Cell delivery injector

Abstract

Provided herein is a system for delivering a therapeutic composition to a patient, comprising: a container configured to contain a therapeutic composition; at least one power drive in operative connection with the container; a plurality of sensors including at least two of (i) a pressure sensor, (ii) a flow sensor, (iii) a count sensor, (iv) a position sensor, (v) a temperature sensor, (vi) a chemical sensor, and (vii) at least one physiological sensor; and at least one processor programmed or configured to receive data from the plurality of sensors and to control the at least one powered driver to inject the therapeutic composition into the patient at a desired flow rate, the flow rate being dependent on the data received from the plurality of sensors.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 425,031, filed on November 14, 2022, the content of which is incorporated herein by reference in its entirety. Technical field

[0003] The present disclosure relates to devices, systems, and methods for delivering cell - based therapies. Background art

[0004] Methods of treating diseases by injecting live cells into the body are expanding rapidly. There are many types of cells used to treat a variety of diseases, and both the types of cells and the disease conditions are expanding rapidly. Cell therapy is the transplantation of intact live cells into a patient to help alleviate or cure a disease. The cells can be from the patient (autologous cells) or a donor (allogeneic cells), and some of them can be genetically modified. Some examples of cell therapy include CAR - T cell therapy, in which T cells engineered to express a chimeric antigen receptor (CAR) are delivered to a patient, such as a patient with certain subtypes of B - cell leukemia or lymphoma. Promising efficacy of cell therapy has also been demonstrated in patients with multiple myeloma. However, various obstacles limit the efficacy and / or prevent the widespread use of cell therapy. These obstacles include cell rupture, which can cause dangerous side effects to the patient. Therefore, there is a need in the art for more robust delivery devices and systems that can address and correct for the various situations that may arise during any such cell delivery treatment. Summary of the invention

[0005] The present disclosure provides a system for delivering a cell therapy to a patient, comprising: a container configured to hold a therapeutic composition comprising one or more cells in suspension; at least one power driver operably connected to the container, the at least one power driver being configured to pressurize the therapeutic composition within the container and at least one fluid line in communication therewith; a control system having a plurality of sensors and at least one processor, the at least one processor being programmed or configured to receive data from the plurality of sensors and to control the at least one power driver at least in part based on the data so as to pressurize the therapeutic composition within the container and the at least one fluid line, thereby injecting the therapeutic composition into the patient at a first flow rate; the plurality of sensors including at least two of the following: a pressure sensor for measuring and providing data indicative of the pressure within the container and the at least one fluid line, a flow sensor for measuring and providing data indicative of the actual flow rate of the suspension within the at least one fluid line, a counting sensor for providing data indicative of a count of at least one of the following within the suspension flowing through at least one fluid line: (i) the number of intact ones of the one or more cells and (ii) the number of ruptured ones of the one or more cells, a position sensor for placement around the location where the suspension is injected into the patient and for providing data indicative of either the occurrence or non-occurrence of extravasation thereat, a temperature sensor for measuring and providing data indicative of the temperature of the suspension within the at least one fluid line, a chemical sensor for detecting and providing data indicative of the occurrence of an immune response in the patient, and at least one physiological sensor for measuring and providing data indicative of at least one parameter of the patient, wherein the at least one processor is further programmed or configured to control the at least one power driver to pressurize the therapeutic composition within the container so as to inject the therapeutic composition into the patient at a second flow rate when it is determined that the data received from the plurality of sensors indicates at least one of the following: the pressure within at least one of the container and the at least one fluid line is greater than a predetermined pressure threshold, the flow rate of the suspension within the at least one fluid line is greater than a predetermined flow rate threshold, the number of ruptured ones of the one or more cells within the suspension is greater than a predetermined rupture threshold, the occurrence of a threat of extravasation around the injection location, the temperature of the suspension within the at least one fluid line is outside a predetermined temperature range, the occurrence of an immune response in the patient as evidenced by data received from at least one of the chemical sensor and the at least one physiological sensor, and an adverse reaction experienced by the patient as evidenced by data received from the at least one physiological sensor.

[0006] The present disclosure also provides a system for delivering a cell therapy to a patient, comprising: a container configured to contain a therapeutic composition, the therapeutic composition comprising one or more cells in suspension; at least one power driver operably connected to the container, the at least one power driver being configured to pressurize the therapeutic composition within the container and at least one fluid line in communication therewith; a plurality of sensors, the plurality of sensors including at least two of the following: (i) a pressure sensor configured to measure and provide data indicative of the pressure within the container and the at least one fluid line, (ii) a flow sensor configured to measure and provide data indicative of the actual flow rate of the suspension within the at least one fluid line, (iii) a counting sensor configured to provide data indicative of the count of at least one of the following within the suspension flowing through at least one fluid line: (i) the number of intact ones of the one or more cells and (ii) the number of ruptured ones of the one or more cells, (iv) a position sensor configured to be placed around the location where the suspension is injected into the patient and configured to provide data indicative of either the occurrence or non-occurrence of extravasation thereat, (v) a temperature sensor configured to measure and provide data indicative of the temperature of the suspension within the at least one fluid line, (vi) a chemical sensor configured to detect and provide data indicative of the occurrence of an immune response in the patient, and (vii) at least one physiological sensor configured to measure and provide data indicative of at least one parameter of the patient; and at least one processor programmed or configured to receive data from the plurality of sensors and to control the at least one power driver at least in part based on the data so as to pressurize the therapeutic composition within the container and the at least one fluid line, thereby injecting the therapeutic composition into the patient at a desired flow rate, the magnitude of the desired flow rate depending on the data received from the plurality of sensors.

[0007] The present disclosure also provides a system for delivering cell therapy to a patient, comprising: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more autologous and / or allogeneic cells and an ultrasound contrast agent; a pump configured to expel the therapeutic composition from the container; at least one processor in communication with the pump; and a plurality of sensors in communication with the at least one processor, the plurality of sensors including at least: a cell counter sensor configured to collect cell data, wherein the cell data includes the number of intact cells and / or lysed cells, a pressure sensor configured to collect pressure data, wherein the pressure data includes a measurement of the pressure within the container and / or one or more fluid lines between the container and the patient, a flow sensor configured to collect flow rate data, wherein the flow rate data includes a measurement of the flow rate within one or more fluid lines between the container and the patient, an ultrasound transducer configured to be placed around a location where the therapeutic composition is injected into the patient and to collect extravasation data, wherein the extravasation data indicates either the occurrence or non-occurrence of extravasation at that location, and at least one physiological sensor configured to collect physiological data, wherein the physiological data includes measurements of immune parameters, blood pressure, heart rate, respiratory rate, and / or temperature; wherein the at least one processor is programmed or configured to: control the pump to pressurize the therapeutic composition so as to deliver the therapeutic composition at a first flow rate, and determine, at least in part based on the cell data, pressure data, flow rate data, extravasation data, and physiological data: that the therapeutic composition should be delivered at the first flow rate, or that the therapeutic composition should be delivered at a second flow rate.

[0008] Other non-limiting aspects are described below:

[0009] In a first aspect, a system for delivering cell therapy to a patient is provided, comprising: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more cells in suspension; at least one power driver operably connected to the container, the at least one power driver being configured to pressurize the therapeutic composition within the container and at least one fluid line in communication therewith; a control system having a plurality of sensors and at least one processor, the at least one processor being programmed or configured to receive data from the plurality of sensors and to control the at least one power driver at least in part based on the data so as to pressurize the therapeutic composition within the container and at least one fluid line, thereby injecting the therapeutic composition into the patient at a first flow rate; the plurality of sensors including at least two of the following: a pressure sensor for measuring and providing data indicative of the pressure within the container and at least one fluid line; a flow sensor for measuring and providing data indicative of the actual flow rate of the suspension within at least one fluid line; a counting sensor for providing data indicative of the count of at least one of the following within the suspension flowing through at least one fluid line: (i) the number of intact ones among the one or more cells and (ii) the number of ruptured ones among the one or more cells; a position sensor for being placed around the location where the suspension is injected into the patient and for providing data indicative of either the occurrence or non-occurrence of extravasation thereat; a temperature sensor for measuring and providing data indicative of the temperature of the suspension within at least one fluid line; a chemical sensor for detecting and providing data indicative of the occurrence of an immune response in the patient; and at least one physiological sensor for measuring and providing data indicative of at least one parameter of the patient; wherein the at least one processor is further programmed or configured to control the at least one power driver to pressurize the therapeutic composition within the container so as to inject the therapeutic composition into the patient at a second flow rate when it is determined that the data received from the plurality of sensors indicates at least one of the following: the pressure within at least one of the container and at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension within at least one fluid line is greater than a predetermined flow rate threshold; the number of ruptured ones among the one or more cells in the suspension is greater than a predetermined rupture threshold; the occurrence of a threat of extravasation around the injection location; the temperature of the suspension within at least one fluid line is outside a predetermined temperature range; the occurrence of an immune response in the patient as evidenced by data received from at least one of the chemical sensor and at least one physiological sensor; and an adverse reaction experienced by the patient as evidenced by data received from at least one physiological sensor.

[0010] In a second aspect, which may be based on the first aspect, the container is one of a syringe, a bag, a bottle, and a vial.

[0011] In a third aspect, which can be based on the first aspect and / or the second aspect, one or more cells include at least one of the following: (i) autologous cells, (ii) allogeneic cells, (iii) a combination of autologous cells and allogeneic cells, (iv) a mixture in which at least one of the autologous cells and allogeneic cells has been modified, (v) genetically engineered cells, and (vi) genetically engineered T cells expressing a chimeric antigen receptor.

[0012] In a fourth aspect, which can be based on any of the foregoing aspects, one of the plurality of sensors is an ultrasonic sensor, and the suspension includes an ultrasonic contrast agent.

[0013] In a fifth aspect, which can be based on any of the foregoing aspects, at least one power driver is a pump system including an injector system.

[0014] In a sixth aspect, which can be based on any of the foregoing aspects, the second flow rate is one of flow stop and flow deceleration.

[0015] In a seventh aspect, which can be based on any of the foregoing aspects, at least one physiological sensor includes at least one of a blood pressure sensor, a heart rate sensor, a respiratory sensor, a temperature sensor, and a chemical sensor.

[0016] In an eighth aspect, which can be based on any of the foregoing aspects, when it is determined that the patient is experiencing an adverse reaction, at least one processor is programmed or configured to cause at least one power driver to deliver a second therapeutic composition to the patient.

[0017] In a ninth aspect, which can be based on any of the foregoing aspects, the second therapeutic composition includes at least one of a crystalloid solution, a colloid solution, and a corticosteroid, wherein the crystalloid solution includes at least one of normal saline, D5W, and lactated Ringer's solution.

[0018] In a tenth aspect, which can be based on any of the foregoing aspects, at least one processor is further programmed or configured to trigger at least one of an alarm and a warning when it is determined that the data received from the plurality of sensors indicates any of the following: the pressure in at least one of the container and at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension in at least one fluid line is greater than a predetermined flow rate threshold; the number of ruptured cells among one or more cells in the suspension is greater than a predetermined rupture threshold; the occurrence of extravasation around the injection site; the temperature of the suspension in at least one fluid line is outside a predetermined temperature range; the occurrence of an immune response in the patient as evidenced by data received from at least one of the chemical sensor and at least one physiological sensor; and an adverse reaction experienced by the patient as evidenced by data received from at least one physiological sensor.

[0019] In an eleventh aspect, which may be based on any of the foregoing aspects, the system includes at least one flow regulator positioned within at least one fluid line, each of the at least one flow regulators being configured to be switchable between an open state and a closed state such that: when it is determined that an increase in the volume of the therapeutic composition is required, at least one processor is programmed or configured to switch at least one flow regulator to the open state, thereby allowing at least one of a diluent and a buffer to be added to the suspension via the at least one fluid line; when it is determined that a decrease in the volume of the therapeutic composition is required, at least one processor is programmed or configured to switch at least one flow regulator to the open state, thereby allowing a portion of the fluid in the suspension to be removed therefrom via the at least one fluid line; and when it is detected that the number of the one or more cells that have ruptured has reached a predetermined rupture threshold, at least one processor is programmed or configured to switch at least one flow regulator to the open state, thereby transferring the suspension to a separate fluid line of the at least one fluid line for at least one of analysis and disposal.

[0020] In a twelfth aspect, there is provided a system for delivering a cell therapy to a patient, the system including: a container configured to hold a therapeutic composition, the therapeutic composition including one or more cells in suspension; at least one power driver operably connected to the container, the at least one power driver being configured to pressurize the therapeutic composition within the container and at least one fluid line in communication therewith; a plurality of sensors, the plurality of sensors including at least two of the following: (i) a pressure sensor for measuring and providing data indicative of the pressure within the container and the at least one fluid line; (ii) a flow sensor for measuring and providing data indicative of the actual flow rate of the suspension within the at least one fluid line; (iii) a counting sensor for providing data indicative of a count of at least one of the following within the suspension flowing through at least one fluid line: (i) the number of the one or more cells that remain intact and (ii) the number of the one or more cells that have ruptured; (iv) a position sensor for placement around the location where the suspension is injected into the patient and for providing data indicative of either the occurrence or non-occurrence of extravasation thereat; (v) a temperature sensor for measuring and providing data indicative of the temperature of the suspension within the at least one fluid line; (vi) a chemical sensor for detecting and providing data indicative of the occurrence of an immune response in the patient; and (vii) at least one physiological sensor for measuring and providing data indicative of at least one parameter of the patient; and at least one processor, the at least one processor being programmed or configured to receive data from the plurality of sensors and at least partially control the at least one power driver based on the data so as to pressurize the therapeutic composition within the container and the at least one fluid line, thereby injecting the therapeutic composition into the patient at a desired flow rate, the magnitude of the desired flow rate depending on the data received from the plurality of sensors.

[0021] In a thirteenth aspect, which may be based on any of the foregoing aspects, the desired flow rate is initially a first flow rate, but changes to a second flow rate when data received by at least one processor from a plurality of sensors indicates at least one of the following: the pressure in at least one of the container and at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension in at least one fluid line is greater than a predetermined flow rate threshold; the number of ruptured cells among one or more cells in the suspension is greater than a predetermined rupture threshold; the occurrence of extravasation around the injection site; the temperature of the suspension in at least one fluid line is outside a predetermined temperature range; the occurrence of an immune response in the patient as evidenced by data received from at least one of a chemical sensor and at least one physiological sensor; and an adverse reaction experienced by the patient as evidenced by data received from at least one physiological sensor.

[0022] In a fourteenth aspect, which may be based on any of the foregoing aspects, the one or more cells include at least one of the following: (i) autologous cells, (ii) allogeneic cells, (iii) a combination of autologous cells and allogeneic cells, (iv) a mixture in which at least one of the autologous cells and allogeneic cells has been modified, (v) genetically engineered cells, and (vi) genetically engineered T cells expressing a chimeric antigen receptor.

[0023] In a fifteenth aspect, which may be based on any of the foregoing aspects, one of the plurality of sensors is an ultrasonic sensor, and the suspension includes an ultrasonic contrast agent.

[0024] In a sixteenth aspect, which may be based on any of the foregoing aspects, at least one power driver is a pump system including an injector system.

[0025] In a seventeenth aspect, which may be based on any of the foregoing aspects, the second flow rate is one of flow stop and flow deceleration.

[0026] In an eighteenth aspect, which may be based on any of the foregoing aspects, at least one physiological sensor includes at least one of a blood pressure sensor, a heart rate sensor, a respiration sensor, a temperature sensor, and a chemical sensor.

[0027] In a nineteenth aspect, which may be based on any of the foregoing aspects, when determining that the patient is experiencing an adverse reaction, at least one processor is programmed or configured to cause at least one power driver to deliver a second therapeutic composition to the patient.

[0028] In a twentieth aspect, which may be based on any of the foregoing aspects, the second therapeutic composition includes at least one of a crystalloid solution, a colloid solution, and a corticosteroid, wherein the crystalloid solution includes at least one of normal saline, D5W, and lactated Ringer's solution.

[0029] In a twenty - first aspect, which may be based on any of the foregoing aspects, at least one processor is further programmed or configured to trigger at least one of an alarm and a warning when determining that data received from a plurality of sensors indicates any of the following: the pressure within at least one of the container and at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension within at least one fluid line is greater than a predetermined flow rate threshold; the number of ruptured cells among one or more cells in the suspension is greater than a predetermined rupture threshold; the occurrence of extravasation around the injection site; the temperature of the suspension within at least one fluid line is outside a predetermined temperature range; the occurrence of an immune response in the patient as evidenced by data received from at least one of a chemical sensor and at least one physiological sensor; and an adverse reaction experienced by the patient as evidenced by data received from at least one physiological sensor.

[0030] In a twenty - second aspect, which may be based on any of the foregoing aspects, the system further includes at least one flow regulator positioned within at least one fluid line, each of the at least one flow regulators being configured to be switchable between an open state and a closed state such that in the following cases: when it is determined that an increase in the volume of the therapeutic composition is required, at least one processor is programmed or configured to switch at least one flow regulator to the open state, thereby allowing at least one of a diluent and a buffer to be added to the suspension via at least one fluid line; when it is determined that a decrease in the volume of the therapeutic composition is required, at least one processor is programmed or configured to switch at least one flow regulator to the open state, thereby allowing a portion of the fluid in the suspension to be removed therefrom via at least one fluid line; and when it is detected that the number of ruptured cells among the one or more cells described above has reached a predetermined rupture threshold, at least one processor is programmed or configured to switch at least one flow regulator to the open state, thereby transferring the suspension to a separate fluid line of at least one fluid line for at least one of analysis and disposal.

[0031] In a twenty-third aspect, a system for delivering cell therapy to a patient is provided, comprising: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more autologous and / or allogeneic cells and an ultrasound contrast agent; a pump configured to expel the therapeutic composition from the container; at least one processor in communication with the pump; and a plurality of sensors in communication with the at least one processor, the plurality of sensors including at least: a cell count sensor configured to collect cell data, the cell data including the number of intact cells and / or lysed cells; a pressure sensor configured to collect pressure data, the pressure data including measurements of the pressure within the container and / or within one or more fluid lines between the container and the patient; a flow sensor configured to collect flow rate data, the flow rate data including measurements of the flow rate within one or more fluid lines between the container and the patient; an ultrasound transducer configured to be placed around a location where the therapeutic composition is injected into the patient and to collect extravasation data, the extravasation data indicating either the occurrence or non-occurrence of extravasation at that location; and at least one physiological sensor configured to collect physiological data, the physiological data including measurements of immune parameters, blood pressure, heart rate, respiratory rate, and / or temperature, wherein the at least one processor is programmed or configured to: control the pump to pressurize the therapeutic composition so as to deliver the therapeutic composition at a first flow rate; and determine, at least in part based on the cell data, the pressure data, the flow rate data, the extravasation data, and the physiological data, that the therapeutic composition should be delivered at the first flow rate; or that the therapeutic composition should be delivered at a second flow rate.

[0032] In a twenty-fourth aspect, which may be based on any of the foregoing aspects, it is determined, at least in part based on: at least in part based on the pressure data and / or the flow rate data, that the pressure and / or the flow rate is too high; at least in part based on the extravasation data, that an extravasation threat is occurring; at least in part based on the cell data, that more than a predetermined threshold number of cells have lysed; and / or at least in part based on the physiological data, that the patient is experiencing an adverse reaction.

[0033] In a twenty-fifth aspect, which may be based on any of the foregoing aspects, in the event that it is determined that: at least one of the flow rate and the pressure is too high; an extravasation threat is occurring; a threshold number of cells have lysed; and / or the patient is experiencing an adverse reaction, the at least one processor is further programmed or configured to control the pump to deliver the therapeutic composition at a second flow rate.

[0034] In a twenty-sixth aspect, which may be based on any of the foregoing aspects, the second flow rate is one of flow stop and flow deceleration.

[0035] In a twenty-seventh aspect, which may be based on any of the foregoing aspects, when it is determined that the flow rate and / or the pressure is too high, there is extravasation, a threshold number of cells have lysed, and / or the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to trigger a warning or an alarm.

[0036] In a twenty-eighth aspect, which may be based on any of the foregoing aspects, the alert is an audible alert, a visual alert, and / or a tactile alert.

[0037] In a twenty-ninth aspect, which may be based on any of the foregoing aspects, when it is determined that the patient is experiencing an adverse reaction, at least one processor is further programmed or configured to cause the pump to deliver a second therapeutic composition to the patient.

[0038] In a thirtieth aspect, which may be based on any of the foregoing aspects, the second therapeutic composition includes at least one of a crystalloid solution, a colloid solution, and a corticosteroid, wherein the crystalloid solution includes at least one of normal saline, D5W, and lactated Ringer's solution.

[0039] In a thirty-first aspect, which may be based on any of the foregoing aspects, the container is one of a syringe, a bag, a bottle, and a vial. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 A schematic diagram of a non-limiting example of an environment for implementing the devices, systems, and / or methods described herein;

[0041] Figure 2 For Figure 1 a schematic diagram of non-limiting aspects or examples of components of one or more devices and / or one or more systems; and

[0042] Figure 3 A flowchart of a non-limiting example of a process for delivering a therapeutic agent to a patient. DETAILED DESCRIPTION

[0043] For the purposes of the description below, the terms "end", "upper", "lower", "right", "left", "vertical", "horizontal", "top", "bottom", "lateral", "longitudinal", and their derivatives shall relate to the orientation disclosed in the drawings. However, it should be understood that the present disclosure may assume various alternative variations and step sequences, unless expressly specified to the contrary. It should also be understood that the specific devices and processes shown in the drawings and described in the following specification are merely exemplary embodiments or aspects of the present disclosure. Accordingly, unless otherwise specified, the specific dimensions and other physical characteristics related to the embodiments or aspects of the disclosure herein should not be considered limiting.

[0044] Any aspect, component, element, structure, act, step, function, instruction, etc. used herein should not be construed as critical or essential unless explicitly stated as such. Additionally, as used herein, the articles "a" and "an" are intended to include one or more items and may be used interchangeably with "one or more" and "at least one". Further, as used herein, the term "group" is intended to include one or more items (e.g., related items, unrelated items, combinations of related and unrelated items, etc.) and may be used interchangeably with "one or more" or "at least one". The term "one" or similar language is used when only one item is intended. Additionally, as used herein, the terms "have", "having", "contain", etc. are intended to be open-ended terms. Further, the phrase "based on" is intended to mean "at least partially based on" unless explicitly stated otherwise.

[0045] As used herein, the terms "communication" and "communicate" may refer to the reception, receipt, transmission, transfer, provision, etc. of information (e.g., data, signals, messages, instructions, commands, etc.). For one unit (e.g., a device, system, component of a device or system, a combination thereof, etc.) to communicate with another unit means that the one unit is capable of receiving information from and / or sending (e.g., transmitting) information to the other unit, directly or indirectly. This can refer to a direct or indirect connection that is inherently wired and / or wireless. Additionally, two units may communicate with each other even if the information transmitted can be modified, processed, relayed, and / or routed between the first and second units. For example, a first unit may communicate with a second unit even if the first unit passively receives information and does not actively send information to the second unit. As another example, if at least one intermediate unit (e.g., a third unit located between the first and second units) processes the information received from the first unit and sends the processed information to the second unit, then the first unit may communicate with the second unit. In some non-limiting embodiments, a message may refer to a network packet (e.g., a data packet, etc.) that includes data.

[0046] As used herein, the term "computing device" may refer to one or more electronic devices that are configured to communicate directly or indirectly with one or more networks or via one or more networks. In some non-limiting embodiments, a computing device may include a mobile device. A mobile device may include a smart phone, a portable computer, a wearable device (e.g., a watch, glasses, lenses, clothing, etc.), a Personal Digital Assistant (PDA), and / or other similar devices. In some non-limiting embodiments, a computing device may include a server, a desktop computer, etc.

[0047] As used herein, the term "system" may refer to one or more computing devices or a combination of computing devices, such as, but not limited to, processors, servers, client devices, software applications, and / or other similar components. Additionally, as used herein, a reference to a "server" or "processor" may refer to the previously recited server and / or processor that is recited as performing a previous step or function, a different server and / or processor, and / or a combination of servers and / or processors. For example, as used in the specification and claims, a first server and / or a first processor that is recited as performing a first step or function may refer to the same or a different server and / or processor that is recited as performing a second step or function.

[0048] Devices, systems, and methods are provided herein for delivering a therapeutic agent (e.g., one or more cells in a suspension) to a patient. The devices, systems, and methods described herein provide a technical solution to problems in the field of therapeutic delivery by integrating multiple sensors and / or data via an algorithm executed by a processor, addressing a number of problems that may be experienced during therapeutic delivery, which currently cannot be adequately solved in a simultaneous manner. The devices, systems, and methods described herein improve the functionality of existing delivery devices, such as cell delivery devices, and improve clinical outcomes.

[0049] Turning Figure 1 , in a non-limiting embodiment, a system 100 is provided herein that includes a container 110 configured to hold a therapeutic composition, a delivery device 120, and one or more sensors 140. Although the delivery device 120 and the container 110 are illustrated as separate components connected by (a) fluid line(s) 115, they may also be integrated together. The system 100 further includes a power driver 122 configured to deliver the therapeutic composition to a patient P. Again, although illustrated as part of the delivery device 120, the power driver 122 may be disposed within the container 110. In a non-limiting embodiment, the power driver 122 includes a pump system or other type of fluid pressurization system. Such a pump system may include an infusion system, a gravity feed system, and / or any combination of components. The delivery device 120 may further include a processor 124, a memory 126 for storing programming instructions to be executed by the processor 124, and a communication interface 128. Aspects of the processor 124, the memory 126, and the communication interface 128 are described below with reference to Figure 2 While the Figure 1A plurality of sensors 140 are shown in a particular arrangement and orientation, but those skilled in the art will understand that the number and arrangement of sensors 140 may be modified to achieve the objectives of the devices, systems, and methods disclosed herein. The sensors 140 may communicate with the processor 124 such that data detected by the sensors 140 may be received and analyzed by the processor 124, e.g., based on programming instructions transmitted to and / or stored in the memory 126.

[0050] The container 110 may be a syringe 110a, an intravenous infusion bag 100b, a vial 110c, a bottle, or any other vessel 110n capable of containing a therapeutic composition for delivery to a patient P. The container 110 may be lined with one or more suitable coatings to reduce adhesion of the therapeutic composition to one or more surfaces within the container 110. In non-limiting embodiments, the container 110 may include one or more sensors 140 or be associated with one or more sensors 140, e.g., during loading, transportation, and use, e.g., by the system 100, to monitor the status of the therapeutic composition received within the container 110. In non-limiting embodiments, such sensors 140 may include optical sensors, force sensors, and / or temperature sensors. In non-limiting embodiments, such optical sensors are configured to permit analysis of one or more cells received within the container 110, e.g., by detection of one or more tracers (e.g., radiolabels, iron oxide nanoparticles, gallium), cell morphology, and / or digital pathology. Non-invasive tracking methods are known to those skilled in the art, e.g., as disclosed in Kircher et al., “Non-invasive cell tracking methods,” Nature Reviews Clinical Oncology 2011, 8:677-688.

[0051] A processor associated with the system 100 described herein may utilize data received from the sensor(s) 140 to control the delivery of a therapeutic composition received within the container 110, as described herein. In a non-limiting embodiment, a processor associated with the system 100 receives data from one or more sensors 140 and may determine whether delivery of the therapeutic composition within the container 110 should be initiated based on data collected by the sensor(s) 140 during loading and / or transportation. For example, if the therapeutic composition contained within the container 110 is exposed to forces, chemical conditions (pH), temperature, mean kinetic temperature, etc. outside of a predetermined acceptable parameter range (e.g., from about 40 degrees Celsius to about 50 degrees Celsius, above about 50 degrees Celsius, and / or between 43 degrees Celsius and 50 degrees Celsius, including all values and sub-ranges therebetween), e.g., above a certain threshold and for a duration exceeding the threshold duration, the therapeutic composition should not be delivered to a patient. The processor 124 may provide an alert, such as an audible, visual, and / or tactile alert, indicating that delivery of the therapeutic composition should not be initiated. In a non-limiting embodiment, when determining that the therapeutic composition should not be delivered to a patient, the processor 124 may prevent the initiation of delivery of the therapeutic composition, and in a non-limiting embodiment, the prevention of delivery may or may not be revoked, e.g., by entering a password or other authentication.

[0052] In a non-limiting embodiment, the container 110 may include one or more ports to allow withdrawal of a portion of the therapeutic composition received therein for one or more external analyses. Non-limiting examples of such analyses include microplate assays, such as alamarBlue ® , PrestoBlue ® , CyQUANT ® and MTT assays, including those available from ThermoFisher Scientific (Watham, MA). Other analyses include fluorescence and / or dye tests (including the tests described in Kim et al., "Application of non-toxic viability dyes for cell counting using an automated cell counter," Analytical Biochemistry. 2016, 492(2): 8-12), visual inspection by using a camera, and / or other analyses suitable for determining the status of the therapeutic composition, such as one or more cells, as known to those skilled in the art.

[0053] In non-limiting embodiments, the fluid line(s) 115 can be flexible and / or rigid and can include one or more lumens therein. In non-limiting embodiments, the container 110 and / or the fluid line(s) 115 can include one or more flow regulators 141, such as valves and / or one or more agitators, such as those described in U.S. Patent No. 6,575,930, the content of which is incorporated herein by reference in its entirety. In non-limiting embodiments, the fluid line(s) 115 include one or more needles disposed at its / their ends to assist in delivering a therapeutic composition to the patient P. Suitable needles are known to those of skill in the art and can include any useful features, depending on the therapeutic composition to be delivered, including various bevels.

[0054] In non-limiting embodiments, the therapeutic composition is one or more cells in suspension. Suitable suspensions for maintaining cell viability are known to those of skill in the art. In non-limiting embodiments, the suspension includes one or more ultrasound contrast agents to permit detection of extravasation, as described below. In non-limiting embodiments, for a disrupted cell suspension, extravasation can be monitored audibly by measuring the sound from bubbles injected into the tissue near the injection site, e.g., by popping. In non-limiting embodiments, extravasation is monitored based on the absence of an ultrasound return signal from bubble disruption at or near the injection site. In addition to extravasation, other parameters can also be monitored with ultrasound, e.g., blood pH as a measure of inflammation, for example, can be measured with ultrasound (see, e.g., "Dynamic solid-state ultrasound contrast agents for monitoring in vivo pH fluctuations" by Walker et al., ACS Sens. 2020, Vol. 5, No. 4, pp. 1190-1197). In non-limiting embodiments, the therapeutic composition includes one or more autologous cells, one or more allogeneic cells, and / or one or more genetically engineered cells, such as chimeric antigen receptor T cells (CAR-T cells). In non-limiting embodiments, the therapeutic composition includes autologous cells, allogeneic cells, a combination of autologous and allogeneic cells, a mixture in which at least one of the autologous and allogeneic cells has been modified, genetically engineered cells, and / or CAR-T cells.

[0055] Continuing reference Figure 1, in non-limiting embodiments, the sensor 140 includes one or more of the counting sensors 140a, configured to count whole cells and / or lysed cells; a pressure sensor 140b, configured to detect the pressure within the container 110 and / or one or more fluid lines 115; a flow sensor 140c, configured to detect the flow rate within one or more fluid lines 115; a position sensor 140d, configured to detect extravasation; and / or a physiological sensor 140e, configured to detect one or more physiological characteristics of the patient P; and / or any other type of sensor 140n. In non-limiting embodiments, the cell counter, pressure, and / or flow sensors may be disposed within the container 110 and / or the fluid line(s) 115 or on the container 110 and / or the fluid line(s) 115. As used herein, the term “lysed cell” refers to a cell that is damaged, inactive, deteriorated, or unable to contribute to the desired therapeutic response of the patient.

[0056] Suitable sensors for counting whole cells and / or lysed cells are known to those of skill in the art and may include those described in https: / / www.nist.gov / programs-projects / cell-counting-cell-therapies. In non-limiting embodiments, suitable sensors for counting include sensors that measure hemolysis as an indirect measure of cell viability, optionally by measuring the conductivity of the cell suspension (see, e.g., Van Buren et al., “A simple method for real-time monitoring of hemolysis,” Sci Rep. 2020; 10, 5101; e.g., “Optofluidic sensor for online hemolysis detection in whole blood” by Zhuo et al., ACS Sens. 2018, Vol. 3, No. 4, pp. 784-791).

[0057] A sensor 140 configured to detect flow rate, viscosity, and / or pressure can be used to determine the microenvironment to which the therapeutic composition is exposed, which can be used in various assays and processes described herein, such as determining the forces applied to the therapeutic composition, such as shear forces, which can have a negative impact on the therapeutic composition (e.g., by causing unacceptable levels of cell lysis). In non-limiting embodiments, one or more sensors 140 can measure one or more parameters of the therapeutic composition exiting the container 110 and / or passing through the fluid line(s) 115, and the processor 124 can, upon receiving data from the sensor(s) 140 (and in non-limiting embodiments, at least in part based on the diameter of the fluid line(s) 115), adjust one or more parameters of the delivery of the therapeutic composition, such as but not limited to the flow rate and / or viscosity of the therapeutic composition. In non-limiting embodiments, one or more sensors 140 can measure the viscosity of the therapeutic composition exiting the container 110 and / or passing through the fluid line(s) 115, and the processor 124 can, upon receiving viscosity data from the sensor(s) 140, adjust the viscosity of the therapeutic composition, such as by adding a lower viscosity fluid (e.g., buffer and / or saline) or causing a lower viscosity fluid (e.g., buffer and / or saline) to be removed from the container 110 and / or the fluid line(s) 115. In non-limiting embodiments, the viscosity can be adjusted by using a siphon (e.g., separating fluid from a fluid containing cells).

[0058] In non-limiting embodiments, one or more sensors 140, such as physiological sensors, can be disposed within or on the patient P. In non-limiting embodiments, the sensor 140 is a position sensor (e.g., a sensor configured to be placed at or near the location where the therapeutic composition is introduced into the patient), and can be a sensor configured to detect extravasation. Sensors and systems for detecting extravasation are known to those of skill in the art and are described, for example, in Hirata et al., "Sensing Technologies for Extravasation Detection: A Review," ACS Sens, 2023, 8:1017-1032. Suitable systems and sensors can include ultrasound, optical sensors, microbubbles, etc. In non-limiting embodiments, the sensor 140 configured to detect extravasation is an ultrasound transducer, and optionally, the therapeutic composition being delivered includes an ultrasound contrast agent. In non-limiting embodiments, the sensor 140 configured to detect extravasation is an optical sensor (e.g., a sensor sold by ivWatch LLC of Newport News, Virginia). In non-limiting embodiments, one or more of the sensors 140 are sensors configured to detect surface tension and / or stiffness at the injection site of the patient, which can be used to assess extravasation.

[0059] In non-limiting embodiments, one or more physiological sensors are one or more of the sensors for detecting a patient's blood pressure, blood pH, heart rate (including ECG / EKG), oxygen saturation (including pulse oximeter), white blood cell count (including non-invasive white blood cell count sensors such as those developed by Leuko Labs, Inc. in Boston, Massachusetts), brain activity (including EEG), pupil dilation, respiratory rate, vocalization (such as a microphone), movement, and / or temperature (including sweating and / or skin flushing). Those skilled in the art will understand that the delivery of any therapeutic composition, such as cell therapy, such as CAR-T therapy, may be accompanied by adverse events, which may trigger immune responses, such as allergic reactions, cytokine storms (also known as cytokine release syndrome) and / or anaphylactic reactions, and any suitable sensors for detecting such adverse events may be used herein, including chemical sensors for detecting one or more parameters indicative of an immune response, including but not limited to sensors for detecting histamine, cytokines, mast cells, immunoglobulins, C-reactive protein (CRP), D-dimer, and growth factor levels. In non-limiting embodiments, the chemical sensor is an electrochemical sensor. Suitable sensors for detecting immune responses include those described in Xu et al., "Real-time monitoring and early warning of in vivo cytokine storms using a wearable non-invasive skin microneedle patch", Advanced Healthcare Materials 2023, 12(18): e2203133.

[0060] In non-limiting embodiments, system 100 includes a communication network 160 to provide connections between the various components of the system, such as between the (multiple) sensors 140, the (multiple) flow regulators 141, and the delivery device 120. The communication network 160 may include one or more wired and / or wireless networks. For example, the communication network 160 may include a cellular network (e.g., Long-Term Evolution (LTE) network, Third Generation (3G) network, Fourth Generation (4G) network, Fifth Generation (5G) network, Sixth Generation (6G) network, Code Division Multiple Access (CDMA) network, etc.), a Public Land Mobile Network (PLMN), a Local Area Network (LAN), a Wide Area Network (WAN), a Metropolitan Area Network (MAN), a telephone network (e.g., Public Switched Telephone Network (PSTN)), a private network, an ad hoc network, an intranet, the Internet, a fiber-based network, a cloud computing network, etc., and / or a combination of some or all of these or other types of networks.

[0061] Figure 1 The number and arrangement of the systems and / or devices shown are provided as an example. Compared with Figure 1 the systems and / or devices shown therein, there may be additional systems and / or devices, fewer systems and / or devices, different systems and / or devices, or differently arranged systems and / or devices. Additionally,Figure 1 The two or more systems and / or devices shown may be implemented within a single system or a single device, or Figure 1 the single system or single device shown may be implemented as multiple distributed systems or devices. Additionally or alternatively, a set of systems or a set of devices of system 100 (e.g., one or more systems, one or more devices) may perform one or more functions described as being performed by another set of systems or another set of devices of system 100.

[0062] Now referring to Figure 2 , a diagram showing example components of device 200 is shown. Device 200 may correspond to cell delivery device 120 and / or communication network 160 (e.g., one or more devices of communication network 160). In some non-limiting embodiments or aspects, cell delivery device 120 and / or communication network 160 may include at least one device 200 and / or at least one component of device 200. As Figure 2 shown, device 200 may include bus 202, processor 204, memory 206, storage component 208, input component 210, output component 212, and / or communication interface 214.

[0063] Bus 202 may include components that permit communication between the components of device 200. In some non-limiting embodiments or aspects, processor 204 may be implemented in hardware, software, or a combination of hardware and software. For example, processor 204 may include a processor (e.g., a central processing unit (CPU), a graphics processing unit (GPU), an accelerated processing unit (APU), etc.), a microprocessor, a digital signal processor (DSP), and / or any processing component that can be programmed to perform functions (e.g., a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), etc.). Memory 206 may include random access memory (RAM), read only memory (ROM), and / or another type of dynamic or static storage device that stores information and / or instructions for use by processor 204 (e.g., flash memory, magnetic memory, optical memory, etc.).

[0064] Storage component 208 may store information and / or software related to the operation and use of device 200. For example, storage component 208 may include a hard disk (e.g., a magnetic disk, an optical disk, a magneto-optical disk, a solid state disk, etc.), a compact disc (CD), a digital versatile disc (DVD), a floppy disk, a cassette tape, a magnetic tape, and / or other types of computer-readable media, as well as corresponding drives.

[0065] The input component 210 may include components that allow the device 200 to receive information, such as via user input (e.g., touch screen display, keyboard, keypad, mouse, buttons, switches, microphone, camera, etc.). Additionally or alternatively, the input component 210 may include sensors for sensing information (e.g., Global Positioning System (GPS) component, accelerometer, gyroscope, actuator, etc.). The output component 212 may include components that provide output information from the device 200 (e.g., display, speaker, one or more light emitting diodes (LEDs), etc.).

[0066] The communication interface 214 may include transceiver-like components (e.g., transceiver, separate receiver and transmitter, etc.) that enable the device 200 to communicate with other devices, such as via a wired connection, wireless connection, or a combination of wired and wireless connections. The communication interface 214 may allow the device 200 to receive information from and / or provide information to another device. For example, the communication interface 214 may include an Ethernet interface, optical interface, coaxial interface, infrared interface, radio frequency (RF) interface, Universal Serial Bus (USB) interface, Wi-Fi interface, cellular network interface, etc.

[0067] The device 200 may perform one or more of the processes described herein. The device 200 may execute these processes based on software instructions stored by a computer-readable medium such as the memory 206 and / or the storage component 208 and executed by a processor 204. A computer-readable medium (e.g., non-transitory computer-readable medium) is defined herein as a non-transitory memory device. A non-transitory memory device includes a memory space located within a single physical storage device or a memory space distributed across multiple physical storage devices.

[0068] The software instructions may be read into the memory 206 and / or the storage component 208 from another computer-readable medium or another device via the communication interface 214. When executed, the software instructions stored in the memory 206 and / or the storage component 208 may cause the processor 204 to perform one or more of the processes described herein. Additionally or alternatively, hardwired circuitry may be used in place of or in combination with software instructions to perform one or more of the processes described herein. Thus, the embodiments or aspects described herein are not limited to any particular combination of hardware circuitry and software.

[0069] The memory 206 and / or the storage component 208 may include a data store or one or more data structures (e.g., database, etc.). The device 200 is capable of retrieving information from, storing information in, or searching for information stored in the data store or one or more data structures in the memory 206 and / or the storage component 208. For example, the information may include encrypted data, input data, output data, transaction data, account data, or any combination thereof.

[0070] Figure 2 The number and arrangement of components shown are provided as an example. In some non-limiting embodiments or aspects, device 200 may include more components, fewer components, different components, or components arranged differently than those shown in Figure 2 . Additionally or alternatively, a set of components (e.g., one or more components) of device 200 may perform one or more functions described as being performed by another set of components of device 200.

[0071] Referring to Figure 1 and Figure 3 , in a non-limiting embodiment, delivery device 120 controls the delivery of a therapeutic composition by processor 124 ( Figure 3 , 300). In a non-limiting embodiment, delivery device 120 controls power driver 122 to deliver the therapeutic composition at a first flow rate ( Figure 3 , 302), which may be a desired flow rate. Through the communication between processor 124 and one or more sensors 140 ( Figure 3 , 304) and between processor 124 and power driver 122, delivery device 120 can adjust the flow rate, pressure, viscosity, etc. ( Figure 3 , 306) based on data received from the sensor(s). The operation adjustment of system 100 may be based on, but not limited to, detecting that the pressure in container 110 and / or one or more fluid lines 115 is greater than a predetermined pressure threshold, determining that the flow rate of the therapeutic composition in one or more fluid lines 115 is greater than a predetermined flow rate threshold, the number of ruptured cells in the therapeutic composition is greater than a predetermined rupture threshold, extravasation is occurring or threatened around the injection site, the temperature of the therapeutic composition in one or more fluid lines 115 is outside a predetermined temperature range, an immune response is occurring or may occur in the patient, and / or the patient is experiencing or may experience an adverse event in the patient. For example, when the data indicates that the number of ruptured cells exceeds a predetermined threshold (optionally stored in memory 126), the pressure in container 110 or one or more fluid lines 115 is too high, the flow rate in one or more fluid lines 115 is too high, the therapeutic composition has leaked from the injection site (extravasation), and / or patient P is experiencing an adverse event (e.g., an immune response), the flow rate may be reduced to a second flow rate ( Figure 3, 308), which may be a desired flow rate, and in non-limiting embodiments, the second flow rate may be zero (e.g., cessation of delivery of the therapeutic composition). Those skilled in the art will understand that various algorithms can be utilized to determine whether the flow rate should be decreased, including, for example but not limited to, applying various weighting factors and / or various thresholds. In non-limiting embodiments, one or more useful algorithms may involve shear stress and / or any of the parameters described herein regarding cell viability, delivery, patient monitoring, and / or patient movement.

[0072] Although cell rupture was illustrated above, a predetermined threshold and / or range may be provided for any parameter for which a sensor is provided, and in non-limiting embodiments, the range / threshold is stored in the memory 126. In non-limiting embodiments, when the data received from one or more sensors 140 is within the appropriate range, the delivery of the therapeutic composition may continue at a first flow rate, where data collection continues ( Figure 3 , 304). In the case where the therapeutic composition is below the expected or desired concentration, for example, if a slightly increased level of ruptured cells is sensed before or during injection, but not in an unsafe manner, the total volume and / or flow rate may be increased in order to deliver a sufficient total dose to achieve the desired therapeutic delivery and therapeutic response. In this example, the second flow rate may be higher than the first flow rate. In non-limiting embodiments, the flow rate may be decreased (e.g., the second flow rate may be lower than the first flow rate), but an increased volume of the therapeutic composition may be delivered (e.g., as described below), such as by delivering the therapeutic composition for an increased amount of time.

[0073] In non-limiting embodiments, in addition to regulating the flow rate, if any predetermined threshold is exceeded, the delivery device 120 may trigger an alarm, thereby reducing the flow rate. Suitable alarms may be auditory, visual, and / or tactile. The alarm may be presented on the delivery device 120 (which may have a user interface, such as a display), and / or since the delivery device 120 includes a communication interface 128, the alarm may be transmitted to a device associated with a healthcare professional (e.g., a nurse, technician, or doctor).

[0074] In non-limiting embodiments, as a supplement or alternative to regulating the flow rate, the system 100 may be configured to regulate the volume of the therapeutic composition based on the processor 124. In non-limiting embodiments, the system may be configured to transfer a portion of the therapeutic composition out of the fluid line(s) 115 for testing and / or disposal, and / or add a buffer and / or diluent to the fluid line(s) 115. For example, but not limited to, as Figure 1As shown, system 100 can be configured such that at one or more locations along one or more fluid lines 115, a flow regulator 141 can be disposed. The flow regulator 141 can be configured to have an open state (e.g., where fluid can pass through the flow regulator 141 and continue along the one or more fluid lines 115) and a closed state (e.g., where fluid cannot pass through the flow regulator 141). In non-limiting embodiments, one or more such flow regulators 141 can allow fluid to be withdrawn from the one or more fluid lines 115 (e.g., reducing volume, increasing viscosity, and / or decreasing viscosity) and / or fluid to be added to the one or more fluid lines 115 (e.g., increasing volume, increasing viscosity, and / or decreasing viscosity). In non-limiting embodiments, the amount of fluid in the one or more fluid lines 115 can be adjusted to allow, for example, aggregation or separation of cells in the one or more fluid lines 115.

[0075] In non-limiting embodiments, one or more sensors 140 can be disposed coextensively with one or more such flow regulators 141 such that one or more parameters of the therapeutic composition can be analyzed prior to continuous delivery through the one or more fluid lines 115. For example, in non-limiting embodiments, one or more sensors 140 can be disposed at or near the flow regulator 141 and can be configured to detect cell lysis in the therapeutic composition in conjunction with the processor 124 (e.g., based on the forces to which the therapeutic composition is exposed during delivery through the one or more fluid lines 115 including any needles, such as described in Wahlberg et al., "In Vitro Biomechanical Characterization of Syringe-Needle Injection for Intracerebral Cell Delivery," Scientific Reports 2018, 8:9194). If the number of lysed cells reaches a certain threshold, one or more of the one or more flow regulators 141 can be opened to allow the therapeutic composition containing the cells to flow into a separate fluid line 116 for further analysis and / or processing. While Figure 1 a particular orientation and arrangement of the one or more sensors 140 and the one or more flow regulators 141 is shown, those skilled in the art will understand that variations can be made.

[0076] In non-limiting embodiments, the fluid line(s) 115 may include one or more filtration and / or microfluidic mechanisms for separating debris from the therapeutic composition and / or for concentrating the therapeutic composition. For example, the fluid line(s) 115 may include one or more filters configured to restrict the flow of debris from lysed cells from being introduced into the patient. Suitable non-limiting examples of concentration and / or filtration mechanisms include microfluidics (e.g., as described in “Continuous-flow microfluidic bioparticle concentrator” by Martel et al., Scientific Reports 2015, 5:11300), fluorescence-activated cell sorting (FACS), flow-through cell concentrators, fluctuations in the fluid line(s) 115, the use of siphon lines (e.g., for separating fluid from a fluid containing cells), magnetic bead sorting, centrifugation, and / or microbubble sorting (e.g., available from Akadeum LifeSciences, Inc., Ann Arbor, Michigan). In non-limiting embodiments, the fluid line(s) 115 may be a dual-lumen catheter that may be used to concentrate the therapeutic composition and / or deliver the therapeutic composition and / or a second therapeutic composition during delivery, as described herein. In non-limiting embodiments, the dual-lumen nature of the fluid line(s) 115 extends to the delivery needle in fluid communication with the fluid line(s) 115.

[0077] In non-limiting embodiments, when the data received from the sensor 140 indicates an adverse event, the delivery device 120 may cause the power driver 122 or a second driver to deliver a second therapeutic composition, e.g., a therapeutic composition for treating the adverse event, via the processor 124. In non-limiting embodiments, the data received from the sensor(s) 140 may indicate that an immune response, e.g., a cytokine storm, may be occurring or is occurring in the patient P. Non-limiting examples of suitable sensors 140 for determining that an immune response, e.g., a cytokine storm, is occurring in a patient include those described in “Real-time monitoring and early warning of in vivo cytokine storm using a wearable non-invasive skin microneedle patch” by Xu et al., Advanced Healthcare Materials 2023, 12(18):2203133.

[0078] In non-limiting embodiments, if data received from the sensor(s) 140 indicate that a cytokine storm may be occurring or is occurring, the processor 124 may initiate, for example, the flushing or delivery of a second therapeutic composition, such as a crystalloid solution, a colloid solution, saline, an immunosuppressant, a beta agonist, epinephrine (or other adrenergic agonist), a cytokine, and / or a cytokine inhibitor (e.g., an IL-7 inhibitor), D5W (aqueous dextrose solution), lactated Ringer's solution, and / or a corticosteroid. In non-limiting embodiments, the power driver 122 or the second driver may include a fluid line (or one or more additional lumens within the fluid line(s) 115) that coextends with the fluid line 115, and the flow regulator(s) 141 may be configured such that multiple configurations are possible, e.g., a closed position of the fluid line(s) 115; an open position of the fluid line(s) 115; a closed position of an additional fluid line (and / or lumen) for connection to a flushing / delivery container; and / or an open position of the additional fluid line(s) (and / or lumen) for connection to a flushing / delivery container. The delivery of the second therapeutic composition may be an alternative to the continuous delivery of the therapeutic composition from the container 110, and / or may occur in parallel with the continuous delivery of the therapeutic composition.

[0079] In non-limiting embodiments, the processor 124 pauses the delivery of the therapeutic composition in response to determining that an immune response, such as a cytokine storm, may be occurring or is occurring in the patient, and / or in response to receiving a signal indicating that the patient call button has been activated. In non-limiting embodiments, the processor 124 automatically pauses the delivery of the therapeutic composition and / or causes the delivery of the second therapeutic composition described herein, either through the system 100 and / or through different systems with which the system 100 may communicate. In non-limiting embodiments, the processor 124 causes the display and / or speaker to provide an indication that the delivery of the therapeutic composition should be paused and / or stopped, and / or that the delivery of the second therapeutic composition described herein should begin, in response to determining that a cytokine storm may be occurring or is occurring in the patient, and / or in response to receiving a signal indicating that the patient call button has been activated. The processor 124 may also provide, for example, through the display and / or speaker, one or more alternative mitigation strategies.

[0080] In a non-limiting embodiment, system 100 may communicate with a database storing one or more records of a patient, such as one or more records of previous treatments using a therapeutic composition, including, for example, the identity of the therapeutic composition, one or more side effects, one or more delivery thresholds of the therapeutic composition that result in side effects (e.g., pressure, flow rate, number of lysed cells, and / or concentration of debris), and / or the identity of one or more second therapeutic compositions that effectively mitigate one or more side effects of the patient. In a non-limiting embodiment, system 100 is configured to deliver one or more second therapeutic agents as described herein before delivering the therapeutic composition. In a non-limiting embodiment, system 100 is configured to provide an alert that one or more second therapeutic agents should be delivered.

[0081] Although the above devices, systems, and methods have been described in detail for purposes of illustration based on presently considered to be the most practical and preferred embodiments or aspects, it is to be understood that such detailed description is for that purpose only and that the disclosure is not limited to the described embodiments or aspects. On the contrary, it is intended to cover modifications and equivalent arrangements within the spirit and scope of the appended claims. For example, it is to be understood that the disclosure contemplates that, to the extent possible, one or more features of any embodiment or aspect may be combined with one or more features of any other embodiment or aspect.

Claims

1. A system for delivering cell therapy to a patient, comprising: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more cells in suspension; at least one power driver operably connected to the container, the at least one power driver being configured to pressurize the therapeutic composition within the container and at least one fluid line in communication therewith; a control system having a plurality of sensors and at least one processor, the at least one processor being programmed or configured to receive data from the plurality of sensors and to control the at least one power driver at least in part based on the data so as to pressurize the therapeutic composition within the container and the at least one fluid line, thereby injecting the therapeutic composition into the patient at a first flow rate; the plurality of sensors comprising at least two of the following: a pressure sensor for measuring and providing data indicative of the pressure within the container and the at least one fluid line; a flow sensor for measuring and providing data indicative of the actual flow rate of the suspension within the at least one fluid line; a counting sensor for providing data indicative of a count of at least one of the following within the suspension flowing through the at least one fluid line: (i) the number of the one or more cells remaining intact and (ii) the number of the one or more cells that have ruptured; a position sensor for placement around the location where the suspension is injected into the patient and for providing data indicative of either the occurrence or non-occurrence of extravasation thereat; a temperature sensor for measuring and providing data indicative of the temperature of the suspension within the at least one fluid line; a chemical sensor for detecting and providing data indicative of the occurrence of an immune response in the patient; and at least one physiological sensor for measuring and providing data indicative of at least one parameter of the patient; wherein the at least one processor is further programmed or configured to control the at least one power driver to pressurize the therapeutic composition within the container so as to inject the therapeutic composition into the patient at a second flow rate when it is determined that data received from the plurality of sensors indicates at least one of the following: the pressure within at least one of the container and the at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension within the at least one fluid line is greater than a predetermined flow rate threshold; the number of the one or more cells that have ruptured within the suspension is greater than a predetermined rupture threshold; the occurrence of a threat of extravasation around the injection location; the temperature of the suspension within the at least one fluid line is outside a predetermined temperature range; the occurrence of an immune response in the patient as evidenced by data received from at least one of the chemical sensor and the at least one physiological sensor; and an adverse reaction experienced by the patient as evidenced by data received from the at least one physiological sensor.

2. The system according to claim 1, wherein the container is one of a syringe, a bag, a bottle, and a vial.

3. The system according to claim 1, wherein the one or more cells comprise at least one of the following: (i) autologous cells, (ii) allogeneic cells, (iii) a combination of the autologous cells and the allogeneic cells, (iv) a mixture in which at least one of the autologous cells and the allogeneic cells has been modified, (v) genetically engineered cells, and (vi) genetically engineered T cells expressing a chimeric antigen receptor.

4. The system according to claim 1, wherein, one of the plurality of sensors is an ultrasonic sensor, and the suspension comprises an ultrasonic contrast agent.

5. The system according to claim 1, wherein, the at least one power driver is a pump system including an injector system.

6. The system according to claim 1, wherein, the second flow rate is one of flow stop and flow deceleration.

7. The system according to claim 1, wherein, the at least one physiological sensor comprises at least one of a blood pressure sensor, a heart rate sensor, a respiration sensor, a temperature sensor, and a chemical sensor.

8. The system according to claim 1, wherein, when determining that the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to cause the at least one power driver to deliver a second therapeutic composition to the patient.

9. The system according to claim 8, wherein the second therapeutic composition comprises at least one of a crystalloid solution, a colloid solution, and a corticosteroid, and wherein the crystalloid solution comprises at least one of normal saline, D5W, and lactated Ringer's solution.

10. The system according to claim 1, wherein, the at least one processor is further programmed or configured to trigger at least one of an alarm and a warning when determining that data received from the plurality of sensors indicates any of the following: the pressure in at least one of the container and the at least one fluid line is greater than the predetermined pressure threshold; the flow rate of the suspension in the at least one fluid line is greater than the predetermined flow rate threshold; the number of ruptured ones of the one or more cells in the suspension is greater than the predetermined rupture threshold; the occurrence of extravasation around the injection site; the temperature of the suspension in the at least one fluid line is outside the predetermined temperature range; the occurrence of an immune response in the patient as evidenced by data received from at least one of the chemical sensor and the at least one physiological sensor; and an adverse reaction experienced by the patient as evidenced by data received from the at least one physiological sensor.

11. The system according to claim 1, further comprising at least one flow regulator positioned within the at least one fluid line, each of the at least one flow regulators being configured to be switchable between an open state and a closed state such that: when determining that an increase in the volume of the therapeutic composition is required, the at least one processor is programmed or configured to switch the at least one flow regulator to the open state, thereby allowing at least one of a diluent and a buffer to be added to the suspension via the at least one fluid line; When it is determined that the volume of the therapeutic composition needs to be reduced, the at least one processor is programmed or configured to switch the at least one flow regulator to the open state, thereby allowing a portion of the fluid in the suspension to be removed therefrom via the at least one fluid line; and When it is detected that the number of the one or more cells that have ruptured has reached the predetermined rupture threshold, the at least one processor is programmed or configured to switch the at least one flow regulator to the open state, thereby transferring the suspension to a separate fluid line of the at least one fluid line for at least one of analysis and disposal.

12. A system for delivering cell therapy to a patient, comprising: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more cells in suspension; at least one power driver operably connected to the container, the at least one power driver being configured to pressurize the therapeutic composition within the container and at least one fluid line in communication therewith; a plurality of sensors, the plurality of sensors including at least two of the following: (i) a pressure sensor for measuring and providing data indicative of the pressure within the container and the at least one fluid line, (ii) a flow sensor for measuring and providing data indicative of the actual flow rate of the suspension within the at least one fluid line, (iii) a counting sensor for providing data indicative of a count of at least one of the following within the suspension flowing through the at least one fluid line: (i) the number of the one or more cells that remain intact and (ii) the number of the one or more cells that have ruptured, (iv) a position sensor for placement around the location where the suspension is injected into the patient and for providing data indicative of either the occurrence or non-occurrence of extravasation thereat, (v) a temperature sensor for measuring and providing data indicative of the temperature of the suspension within the at least one fluid line, (vi) a chemical sensor for detecting and providing data indicative of the occurrence of an immune response in the patient; and (vii) at least one physiological sensor for measuring and providing data indicative of at least one parameter of the patient; and at least one processor, the at least one processor being programmed or configured to receive data from the plurality of sensors and to control the at least one power driver at least in part based on the data so as to pressurize the therapeutic composition within the container and the at least one fluid line, thereby injecting the therapeutic composition into the patient at a desired flow rate, the magnitude of the desired flow rate depending on the data received from the plurality of sensors.

13. The system according to claim 12, wherein the desired flow rate is initially a first flow rate, but changes to a second flow rate when the data received by the at least one processor from the plurality of sensors indicates at least one of the following: the pressure within at least one of the container and the at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension within the at least one fluid line is greater than a predetermined flow rate threshold; The number of ruptured ones among the one or more cells in the suspension is greater than a predetermined rupture threshold; The occurrence of extravasation around the injection site; The temperature of the suspension within the at least one fluid line is outside a predetermined temperature range; The occurrence of an immune response in the patient as evidenced by data received from at least one of the chemical sensor and the at least one physiological sensor; and An adverse reaction experienced by the patient as evidenced by data received from the at least one physiological sensor.

14. The system according to claim 12, wherein the one or more cells include at least one of the following: (i) autologous cells, (ii) allogeneic cells, (iii) a combination of the autologous cells and the allogeneic cells, (iv) a mixture in which at least one of the autologous cells and the allogeneic cells has been modified, (v) genetically engineered cells, and (vi) genetically engineered T cells expressing a chimeric antigen receptor.

15. The system according to claim 12, wherein one of the plurality of sensors is an ultrasonic sensor, and the suspension includes an ultrasonic contrast agent.

16. The system according to claim 12, wherein, The at least one power driver is a pump system including an injector system.

17. The system according to claim 12, wherein, The second flow rate is one of flow stop and flow deceleration.

18. The system according to claim 12, wherein, The at least one physiological sensor includes at least one of a blood pressure sensor, a heart rate sensor, a respiration sensor, a temperature sensor, and a chemical sensor.

19. The system according to claim 12, wherein, When determining that the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to cause the at least one power driver to deliver a second therapeutic composition to the patient.

20. The system according to claim 19, wherein the second therapeutic composition includes at least one of a crystalloid solution, a colloid solution, and a corticosteroid, and wherein the crystalloid solution includes at least one of normal saline, D5W, and lactated Ringer's solution.

21. The system according to claim 12, wherein, The at least one processor is further programmed or configured to trigger at least one of an alarm and a warning when determining that data received from the plurality of sensors indicates any of the following: The pressure within at least one of the container and the at least one fluid line is greater than a predetermined pressure threshold; The flow rate of the suspension within the at least one fluid line is greater than a predetermined flow rate threshold; The number of ruptured ones among the one or more cells in the suspension is greater than a predetermined rupture threshold; The occurrence of extravasation around the injection site; The temperature of the suspension within the at least one fluid line is outside a predetermined temperature range; The occurrence of an immune response in the patient as evidenced by data received from at least one of the chemical sensor and the at least one physiological sensor; and An adverse reaction experienced by the patient as evidenced by data received from the at least one physiological sensor.

22. The system according to claim 12, further comprising at least one flow regulator positioned within the at least one fluid line, each of the at least one flow regulators being configured to be switchable between an open state and a closed state such that: when it is determined that an increase in the volume of the therapeutic composition is required, the at least one processor is programmed or configured to switch the at least one flow regulator to the open state, thereby allowing at least one of a diluent and a buffer to be added to the suspension via the at least one fluid line; when it is determined that a decrease in the volume of the therapeutic composition is required, the at least one processor is programmed or configured to switch the at least one flow regulator to the open state, thereby allowing a portion of the fluid in the suspension to be removed therefrom via the at least one fluid line; and when it is detected that the number of ruptured cells among the one or more cells above has reached a predetermined rupture threshold, the at least one processor is programmed or configured to switch the at least one flow regulator to the open state, thereby transferring the suspension to a separate fluid line of the at least one fluid line for at least one of analysis and disposal.

23. A system for delivering cell therapy to a patient, comprising: a container configured to contain a therapeutic composition, the therapeutic composition comprising one or more autologous and / or allogeneic cells and an ultrasound contrast agent; a pump configured to discharge the therapeutic composition from the container; at least one processor in communication with the pump; and a plurality of sensors in communication with the at least one processor, the plurality of sensors including at least: a counting sensor configured to collect cell data, the cell data including the number of intact cells and / or ruptured cells; a pressure sensor configured to collect pressure data, the pressure data including measurements of the pressure within the container and / or within one or more fluid lines between the container and the patient; a flow sensor configured to collect flow data, the flow data including measurements of the flow rate within one or more fluid lines between the container and the patient; an ultrasound transducer configured to be placed around the location where the therapeutic composition is injected into the patient and to collect extravasation data, the extravasation data indicating either the occurrence or non-occurrence of extravasation at that location; at least one physiological sensor configured to collect physiological data, the physiological data including measurements of immune parameters, blood pressure, heart rate, respiratory rate, and / or temperature, wherein the at least one processor is programmed or configured to: control the pump to pressurize the therapeutic composition, thereby delivering the therapeutic composition at a first flow rate; and determine, at least in part based on the cell data, the pressure data, the flow data, the extravasation data, and the physiological data: that the therapeutic composition should be delivered at the first flow rate; or that the therapeutic composition should be delivered at a second flow rate.

24. The system according to claim 23, wherein the determination is at least based on: Determine that the pressure and / or the flow rate are too high, at least in part based on the pressure data and / or the flow rate data; Determine that an extravasation threat is occurring, at least in part based on the extravasation data; Determine that more cells than a predetermined threshold have ruptured, at least in part based on the cell data; and / or Determine that the patient is experiencing an adverse reaction, at least in part based on the physiological data.

25. The system according to claim 24, wherein, when determining the following situations, the at least one processor is further programmed or configured to control the pump to deliver the therapeutic composition at the second flow rate, and the following situations include: at least one of the flow rate and the pressure is too large; an extravasation threat is occurring; a threshold number of cells have ruptured; and / or the patient is experiencing an adverse reaction.

26. The system according to claim 25, wherein, the second flow rate is one of flow stop and flow deceleration.

27. The system according to claim 26, wherein, when determining that the flow rate and / or the pressure are too high, there is extravasation, a threshold number of cells have ruptured, and / or the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to trigger a warning or an alarm.

28. The system according to claim 27, wherein the alarm is an auditory alarm, a visual alarm, and / or a tactile alarm.

29. The system according to claim 27, wherein, when determining that the patient is experiencing an adverse reaction, the at least one processor is further programmed or configured to cause the pump to deliver a second therapeutic composition to the patient.

30. The system according to claim 29, wherein the second therapeutic composition includes at least one of a crystalloid solution, a colloid solution, and a corticosteroid, and wherein the crystalloid solution includes at least one of normal saline, D5W, and lactated Ringer's solution.

31. The system according to claim 23, wherein the container is one of a syringe, a bag, a bottle, and a vial.

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