Modular biological cell processing system

Abstract

A system for collecting, sorting and concentrating blood components from whole blood for reinfusion is provided. The system may also include cell modification. 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 202480012078.7 (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 / 015424 2024.02.12 (87) PCT International Application Publication Data WO2024 / 173262 EN 2024.08.22 (71) Applicant: Fenwo Ltd. Address: USA (72) Inventors: Christopher J. Wegner, James G. Madsen, Kyle Thompson, Alexander Dodge, Page Boswell (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: Modular Biological Cell Processing System (57) Abstract: A system is provided for collecting, sorting, and concentrating blood components from whole blood for re-infusion. The system may also include cell modifications. The system includes a blood processing device and a fluid flow loop. Claims 2 pages, Description 15 pages, Drawings 21 pages, CN 120936392 A 2025.11.11 CN 1 20 93 63 92 A 1. A fluid flow loop for a blood processing system, comprising: a microfluidic sorter module; a cell concentrator 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; a blood source access device; and a plurality of conduits fluidly connecting the components of the fluid flow loop. 2. The fluid flow loop of claim 1, wherein the fluid flow loop further comprises at least one cell modification module. 3. The fluid flow loop of claim 2, wherein the at least one cell modification module comprises a cell selection module. 4. The fluid flow loop of any preceding claim, wherein the at least one fluid source container is a buffer container. 5. The fluid flow loop of any preceding claim, wherein the at least one fluid source container is a solution container. 6. The fluid flow loop of any preceding claim, wherein the microfluidic sorter 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 reusable hardware including a controller configured and / or programmed to initiate and at least partially control the processing of biological cells through 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 biological cells from a source access device through the fluid flow loop; perform sorting of blood into two or more cellular components using the sorting module; and concentrate at least one cellular component of the blood using the cell concentrator module to produce at least one concentrated 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 concentrated cellular component through a cell modification module. 13. The blood processing system of claim 12, 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 concentrated cellular component through the gene delivery module. 14. The blood processing system of claim 12, wherein the controller is configured to perform modification of the at least one concentrated cellular component of the blood by operating the at least one pump and the valve system to deliver at least one concentrated cellular component through the cell selection module. 15. The blood processing system of claim 10, wherein the microfluidic sorter module is configured to sort 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 the at least one pump and the valve system to collect the at least one concentrated 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 concentrated cellular component to the patient. Claims 2 / 2 Page 3 CN 120936392 A Modular Biological Cell 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 biological cells comprising blood and blood components, and their processing. More specifically, this disclosure relates to systems and methods for collecting biological cells (e.g., blood components) and processing / modifying the 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 aid in donation purposes and in the treatment of individuals with potentially harmful or detrimental conditions or diseases.

[0006] When such systems are 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 systems can also be used to provide patients with blood components for cell therapy. 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 gap between the time spent collecting, modifying, or otherwise processing cells and then re-infusing the cells as part of a treatment to the patient.

[0009] Therapies such as CAR-T therapy have shown incredible efficacy in the clinical treatment of hematologic malignancies; however, many patients are disqualified from treatment because the vein-to-vein time for administering these autologous genetically modified therapies is too long. Therefore, there is a need for rapid manufacturing 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 that can collect, concentrate, modify, and prepare cells for re-infusion and / or efficiently re-infuse cells without significant delays.

[0011] Several aspects of this subject matter exist, which may be implemented individually or together in the apparatus, systems, and methods 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 claims to such aspects individually or in combinations different from those set forth in the appended claims. Specification 1 / 15 pages 4 CN 120936392 A

[0012] In one aspect, a fluid flow circuit for a blood processing system includes a microfluidic sorter module, a cell concentrator 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.

[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] FIG10 is a schematic diagram of a first separation step in the disposable fluid flow circuit of FIG8;

[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;

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

[0031] Figure 17 is a schematic diagram of one embodiment of the biological cell processing system;

[0032] Figure 18 is a schematic diagram of one embodiment of the biological cell processing system;

[0033] Figure 19 is a schematic diagram of one embodiment of the biological cell processing system;

[0034] Figure 20 is a schematic diagram of the pressure control system of one embodiment of the biological cell processing system;

[0035] Figure 21 is a schematic diagram of the fluid flow path of one embodiment of the biological cell processing system; and

[0036] Figure 22 is a schematic diagram of the fluid flow path of one embodiment of the biological cell processing system. Detailed Description

[0037] 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.

[0038] The present disclosure will be more fully understood from the following description taken in conjunction with the accompanying drawings. Some of the figures in the drawings may have been simplified for the purpose of illustrating other elements more clearly.Unless explicitly described in the corresponding written description, such simplification of the drawings does not necessarily indicate the presence or absence of a particular element in any of the exemplary embodiments. The drawings are not necessarily to scale. Specification 2 / 15 pages 5 CN 120936392 A

[0039] 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 reinfusion into a patient.

[0040] “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 system of this disclosure, it will be understood that some operator activities may still be involved, including loading the disposable fluid circuit and inputting processing parameters. Additional manual steps may also be required. However, reusable devices can process blood with disposable circuits as described below without extensive operator intervention.

[0041] As shown in Figures 1 and 2, the blood processing system comprises two main components: a durable and reusable blood or cell 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.

[0042] The blood processing systems and methods according to this disclosure are described using blood processing devices or systems and various cell separation, concentration, and 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.

[0043] 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 20 may include movable or mobile components, such as wheels, for moving the device to or from a patient's bed or chair. The device may be placed at least substantially or even entirely at a patient care site, i.e., at the bedside. The device may support all manufacturing unit operations within a single system, as described below.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.

[0044] 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.

[0045] 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.

[0046] The blood processing device 20 may also include a plurality of pumps (by way of example, FIG. 6 includes two possible pumps 30, 32) as part of a user adjacent section to initiate and flow fluid through the fluid flow loop 10. If the user adjacent section is not used or a passive user adjacent section is used, such as shown in FIG. 7, the blood processing device does not need to include these pumps. Specification 3 / 15 pages 6 CN 120936392 A The pumps may be configured differently or similarly and / or operate similarly or differently from each other. In embodiments, the pumps are configured as peristaltic pumps, which may generally be configured as described in U.S. Patent No. 5,868,696. When using the user-adjacent portion of the fluid flow loop, each pump can engage a different line and can be selectively operated under the command of controller 16 to allow fluid to flow through a portion of the fluid flow loop 10.

[0047] 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 can send a signal to controller 16 indicating the presence or absence of air in the conduit.If a signal indicates the presence of air in the conduit, 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). An air detector may alternatively or additionally be used as part of the fluid flow control of fluid flow loop 10.

[0048] 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 through 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 acoustic methods can produce relative density measurements.

[0049] Furthermore, the plunger position of any of the injection pumps 54, 56, 58, 60 of fluid flow loop 10 (shown in Figure 8 and described below) may 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 (FIG. 6)) can be configured to monitor the pressure of the donor's vein during blood extraction and return. Controller 16 can receive signals from the pressure sensors indicating pressure within the fluid flow loop 10, and if the signals indicate a low-pressure or high-pressure condition, controller 16 can activate an alarm or error condition to alert the operator to the condition and / or attempt to bring the pressure to an acceptable level without operator intervention.

[0050] As described above, the blood processing device 20 includes a controller, such as controller 16 shown in FIG. 3C. Although shown in the upper portion of the blood processing device 20, the controller can 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.

[0051] 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 via the controller may be stored on the memory / multiple memories associated with the microprocessor, which may include one or more tangible, non-transitory computer-readable storage devices having computer-executable instructions stored thereon that, when executed by the microprocessor, cause the microprocessor to perform one or more actions as described below.

[0052] The controller may be coupled to one or more structures of the blood processing apparatus 20, and may also be coupled to a structure of the fluid flow loop 10 (FIG. 8) to, for example, receive information (e.g., in the form of signals) from these structures or provide commands (e.g., in the form of signals) to these structures to control the operation of the 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 the given structure. The controller may be directly electrically connected to these structures to couple to these structures, or the controller may be directly connected to other intermediate devices directly connected to these structures to couple to these structures.

[0053] The controller is configured and / or programmed to perform at least one blood processing procedure (e.g., shown in FIG. 9 to FIG. 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.

[0054] More specifically, during the execution of 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. Thus, although specific components of the blood processing system may be described herein as performing specific functions, it should be understood that the component is controlled by the controller to initiate and / or perform that function.

[0055] User interface screen 14 (e.g., a touchscreen) may be associated with the 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 can be used as a display for providing operators with instructions (e.g., for connecting or disconnecting blood sources from flow circuit 10) and information (e.g., warning operators of blockages in the fluid flow conduits of flow circuit 10) and for providing process status.

[0056] Blood processing apparatus 20 may include computer equipment that allows the blood processing apparatus including controller 16 to communicate with other blood processing apparatuses via a local area network (whether via wiring, cable, etc. or wirelessly), or via a local area network, wide area network, or the Internet with other blood processing apparatuses or other computer equipment (e.g., servers). According to such an embodiment, the apparatus may include an internal transmitter / receiver device.

[0057] Figures 3A to 3C illustrate the steps of inserting and loading the fluid flow loop 10 into the blood processing device 20 to create a single modular 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.

[0058] 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 initiating a given blood processing and modification procedure, the operator loads the fluid flow loop 10 into the blood (cell) 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.

[0059] Different fluid flow loops used in combination with a blood processing device may vary slightly in terms of components, depending on the blood or cell processing procedure and the cells obtained using the system. Therefore, different fluid flow loops can be used in combination with a specific blood processing procedure. The fluid loop is fully customizable, and therefore various components can be added and removed. Generally, the fluid flow loop 10 may include pumps, reservoirs, valve components, fluid inlet and outlet containers, separation devices, concentration devices, and at least one cell modification module or a combination thereof, as shown in FIG8.

[0060] The fluid flow loop may include two distinct sections: a first user-adjacent section (22 or 23, as shown in Figures 6 and 7) used when connecting the system to a donor, and a second processing section 25 (as shown in Figure 8). The user-adjacent section may be selected based on whether the processing is active (reinfusion back to the donor) or passive (collecting the dose for later infusion). Figure 6 shows a schematic diagram of a first possible user-adjacent section 22 with components and active processing. Figure 7 shows a schematic diagram of a second possible user-adjacent section 23 with components and passive processing.

[0061] Each of the two user adjacent portions 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 double 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. Both user adjacent portions also include donor isolation clips 28. A main line L1 is also present in both portions, connecting the fluid handling portion 25 (FIG. 8) to the user adjacent portion of the fluid flow loop 10.

[0062] In the active user adjacent portion 22 of the fluid flow loop 10 shown in FIG. 6, two separate flow lines are connected to the blood source access device 26, with the first line L3 connected to the anticoagulant container 24 and the second line L2 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 from the patient.

[0063] The passive user adjacent portion 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.

[0064] The passive or active user adjacent portion may also include multiple pumps (FIG. 6 includes two possible pumps 30, 32) for flowing fluid 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 typically 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 command of the controller 16 to flow fluid through a portion of the fluid flow loop 10.

[0065] Turning now to the fluid processing section 25, a possible fluid processing section 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 inlet containers included on the processing section 25 of the fluid flow circuit 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 four optional solution or liquid containers 64, 66, 68, 70. However, the amount of buffer containers and the amount and / or presence of solution or liquid containers may vary based on the cell modification treatment used.

[0066] Output containers may also be integrally formed with or connected to the fluid flow circuit 10. These containers are designed to contain different cell fractions, used buffer solutions, prepared suspensions, or samples thereof. These containers may include waste containers 52 or final dose containers 50, as also shown in Figure 8. In treatments where the modified dose is not immediately returned to the patient (and removed from the system), the dose container 50 may be a removable container that is transferred after the process.

[0067] The fluid flow circuit may include valves or valve arrays (V1 to V21 as shown in Figures 8 to 16). Valves may be stopcock valves. 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. Other types of valves, such as solenoid-driven valves, are described below.

[0068] 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 syringe pump assemblies that interface with an air control system on the hardware of the blood processing device 20. 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 cap for the syringe is present. In embodiments, the pump may generally be configured as described in U.S. Patent Application No. 2021 / 0121827, which is incorporated herein by reference in its entirety. The plunger position may be tracked by sensing elements on the hardware. The pump may operate in a pressure target mode or a flow rate target mode, depending on the control scheme required for the processing step. The pump may also be configured as a pneumatic injection pump as described in U.S. Application No. 63 / 615,004, filed December 27, 2023 and incorporated herein by reference.

[0069] The fluid flow circuit may include a plurality of reservoirs 40, 42, 44. The reservoirs are used as passive containers for containing fluid before, during and after the processing steps. The reservoirs may be ventilated using sterile filters so that inflow or outflow from the reservoir does not cause pressurization of the container. Although Figure 8 shows a fluid flow circuit with three reservoirs, fluid flow circuit 10 may include more or fewer reservoirs.

[0070] The reusable hardware processing device may include at least one weighing scale associated with at least one of the containers in the fluid flow circuit.A weighing scale may be associated with the first buffer container 46, the first buffer container 48, one or more of the four solution or liquid containers 64, 66, 68, 70, any of the reservoirs 40, 42, 44, the dose or sample container 50, and the waste container 52. Any container in the loop configured to contain fluid for a period of time may include a weighing scale for monitoring the amount of liquid added or removed.

[0071] The fluid flow loop 10 may include a separation module 62 (FIG. 8). As described in more detail below, the microfluidic separation module 62 may be used to continuously separate microparticles or cells. The microfluidic separation module may include multiple channels for separating according to cell characteristics such as diameter. For example, a critical diameter of about 7 μm can separate nucleated leukocytes from erythrocytes and platelets. The separator module 62 shown in FIG. 8 shows two outputs 62c and 62d. The first output 62d is for cells larger than the specified critical diameter, and the second output 62c is 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 modules may include a rotating membrane separator or centrifuge chamber used in other blood processing 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 and 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.

[0072] The fluid flow loop 10 may include a concentrator module, or a microfluidic concentrator module 72 may be employed 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 can be achieved through this method.

[0073] The fluid flow loop 10 may also be configured to interface with at least one cell modification module or include at least one cell modification module (see page 7 / 15 of specification CN 120936392 A). In one example, these modules may perform cell and / or gene therapy. Thus, the fluid flow loop 10 may be configured to interface with one or more modules, including a gene delivery module and a cell selection module.

[0074] The gene delivery module 74 may also be part of the fluid flow loop 10 shown in FIG8. This module may 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. The gene delivery module may include the electroporation device disclosed in US Patent Publication No. 2020 / 0282116.

[0075] The cell selection module 76, for example, an affinity-based cell selection module, may also be part of the fluid flow loop 10 shown in FIG8. The cell selection module 76 may 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 may be implemented using positive or negative selection methods. The cell selection module may include an affinity column as described in U.S. Patent Application No. 63 / 613,500, filed December 21, 2023.

[0076] Alternatively, the fluid flow loop 10 may utilize an existing portion 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) or both integrated with the fluid flow loop. Blood cells can be formulated, mixed, or incubated in the reservoir, or moved between components of the fluid flow circuit 10.

[0077] 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. In one embodiment, the fluid flow circuit may include a housing. The housing may be rigid or flexible. The fluid flow circuit 10 includes lines L1 to L32 (shown in detail in FIG8), and more or fewer lines may be added or removed depending on the desired configuration of the fluid flow circuit 10 and the attached modules.

[0078] Various additional components may be incorporated into the fluid flow circuit.For example, a return line filter can be associated with a 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 separated components (e.g., red blood cells or platelets) flowing into the reservoir. Filters can also be present on the line for adding materials (e.g., containers 40, 46, 48, 64, 66, 68, and 70) to filter or sterilize the material as it enters the fluid loop. Additionally, a cell counting component can be added. An overflow detection module or device may also be included.

[0079] Before initiating the blood processing procedure, if any fluid containers are not integrally formed with the fluid flow loop 10, they can be connected to the fluid flow loop 10 (e.g., by piercing a diaphragm in the conduit of the fluid flow loop 12 or via a Luer connector), and then the fluid flow loop 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 loop 10 can be performed by the controller 16 to ensure that the various components are properly connected and functioning.

[0080] To begin the blood processing procedure, the operator can select a procedure from a variety of procedures that the device 10 can perform (e.g., using the user interface screen 14, see FIG. 3C). 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 predicted WBC count, the predicted subset of WBC counts 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 measurement values, such as height, weight, etc., may be added.

[0081] 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 system 21 are functioning properly), a blood source is connected to the fluid flow loop 10 (e.g., by bloodletting of the donor or attaching a whole blood container), and the blood processing can begin. The blood source may include a donor, a container of blood, or other cell suspensions. Blood or other cell starting material may be whole blood, blood components obtained through, for example, apheresis, or other nucleated cell suspensions.

[0082] Blood is introduced into the system via an active or passive user-adjacent portion of the fluid flow loop 10 or by connection to a blood or blood component container. Blood flows from the donor into the main line L1 and the reservoir 40.In the initial stage, selected components of the fluid flow circuit 10 are pre-charged with blood 41 from a blood source (particularly stored in reservoir 40), referred to herein as the “blood pre-charge” stage and shown in FIG. 9. Pre-charging of the fluid flow circuit 10 with different pre-charge fluids, such as saline, is also within the scope of this disclosure.

[0083] During the blood pre-charge stage, whole blood is drawn from the reservoir into the fluid flow circuit 10 via line L2. The blood travels through L1 to the patient-adjacent portion of the fluid flow circuit 10. Although not shown in FIG. 9, other components of the fluid flow circuit, such as components of the processing section 25 of the fluid flow circuit 10, may be pre-charged.

[0084] The separation stage can then be initiated. In the first step of this stage, as shown in FIG. 10, blood 41 and buffer solution 47 loaded into pump 54 are loaded into pumps 56 and 58. Blood or blood components 41 from reservoir 40 are drawn into or loaded into pump 54 via lines L2, L1, valve V1, and line L4. Buffer 47 from container 46 is drawn into pumps 56 and 58. Specifically, the buffer flows from container 46 through line L9 and valve V5 to line L10, through valve V4 and line L30 to pump 56, or through line L9 and valve V5 to line L11, through valve V6 and line L31 to pump 58. Buffer 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 62 at inlet 62b. Pump 54 also pushes blood component 55 into separation module 62 through line L4, valve V1, valve V2, and line L5 at inlet 62a. Cells are separated based on size. Larger cells / particles 43, such as leukocytes, are separated and introduced into reservoir 42 via outlet 62d, line L8, valves V8 and V7, and line L13. Smaller cells / particles 53, such as erythrocytes and platelets, are guided to waste container 52 via outlet 62c, line L7, line L1, valves V21 and line 29. The separation module may be performed differently depending on the desired separation and the specific cells to be modified.

[0085] The cell concentration process shown in FIG. 12 can then be performed. Large cell material 43 is loaded or drawn from reservoir 42 into pump 60 via line L13, valves V7, V8 and V9, and line L14. Pump 60 is then pressurized to operating pressure and 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 via outlet 72b to reach line L20, reach line L7, through valve 21, and to reach line L29. Concentrated cells 45 are directed toward reservoir 44 via outlet 72c to reach line L23, through valve 18, line L1, and valve V19 to reach line L27. The concentrated cells can then be diluted and then optionally reconcentrated until the cells reach a target concentration by re-drawing them from reservoir 44 into pump 60 and repeating concentration module 72. Cell concentration can be sensed during concentration or transfer.

[0086] A cell preparation stage or process can also be performed. This can be performed on concentrated cells 45 (as shown in Figures 13 and 14) or on separated 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 line L21 and line L1, reaching valves 9 and 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. Cells bind to the solution and can be incubated into a suspension 67. During the containment or incubation step, the suspension can 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 FIG. 11. 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 may be pumped back and forth between reservoir 42 and pump 60 to prevent precipitation.

[0087] The gene delivery stage process shown in FIG. 15 may also be performed. Cells 69, which have been prepared with the gene-modified solution, may be directed from pump 60 to gene delivery module 74, in which the payload is applied to the cells. Similar to the processes shown in FIG. 13 and FIG. 14, cells 69 may 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 formulation stage. The cells 69 can then be drawn into pump 60. As shown in FIG15, the formulated cells are drawn 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 introduce the payload using electroporation, mechanical perforation, or other flow-through transfection methods. The modified cells 70 exit module 74 at outlet 74b to lines L32 and L23, and through valves v18 and v19 to line L27.

[0088] The gene delivery stage process can also be performed without passing through gene delivery module 74. Instead, a gene solution is simply added during the cell formulation stage described above (to large cell material 43). 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, prepared with antibodies, beads, or other solutions that can identify cells based on surface markers or phenotypes, can be transferred to the selection chamber 76. Similar to the processes shown in Figures 13 and 14, cells 72 can be formed first by pulling the cell-identifying 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 large cell material 43 or cells that have been modified, for example, through a cell concentration stage, formulation stage, or gene delivery stage. Cells 72 can then be pulled into pump 60. As shown in Figure 16, cells 72 travel from pump 60 through line L14, valve v9 to line L1, through valves v15, v16, and v17 to L26, and enter the 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.

[0089] While 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 cellular 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 need not be performed in a specified order, and each stage may be performed multiple times. Most importantly, the cells are isolated and modified in the same process and system.

[0090] Once the cells have been modified in at least one of the described cell modification modules, these cells may be directed to 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 may be removed from the loop.Modified cells can be transferred back to and from the donor / patient by guiding cells through line L1 of the processing portion 25 of the fluid flow loop 10 to the patient-adjacent portion 22 of the fluid flow loop. Various pumps and valves can be used to guide the fluid back to the patient. The patient-adjacent portion 22 of the fluid flow loop can be activated and guide the fluid flow back to the patient.

[0091] Several factors exist that can be used to determine whether cells are collected in dose order or reinfused back to the patient. These factors include guidelines imposed by regulatory agencies (such as the FDA), the required duration of the treatment and whether patient connection is acceptable during the duration (if the treatment takes several hours, perhaps the patient does not need to be connected during the duration of the treatment), the need for extensive release testing prior to reinfusion, or whether the cells require additional treatment (e.g., culture / expansion, offline administration, etc.).

[0092] More specific embodiments of the systems and methods described above are depicted in Figures 17 through 22, and will now be described. It will be understood that such systems and methods can utilize many of the aspects and features previously described to provide a single modular system configured for use at the point of care, i.e., at the bedside. For example, the device 221 shown in Figure 17 can be the mobile modular device 21 of Figures 2, 3B, and 3C. Figure 17 illustrates a biological cell processing system 221 comprising the device 20 of this disclosure and a fluid flow loop 10, as well as possible processes indicated by 1 to 3. At step 1, the blood processing system receives blood from a source, such as whole blood, blood components typically obtainable via apheresis, or other nucleated cell suspensions 220, where the source can be a donor or a blood bag containing previously collected blood or blood components. The system uses protocols or processes from an internal or external data source 224 and performs various processing within the system. The system can also share generated data with the external source 224 (at this or other steps). The data can be instrument status, error logs, process data / records, or real-time sensor data. At step 2, additional fluids or reagents, such as additives or solutions 222, are added to the system via at least one module. There are two alternative steps 3, in which the final product can be returned to the patient 225 or collected in a bag or other output receiver 223. This entire process may occur in less than a day, less than 12 hours, or even less than 6 hours.

[0093] Figures 18 and 19 show two block diagrams of a blood processing system, differing in the type of blood source used. System 321 includes a bag or container as its source containing previously collected blood, blood components obtained by apheresis, or other nucleated cell suspensions 326 (e.g., obtained by apheresis), and system 421 uses a donor 430 and includes a donor management module 428.The donor management module can be one of the first parts discussed above and adjacent to the passive or active user shown in Figures 6 and 7. Systems 321 and 421 each include fluid handling and control systems 300 and 400 as central and containment components for other modules and inputs / outputs. Multiple different modules can be added to or removed from the system (so that only one, two, or three modules may exist, rather than all four). These modules may include microfluidic sorters 310 and 410, microfluidic concentrators 312 and 412, and optional cell selection modules 314 and 414 and “cargo delivery” modules 316 and 416. Inputs to the system may include processing buffers and solutions 320 and 420. Outputs to the system may include waste materials 322 and 422 and samples or outputs 324 and 424.

[0094] While systems 221, 321, and 421 use microfluidic components, the system may also allow the processing of large volumes of whole blood or blood components obtained from whole blood. The flow rate through the system can range from 5 mL / min to 70 mL / min. Systems 221, 321, and 421 as a whole can process up to 500 mL of whole blood, with extraction or discharge from the blood source lasting up to one hour.

[0095] Systems 221, 321, and 421 can utilize pneumatic syringe pumps as described above to deliver starting cell material, buffer solutions, or other reagents and additives to microfluidic sorters and concentrators. The system may also include a pressure control system 79 as shown in Figure 20. The syringe pump 85 system includes a pressure tank 80 and a vacuum tank 81, as well as associated pressure regulators 82 and vacuum regulators 83. A three-way valve 84 includes normally open (NO) or normally closed (NC) and common (COM) connections. The system also includes a bidirectional normally open valve 86 that can be used as a vent. These tanks are maintained at 90 psi to 110 psi and <-10 psi. Each syringe has an injection controller with a regulator for setting the injection pressure. Specification page 11 / 15 14 CN 120936392 A

[0096] The valve system of the current embodiment of the blood processing systems 221, 321, 421 may include a plug valve or a solenoid valve. Fluid flow circuits 100 and 200 in Figures 21 and 22 respectively show fluid flow paths with a plug valve (Figure 21) and a solenoid valve (Figure 22).

[0097] More specifically, Figure 21 shows the fluid flow circuit 100 of the blood processing system of the current embodiment. Valves V101 to V123 may be plug valves of any known type.The fluid flow loop 100 connects and establishes fluid communication between and among the components, which are similar to those described above, including: a first buffer container 146, a second buffer container 148, reservoirs 140, 142 and 144, a sample / dose container 150, a waste container 152, pumps 154, 156, 158 and 160, and solution or liquid containers 164, 166 and 168. The fluid flow loop 100 may also include air detectors A100 to A104. The fluid flow loop 100 also includes a microfluidic sorter module 162, a cell concentrator module 172, and optional cargo delivery module 174 and cell selection module 176.

[0098] Figure 22 illustrates the fluid flow loop 200 of the blood processing system of the present embodiment. Valves V201 to V233 can be any known type of solenoid valve. The valve may be part of a solenoid drive housing of the type shown in U.S. Patent Publication No. 2017 / 0290972, filed March 29, 2017, which is incorporated by reference. The fluid flow loop 100 connects and establishes fluid communication between or among its components, which are similar to those described above, including: a first buffer container 246, a second buffer container 248, reservoirs 240, 242, and 244, a sample / dose container 250, a waste container 252, pumps 254, 256, 258, and 260, and solution or liquid containers 264, 266, and 268. The fluid flow loop 200 may also include an air detector, although not specifically shown. The fluid flow loop 200 also includes a microfluidic sorter module 262, a cell concentrator module 272, and optionally a carrier delivery module 274 and a cell selection module 276.

[0099] Microfluidic sorter modules 162, 262 may have properties common to the separation modules described above, such as those shown in the schematic diagram of fluid flow loop 25 in FIG8. The microfluidic sorter modules 162, 262 may be substantially or entirely passive separation operations, independent of moving parts or complex systems such as centrifugation or spin membrane separation. In embodiments, the microfluidic sorter module may be a chip or a cartridge. A chip may have multiple layers, including an interface layer capable of fluidly connecting with other components such as pipes. The chip may also have a capping layer for sealing the lower fluid layer. The fluid layer includes microfluidic channels and performs cell sorting and concentration. The microfluidic chip or cartridge may operate based on inertia to sort cells. If whole blood is introduced into the microfluidic sorting module, dilution is required. Apheresis products do not require the same dilution. The microfluidic chip or cartridge used in the microfluidic sorter module may be of the type described in U.S. Patent No. 10,150,116.

[0100] Cell concentrator modules 172, 272 may include the properties associated with the concentrator module described above, such as those shown in the schematic diagram of fluid flow loop 25 in FIG8. Cell concentrator modules 172, 272 may include a plurality of concentrator channels. In one embodiment, the concentrator includes at least 200 channels, and in another embodiment, it includes at least 250 concentrator channels. The concentrator may be passively operated without any moving parts or complex control systems. The concentrator module may operate at a rate greater than 100 mL / min. The cell concentrator may be operated to concentrate at least one cellular component by a factor of 10. In one example, a microfluidic sorter module separates nucleated cells from anucleated cells. These nucleated cells may then be concentrated in the cell concentrator module. The cell concentrator module may include cell concentrator technology of the type described in U.S. Patent No. 10,150,116. The microfluidic sorter module and the cell concentrator module may be connected and added to or removed from the system as a component, or they may each be separate components.

[0101] The fluid flow loop may include delivery modules 174, 274 or features that utilize microfluidic mechanical perforation to enable intracellular delivery of carriers (e.g., genes). Cells and target materials in the suspension undergo high-speed cell deformation, which results in temporary rupture of the cell membrane and allows the target material to enter the cell. The membrane is then resealed. Delivery Specification 12 / 15 pages 15 CN 120936392 A Modules 174, 274 may include delivery materials such as mRNA, siRNA, saRNA, polymers, proteins and peptides, antibodies, viruses, marker molecules, small molecules, and CRISPR RNPs. Validated cell types may include peripheral blood mononuclear cells, T cells, B cells, monocytes, natural killer (NK) cells, hematopoietic stem cells, induced pluripotent stem cells, and erythrocytes.

[0102] The fluid flow loop may include cell selection modules 176, 276, which may be column-based and have immunophenotypic cell selection. In one embodiment, cell selection modules 176, 276 may include a cell selection column based on nonmagnetic affinity chromatography, which operates to separate target cells (e.g., CD3+) from a population comprising non-target cells. This process uses a polymer matrix having a ligand and a ligand-binding partner that binds to the target antigen (target cell, CD3+). A competing molecule is then added to release the target cells. The resulting target cells may require buffer washing to become label-free.The cell selection technology used may be the cell selection technology described in Next Generation Automated Traceless Cell Chromatogra phy Platform for GMP-compliant Cell Isolation and Activation. Scientific Reports (2022) 12:6572.

[0103] Any components not specifically described in relation to blood processing systems 221, 321, 421 are the same as or similar to those described above in relation to blood processing system 21. Blood processing systems 221, 321, 421 include at least a controller and fluid flow loops 100, 200. The fluid flow loop includes at least a microfluidic sorter module, a cell concentrator module, at least one pump, at least one fluid reservoir for containing fluid during the blood processing procedure, a valve system, at least one fluid source container, a blood source access device, and a plurality of conduits fluidly connecting the components of the fluid flow loop. The fluid flow loop may optionally include at least one cell modification module, such as a carrier delivery module and a cell selection module. As described above, the blood processing system may include other components, such as sensors, air detectors, additional pumps, and weighing scales.

[0104] Example

[0105] The following collection and processing workflow can be accomplished using a combination of the states and processes previously described. 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. Subsequently, magnetic microparticles coated with streptavidin are introduced into the system and reservoir 44, and the mixture is incubated. The mixture is then transferred to a selection module 76, in which labeled cells bind in a chamber. Unlabeled, unbound target CD3+ cells are removed from the selection chamber into a reservoir, such as reservoir 42 or 44. The cells are then transferred 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 via gene delivery module 74 to another storage unit. 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 vessel or re-infused into a patient.

[0106] Thus, improved methods and systems for processing blood components have been disclosed. Advantageously, the modular fluid flow circuit 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.

[0107] Aspect

[0108] Aspect 1. A fluid flow circuit for a blood processing system, comprising: a microfluidic sorter module; a cell concentrator 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; a blood source access device; and a plurality of conduits fluidly connecting the components of the fluid flow circuit.

[0109] Aspect 2. The fluid flow circuit according to aspect 1, wherein the fluid flow circuit further comprises at least one cell modification module.

[0110] Aspect 3. The fluid flow loop according to aspect 2, wherein at least one cell modification module includes a cell selection module.

[0111] Aspect 4. The fluid flow loop according to any of the preceding aspects, wherein at least one fluid source container is a buffer container.

[0112] Aspect 5. The fluid flow loop according to any of the preceding aspects, wherein at least one fluid source container is a solution container.

[0113] Aspect 6. The fluid flow loop according to any of the preceding aspects, wherein a microfluidic sorter module is configured to separate blood components based on size.

[0114] Aspect 7. The fluid flow loop according to any of the preceding aspects, wherein at least one pump includes a plurality of pneumatic injection pumps.

[0115] Aspect 8. A blood processing system comprising: a fluid flow loop according to any of the preceding aspects; and reusable hardware including a controller configured and / or programmed to initiate and at least partially control the processing of biological cells through the fluid flow loop.

[0116] Aspect 9. The blood processing system according to aspect 8, wherein the blood processing system is a modular system.

[0117] Aspect 10. The blood processing system according to aspect 8, wherein the controller is configured to: operate at least one pump and valve system to deliver biological cells from a source access device through a fluid flow loop; perform sorting of blood into two or more cellular components using a sorting module; and concentrate at least one cellular component of the blood using a cell concentrator module to produce at least one concentrated cellular component.

[0118] Aspect 11. The blood processing system according to 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.

[0119] 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 cell modification module.

[0120] Aspect 13. The blood processing system according to aspect 12, 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 concentrated cellular component through a gene delivery module.

[0121] Aspect 14. The blood processing system according to aspect 12, wherein the controller is configured to: perform modification of at least one concentrated cellular component of blood by operating at least one pump and valve system to deliver at least one concentrated cellular component through a cell selection module.

[0122] Aspect 15. The blood processing system according to aspect 10, wherein the microfluidic sorter module is configured to sort blood into two or more components based on the size of two or more components.

[0123] Aspect 16. The blood processing system according to aspect 15, wherein the size is the diameter of the cell.

[0124] Aspect 17. The blood processing system according to aspect 10, wherein the cellular components include at least one of white blood cells, red blood cells, and platelets.

[0125] 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 concentrated cellular component in a container.

[0126] 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.

[0127] 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 concentrated cellular component to the patient.Instruction manual, page 15 / 15, 18 CN 120936392 A, Figure 1, Figure 2; Instruction manual, Figure 1 / 21, page 19 CN 120936392 A, Figure 3A, Figure 3B; Instruction manual, Figure 2 / 21, page 20 CN 120936392 A, Figure 3C, Figure 4; Instruction manual, Figure 3 / 21, page 21 CN 120936392 A, Figure 5; Instruction manual, Figure 4 / 21, page 22 CN 120936392 A, Figure 6; Instruction manual, Figure 5 / 21, page 23 CN 120936392 A, Figure 7; Instruction manual, Figure 6 / 21, page 24 CN 120936392 A, Figure 8; Instruction manual, Figure 7 / 21, page 25 CN 120936392 A, Figure 9; Instruction manual, Figure 8 / 21, page 26 CN 120936392 A, Figure 10; Instruction manual, Figure 9 / 21, page 27 CN Figure 11, Appendix to the Instruction Manual, Page 10 / 21, 28 CN 120936392 A; Figure 12, Appendix to the Instruction Manual, Page 11 / 21, 29 CN 120936392 A; Figure 13, Appendix to the Instruction Manual, Page 12 / 21, 30 CN 120936392 A; Figure 14, Appendix to the Instruction Manual, Page 13 / 21, 31 CN 120936392 A; Figure 15, Appendix to the Instruction Manual, Page 14 / 21, 32 CN 120936392 A; Figure 16, Appendix to the Instruction Manual, Page 15 / 21, 33 CN 120936392 A; Figure 17, Appendix to the Instruction Manual, Page 16 / 21, 34 CN 120936392 A; Figure 18, Appendix to the Instruction Manual, Page 17 / 21, 35 CN 120936392 A; Figure 19, Appendix to the Instruction Manual, Page 18 / 21, 36 CN 120936392 A Figure 20 Appendix to the Instruction Manual, Page 19 / 21, 37 CN 120936392 A Figure 21 Appendix to the Instruction Manual, Page 20 / 21, 38 CN 120936392 A Figure 22 Appendix to the Instruction Manual, Page 21 / 21, 39 CN 120936392 A.

Claims

1. A fluid flow circuit for a blood processing system, comprising: Microfluidic sorter module; Cell concentrator module; At least one pump; At least one fluid reservoir for containing fluid during blood processing; Valve system; At least one fluid source container; Blood source access device; as well as Multiple conduits that fluidly connect the components of the fluid flow circuit.

2. The fluid flow circuit according to claim 1, wherein, The fluid flow circuit also includes at least one cell modification module.

3. The fluid flow circuit according to claim 2, wherein, The at least one cell modification module includes a cell selection module.

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

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

6. The fluid flow circuit according to any one of the preceding claims, wherein, The microfluidic sorter 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 includes multiple pneumatic injection pumps.

8. A blood processing system, comprising: The fluid flow circuit according to any one of the preceding claims; as well as A reusable hardware device comprising a controller configured and / or programmed to initiate and at least partially control the processing of biological cells through the fluid flow loop.

9. The blood processing system according to claim 8, wherein, The blood processing system is a modular system.

10. The blood processing system according to claim 8, wherein, The controller is configured to operate the at least one pump and the valve system to deliver biological cells from the source access device through the fluid flow loop; The sorting module is used to perform the sorting of blood into two or more cellular components; and The cell concentrator module is used to concentrate at least one cellular component of blood to produce at least one concentrated cellular component.

11. The blood processing system according to claim 10, wherein, The controller is also configured to operate the at least one pump and the valve system to deliver the solution to the at least one cellular component.

12. The blood processing system according to claim 10, wherein, The controller is configured to operate the at least one pump and the valve system to deliver at least one concentrated cellular component through the cell modification module.

13. The blood processing system according to claim 12, 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 concentrated cellular component through the gene delivery module.

14. The blood processing system according to claim 12, wherein, The controller is configured to perform modification of the blood by operating the at least one pump and the valve system to deliver at least one concentrated cellular component through the cell selection module.

15. The blood processing system according to claim 10, wherein, The microfluidic sorter module is configured to sort blood into two or more components based on the size of the two or more components.

16. The blood processing system according to claim 15, wherein, The size mentioned is the diameter of the cell.

17. The blood processing system according to claim 10, wherein, The cellular components include at least one of white blood cells, red blood cells, and platelets.

18. The blood processing system according to claim 10, wherein, The controller is also configured to operate the at least one pump and the valve system to collect the at least one concentrated cellular component in a container.

19. The blood processing system according to claim 10, wherein, The blood from the blood source access device is drawn directly from the patient.

20. The blood processing system according to claim 19, wherein, The controller is also configured to operate the at least one pump and the valve system to initiate the reinfusion of the at least one concentrated cellular component into the patient.

Images