the second valve, and the first valve being in selective fluid communication with the first tube via the first valve and the second valve. Section 29 Item 29. The kit of item 28, wherein when the third fluid reservoir is connected to the valve assembly, the third fluid reservoir is in selective fluid communication with the first tube via the third valve, the first valve, and the second valve. Section 30 29. The kit of paragraph 28, wherein the third tube is in selective fluid communication with the first fluid reservoir via the third valve and the second valve when the third tube is connected to the valve assembly. Section 31 fluidly coupling a first coupling member of the first subassembly to a valve assembly of a second subassembly, wherein the second subassembly includes a first fluid reservoir and a second fluid reservoir fluidly coupled to the valve subassembly, the first fluid reservoir being selectively fluidly coupled to the second fluid reservoir via the valve assembly, the first subassembly including a patient access port, a first coupling member and a second coupling member, the first coupling member and the second coupling member being in fluid communication with the patient access port, the first coupling member being coupled to the valve assembly, and the first fluid reservoir of the second subassembly being in selective fluid communication with the patient access port via a first flow path; fluidly coupling a second coupling member of the first subassembly to the valve assembly, wherein the first fluid reservoir is in selective fluid communication with the patient access port via a second fluid flow path different from the first fluid flow path; connecting a third fluid reservoir to the valve assembly, wherein the third fluid reservoir is in selective fluid communication with the patient access port via the second fluid path; A method comprising: Section 32 32. The method of paragraph 31, wherein the first fluid reservoir comprises an anticoagulant. Item 33 32. The method of paragraph 31, wherein the second fluid reservoir comprises a medication. Section 34 34. The method of claim 33, wherein the medicament comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, or dinitroazetidine. Section 35 Item 34. The method of item 33, wherein the medicament comprises propofol. Section 36 34. The method of paragraph 33, wherein the medicament comprises nitric oxide. Section 37 34. The method of paragraph 33, wherein the medicament comprises ozone. Section 38 32. The method of paragraph 31, wherein the third fluid reservoir comprises a saline solution. Section 39 32. The method of paragraph 31, wherein the third fluid reservoir contains Ringer's lactate solution. Section 40 patient access subassembly; a first fluid reservoir configured to contain a first fluid substance; a second fluid reservoir configured to contain a second fluid substance; and an assembly having a first configuration in which the patient access subassembly is in fluid communication with a first fluid reservoir via a first tube, a second configuration in which the first fluid reservoir is in fluid communication with a second fluid reservoir, and a third configuration in which the first fluid reservoir is in fluid communication with the patient access subassembly via the second tube, wherein in the third configuration the first fluid reservoir is fluidly isolated from the first tube; 1. An apparatus comprising: Section 41 Item 41. The device of item 40, further comprising a third tube and a filter, the filter being fluidly connected to the assembly via the second tube and fluidly connected to the patient access component via the third tube. Section 42 41. The device of paragraph 40, wherein the first fluid substance comprises an anticoagulant. Section 43 43. The device of paragraph 42, wherein the first fluid substance comprises an antioxidant. Section 44 41. The device of paragraph 40, wherein the second fluid substance is a medicine. Section 45 45. The method of claim 44, wherein the medicament comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, or dinitroazetidine. Section 46 45. The method of paragraph 44, wherein the medicament comprises propofol. Section 47 45. The method of paragraph 44, wherein the medicament comprises nitric oxide. Section 48 45. The method of paragraph 44, wherein the medicament comprises ozone. Section 49 a patient access subassembly configured to provide vascular access to a patient; a first fluid reservoir configured to contain a first fluid substance; a second fluid reservoir configured to contain a second fluid substance; and an assembly including a first valve, a second valve, and a third valve, wherein the first fluid reservoir is in selective fluid communication with the second fluid reservoir via the first valve and the second valve, a patient access subassembly in selective fluid communication with the first fluid reservoir via the first valve, and a third valve configured to be coupled to the third fluid reservoir, the third fluid reservoir in selective fluid communication with the patient access subassembly via the first valve and the second valve; 1. An apparatus comprising: Item 50 1. An apparatus, wherein a first valve has a first position, a second position, and a third position, a second valve has a first position and a second position, and a third valve has a first position and a second position; when the first valve is in the first position and the third valve is in the first position, the first fluid reservoir is in fluid communication with the patient access subassembly via the first fluid path; the first fluid reservoir is in fluid communication with the second fluid reservoir when the first valve is in the second position and the second valve is in the first position; Item 49. The device of item 49, wherein when the first valve is in the second position and the third valve is in the second position, the first fluid reservoir is in fluid communication with the patient access subassembly via the second fluid path. Section 51 Item 51. The device of item 50, wherein the third fluid reservoir is connected to the third valve, and when the third valve is in the second position, the first valve is in the third position, and the second valve is in the second position, the third fluid reservoir is in fluid communication with the patient access subassembly via the second fluid path. Section 52 50. The device of paragraph 49, further comprising a third fluid reservoir. Section 53 50. The device of paragraph 49, further comprising at least one of a first syringe containing a first fluid reservoir, a second syringe containing a second fluid reservoir, and a third syringe containing a third fluid reservoir. Section 54 50. The device of claim 49, wherein the first fluidic substance comprises an anticoagulant and the second fluidic substance comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone or dinitroazetidine, and further comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone or dinitroazetidine. Section 55 50. The device of paragraph 49, wherein the first fluid material comprises an anticoagulant and the second fluid material comprises propofol, further comprising an anticoagulant and propofol. Section 56 50. The device of paragraph 49, wherein the first fluid material comprises an anticoagulant and the second fluid material comprises a nitric oxide donor, further comprising an anticoagulant and a nitric oxide donor. Section 57 50. The device of paragraph 49, wherein the first fluid material comprises an anticoagulant and the second fluid material comprises ozone, further comprising an anticoagulant and ozone.

Claims

1. A device for injecting medicine, comprising: patient access subassembly; a first fluid reservoir containing a first fluid substance; a second fluid reservoir containing a second fluid substance; a base fluidly coupled to the patient access subassembly, the first fluid reservoir, and the second fluid reservoir; 1. An assembly comprising a processor, wherein the processor: receiving blood substances from patients; mixing the blood substance with the first fluid substance to form a third fluid substance; mixing the third fluid material with the second fluid material to form a fourth fluid material; and Transfer the fourth fluid substance to the patient access subassembly and drain it back to the patient. put out adapted to control the base for wherein the device can be configured such that fluid communication is achieved between any of the first fluid reservoir, the second fluid reservoir, and the patient access subassembly.

2. receiving a blood substance from a patient occurs via a first flow path; transferring the fourth fluid substance to the patient access subassembly and discharging it back to the patient via the second flow path; The device of claim 1 , wherein the first flow path is different from the second flow path.

3. 3. The device of claim 1 or 2, wherein the first fluidic substance comprises an anticoagulant.

4. The device of any one of claims 1 to 3, wherein the second fluid substance comprises a medicine.

5. 5. The device of claim 4, wherein the pharmaceutical agent comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, or dinitroazetidine.

6. 5. The device of claim 4, wherein the pharmaceutical agent is selected from the group consisting of propofol, nitric oxide donors, and ozone.

7. The device of any one of claims 1 to 6, wherein the blood material comprises at least one of packed red blood cells, white blood cells, or platelets.

8. patient access subassembly; a first fluid reservoir containing a first fluid substance; a second fluid reservoir containing a second fluid substance; a base fluidly coupled to the patient access subassembly, the first fluid reservoir, and the second fluid reservoir, the base including at least one of a cassette / pumping assembly, an air detector, and a display screen; and 1. An assembly comprising a processor, wherein the processor: receiving blood substances from patients; mixing the blood substance with the first fluid substance to form a third fluid substance; mixing the third fluid material with the second fluid material to form a fourth fluid material; and Transfer the fourth fluid substance to the patient access subassembly and drain it back to the patient. put out adapted to control the base for 10. An apparatus comprising: a first fluid reservoir; a second fluid reservoir; and a patient access subassembly; wherein the apparatus can be configured such that fluid communication is achieved between any of the first fluid reservoir, the second fluid reservoir, and the patient access subassembly.

9. 10. The device of claim 1 or 8, further comprising a filter, the filter fluidly connected to the patient access subassembly via tubing, the filter configured to trap microbubbles and remove debris from the fourth fluidic substance, and then drain the fourth fluidic substance back to the patient.

10. 10. The device of claim 8 or 9, wherein the first fluidic substance comprises an anticoagulant.

11. 10. The device of claim 8 or 9, wherein the first fluid substance comprises an antioxidant.

12. The device according to any one of claims 8 to 11, wherein the second fluid substance is a medicine.

13. 13. The device of claim 12, wherein the pharmaceutical agent comprises at least one of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, a derivative of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone, or dinitroazetidine.

14. 13. The device of claim 12, wherein the pharmaceutical agent is selected from the group consisting of propofol, nitric oxide, and ozone.

15. 10. The device of any one of claims 1, 2, or 4-9, wherein the first fluid substance comprises an antioxidant, and the antioxidant comprises vitamin C or N-acetylcysteine.

16. 16. The device of any preceding claim, wherein the blood substance comprises a volume of 125 mL of blood.

17. The device of any one of claims 1 to 16, wherein the blood substance comprises whole blood.

18. The device according to any one of claims 8 to 17, wherein the device is automated or semi-automated.

19. 11. The device of claim 3 or 10, wherein the anticoagulant is selected from the group consisting of ACD-A, ACD-B, EDTA and heparin.

20. 12. The device of claim 11, wherein the antioxidant comprises vitamin C or N-acetylcysteine.

21. 13. The device of claim 4 or 12, wherein the medication comprises a chemotherapeutic agent.

22. 22. The device of claim 21, wherein the chemotherapeutic agent is selected from the group consisting of an antitumor platinum coordination complex, antimetabolite, a mitotic inhibitor, an anticancer antibiotic, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a proteasome inhibitor, a histone deacetylase inhibitor, a nitrogen mustard alkylating agent, a nitrosourea alkylating agent, a non-classical alkylating agent, an estrogen antagonist, an androgen antagonist, an mTOR inhibitor, and a tyrosine kinase inhibitor.

23. 10. The device of claim 9, wherein the filter comprises a pore size in the range of 150 microns to 260 microns.

24. 24. The apparatus of any one of claims 8 to 23, wherein the base comprises a cassette / pumping assembly, and wherein at least one cassette of the cassette / pumping assembly is disposable and replaceable.

25. 25. The device of claim 24, wherein the cassette / pumping assembly is connected to the patient's vasculature via a fluid line.

26. The cassette / pumping assembly: withdrawing a predetermined amount of blood material from the patient's vasculature at a predetermined rate; The first fluid material is mixed with a mixing vessel adapted to mix the blood material and the first fluid material. drawing the mixture into a mating module to form a third fluid material; and A third fluid material is provided in the second fluid material. and drawing the mixture into a mixing module to form a fourth fluid material.

26. The apparatus of claim 24 or 25, configured to:

27. 27. The device of claim 26, wherein the predetermined rate is in the range of 20 mL / min to 100 mL / min.

28. The device, wherein the base further comprises an air detector, the air detector coupled to the fluid line: transferring a fourth fluid substance to the patient access subassembly; During the expulsion of the fourth fluid substance from the assembly and return to the patient, Monitoring fluid lines; and In response to the detection of air during transfer, an alarm is sent to the display screen. believe The apparatus according to any one of claims 24 to 27, configured to:

29. The assembly processor and controlling the base to transfer the fourth fluid substance to the patient access subassembly and maintain the fourth fluid substance in the first fluid reservoir for a period of time before expelling the fourth fluid substance from the patient access subassembly back to the patient. The apparatus of any one of claims 8 to 28, further configured to:

30. 30. The apparatus of claim 29, wherein the period of time comprises at least 2 minutes.

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