Blood treatment system

Abstract

Systems for collecting, separating, concentrating and modifying blood components from whole blood for reinfusion are provided. A system includes a blood treatment device and a fluid flow circuit.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 63 / 484,636, filed February 13, 2023, the contents of which are incorporated by reference herein. BACKGROUND TECHNICAL FIELD

[0003] The present disclosure relates to blood processing. More particularly, the present disclosure relates to systems and methods for collecting blood components and processing / modifying cells prior to reinfusion to a patient.

[0004] Description of Related Art

[0005] Various blood processing systems make it possible to separate blood into two or more constituent parts, which can be helpful for donation purposes as well as for treatment of individuals with potentially harmful or harmful conditions or diseases.

[0006] When such systems are used for blood component donation, whole blood is typically drawn from a donor, specific blood components or fractions are removed and collected, and the remaining blood components are returned to the donor.

[0007] Such systems can also be used to provide blood components for cell therapy to a patient or individual. For these therapies, typically specific cells or other blood components are separated from whole blood and modified, enriched, and / or expanded prior to returning the collected components to the patient as part of the therapeutic treatment. For example, one such therapy, chimeric antigen receptor (CAR) T-cell therapy, alters a patient’s T-cells and adds artificial receptors to the cells that attach to cancer cell antigens. These modified T-cells are returned to the patient and can help target and destroy specific cancer cells.

[0008] These modified therapeutic cells are typically produced in manufacturing facilities separate from the blood collection sites. This manufacturing process can be lengthy and arduous and results in a considerable interval between the collection of the cells and the reinfusion of the modified or treated cells.

[0009] Therapies such as CAR-T therapy have shown incredible efficacy in the clinic for hematological malignancies, however, many patients lose eligibility for treatment because the vein-to-vein time for administering these autologous gene-modified therapies is too long. Thus, there is a need for rapid manufacturing and reinfusion of therapeutic cells, such as but not limited to, gene-modified autologous cells.

[0010] Accordingly, it would be desirable to provide an integrated system that can collect cells, concentrate cells, modify cells, and prepare cells for reinfusion and / or reinfuse cells. SUMMARY

[0011] There are several aspects of the present subject matter that can be separately or collectively implemented in the devices and systems described and claimed below. These aspects can be used separately or in combination with other aspects of the subject matter described herein, and the description of these aspects is not intended to exclude the separate use of these aspects or the use of such aspects in combination with other aspects than the ones described here, or in combination with the combinations set forth in the attached claims.

[0012] In one aspect, a fluid flow circuit for a blood treatment system includes a separation module, at least one pump, at least one fluid reservoir for containing fluid during blood treatment, a valve system, at least one fluid source container, at least one cell modification module, a blood source access device; and a plurality of conduits fluidically connecting components of the fluid flow circuit. BRIEF DESCRIPTION OF DRAWINGS

[0013] FIG. 1 is a schematic view of an exemplary fluid flow circuit;

[0014] FIG. 2 is a schematic view of a blood treatment device;

[0015] FIG. 3A is a perspective view of an exemplary fluid flow circuit;

[0016] FIG. 3B is a perspective view of an open blood treatment device with a plug-in fluid flow circuit;

[0017] FIG. 3C is a perspective view of a blood treatment system;

[0018] FIG. 4 is a front perspective view of an exemplary fluid flow circuit;

[0019] FIG. 5 is a back perspective view of an exemplary fluid flow circuit;

[0020] FIG. 6 is a schematic view of an exemplary first portion of a disposable fluid flow circuit;

[0021] FIG. 7 is a schematic view of another exemplary first portion of a disposable fluid flow circuit;

[0022] FIG. 8 is a schematic view of an exemplary second portion of a disposable fluid flow circuit;

[0023] FIG. 9 yes FIG. 8 A schematic diagram of the pre-charge step in a single-use fluid flow circuit;

[0024] FIG. 10 yes FIG. 8 A schematic diagram of the first separation step in a single-pass fluid flow circuit;

[0025] FIG. 11 yes FIG. 8 A schematic diagram of the second separation step in a single-pass fluid flow loop;

[0026] FIG. 12 yes FIG. 8 A schematic diagram of the cell concentration step in a single-use fluid flow circuit;

[0027] FIG. 13 yes FIG. 8 A schematic diagram of the first cell preparation step in a disposable fluid flow circuit;

[0028] FIG. 14 yes FIG. 8 A schematic diagram of the second cell preparation step in a disposable fluid flow circuit;

[0029] FIG. 15 yes FIG. 8 A schematic diagram of the gene delivery steps in a single-use fluid flow loop; and

[0030] FIG. 16 yes FIG. 8 A schematic diagram of the cell selection steps in a disposable fluid flow circuit. Detailed Implementation

[0031] The embodiments disclosed herein are for the purpose of providing a description of the subject matter, and it will be understood that the subject matter may be embodied in various other forms and combinations not shown in detail. Therefore, the specific designs and features disclosed herein should not be construed as limiting the subject matter as defined in the appended claims.

[0032] The present disclosure will be more fully understood from the following description taken in conjunction with the accompanying drawings. For the purpose of illustrating other elements more clearly, some of the figures may have been simplified by omitting selected elements. Such simplification of elements in some figures does not necessarily indicate the presence or absence of a particular element in any of the exemplary embodiments unless it can be clearly described in the corresponding written description. The figures are not necessarily to scale.

[0033] The present disclosure includes exemplary embodiments of fluid flow circuits and blood processing devices that can be combined to form an automated blood processing system for collecting, separating, concentrating, and modifying blood cells for reinfusion back to a patient.

[0034] "Blood" includes, but is not limited to, blood and blood components, and "cells" or "biological cells" include, but are not limited to, blood cells such as red blood cells, white blood cells, and t-cells. By "automated" it is meant that the apparatus can be programmed to perform the processing steps of a biological fluid processing method without substantial involvement of an operator. Of course, even in the automated systems of the present disclosure, it will be understood that some operator activity can be involved, including loading of the disposable fluid circuit and inputting of processing parameters. Additional manual steps can also be required. However, the apparatus that can be reused can process blood through a disposable circuit as described below without substantial intervention by an operator.

[0035] As shown in FIG. 1 and FIG. 2 , the blood processing system includes two main components: a durable and reusable blood processing apparatus 20 FIG. 2 and a disposable fluid flow circuit FIG. 1 (collectively referred to herein as element 10). The blood processing apparatus includes components that control and monitor fluid flow through the disposable flow circuit 10 as well as a controller 16 FIG. 3C that controls and / or directs the operation of the other components of the blood processing apparatus 20 to perform a blood processing procedure selected by an operator, as will be described in greater detail.

[0036] The blood processing systems and methods according to the present disclosure are described as using a blood processing apparatus or system and different cell modification modules. However, it will be understood that the principles described herein are not limited to a particular configured apparatus and / or to a particular sequence of steps or stages. Rather, the blood processing systems and methods described herein can be implemented using various different configured blood processing apparatuses and fluid flow circuits that perform the blood processing procedures in different ways.

[0037] As shown in FIG. 2 , FIG. 3B and FIG. 3CAs shown, the blood processing device 20 can be modular and designed with multiple components that work in conjunction with various fluid flow loops 10 to process blood components. The device may include movable or mobile components, such as wheels, for moving the device to or from a patient's bed or chair. The blood processing device may include valves or valve components, an air control system, a pump, detectors, sensors, a controller, a user interface, and any other components that may be used to assist in moving fluid through the fluid flow loops 10.

[0038] The blood processing device 20 may include a valve or motor associated with a valve portion of the fluid flow circuit 10. The valve may be configured to interact with a conduit mounted to the device 20 via the fluid flow circuit 10. By way of example only, the valve may be a solenoid clamp valve, a motor-driven rotary clamp valve, a linear actuator, a stopcock, or any other type of automated clamping or valve device known in the art. In an exemplary embodiment, the blood processing device 20 includes a valve motor compatible with the valve portion on the fluid flow circuit 10.

[0039] The blood processing device 20 may also include an air control system for supplying air to, for example, a pneumatic syringe pump assembly discussed further below. The air control system may include a vacuum and / or pressure source, such as a diaphragm pump. The vacuum or pressure source can pump filtered air into and out of the pump. Examples and other details of components that may be used in the blood processing device 20 are described in U.S. Patent Publications 10,926,895, 11,191,880, 10,781,001, and U.S. Patent Application 17 / 026,156.

[0040] Blood processing device 20 may also include multiple pumps ( FIG. 6 Includes two possible pumps 30, 32) to allow fluid to flow through the fluid flow circuit 10. The pumps may be configured differently or similarly and / or operate similarly or differently from each other. In one embodiment, the pumps are configured as peristaltic pumps, which can typically be configured as described in U.S. Patent No. 5,868,696. Each pump may engage a different line and can be selectively operated under command of the controller 16 to allow fluid to flow through a portion of the fluid flow circuit 10.

[0041] The blood processing device 20 shown may also include FIG. 8An air detector (e.g., an ultrasonic bubble detector), labeled "A" in the schematic diagram of the fluid flow loop 10, houses the conduit through which fluid flows to the receiver. Preventing air from reaching the receiver (whether a human receiver (e.g., the same person used as a blood source) or a non-human receiver (e.g., a storage bag or container)) may be advantageous, thus the air detector can send a signal to controller 16 indicating the presence or absence of air in the conduit. If the signal indicates the presence of air in the conduit, controller 16 can activate an alarm or error condition to alert the operator and / or take corrective action to prevent air from reaching the receiver (e.g., by reversing the flow of fluid through the conduit or redirecting the flow to a vent). The air detector may alternatively or additionally be used as part of the fluid flow control of the fluid flow loop 10.

[0042] The illustrated blood processing device 20 may also include one or more sensors or sensing elements for sensing the condition or characteristics of blood components. For example, in one embodiment, a cell density sensor 78 (e.g., FIG. 8 to FIG. 16 (As shown on the midline L1) to detect absolute or relative changes in cell concentration. Optical devices utilizing methods such as light transmission, scattering, or spectroscopy can be used. Devices utilizing electrical methods such as capacitance are also useful. Even devices using acoustic methods can produce relative density measurements.

[0043] In addition, the plunger position of any of the injection pumps 54, 56, 58, and 60 in the fluid flow circuit 10 (e.g.) FIG. 8 (As shown) can be tracked by sensing elements. Additionally, pressure sensors can be incorporated into the system to monitor pressure at various locations within the fluid flow loop 10. For example, if the blood source is a human donor, one or more pressure sensors (e.g., donor pressure sensor 34) can be used. FIG. 6 The controller 16 can be configured to monitor the pressure of the donor's vein during blood extraction and return. The controller 16 can receive a signal from a pressure sensor indicating the pressure within the fluid flow loop 10, and if the signal indicates a low or high pressure condition, the controller 16 can activate an alarm or error condition to alert the operator and / or attempt to bring the pressure to an acceptable level without operator intervention.

[0044] As described above, the blood processing device 20 includes a controller, such as FIG. 3CThe controller 16 is shown. Although shown in the upper portion of the blood processing apparatus 20, the controller may be incorporated into different parts of the blood processing apparatus. According to the embodiments described herein, the controller may include a programmable microprocessor that can be programmed to operate the blood processing apparatus 20 and system 21 according to processing.

[0045] According to other embodiments, the controller may include one or more circuits designed to perform the actions described herein. Additionally, the controller may include one or more memories. Instructions that program the microprocessor via the controller may be stored on memory / multiple memories associated with the microprocessor, including one or more tangible, non-transitory computer-readable memories having computer-executable instructions stored thereon that, when executed by the microprocessor, cause the microprocessor to perform one or more actions as described below.

[0046] The controller can be coupled to one or more structures of the blood processing device 20, and can also be coupled to a structure of the fluid flow circuit 10. FIG. 8 The controller can control the operation of these structures, for example, by receiving information (e.g., in the form of signals) from these structures or by providing commands (e.g., in the form of signals) to these structures. The controller can be coupled to sensors, valves, and pumps to provide commands to these devices to control their operation. The controller can also receive information from a given structure (e.g., one of the structures already mentioned) and provide commands to that given structure. The controller can be directly electrically connected to these structures to couple to them, or the controller can be directly connected to other intermediate devices directly connected to these structures to couple to them.

[0047] The controller is configured and / or programmed to perform at least one blood processing procedure (e.g. FIG. 9 to FIG. 16 (as shown in the diagram), but more advantageously, the controller is configured and / or programmed to perform various types of blood processing procedures that may include separation and cell modification sections.

[0048] More specifically, during any blood processing procedure, the controller is configured and / or programmed to control the flow and volume of fluid from one component to another. This may include instructing valves to open and close at specific points during the process, or initiating the transfer of fluid from one container to another. Therefore, although this document may describe a specific component of a blood processing system performing a specific function, it should be understood that the component is controlled by the controller to initiate and / or perform that function.

[0049] User interface screen 14 (e.g., touchscreen) can be connected to (e.g., ... FIG. 3CThe user interface screen 14 can enable an operator to interact with a system controller (e.g., microprocessor) of the device 20 to provide instructions to the controller (e.g., to perform a particular process), as well as to provide information to the controller to be used during the process (e.g., a white blood cell (WBC) pre-count of the blood of the blood source). The user interface screen 14 can serve as a display for providing instructions to the operator (e.g., for connecting or disconnecting the blood source with the flow circuit 10) and information (e.g., alerting the operator to a blockage in a fluid flow conduit of the flow circuit 10) and providing a display of the status of the process.

[0050] The blood treatment device 20 can include a computer device that allows the blood treatment device, including the controller 16, to communicate with other blood treatment devices over a local area network, whether via wiring, cable, etc. or wirelessly, or to communicate with other blood treatment devices or other computer devices (e.g., servers) over a local area network, a wide area network, or the Internet. According to such an embodiment, the device can include an internal transmitter / receiver device.

[0051] FIG. 3A to FIG. 3C The steps of inserting and loading the fluid flow circuit 10 into the blood treatment device 20 to create the blood treatment system 21 are shown. The fluid flow circuit 10 FIG. 3A is inserted into the open cabinet FIG. 3B of the blood treatment device, and in a third step FIG. 3C , components are connected as needed before closing the cabinet. The blood treatment system 21, including the blood treatment device 20 and the fluid flow circuit, is a single modular system that is capable of performing an entire blood treatment process without moving to external components or devices.

[0052] As for the fluid flow circuit or flow device 10 (described in detail in FIG. 4 to FIG. 8 ), it is intended to be sterile, single-use, disposable. FIG. 4 and FIG. 5 includes a perspective view of the fluid flow circuit 10, and FIG. 8 is a schematic view of the fluid flow circuit. FIG. 9 to FIG. 16Different stages of an exemplary process are shown. The fluid flow circuit is modular and different customizable configurations of fluid flow circuits can be loaded into the blood treatment device 20. Prior to initiating a given blood treatment and modification process, an operator loads the fluid flow circuit 10 into the blood treatment device 20. The controller 16 implements the process based on a pre-set protocol, while taking into account other inputs from the operator. Upon completion of the process, the operator removes the fluid flow circuit 10 from association with the blood treatment device 20. If any portion of the fluid flow circuit 10 contains a constituent (e.g., a dose), the constituent is removed from the device 20 and retained for storage, infusion, or further processing. The remaining portion of the fluid flow circuit 10 is removed from the blood treatment device 20 and discarded.

[0053] Different fluid flow circuits used in combination with the blood treatment device can vary slightly in components depending on the blood treatment process and the resulting cells performed using the system. Thus, different fluid flow circuits can be used in conjunction with a particular blood treatment process. Generally, the fluid flow circuit 10 can include a pump, reservoirs, valve components, fluid input and output containers, a separation device, a concentration device, and at least one cell modification module, or combinations thereof, as shown in FIG. 1. FIG. 8

[0054] The fluid flow circuit can include two different portions: a first user-adjacent portion (22 or 23, as shown in FIGS. 2 and 3, respectively) and a second treatment portion 25 (as shown in FIG. 4). The user-adjacent portion can be selected based on whether the process is active (reinfusing back to the donor) or passive (collecting a dose for later infusion). FIG. 6 FIG. 7 The fluid flow circuit can include two different portions: a first user-adjacent portion (22 or 23, as shown in FIGS. 2 and 3, respectively) and a second treatment portion 25 (as shown in FIG. 4). The user-adjacent portion can be selected based on whether the process is active (reinfusing back to the donor) or passive (collecting a dose for later infusion). FIG. 8 FIG. 6 A schematic of possible components and active processing is shown. FIG. 7 A schematic of possible components and passive processing is shown.

[0055] Both user-adjacent portions include at least one blood source access device 26 (e.g., a phlebotomy needle) for both drawing blood from a blood source and delivering fluid to the blood source. Optionally, two blood source access devices (e.g., dual needles) can be used, one for drawing blood from the source into the fluid flow circuit 10 and the other for returning fluid to the source. In another embodiment, a blood source (e.g., a previously collected bag) can be attached to the system. Both user-adjacent portions also include a donor isolation clamp 28. A main line LI is also present in both portions, connecting the fluid treatment portion 25 ( FIG. 8 ) to the user-adjacent portions of the fluid flow circuit 10.

[0056] In FIG. 6 ​​​In the active user adjacent portion 22 of the fluid flow circuit 10 shown in FIG. 1, two separate flow lines are connected to the blood source access set 26, a first line L3 is connected to the anticoagulant container 24 and a second line L2 is connected to the reservoir 40. The blood treatment device 20 can include an associated anticoagulant pump 30 and an extraction / return pump 32 for moving fluid to and from the patient.

[0057] FIG. 7 The passive user adjacent portion 23 shown in FIG. 1 need only be connected to the reservoir 40 and optional level sensing element 38, and thus includes only line L1. Anticoagulant can be added to the reservoir 40 prior to treatment.

[0058] The passive or active user adjacent portion can also include a plurality of pumps (two possible pumps 30, 32) that move fluid through the fluid flow circuit 10. The pumps can be configured differently or similarly and / or operate similarly or differently from one another. In an embodiment, the pumps are configured as peristaltic pumps, which can be configured generally as described in U.S. Patent No. 5,868,696. Each pump can engage a different line and can be selectively operated under the command of the controller 16 to move fluid through a portion of the fluid flow circuit 10. FIG. 6

[0059] Turning now to the fluid treatment portion 25, FIG. 8 A possible fluid treatment portion 25 of the fluid flow circuit 10 is shown in FIG. 1. The fluid flow circuit 10 can include a plurality of fluid input containers and fluid output containers. Each container can be integrally formed with the fluid flow circuit 10 or each container can be connected to the fluid flow circuit (e.g., by piercing a septum of a tubing of the fluid flow circuit, via a luer connector, or by a sterile connection using a sterile welding system) prior to the fluid flow circuit being connected to the blood treatment device, thereby forming the blood treatment system 21. The containers can be composed of any desired medical grade material, such as medical grade plastic. The fluid input containers included on the treatment portion 25 of the fluid flow circuit can include at least one buffer container 46 and at least one solution or liquid container 64. The solution or liquid container can be configured to hold a liquid chemical composition for mixing with blood or a blood cell component. FIG. 8 An optional first buffer container 46 and a second buffer container 48 are shown, as well as an optional four solution or liquid containers 64, 66, 68, 70. However, the number of buffer containers and the number and / or presence of solution or liquid containers can vary based on the cell modification process being used.

[0060] ​Output containers can also be integral to the fluid flow circuit 10 or can be connected to the fluid flow circuit 10. These containers are intended to hold different cell fractions, used buffers, prepared suspensions, or to hold samples thereof. These containers can include waste containers 52 or final dose containers 50 as shown in FIG. 8 The dose container 50 can be a removable container that is transferred after the process, in the event that the modified dose is not immediately returned to the patient (and removed from the system).

[0061] The fluid flow circuit can include valves or valve arrays (e.g., V1-V21 as shown in FIG. 8 to FIG. 16 The valves can be stopcocks. These valves interface / collaborate with motors that are part of the blood treatment device hardware. The valves can be used to direct flow between different elements of the fluid flow circuit.

[0062] The fluid flow circuit can also include pumps 54, 56, 58, 60. Although FIG. 8 four pumps are shown in , the fluid flow circuit can use more or fewer pumps. The pumps are preferably pneumatic syringe pump assemblies that interface with the air control system on the blood treatment device 20 hardware. Positive or negative pressure can be applied to displace the syringe plunger. Positive pressure translates to fluid flow out of the pump, and negative pressure translates to fluid flow into the pump. Optionally, there is a sterile filter that is in-line with the cover of the syringe. In embodiments, the pumps can generally be configured as described in U.S. Patent Application No. 2021 / 0121827, which is incorporated by reference herein in its entirety. The plunger position can be tracked by sensing elements on the hardware. The pumps can operate in pressure target mode or flow rate target mode, depending on the control scheme required for that treatment step.

[0063] The fluid flow circuit can include multiple reservoirs 40, 42, 44. The reservoirs are used as passive containers for holding fluid before, during, and after treatment steps. The reservoirs can be vented using sterile filters so that inflow or outflow from the reservoir does not cause the container to pressurize. Although FIG. 8 three reservoirs are shown, more or fewer reservoirs can be included in the fluid flow circuit 10.

[0064] The fluid flow circuit 10 can include a separation module 62 FIG. 8 The microfluidic separation module 62 can be employed to continuously separate microparticles or cells. The microfluidic separation module can include multiple channels for separation by cell properties, such as diameter. For example, a critical diameter of about 7 um can separate nucleated white blood cells from red blood cells and platelets. As FIG. 8The separator module 62 shown in FIG. 6 shows two outputs 62c and 62d. The first output 62d is for cells larger than a specified critical diameter, and the second output 62c is for cells smaller than a specified critical diameter. These separator modules can also be used to shift a target cell population into a new buffer, effectively "washing" the cell suspension. In alternative embodiments, the separator module can include a spin membrane separator or a centrifugal separation chamber used in other blood treatment devices such as those described in more detail in U.S. Patent No. 4,526,515 to DeVries, U.S. Patent No. 5,194,145 to Schoendorfer, U.S. Patent No. 6,312,607 to Brown et al., U.S. Patent No. 6,524,231 to Westberg et al., U.S. Patent No. 4,094,461 to Kellogg et al., U.S. Patent No. 7,052,606 to Gibbs et al., U.S. Patent No. 4,300,717 to Latham, U.S. Patent No. 8,075,468, and U.S. Patent Application Publication No. 2009 / 0215602 to Min et al., all of which are incorporated herein by reference. If a spin membrane separator or centrifugal separator is used, the blood treatment device can include the appropriate hardware components.

[0065] The fluid flow circuit 10 can include a concentrator module, or can employ a microfluidic concentrator module 72 to continuously concentrate microparticles or cells, such as FIG. 8 As shown in FIG. 6, a single input stream at the inlet 72a generates a concentrated output stream at the outlet 72c and a supernatant output stream at the outlet 72b. The concentrator module 72 can operate at a fixed concentration rate (e.g., 10x) per pass through the module. The desired cell concentration can be achieved by performing a series of fixed concentration and dilution steps. In one example, white blood cells can be concentrated 25x. Alternatively, the concentrator module can achieve a variable concentration by passing through the module multiple times and including dilution between passes. As an example, a concentration such as 15x can be achieved by this method.

[0066] The fluid flow circuit 10 can also be configured to interface with or include at least one cell modification module. In one example, these modules can perform cell and / or gene therapy. Thus, the fluid flow circuit 10 can be configured to interface with one or more of a gene delivery module and a cell selection module.

[0067] The gene delivery module 74 can also be as described in FIG. 8A portion of the fluid flow circuit 10 is shown in FIG. 1. This module can be employed to manage intracellular payloads and cell suspensions. The gene delivery module can include an inlet 74a and an outlet 74b. Examples of the module can be an electroporator, a mechanical porator, a sonicator, a lyso- porator, or other flow-through transfection techniques and / or devices that introduce a therapeutic payload.

[0068] The cell selection module 76, for example, an affinity-based cell selection module, can also be as FIG. 8 A portion of the fluid flow circuit 10 is shown in FIG. 1. This module can be employed to manage intracellular payloads and cell suspensions. The gene delivery module can include an inlet 74a and an outlet 74b. Examples of the module can be an electroporator, a mechanical porator, a sonicator, a lyso- porator, or other flow-through transfection techniques and / or devices that introduce a therapeutic payload.

[0069] Alternatively, the fluid flow circuit 10 can utilize existing portions of the fluid flow circuit 10 as a cell modification module, for example, for cell formulation. In these cases, a solution or liquid chemical additive can be added to the blood cells in a reservoir (e.g., 42, 44) or a pump (e.g., 60) or both that are integrated with the fluid flow circuit. The blood cells can be formulated, mixed, or incubated in this reservoir or moved between components of the fluid flow circuit 10.

[0070] As described above, the various components of the fluid flow circuit 10 can be connected by flexible tubing or any other suitable fluid flow conduit. The fluid flow circuit 10 includes lines LI through L32 (shown in detail in FIG. 2), and depending on the desired configuration of the fluid flow circuit 10 and the modules attached, more or fewer lines can be added or subtracted. FIG. 9

[0071] Various additional components can be incorporated into the fluid flow circuit. For example, a return line filter can be associated with a line leading to a fluid recipient, the filter can be positioned upstream of one or more of the fluid containers to remove a substance (e.g., white blood cells) from a separated component (e.g., red blood cells or platelets) flowing into the reservoir.

[0072] Prior to starting a blood processing procedure, if any fluid containers are present that are not integral to the fluid flow circuit 10, the fluid containers can be connected to the fluid flow circuit 10 (e.g., by puncturing a septum of a tubing of the fluid flow circuit 12 or via a luer connector) and then the fluid flow circuit 10 is installed to the blood separation device 20. Additionally, any inlet containers can be filled with the appropriate fluid, such as a buffer or a solution. An integrity check of the fluid flow circuit 10 can be performed by the controller 16 to ensure that the various components are properly connected and functioning. ​

[0073] To begin a blood processing procedure, an operator can select a procedure from among the various procedures that the device 10 is capable of performing (e.g., using the user interface screen 14). The operator can input various information requested by the system controller that enables the controller to better perform the procedure. The controller can be provided with the desired cell modification treatment, the solution used, the type of blood cells being modified, the total blood volume required for the treatment or the source of blood, the WBC pre-count or the initial WBC concentration of the blood of the source of blood, and the WBC post-count or target platelet concentration that the blood of the source of blood is to achieve at the end of the procedure. The total blood volume to be processed can also be provided to the system controller. In addition, various patient measurements, such as height, weight, etc., can also be added.

[0074] When the system controller has received all of the necessary inputs, performed the necessary preliminary calculations and status checks (e.g., to confirm that the flow circuit 10 is properly installed and that the various components of the system 21 are functioning properly), the source of blood is connected to the fluid flow circuit 10 (e.g., by phlebotomizing a donor or attaching a container of whole blood), and the blood processing procedure can begin.

[0075] Blood is introduced into the system through the active or passive user adjacent portions of the fluid flow circuit 10. Blood flows from the donor into the primary line LI and the reservoir 40. During an initial phase, selected components of the fluid flow circuit 10 are primed using blood 41 from the source of blood, particularly as stored in the reservoir 40, referred to herein as the "blood prime" phase and shown in FIG. 9 It is within the scope of the present disclosure to prime the fluid flow circuit 10 using a different priming fluid, such as saline.

[0076] During the blood prime phase, whole blood is drawn from the reservoir via line L2 into the fluid flow circuit 10. The blood travels through LI to the patient adjacent portions of the fluid flow circuit 10. Although not shown in FIG. 10 Other components of the fluid flow circuit, such as components of the treatment portion 25 of the fluid flow circuit 10, can be subjected to a priming process.

[0077] The separation phase can then be initiated. During the separation phase, blood is drawn from the reservoir 40 via line L2 into the fluid flow circuit 10. The blood travels through LI to the patient adjacent portions of the fluid flow circuit 10. The blood is separated into a first component, such as red blood cells, and a second component, such as plasma. The first component is collected in a first container 42, and the second component is collected in a second container 44. The separation phase is shown in FIG. 11In the first step of this stage shown, blood 41 and buffer solution 47 loaded into pump 54 are loaded into pumps 56 and 58. Blood or blood component 41 from reservoir 40 is drawn into or loaded into pump 54 via lines L2, L1, valve V1, and line L4. Buffer solution 47 from container 46 is drawn into pumps 56 and 58. Specifically, the buffer solution flows from container 46 via line L9 and valve V5 to line L10, via valve V4 and line L30 to pump 56, or via line L9 and valve V5 to line L11, via valve V6 and line L31 to pump 58. Buffer solution 47 may also optionally be directed to pump 54. FIG. 12 In the second step of the separation stage shown, pumps 56 and 58 are pressurized to the operating pressure and flow into separator module 62. Pumps 56 and 58 can be arranged sequentially to provide continuous flow. Buffer 47 is pushed from pump 56 or pump 58 through line L12, valve V3, and line L6 into separation module 62b. Pump 54 also pushes blood components 55 into separation module 62 through line L4, valve V1, valve V2, and line L5 into separation module 62a. Cells are separated based on size. Larger cells / particles 43, such as leukocytes, are separated and introduced into reservoir 42 through outlet 62d, through line L8, through valves V8 and V7, to line L13. Smaller cells / particles 53, such as erythrocytes and platelets, are guided to waste container 52 by traveling from outlet 62c through lines L7, line L1, valve V21, and line 29. The separation module can be operated differently depending on the desired separation and the specific cells to be modified.

[0078] Then you can execute FIG. 13 The cell concentration process is shown in the diagram. Large cell material 43 is loaded or drawn from reservoir 42 through line L13, valves V7, V8, and V9 to line L14 and into pump 60. Pump 60 is then pressurized to operating pressure and the large cell material is pushed through line L14 and valve V9 to line L1, and then through valve V15 and line L22 to inlet 72a of concentrator module 72. Concentrator module produces concentrated cells 45 and supernatant 59. Supernatant 59 is directed toward waste container 52 through outlet 72b to line L20, to line L7, through valve 21, and to line L29. Concentrated cells 45 are directed toward reservoir 44 through outlet 72c to line L23, through valve 18, line L1, and valve V19 to line L27. The concentrated cells can then be diluted and optionally reconcentrated by re-absorbing them from reservoir 44 into pump 60 and repeating concentration module 72 until the cells reach the target concentration. Cell concentration can be sensed during concentration or transfer.

[0079] It can also perform cell preparation stages or processes. This can be done on concentrated cells 45 (e.g. FIG. 14 and FIG. 13(As shown) or on isolated cell material, such as large cell material 43. Concentrated cells 45 or large cell material 43 can be processed with at least one solution, buffer, or combination of solution and buffer from reservoirs 42, 44. In the exemplary method, FIG. 14 The first step shown involves drawing the measured volume of solution 65 into pump 60. Solution 65 from container 64 travels through line L15, valves 10, 11, 12, 13, 14 to lines L21 and L1, reaching valve 9 and line L14. FIG. 11 In the second step of the cell preparation stage of the exemplary method shown, solution 65 is pumped toward reservoir 44, which may include concentrated cells 45. Specifically, the solution travels through line L14 and valve v9 to line L1, and through valves v15, v16, v17, v18, and v19 to line L27. The cells bind to the solution and can be incubated into a suspension 67. During the containment or incubation step, the suspension may be pumped back and forth between reservoir 44 and pump 60 to prevent precipitation. In an alternative second step of the cell preparation stage (when added to large cell material 43), solution 65 may alternatively be pumped toward reservoir 42, which is in FIG. 15 The separation stage shown is followed by the containment of large cell material 43. Specifically, the solution travels through line L14 and valve v9 to line L1, and through valves v8 and v7 to line L13. Cells bind to the solution and can be incubated in reservoir 42. During incubation, the suspension can be pumped back and forth between reservoir 42 and pump 60 to prevent precipitation.

[0080] It can also be executed as follows FIG. 13 The gene delivery process is shown in the diagram. Cells 69, prepared with a gene-modified solution, can be guided from pump 60 to gene delivery module 74, where the payload is applied to the cells. FIG. 14 and FIG. 15 The process shown is similar, and cells 69 can be formed by first pulling a genetically modified solution into pump 60 and then pushing the solution into one of reservoirs 42 or 44 containing blood component cells. These cells 69 can be formed from large cell material 43 or cells that have already been modified, such as through a cell concentration or formulation stage. The cells 69 can then be pulled into pump 60. FIG. 13 As shown, the prepared cells travel from pump 60 through line L14 and valve v9 to line L1, through valves v15 and v16 to L25, and through inlet 74a into gene delivery module 74. This module 74 can introduce the payload using electroporation, mechanical perforation, or other flow-through transfection methods. The modified cells 70 exit module 74 at outlet 74b, reaching lines L32 and L23, and through valves v18 and v19 to line L27.

[0081] The gene delivery phase process can also be accomplished without passing through the gene delivery module 74. Rather, the gene solution is simply added to the cell preparation phase (to the large cell material 43) described above. For example, the lipid nanoparticles can be incubated with the cells in order to introduce their payload to them. Alternatively, the cell selection phase process can also occur or be performed. Cells 72 that have been prepared with antibodies, beads, or other solutions that can identify the cells based on surface markers or phenotypes can be passed into the selection chamber 76. The cells 72 can be formed by the large cell material 43 or cells that have been modified such as by the cell concentration phase, the preparation phase, or the gene delivery phase. The cells 72 can then be pulled into the pump 60. As shown in FIG. 14 and FIG. 16 Similar to the process shown in FIG. 6, the cells 72 can first be formed by pulling a cell identification solution into the pump 60 and pushing the solution into one of the reservoirs 42 or 44 that includes blood component cells. These cells 72 can be formed from the large cell material 43 or cells that have been modified such as by the cell concentration phase, the preparation phase, or the gene delivery phase. The cells 72 can then be pulled into the pump 60. As shown in FIG. 8 The cells 72 from the pump 60 pass through line L14, valve v9 to line LI, through valves v15, v16, and v17 to L26, and through inlet 76a into the cell selection module 76. The cells can be positively or negatively separated, and the target cell component can be directed toward the appropriate reservoir or output container.

[0082] While possible cell modification phases have been described, it is not necessary that every phase be performed on the collected blood cells in any given blood processing process, but rather can depend on the final cell composition requirements. The cells can be modified in at least one phase, and can also be modified in all phases or a combination of some of the phases. The phases do not have to be performed in the order specified, and each phase can be performed multiple times. Most importantly, the cells are isolated and modified in the same process and system.

[0083] Once the cells are modified in at least one of the described cell modification modules, the cells can be directed to a dose / sample container 50 Examples ), or alternatively returned to the donor / patient through the fluid flow circuit. If directed to the container 50, the container can be removed from the circuit. By directing the cells through line LI of the processing portion 25 of the fluid flow circuit 10 back to the patient adjacent portion 22 of the fluid flow circuit, the modified cells can be passed back and up to the donor / patient. Various pumps and valves can be used to direct the fluid back to the patient. The patient adjacent portion 22 of the fluid flow circuit can be activated and direct the fluid flow back to the patient.

[0084] There are several factors that can be used to determine whether the cells are collected for a dose or reinfused back to the patient. These factors include guidelines imposed by regulatory agencies such as the FDA, the duration of processing required, and whether patient connection is acceptable during the duration (if the processing takes hours, perhaps the patient does not need to be connected during the duration of the processing), the need for extensive release testing prior to reinfusion, or whether the cells need additional processing (e.g., culturing / amplification, off-line dosing, etc.).

[0085] Aspects

[0086] The following collection and processing workflow can be accomplished using a combination of the previously described states and processes. Using the fluid flow circuit, the system collects a target volume of anticoagulated whole blood from the patient into reservoir 40 based on the target cell peripheral blood count. The anticoagulated whole blood is separated in the separation module and the white blood cells are isolated in reservoir 42. The white blood cells are then passed through the concentration module 72 and concentrated 25-fold, which can include multiple passes through the concentration module. A biotinylated antibody additive is introduced into the system and white blood cells and incubated with the biotinylated antibody in reservoir 44, which is used to label all cells except CD3+ cells. After that, streptavidin-coated magnetic microparticles are introduced to the system and reservoir 44 and the mixture is incubated. The mixture is then transferred to the selection module 76, where the labeled cells are bound in the chamber. The unlabeled, unbound target CD3+ cells are removed from the selection chamber to a reservoir, such as reservoir 42 or 44. The cells are then passed into the concentration module 72 and the isolated CD3+ cells are concentrated 10-fold. A genetic modification solution (e.g., mRNA, CRISPR-Cas9, transposon / transposase) is introduced into the system and into the holding reservoir with the CD3+ cells. The cells are then transferred through the genetic delivery module 74 and to another reservoir. The cells can then be washed using a buffer in the separation module 62. The cells are then passed through the cell concentration module 72 and concentrated to a target reinfusion target. These concentrated cells are then transferred to a dose container or reinfused to the patient.

[0087] Accordingly, an improved method and system for processing blood components has been disclosed. Advantageously, the modular fluid flow circuit described herein includes both cell separation and cell modification components and can produce both isolated and modified cells in a single modular system in one process. The description provided above is meant only to be illustrative and is not meant to limit the scope of the application to any particular method, system or apparatus or device described herein, except as explicitly claimed above.

[0088] ​

[0089] Aspect 1. A fluid flow circuit for a blood processing system, comprising: a separation module; at least one pump; at least one fluid reservoir for containing fluid during blood processing; a valve system; at least one fluid source container; at least one cell modification module; a blood source access device; and a plurality of conduits fluidically connecting components of the fluid flow circuit.

[0090] Aspect 2. The fluid flow circuit of aspect 1, wherein the fluid flow circuit further comprises a concentration module.

[0091] Aspect 3. The fluid flow circuit of any of the preceding claims, wherein the at least one cell modification module comprises a cell selection module.

[0092] Aspect 4. The fluid flow circuit of any of the preceding aspects, wherein the at least one fluid source container is a buffer container.

[0093] Aspect 5. The fluid flow circuit of any of the preceding aspects, wherein the at least one fluid source container is a solution container.

[0094] Aspect 6. The fluid flow circuit of any of the preceding aspects, wherein the separation module is configured to separate blood components based on size.

[0095] Aspect 7. The fluid flow circuit of any of the preceding aspects, wherein the at least one pump comprises a plurality of pneumatic syringe pumps.

[0096] Aspect 8. A blood processing system, comprising: the fluid flow circuit of any of the preceding aspects; and a controller configured and / or programmed to control operation of the fluid flow circuit.

[0097] Aspect 9. The blood processing system of aspect 8, wherein the blood processing system is a modular system.

[0098] Aspect 10. The blood processing system of claim 8, wherein the controller is configured to: operate the at least one pump and the valve system to convey blood from the blood source access device through the fluid flow circuit; perform separation of the blood into two or more cell components using the separation module; and perform modification of at least one cell component of the blood to produce at least one modified cell component using the at least one cell modification module.

[0099] Aspect 11. The blood processing system of aspect 10, wherein the controller is further configured to: operate the at least one pump and the valve system to convey a solution to the at least one cell component.

[0100] Aspect 12. The blood processing system of aspect 10, wherein the controller is configured to operate the at least one pump and valve system to pass the at least one concentrated cellular component through the concentration module.

[0101] Aspect 13. The blood processing system of aspect 10, wherein the controller is configured to perform a modification of at least one cellular component of the blood by operating the at least one pump and valve system to pass the at least one cellular component through the gene delivery module.

[0102] Aspect 14. The blood processing system of aspect 10, wherein the controller is configured to perform a modification of at least one cellular component of the blood by operating the at least one pump and valve system to pass the at least one cellular component through the cell selection module.

[0103] Aspect 15. The blood processing system of aspect 10, wherein the separation module is configured to separate the blood into two or more components based on a size of the two or more components.

[0104] Aspect 16. The blood processing system of aspect 15, wherein the size is a diameter of the cells.

[0105] Aspect 17. The blood processing system of aspect 10, wherein the cellular component comprises at least one of white blood cells, red blood cells, and platelets.

[0106] Aspect 18. The blood processing system of aspect 10, wherein the controller is further configured to operate the at least one pump and valve system to collect the at least one modified cellular component in a container.

[0107] Aspect 19. The blood processing system of aspect 10, wherein the blood from the blood source access device is drawn directly from a patient.

[0108] Aspect 20. The blood processing system of aspect 19, wherein the controller is further configured to operate the at least one pump and valve system to initiate reinfusion of the at least one modified cellular component to the patient.

Claims

1. A fluid flow circuit for a blood treatment system, comprising: a separation module; at least one pump; at least one fluid reservoir for containing fluid during a blood treatment process; a valve system; at least one fluid source container; at least one cell modification module; a blood source access device; and a plurality of conduits fluidly connecting components of the fluid flow circuit. The fluid flow circuit further comprises a concentration module.

2. The fluid flow circuit of claim 1, wherein, The at least one cell modification module comprises a cell selection module.

3. The fluid flow circuit of any of the preceding claims, wherein, The at least one fluid source container is a buffer container.

4. The fluid flow circuit of any of the preceding claims, wherein, The at least one fluid source container is a solution container.

5. The fluid flow circuit of any of the preceding claims, wherein, The separation module is configured to separate blood components based on size.

6. The fluid flow circuit of any of the preceding claims, wherein, The at least one pump comprises a plurality of pneumatic injection pumps.

7. The fluid flow circuit of any of the preceding claims, wherein, 8. A blood treatment system, comprising: a fluid flow circuit according to any one of the preceding claims; and a controller configured and / or programmed to control operation of the fluid flow circuit. The blood treatment system is a modular system. The controller is configured to:

9. The blood treatment system according to claim 8, wherein operate the at least one pump and the valve system to convey blood from the blood source access device through the fluid flow circuit; 10. The blood treatment system according to claim 8, wherein perform separation of the blood into two or more cell components using the separation module; and perform modification of at least one cell component of the blood to produce at least one modified cell component using the at least one cell modification module. The controller is further configured to:

11. The blood treatment system according to claim 10, wherein operate the at least one pump and the valve system to convey a solution to the at least one cell component.

12. The blood treatment system according to claim 10, wherein The controller is configured to:

13. The blood treatment system according to claim 10, wherein operate the at least one pump and the valve system to convey at least one cell component through a concentration module.

14. The blood treatment system according to claim 10, wherein The controller is configured to perform modification of the at least one cell component of the blood by operating the at least one pump and the valve system to convey the at least one cell component through a gene delivery module.

15. The blood treatment system according to claim 10, wherein, The controller is configured to perform modification of the at least one cell component of the blood by operating the at least one pump and the valve system to convey the at least one cell component through a cell selection module.

16. The blood treatment system according to claim 15, wherein The separation module is configured to separate blood into two or more components based on size of the two or more components.

17. The blood treatment system according to claim 10, wherein The size is a diameter of a cell.

18. The blood treatment system according to claim 10, wherein The cell component comprises at least one of white blood cells, red blood cells, and platelets.

19. The blood treatment system according to claim 10, wherein The controller is further configured to:

20. The blood treatment system according to claim 19, wherein operate at least one pump and the valve system to collect the at least one modified cell component in a container. Blood from the blood source access device is drawn directly from a patient. The controller is further configured to: operate the at least one pump and the valve system to initiate reinfusion of the at least one modified cell component to the patient.

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