Blood processing 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

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480012075.3 (22) Application Date 2024.02.12 (30) Priority Data 63 / 484,636 2023.02.13 US (85) PCT International Application Entering National Phase Date 2025.08.11 (86) PCT International Application Application Data PCT / US2024 / 015404 2024.02.12 (87) PCT International Application Publication Data WO2024 / 173257 EN 2024.08.22 (71) Applicant: Fenwo Ltd. Address: USA (72) Inventors: Christopher J. Wegner, James G. Madsen, Alexander Dodge, Kyle Thompson, Alison Hogg (74) Patent Agency: Beijing J&J Intellectual Property Agency Co., Ltd. 11227 Patent Attorney: Cui Junhong (51) Int.Cl. A61M 1 / 02 (2006.01) A61M 1 / 36 (2006.01) A61M 1 / 38 (2006.01) (54) Invention Title: Blood Processing System (57) Abstract: A system is provided for collecting, separating, concentrating, and modifying blood components from whole blood for re-infusion. The system includes a blood processing device and a fluid flow circuit. Claims 2 pages, Description 11 pages, Drawings 14 pages, CN 120916796 A 2025.11.07 CN 1 20 91 67 96 A 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 a blood processing procedure; 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 the components of the fluid flow circuit. 2. The fluid flow circuit of claim 1, wherein the fluid flow circuit further comprises a concentration module. 3. The fluid flow circuit of any preceding claim, wherein the at least one cell modification module comprises a cell selection module. 4. The fluid flow circuit of any preceding claim, wherein the at least one fluid source container is a buffer container. 5. The fluid flow circuit of any preceding claim, wherein the at least one fluid source container is a solution container. 6. The fluid flow circuit of any preceding claim, wherein the separation module is configured to separate blood components based on size. 7. The fluid flow circuit according to any one of the preceding claims, wherein the at least one pump comprises a plurality of pneumatic injection pumps.8. A blood processing system comprising: a fluid flow loop according to any one of the preceding claims; and a controller configured and / or programmed to control the operation of the fluid flow loop. 9. The blood processing system of claim 8, wherein the blood processing system is a modular system. 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 deliver blood from the blood source access device through the fluid flow loop; perform separation of the blood into two or more cellular components using the separation module; and perform modification of at least one cellular component of the blood using the at least one cell modification module to produce at least one modified cellular component. 11. The blood processing system of claim 10, wherein the controller is further configured to: operate the at least one pump and the valve system to deliver a solution to the at least one cellular component. 12. The blood processing system of claim 10, wherein the controller is configured to: operate the at least one pump and the valve system to deliver at least one cellular component through a concentration module. 13. The blood processing system of claim 10, wherein the controller is configured to perform modification of the at least one cellular component of the blood by operating the at least one pump and the valve system to deliver at least one cellular component through the gene delivery module. 14. The blood processing system of claim 10, wherein the controller is configured to perform modification of the at least one cellular component of the blood by operating the at least one pump and the valve system to deliver at least one cellular component through the cell selection module. 15. The blood processing system of claim 10, wherein the separation module is configured to separate the blood into the two or more components based on the size of the two or more components. 16. The blood processing system of claim 15, wherein the size is the diameter of a cell. 17. The blood processing system of claim 10, wherein the cellular component includes at least one of white blood cells, red blood cells, and platelets. 18. The blood processing system of claim 10, wherein the controller is further configured to operate at least one pump and the valve system to collect the at least one modified cellular component in a container. 19. The blood processing system of claim 10, wherein the blood from the blood source access device is drawn directly from the patient.20. The blood processing system of claim 19, wherein the controller is further configured to: operate the at least one pump and the valve system to initiate the reinfusion of the at least one modified cellular component to the patient. Claims 2 / 2 Page 3 CN 120916796 A Blood Processing System

[0001] Cross-Reference to Related Applications

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

[0003] This disclosure relates to blood processing. More specifically, this 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 enable the separation of blood into two or more components, which may be helpful for donation purposes and for the treatment of individuals suffering from potentially harmful or detrimental conditions or diseases.

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

[0007] Such a system can also be used to provide blood components for cell therapy to patients or individuals. For these treatments, it is typical to separate specific cells or other blood components from whole blood and modify, enrich, and / or expand them before returning the collected components to the patient as part of a treatment process. For example, one such therapy, chimeric antigen receptor (CAR) T-cell therapy, alters the patient's T cells and adds artificial receptors to cells attached 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 blood collection sites. This manufacturing process can be lengthy and cumbersome, resulting in a considerable interval between cell collection and the subsequent infusion of modified or treated cells.

[0009] Therapies such as CAR-T therapy have shown incredible efficacy in the clinical treatment of hematologic malignancies; however, many patients are ineligible for treatment due to the excessively long vein-to-vein time required to administer these autologous genetically modified therapies. Therefore, there is a need for the rapid manufacture and re-infusion of therapeutic cells (such as, but not limited to, genetically modified autologous cells).

[0010] Therefore, it is desirable to provide an integrated system capable of collecting, concentrating, modifying, and preparing cells for re-infusion and / or re-infusion of cells. Summary of the Invention

[0011] Several aspects of this subject matter exist, which can be implemented individually or together in the apparatuses and systems described and claimed below.These aspects may be used alone or in combination with other aspects of the subject matter described herein, and the description of these aspects together is not intended to exclude their use alone, or to exclude the claim of such aspects alone or in combinations different from those set forth in the appended claims.

[0012] In one aspect, a fluid flow circuit for a blood processing system includes 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 fluidly connecting the components of the fluid flow circuit. Instruction Manual 1 / 11 Page 4 CN 120916796 A Description of Drawings

[0013] FIG1 is a schematic diagram of an exemplary fluid flow circuit;

[0014] FIG2 is a schematic diagram of a blood processing device;

[0015] FIG3A is a perspective view of an exemplary fluid flow circuit;

[0016] FIG3B is a perspective view of an open blood processing device having an insertable fluid flow circuit;

[0017] FIG3C is a perspective view of a blood processing system;

[0018] FIG4 is a front perspective view of an exemplary fluid flow circuit;

[0019] FIG5 is a rear perspective view of an exemplary fluid flow circuit;

[0020] FIG6 is a schematic diagram of an exemplary first portion of a disposable fluid flow circuit;

[0021] FIG7 is a schematic diagram of another exemplary first portion of a disposable fluid flow circuit;

[0022] FIG8 is a schematic diagram of an exemplary second portion of a disposable fluid flow circuit;

[0023] FIG9 is a schematic diagram of a pre-filling step in the disposable fluid flow circuit of FIG8;

[0024] Figure 10 is a schematic diagram of the first separation step in the disposable fluid flow loop of Figure 8;

[0025] Figure 11 is a schematic diagram of the second separation step in the disposable fluid flow loop of Figure 8;

[0026] Figure 12 is a schematic diagram of the cell concentration step in the disposable fluid flow loop of Figure 8;

[0027] Figure 13 is a schematic diagram of the first cell preparation step in the disposable fluid flow loop of Figure 8;

[0028] Figure 14 is a schematic diagram of the second cell preparation step in the disposable fluid flow loop of Figure 8;

[0029] Figure 15 is a schematic diagram of the gene delivery step in the disposable fluid flow loop of Figure 8; and

[0030] Figure 16 is a schematic diagram of the cell selection step in the disposable fluid flow loop of Figure 8. Detailed Description

[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 figures in the accompanying drawings 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] This 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 re-infusion into a patient.

[0034] “Blood” includes, but is not limited to, blood and blood components, and “cells” or “biological cells” includes, but is not limited to, blood cells, such as red blood cells, white blood cells, and T cells. “Automated” means that the device can be programmed to perform the processing steps of a biological fluid processing method without extensive operator intervention. Of course, even in the automated systems of this disclosure, it will be understood that some operator activities may still be involved, including loading a disposable fluid circuit and inputting processing parameters. Additional manual steps may also be required. However, reusable devices can process blood using disposable circuits as described below without extensive operator intervention.

[0035] As shown in Figures 1 and 2, the blood processing system comprises two main components: a durable and reusable blood processing device 20 (Figure 2) and a disposable fluid flow loop (Figure 1) (collectively referred to herein as element 10). The blood processing device includes components for controlling and monitoring fluid flow through the disposable flow loop 10, and a controller 16 (Figure 3C) that controls and / or directs the operation of other components of the blood processing device 20 to perform a blood processing procedure selected by the operator, as will be described in more detail.

[0036] The blood processing systems and methods according to this disclosure are described using blood processing devices or systems and various cell modification modules. However, it should be understood that the principles described herein are not limited to a particular configuration of the device and / or a particular sequence of steps or stages. Rather, the blood processing systems and methods described herein can be implemented using various different configurations of blood processing devices and fluid flow loops that perform blood processing procedures in different ways.

[0037] As shown in Figures 2, 3B, and 3C, the blood processing device 20 may 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, controllers, a user interface, and any other components that may be used to assist in moving fluid through the fluid flow circuit 10.

[0038] The blood processing device 20 may include a valve or motor associated with the valve portion of the fluid flow circuit 10. The valve may be configured to interact with a conduit mounted to the device 20 of the fluid flow circuit 10. By way of example only, the valve may be an electromagnetic 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 components 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 injection 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 may pump filtered air into and out of the pump. Examples and other details of components that can be used in the blood processing device 20 are described in U.S. Patent Publications Nos. 10,926,895, 11,191,880, 10,781,001, and U.S. Patent Application No. 17 / 026,156.

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

[0041] The illustrated blood processing device 20 may also include an air detector (e.g., an ultrasonic bubble detector) marked "A" in the schematic diagram of the fluid flow loop in FIG8, which houses the conduit of the fluid flow loop 10 that allows fluid to flow to the receiver. Preventing air from reaching the receiver (whether a human receiver (e.g., the same person used as the blood source) or a non-human receiver (e.g., a storage bag or container)) may be advantageous, so the air detector may send a signal to the controller 16 indicating the presence or absence of air in the conduit. If the signal indicates the presence of air in the conduit, the controller 16 may activate an alarm or error condition to warn the operator of the condition 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 apparatus 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., shown on line L1 in Figures 8 to 16) may be used to detect absolute or relative changes in cell concentration. Optical devices utilizing methods such as light transmission, scattering, or spectroscopy may be used. Devices utilizing electrical methods such as capacitance are also useful. Even devices using the acoustic method (page 3 / 11, CN 120916796 A) can produce relative density measurements.

[0043] Furthermore, the plunger position of any of the injection pumps 54, 56, 58, 60 of the fluid flow loop 10 (as shown in Figure 8) can be tracked by sensing elements. Additionally, pressure sensors may 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 (Figure 6)) may 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-pressure or high-pressure condition, the controller 16 can activate an alarm or error condition to warn the operator of the condition 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 the controller 16 shown in FIG. 3C. Although shown in the upper portion of the blood processing device 20, the controller may be incorporated into different parts of the blood processing device. According to the embodiments described herein, the controller may include a programmable microprocessor that can be programmed to operate the blood processing device 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 for programming the microprocessor can be stored on memory associated with the microprocessor, which may include one or more tangible, non-transitory computer-readable storage devices having computer-executable instructions stored thereon, which, when executed by the microprocessor, can cause the microprocessor to perform one or more actions as described below.

[0046] The controller may be coupled to one or more structures of the blood processing device 20 and may also be coupled to the structure of the fluid flow loop 10 (FIG. 8) to control the operation of the structure, 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 may be coupled to sensors, valves, and pumps to provide commands to these devices to control their operation. The controller may also receive information from a given structure (e.g., one of the structures already mentioned) and provide commands to that structure. The controller may be directly electrically connected to these structures to couple to them, or the controller may 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., as shown in Figures 9 through 16), but more advantageously, the controller is configured and / or programmed to perform multiple types of blood processing procedures that may include separation and cell modification sections.

[0048] More specifically, in performing any blood processing procedure, the controller is configured and / or programmed to control the flow and amount 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. Thus, although this document may describe specific components of a blood processing system performing specific functions, 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., a touchscreen) may be associated with blood processing device 20 (as shown in FIG. 3C). User interface screen 14 may enable an operator to interact with the system controller (e.g., a microprocessor) of device 20 to provide instructions to the controller (e.g., to perform a specific process) and to provide the controller with information to be used during the process (e.g., the estimated white blood cell (WBC) count of the blood from the blood source). User interface screen 14 may serve as a display for providing the operator with instructions (e.g., to connect or disconnect the blood source from flow loop 10) and information (e.g., warning the operator of blockages in the fluid flow conduits of flow loop 10) and providing process status.

[0050] The blood processing device 20 may include a computer device that allows the blood processing device, including the controller 16, to communicate with other blood processing devices via a local area network (whether via cabling, cables, etc. or wirelessly), or via a local area network, wide area network, or the Internet. According to such an embodiment, the device may include an internal transmitter / receiver device.

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

[0052] As for the fluid flow loop or flow device 10 (described in detail in Figures 4 to 8), it is intended to be sterile, single-use, disposable. Figures 4 and 5 include perspective views of the fluid flow loop 10, and Figure 8 is a schematic diagram of the fluid flow loop. Figures 9 to 16 illustrate different stages of an exemplary process. The fluid flow loop is modular, and different customizable configurations of the fluid flow loop can be loaded into the blood processing device 20. Before starting a given blood processing and modification process, the operator loads the fluid flow loop 10 into the blood processing device 20. The controller 16 implements the process based on a preset protocol, while taking into account other inputs from the operator. After the process is completed, the operator removes the fluid flow loop 10 from its association with the blood processing device 20. If any portion of the fluid flow loop 10 contains a component (e.g., a dose), that component is removed from the device 20 and retained for storage, infusion, or further processing. The remaining portion of the fluid flow loop 10 is removed from the blood processing device 20 and discarded.

[0053] Different fluid flow loops used in combination with a blood processing device may vary slightly in terms of components, depending on the blood processing procedure and the cells obtained using the system. Thus, different fluid flow loops can be used in combination with a particular blood processing procedure. Generally, the fluid flow loop 10 may include a pump, reservoir, valve components, fluid inlet and outlet containers, separation device, concentration device, and at least one cell modification module or a combination thereof, as shown in FIG8.

[0054] The fluid flow loop may include two distinct portions: a first user-adjacent portion (22 or 23, as shown in FIG6 and FIG7) and a second processing portion 25 (as shown in FIG8). The user-adjacent portion may be selected based on whether the process is active (reinfusion back to the donor) or passive (collecting the dose for later infusion). FIG6 shows a schematic diagram of possible components and active processing. Figure 7 shows a schematic diagram of possible components and passive processing.

[0055] Each of the two user adjacent sections includes at least one blood source access device 26 (e.g., a bleeding needle) for both drawing blood from a blood source and transferring fluid to the blood source. Optionally, two blood source access devices (e.g., a dual needle) may be used, one for drawing blood from the source into the flow loop 10, and the other for returning fluid to the source. In another embodiment, the blood source (e.g., a previously collected bag) may be attached to the system. The two user adjacent sections also include a donor isolation clip 28.The main line L1 is also present in both sections, connecting the fluid processing section 25 (FIG. 8) to the user-adjacent section of the fluid flow loop 10.

[0056] In the active user-adjacent section 22 of the fluid flow loop 10 shown in FIG. 6, two separate flow lines are connected to the blood source access device 26, the first line L3 is connected to the anticoagulant container 24 and the second line L2 is connected to the reservoir 40. The blood processing device 20 may include an associated anticoagulant pump 30 and a draw / return pump 32 for moving fluid to and removing fluid from the patient.

[0057] The passive user-adjacent section 23 shown in FIG. 7 only needs to be connected to the reservoir 40 and an optional level sensing element 38, and therefore only includes line L1. Anticoagulant can be added to the reservoir 40 prior to processing.

[0058] The passive or active user-adjacent section may also include multiple pumps that allow fluid to flow through the fluid flow loop 10 (FIG. 6 includes two possible pumps 30, 32). The pumps may be configured differently or similarly and / or operate similarly or differently from each other. In an embodiment, the pump is configured as a peristaltic pump, which can typically be configured as described in U.S. Patent No. 5,868,696, page 5 / 11, CN 120916796 A. Each pump may engage a different line and may be selectively operated under the command of controller 16 to allow fluid to flow through a portion of the fluid flow circuit 10.

[0059] Turning now to fluid handling portion 25, a possible fluid handling portion 25 of the fluid flow circuit 10 is shown in FIG8. The fluid flow circuit 10 may include a plurality of fluid inlet containers and fluid outlet containers. Each container may be integrally formed with the fluid flow circuit 10, or each container may be connected to the fluid flow circuit (e.g., by piercing a diaphragm of a conduit in the fluid flow circuit, via a Luer connector, or by aseptic connection using a sterile welding system) before the fluid flow circuit is connected to the blood processing device, thereby forming the blood processing system 21. The containers may be composed of any desired medical-grade material, such as medical-grade plastic. The fluid input container included on the processing section 25 of the fluid flow loop may include at least one buffer container 46 and at least one solution or liquid container 64. The solution or liquid container may be configured to contain a liquid chemical composition for mixing with blood or blood cell components. Figure 8 illustrates an optional first buffer container 46 and a second buffer container 48, as well as an optional four solution or liquid containers 64, 66, 68, 70. However, the amount of buffer container and the amount and / or presence of solution or liquid container may vary based on the cell modification process used.

[0060] The output container may also be integrally formed with the fluid flow loop 10, or may be connected to the fluid flow loop 10.These containers are designed to hold different cell fractions, used buffer solutions, prepared suspensions, or their samples. These containers may include waste container 52 or final dose container 50, as also shown in Figure 8. Dose container 50 may be a removable container that is transferred after the process if the modified dose is not immediately returned to the patient (and removed from the system).

[0061] The fluid flow circuit may include valves or valve arrays (V1 to V21 as shown in Figures 8 to 16). Valves may be stopcocks. These valves cooperate / interface with motors that are part of the blood processing device hardware. Valves may be used to guide flow between different elements of the fluid flow circuit.

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

[0063] The fluid flow loop may include multiple reservoirs 40, 42, 44. The reservoirs are used as passive containers for containing fluid before, during, and after the processing step. The reservoirs may be vented using sterile filters so that inflow or outflow from the reservoir does not cause pressurization of the container. Although FIG8 shows a fluid flow loop with three reservoirs, fluid flow loop 10 may include more or fewer reservoirs.

[0064] Fluid flow loop 10 may include a separation module 62 (FIG. 8). The microfluidic separation module 62 may be used to continuously separate particles or cells. The microfluidic separation module may include multiple channels for separation according to cell characteristics (e.g., diameter). For example, a critical diameter of approximately 7 μm can separate nucleated leukocytes from erythrocytes and platelets. The separator module 62 shown in Figure 8 illustrates two outputs, 62c and 62d. The first output 62d is used for cells larger than the specified critical diameter, and the second output 62c is used for cells smaller than the specified critical diameter. These separator modules can also be used to transfer target cell populations to new buffer solutions, effectively “washing” the cell suspension.In alternative embodiments, the separator module may include a rotary membrane separator or centrifuge chamber used in other blood processing devices, such as those described in more detail in, for example, 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. (page 6 / 11, CN 120916796 A), 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 to Latham, and U.S. Patent Application Publication No. 2009 / 0215602 to Min et al., all of which are incorporated herein by reference. If a rotating membrane separator or centrifuge is used, the blood processing apparatus may include suitable hardware components.

[0065] The fluid flow loop 10 may include a concentrator module, or may employ a microfluidic concentrator module 72 to continuously concentrate microparticles or cells, as shown in FIG8, generating a concentrated output stream at outlet 72c and a supernatant output stream at outlet 72b from a single input stream at inlet 72a. The concentrator module 72 may operate at a fixed concentration rate (e.g., 10-fold) each time it passes through the module. The desired cell concentration can be achieved by performing a series of fixed concentration and dilution steps. In one example, leukocytes may be concentrated 25-fold. Alternatively, the concentrator module may achieve variable concentrations by passing through the module multiple times and including dilution between passes. As an example, concentrations such as 15-fold may be achieved by this method.

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

[0067] The gene delivery module 74 can also be part of the fluid flow loop 10 shown in FIG8. This module can be used to manage intracellular payloads and cell suspensions. The gene delivery module may include an inlet 74a and an outlet 74b. Examples of the module may be an electroporator, a mechanical porator, an acoustic porator, a dissolution porator, or other flow-through transfection techniques and / or devices for introducing therapeutic payloads.

[0068] The cell selection module 76, for example, an affinity-based cell selection module, can also be part of the fluid flow loop 10 shown in FIG8.A cell selection module 76 can be used to phenotypically isolate a target cell population from a bulk cell suspension. The cell selection module 76 may include an inlet 76a, which may also serve as an outlet. Techniques such as magnetic beads, affinity chromatography, or filtration can be implemented using positive or negative selection methods.

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

[0070] As described above, the various components of the fluid flow loop 10 may be connected via flexible tubing or any other suitable fluid flow conduit. The fluid flow circuit 10 includes lines L1 to L32 (shown in detail in FIG8), and more or fewer lines can be added or removed depending on the desired configuration of the fluid flow circuit 10 and the attached modules.

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

[0072] Before starting the blood processing procedure, if any fluid containers are not integrally formed with the fluid flow circuit 10, they can be connected to the fluid flow circuit 10 (e.g., by piercing the diaphragm of the conduit 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 container can be filled with a suitable fluid, such as a buffer or 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 operating.

[0073] To begin the blood processing procedure, the operator can select a procedure from among the various procedures that the device 10 can perform (e.g., using the user interface screen 14 on page 10 of the specification 7 / 11, CN 120916796 A). The operator can input various information requested by the system controller to enable the controller to better perform the procedure. The controller may be provided with the desired cell modification treatment, the solution used, the type of blood cells to be modified, the total blood volume required for processing or the blood source, the expected WBC count or the initial WBC concentration of the blood source, and the post-WBC count or target platelet concentration to be achieved in the blood source at the end of the procedure. The total blood volume to be processed may also be provided to the system controller. In addition, various patient measurements, such as height, weight, etc., may be added.

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

[0075] Blood is introduced into the system through the active or passive user-adjacent portion of the fluid flow loop 10. Blood flows from the donor into the main line L1 and the reservoir 40. In the initial phase, selected components of the fluid flow loop 10 are pre-charged using blood 41 from the blood source (particularly stored in the reservoir 40), referred to herein as the “blood pre-charging” phase and shown in FIG. 9. Pre-charging the fluid flow loop 10 using different pre-charging fluids, such as saline, is also within the scope of this disclosure.

[0076] During the blood pre-charging phase, whole blood is drawn from the reservoir into the fluid flow loop 10 via line L2. The blood travels through L1 to the patient-adjacent portion of the fluid flow loop 10. Although not shown in Figure 9, other components of the fluid flow circuit, such as the components of the processing section 25 of the fluid flow circuit 10, can be pre-charged.

[0077] The separation stage can then be initiated. In the first step of this stage shown in Figure 10, blood 41 and buffer solution 47 loaded to 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 is drawn 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. In the second step of the separation stage shown in Figure 11, 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 to waste container 52. The separation module can be executed differently depending on the desired separation and the specific cells to be modified.

[0078] The cell concentration process shown in FIG12 can then be performed. Large cell material 43 is loaded or drawn from the reservoir 42 through line L13, valves V7, V8 and V9 to line L14 into the pump 60. The pump 60 is then pressurized to the 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 the inlet 72a of the concentrator module 72. The concentrator module produces concentrated cells 45 and supernatant 59. The supernatant 59 is directed toward the waste container 52 through outlet 72b to line L20, to line L7, through valve 21 and to line L29. The concentrated cells 45 are directed toward the 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 then optionally reconcentrated by drawing them back into pump 60 from reservoir 44 and repeating concentration module 72 until the cells reach the target concentration. Cell concentration can be sensed during the concentration or transfer state.

[0079] A cell preparation stage or process can also be performed. This can be done on concentrated cells 45 (as shown in Figures 13 and 14) or on isolated cell material such as large cell material 43. Concentrated cells 45 or large cell material 43 can be treated with at least one solution, buffer, or combination of solution and buffer from reservoirs 42, 44. In an exemplary method, the first step shown in Figure 13 includes drawing a 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 to reach valve 9 and line L14. In the second step of the cell preparation stage of the exemplary method shown in Figure 14, 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 contains large cell material 43 after the separation stage shown in Figure 11. Specifically, the solution travels through line L14 and valve v9 to line L1, and through valves v8 and v7 to line L13. The cells bind to the solution and can be incubated in reservoir 42. During incubation, the suspension can be pumped back and forth between the reservoir 42 and the pump 60 to prevent precipitation.

[0080] The gene delivery stage process shown in Figure 15 can also be performed.Cells 69, prepared with a gene-modified solution, can be guided from pump 60 to gene delivery module 74, where a payload is applied to the cells. Similar to the processes shown in Figures 13 and 14, cells 69 can be formed by first pulling the gene-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 been modified, for example, through a cell concentration or preparation stage. The cells 69 can then be pulled into pump 60. As shown in Figure 15, the prepared cells travel from pump 60 through line L14, valve v9 to line L1, through valves v15 and v16 to L25, and through inlet 74a into gene delivery module 74. Module 74 can utilize electroporation, mechanical perforation, or other flow-through transfection methods to introduce the payload. The modified cells 70 exit module 74 at outlet 74b to reach lines L32 and L23, and through valves v18 and v19 to reach line L27.

[0081] The gene delivery stage process can also be completed without passing through gene delivery module 74. Instead, a gene solution is simply added to the cell formulation stage (to the large cell material 43) described above. For example, lipid nanoparticles can be incubated with the cells to introduce their payload. Alternatively, a cell selection stage process can also occur or be performed. Cells 72, which have been formulated with antibodies, beads, or other solutions that can identify cells based on surface markers or phenotypes, can be transferred to selection chamber 76. Similar to the processes shown in Figures 13 and 14, cells 72 can be formed first by pulling a cell labeling solution into pump 60 and pushing the solution into one of reservoirs 42 or 44 containing blood component cells. These cells 72 can be formed from the large cell material 43 or cells that have been modified, such as through a cell concentration stage, formulation stage, or gene delivery stage. Cells 72 can then be drawn into pump 60. As shown in FIG16, cells 72 travel from pump 60 through line L14, valve v9 to line L1, through valves v15, v16 and v17 to L26, and enter cell selection module 76 through inlet 76a. Cells can be positively or negatively separated, and the target cell component can be directed toward the appropriate reservoir or output container.

[0082] Although possible cell modification stages have been described, it is not necessary to perform every stage on the collected blood cells in any given blood processing procedure, but may depend on the final cell composition requirements. Cells may be modified in at least one stage, and may also be modified in all stages or a combination of some of the stages. The stages do not have to be performed in a specified order, and each stage may be performed multiple times. Most importantly, cells are separated and modified in the same process and system.

[0083] Once cells have been modified in at least one of the described cell modification modules, these cells can be directed to the dose / sample container 50 (FIG. 8) or optionally returned to the donor / patient via a fluid flow loop. If directed to container 50, the container can be removed from the loop. Modified cells can be transferred back to and until the donor / patient by directing the cells back through line L1 of section 25 of the fluid flow loop 10 to the patient-adjacent portion 22. Various pumps and valves can be used to direct fluid back to the patient. The patient-adjacent portion 22 of the fluid flow loop can be activated and direct fluid flow back to the patient.

[0084] Several factors exist that can be used to determine whether cells are collected in dose order or re-infused back to the patient. These factors include guidelines imposed by regulatory agencies (such as the FDA), the required duration of treatment, and whether patient connectivity is acceptable during the duration (if treatment takes several hours, the patient may not need connectivity during the duration of treatment), the need for extensive release testing prior to re-infusion, or whether the cells require additional treatment (e.g., culture / expansion, offline administration, etc.).

[0085] Example

[0086] The following collection and processing workflow can be accomplished using a combination of the states and processes described previously. Using a fluid flow loop, the system collects a target volume of anticoagulated whole blood from the patient into reservoir 40 based on the projected number of target cells in peripheral blood. The anticoagulated whole blood is separated in a separation module, and leukocytes are isolated in reservoir 42. The leukocytes are then passed through a concentration module 72 and concentrated 25-fold, which may include multiple passes through the concentration module. A biotinylated antibody additive is introduced into the system and the leukocytes and incubated in reservoir 44 with a biotinylated antibody used to label all cells except CD3+ cells. Next, streptavidin-coated magnetic microparticles are introduced into the system and reservoir 44, and the mixture is incubated. The mixture is then transferred to selection module 76, where labeled cells bind in a chamber. Unlabeled, unbound target CD3+ cells are removed from the selection chamber and transferred to a reservoir, such as reservoir 42 or 44. The cells are then passed to concentration module 72, where the isolated CD3+ cells are concentrated 10-fold. Gene modification solutions (e.g., mRNA, CRISPR-Cas9, transposons / transposases) are introduced into the system and into a storage bank containing CD3+ cells. The cells are then transferred through gene delivery module 74 and transferred to another reservoir. These cells can then be washed with buffer in separation module 62. The cells are then passed through cell concentration module 72 and concentrated to the target for re-infusion. These concentrated cells are then transferred to a dosing container or re-infused to the patient.

[0087] Therefore, improved methods and systems for processing blood components have been disclosed. Advantageously, the modular fluid flow loop described herein includes cell separation and cell modification components, and can produce separated and modified cells in a single modular system in one process. The description provided above is intended for illustrative purposes only and is not intended to limit the scope of the invention to any particular method, system, or device or apparatus described herein, except as expressly described above.

[0088] Aspects

[0089] Aspect 1. A fluid flow loop 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 fluidly connecting the components of the fluid flow loop.

[0090] Aspect 2. The fluid flow loop according to aspect 1, wherein the fluid flow loop further comprises a concentration module.

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

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

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

[0094] Aspect 6. The fluid flow circuit according to 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 according to any of the preceding aspects, wherein at least one pump comprises a plurality of pneumatic injection pumps.

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

[0097] Aspect 9. The blood processing system according to 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 at least one pump and valve system to deliver blood from a blood source access device through a fluid flow loop; use a separation module to perform separation of blood into two or more cellular components; and use at least one cell modification module to perform modification of at least one cellular component of the blood to produce at least one modified cellular component.

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

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

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

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

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

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

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

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

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

[0108] Aspect 20. The blood processing system according to aspect 19, wherein the controller is further configured to operate at least one pump and valve system to initiate the re-infusion of at least one modified cellular component to the patient.Instruction Manual 11 / 11 Page 14 CN 120916796 A Figure 1 Figure 2 Instruction Manual Figure 1 / 14 Page 15 CN 120916796 A Figure 3A Figure 3B Figure 3C Instruction Manual Figure 2 / 14 Page 16 CN 120916796 A Figure 4 Figure 5 Instruction Manual Figure 3 / 14 Page 17 CN 120916796 A Figure 6 Instruction Manual Figure 4 / 14 Page 18 CN 120916796 A Figure 7 Instruction Manual Figure 5 / 14 Page 19 CN 120916796 A Figure 8 Instruction Manual Figure 6 / 14 Page 20 CN 120916796 A Figure 9 Instruction Manual Figure 7 / 14 Page 21 CN 120916796 A Figure 10 Instruction Manual Figure 8 / 14 Page 22 CN 120916796 A Figure 11 Instruction Manual Figure 9 / 14 Page 23 CN 120916796 A Figure 12 Instruction Manual Appendix 10 / 14 Page 24 CN 120916796 A Figure 13 Instruction Manual Appendix 11 / 14 Page 25 CN 120916796 A Figure 14 Instruction Manual Appendix 12 / 14 Page 26 CN 120916796 A Figure 15 Instruction Manual Appendix 13 / 14 Page 27 CN 120916796 A Figure 16 Instruction Manual Appendix 14 / 14 Page 28 CN 120916796 A.

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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