Cell Delivery Injector

Abstract

A system for delivering a therapeutic composition to a patient, the system including: a container configured to hold the therapeutic composition; at least one powered driver operatively connected to the container; a plurality of sensors including at least two of: (i) a pressure sensor, (ii) a flow sensor, (iii) a counting sensor, (iv) a site 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 control the at least one powered driver to infuse the therapeutic composition into the patient at a desired flow rate, the magnitude of which is dependent on the data received from the plurality of sensors.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 425,031, filed November 14, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present disclosure relates to devices, systems, and methods for delivering cell-based therapies. [Background technology]

[0003] The treatment of disease through the infusion of living cells into the body is rapidly expanding. There are many types of cells being used to treat an equally diverse array of diseases, and both the cell types and disease states are rapidly expanding. Cell therapy is the transfer of intact, live cells into a patient to help alleviate or cure disease. The cells can be derived from the patient (autologous cells) or a donor (allogeneic cells), some of which may be genetically modified. Some examples of cell therapy include CAR-T cell therapy, in which T cells genetically engineered to express a chimeric antigen receptor (CAR) are delivered to patients with specific subtypes of B-cell leukemia or lymphoma, for example. Promising efficacy of cell therapy has also been demonstrated in patients with multiple myeloma. However, various barriers limit efficacy and / or prevent widespread use of cell therapy. These barriers include cell rupture, which can cause dangerous side effects in patients. Therefore, there is a need in the art for more robust delivery devices and systems that can account for and compensate for the various conditions that may arise during any such cell delivery process. Summary of the Invention [Means for solving the problem]

[0004] Provided herein is a system for delivering cell therapy to a patient, the system including: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more cells in suspension; at least one powered drive operatively connected to the container, the powered drive configured to pressurize the therapeutic composition in the container and at least one fluid line in communication with the container; a control system having a plurality of sensors; and at least one processor programmed or configured to receive data from the plurality of sensors and, based at least in part on the data, control the at least one powered drive to pressurize the therapeutic composition in the container and in the at least one fluid line, thereby infusing the therapeutic composition into the patient at a first flow rate, wherein the plurality of sensors include pressure sensors for measuring and providing data indicative of the pressure in the container and in the at least one fluid line; and a flow sensor for measuring and providing data indicative of the actual flow rate of the suspension in the at least one fluid line; and (i) a control system having: a pressure sensor for measuring and providing data indicative of the pressure in the container and in the at least one fluid line; and at least two of: (i) a counting sensor for providing data indicative of a count in the suspension flowing through the at least one fluid line of at least one of (i) a number of ruptured cells and (ii) a number of ruptured cells; a site sensor disposed around a site of injection of the suspension into the patient for providing data indicative of one of the occurrence or non-occurrence of extravasation at the injection site; a temperature sensor for measuring and providing data indicative of a temperature of the suspension in 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 configured to receive data from the plurality of sensors indicating that: a pressure within at least one of the container and the at least one fluid line is greater than a predetermined pressure threshold; a flow rate of the suspension in the at least one fluid line is greater than a predetermined flow rate threshold; a number of ruptured cells or cells in the suspension is greater than a predetermined rupture threshold; and a risk of extravasation around the injection site.and further programmed or configured to, upon determining that the temperature of the suspension in the at least one fluid line is outside a predetermined temperature range, indicating at least one of 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 the occurrence of an adverse reaction experienced by the patient as evidenced by data received from the at least one physiological sensor, control the at least one powered driver to pressurize the therapeutic composition in the container, thereby infusing the therapeutic composition into the patient at a second flow rate.

[0005] Also provided herein is a system for delivering cell therapy to a patient, the system comprising: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more cells in a suspension; at least one powered drive operatively connected to the container, the powered drive configured to pressurize the therapeutic composition in the container and at least one fluid line in communication with the container; and a plurality of sensors, including: (i) a pressure sensor for measuring and providing data indicative of pressure in the container and in the at least one fluid line; (ii) a flow sensor for measuring and providing data indicative of an actual flow rate of the suspension in the at least one fluid line; and (iii) a count sensor for providing data indicative of a count in the suspension flowing through the at least one fluid line of at least one of: (i) a number of one or more cells that remain intact and (ii) a number of one or more cells that have ruptured. (iv) a site sensor positioned around a site of injection of the suspension into the patient for providing data indicative of one of the occurrence or non-occurrence of extravasation at the injection site; (v) a temperature sensor for measuring and providing data indicative of the temperature of the suspension in 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 programmed or configured to receive data from the plurality of sensors and, based at least in part on the data, control at least one powered driver to pressurize the therapeutic composition in the container and in the at least one fluid line, thereby injecting the therapeutic composition into the patient at a desired flow rate magnitude dependent on the data received from the plurality of sensors.

[0006] Also provided herein is a system for delivering cell therapy to a patient, the system comprising: a container configured to hold a 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 counting sensor configured to collect cell data, the cell data including a number of intact cells and / or ruptured cells; a pressure sensor configured to collect pressure data, the pressure data including a measurement of pressure in the container and / or in one or more fluid lines between the container and the patient; and a flow sensor configured to collect flow data, the flow data including a measurement of flow rate in one or more fluid lines between the container and the patient. and a plurality of sensors including: an ultrasound transducer positioned around an injection site of a therapeutic composition into the patient and configured to collect extravasation data, the extravasation data indicating one of the occurrence and non-occurrence of extravasation at the injection site; and at least one physiological sensor configured to collect physiological data, the physiological data including measurements of an immune parameter, blood pressure, heart rate, respiratory rate, and / or temperature; and at least one processor programmed or configured to control a pump to pressurize the therapeutic composition and deliver the therapeutic composition at a first flow rate, and determine whether the therapeutic composition should be delivered at the first flow rate or whether the therapeutic composition should be delivered at a second flow rate based at least in part on the cellular data, the pressure data, the flow data, the extravasation data, and the physiological data.

[0007] Further non-limiting aspects are described below.

[0008] In a first aspect, provided herein is a system for delivering cell therapy to a patient, the system including: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more cells in suspension; at least one powered drive operatively connected to the container, the powered drive configured to pressurize the therapeutic composition in the container and at least one fluid line in communication with the container; a control system having a plurality of sensors; and at least one processor programmed or configured to receive data from the plurality of sensors and, based at least in part on the data, control the at least one powered drive to pressurize the therapeutic composition in the container and in the at least one fluid line, thereby infusing the therapeutic composition into the patient at a first flow rate, wherein the plurality of sensors include: a pressure sensor for measuring and providing data indicative of the pressure in the container and in the at least one fluid line; a flow sensor for measuring and providing data indicative of the actual flow rate of the suspension in the at least one fluid line; and (i) one or more sensors that remain intact. and (ii) a counting sensor for providing data indicative of a count in the suspension flowing through the at least one fluid line of at least one of (i) a number of cells in the suspension and (ii) a number of one or more ruptured cells; a site sensor disposed around a site of injection of the suspension into the patient for providing data indicative of one of the occurrence or non-occurrence of extravasation at the injection site; a temperature sensor for measuring and providing data indicative of a temperature of the suspension in 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 configured to receive data from the plurality of sensors indicative of: a pressure within at least one of the container and the at least one fluid line being greater than a predetermined pressure threshold; a flow rate of the suspension in the at least one fluid line being greater than a predetermined flow rate threshold; a number of one or more ruptured cells in the suspension being greater than a predetermined rupture threshold; and an occurrence of a risk of extravasation around the injection site.and further programmed or configured to, upon determining that the temperature of the suspension in the at least one fluid line is outside a predetermined temperature range, indicating at least one of 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 the occurrence of an adverse reaction experienced by the patient as evidenced by data received from the at least one physiological sensor, control the at least one powered driver to pressurize the therapeutic composition in the container, thereby infusing the therapeutic composition into the patient at a second flow rate.

[0009] In a second aspect that can be based on the first aspect, the container is one of a syringe, a bag, a bottle, and a vial.

[0010] In a third aspect, which may be based on the first and / or second aspect, the one or more cells comprise at least one of (i) autologous cells, (ii) allogeneic cells, (iii) a combination of autologous and allogeneic cells, (iv) a mixture of at least one modified autologous and allogeneic cells, (v) genetically engineered cells, and (vi) genetically engineered T cells expressing a chimeric antigen receptor.

[0011] In a fourth aspect that may be based on any of the preceding aspects, one of the plurality of sensors is an ultrasound sensor, and the suspension includes an ultrasound contrast agent.

[0012] In a fifth aspect that may be based on any of the preceding aspects, the at least one powered drive is a pump system that includes an injector system.

[0013] In a sixth aspect, which may be based on any of the preceding aspects, the second flow rate is one of a stopped flow and a reduced flow.

[0014] In a seventh aspect that may be based on any of the preceding aspects, 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.

[0015] In an eighth aspect, which may be based on any of the preceding aspects, upon determining that the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to cause the at least one powered driver to deliver a second therapeutic composition to the patient.

[0016] In a ninth aspect that may be based on any of the preceding aspects, the second therapeutic composition comprises at least one of a crystalloid solution, a colloid solution, and a corticosteroid, and the crystalloid solution comprises at least one of saline, D5W, and lactated Ringer's.

[0017] In a tenth aspect that may be based on any of the preceding aspects, the at least one processor is further programmed or configured to trigger at least one of an alarm and a warning when it determines that the data received from the plurality of sensors indicates any of the following: a pressure inside at least one of the container and the at least one fluid line is greater than a predetermined pressure threshold; a flow rate of the suspension in the at least one fluid line is greater than a predetermined flow rate threshold; a number of one or more ruptured cells in the suspension is greater than a predetermined rupture threshold; the occurrence of extravasation around the injection site; a temperature of the suspension in the at least one fluid line being 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.

[0018] In an eleventh aspect that may be based on any of the preceding aspects, the system includes at least one flow regulator disposed in the at least one fluid line, each of the at least one flow regulator configured to be switchable between an open state and a closed state, wherein the at least one processor is programmed or configured to: upon determining that a volume of the therapeutic composition needs to be increased, 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; upon determining that a volume of the therapeutic composition needs to be decreased, 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 fluid in the suspension to be removed from the suspension via the at least one fluid line; and upon detecting that the number of the one or more ruptured cells 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 diverting the suspension to a separate one of the at least one fluid line for at least one of analysis and disposal.

[0019] In a twelfth aspect, a system for delivering cell therapy to a patient is provided, the system comprising: a container configured to hold a therapeutic composition, the therapeutic composition comprising one or more cells in a suspension; at least one powered drive operatively connected to the container, the powered drive configured to pressurize the therapeutic composition in the container and at least one fluid line in communication with the container; and a plurality of sensors, (i) a pressure sensor for measuring and providing data indicative of the pressure in the container and in the at least one fluid line; (ii) a flow sensor for measuring and providing data indicative of an actual flow rate of the suspension in the at least one fluid line; and (iii) a counting sensor for providing data indicative of at least one of (i) a number of one or more cells that remain intact and (ii) a number of one or more cells that have ruptured in the suspension flowing through the at least one fluid line. (iv) a site sensor disposed about a site of injection of the suspension into the patient for providing data indicative of one of the occurrence or non-occurrence of extravasation at the injection site; (v) a temperature sensor for measuring and providing data indicative of the temperature of the suspension in 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 programmed or configured to receive data from the plurality of sensors and, based at least in part on the data, control the at least one powered driver to pressurize the therapeutic composition in the container and in the at least one fluid line to thereby inject the therapeutic composition into the patient at a desired flow rate magnitude responsive to the data received from the plurality of sensors.

[0020] In a thirteenth aspect that may be based on any of the preceding aspects, the desired flow rate is initially a first flow rate but is changed to a second flow rate when data received by the at least one processor from the plurality of sensors indicates at least one of: a pressure inside at least one of the container and the at least one fluid line being greater than a predetermined pressure threshold; a flow rate of the suspension in the at least one fluid line being greater than a predetermined flow rate threshold; a number of one or more ruptured cells in the suspension being greater than a predetermined rupture threshold; the occurrence of extravasation around the injection site; a temperature of the suspension in the at least one fluid line being 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.

[0021] In a fourteenth aspect that may be based on any of the preceding aspects, the one or more cells comprise at least one of (i) autologous cells, (ii) allogeneic cells, (iii) a combination of autologous and allogeneic cells, (iv) a mixture of at least one modified autologous and allogeneic cells, (v) genetically engineered cells, and (vi) genetically engineered T cells expressing a chimeric antigen receptor.

[0022] In a fifteenth aspect that may be based on any of the preceding aspects, one of the plurality of sensors is an ultrasound sensor, and the suspension includes an ultrasound contrast agent.

[0023] In a sixteenth aspect that can be based on any of the preceding aspects, the at least one powered drive device is a pump system including an injector system.

[0024] In a seventeenth aspect that can be based on any of the preceding aspects, the second flow rate is one of a stopped flow and a reduced flow.

[0025] In an eighteenth aspect that may be based on any of the preceding aspects, 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.

[0026] In a nineteenth aspect, which may be based on any of the preceding aspects, upon determining that the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to cause the at least one powered driver to deliver a second therapeutic composition to the patient.

[0027] In a twentieth aspect that can be based on any of the preceding aspects, the second therapeutic composition comprises at least one of a crystalloid solution, a colloid solution, and a corticosteroid, and the crystalloid solution comprises at least one of saline, D5W, and lactated Ringer's.

[0028] In a 21st aspect that may be based on any of the preceding aspects, the at least one processor is further programmed or configured to trigger at least one of an alarm and a warning when it determines that the data received from the plurality of sensors indicates any of the following: a pressure inside at least one of the container and the at least one fluid line is greater than a predetermined pressure threshold; a flow rate of the suspension in the at least one fluid line is greater than a predetermined flow rate threshold; a number of one or more ruptured cells in the suspension is greater than a predetermined rupture threshold; the occurrence of extravasation around the injection site; a temperature of the suspension in the at least one fluid line being 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.

[0029] In a twenty-second aspect that may be based on any of the preceding aspects, the system further includes at least one flow regulator disposed in the at least one fluid line, each of the at least one flow regulator configured to be switchable between an open state and a closed state, wherein upon determining that a volume of the therapeutic composition needs to be increased, 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; and upon determining that a volume of the therapeutic composition needs to be decreased, 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 fluid in the suspension to be removed from the suspension via the at least one fluid line; and upon detecting that the number of the one or more ruptured cells 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 diverting the suspension to a separate one of the at least one fluid line for at least one of analysis and disposal.

[0030] In a twenty-third aspect, there is provided a system for delivering cell therapy to a patient, the system comprising: a container configured to hold a 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 counting sensor configured to collect cell data, the cell data including a number of intact cells and / or ruptured cells; a pressure sensor configured to collect pressure data, the pressure data including a measurement of pressure in the container and / or in one or more fluid lines between the container and the patient; and a flow sensor configured to collect flow data, the flow data including a measurement of flow rate in one or more fluid lines between the container and the patient. and a plurality of sensors including: an ultrasound transducer positioned around an injection site of a therapeutic composition into the patient and configured to collect extravasation data, the extravasation data indicating one of the occurrence and non-occurrence of extravasation at the injection site; and at least one physiological sensor configured to collect physiological data, the physiological data including measurements of an immune parameter, blood pressure, heart rate, respiratory rate, and / or temperature; and at least one processor programmed or configured to control a pump to pressurize the therapeutic composition and deliver the therapeutic composition at a first flow rate, and determine whether the therapeutic composition should be delivered at the first flow rate or whether the therapeutic composition should be delivered at a second flow rate based at least in part on the cellular data, the pressure data, the flow data, the extravasation data, and the physiological data.

[0031] In a 24th aspect, which may be based on any of the preceding aspects, the determination is based at least in part on a determination that the pressure and / or flow rate is too high, based at least in part on pressure and / or flow rate data; a determination that a risk of extravasation is occurring, based at least in part on extravasation data; a determination that cells exceeding a predetermined threshold have ruptured, based at least in part on cell data; and / or a determination that the patient is experiencing an adverse reaction, based at least in part on physiological data.

[0032] In a 25th aspect, which may be based on any of the preceding aspects, the at least one processor is further programmed or configured to control the pump to deliver the therapeutic composition at a second flow rate upon determining that at least one of the flow rate and pressure is too high, that a risk of extravasation is occurring, that a threshold number of cells have ruptured, and / or that the patient is experiencing an adverse reaction.

[0033] In a 26th aspect, which can be based on any of the preceding aspects, the second flow rate is one of a stopped flow and a reduced flow.

[0034] In a 27th aspect, which may be based on any of the preceding aspects, the at least one processor is programmed or configured to trigger an alarm or warning upon determining that the flow rate and / or pressure is too high, that there is extravasation, that a threshold number of cells have ruptured, and / or that the patient is experiencing an adverse reaction.

[0035] In a 28th aspect that may be based on any of the preceding aspects, the alarm is an audible alarm, a visual alarm, and / or a tactile alarm.

[0036] In a 29th aspect, which may be based on any of the preceding aspects, upon determining that the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to cause the pump to deliver a second therapeutic composition to the patient.

[0037] In a 30th aspect that can be based on any of the preceding aspects, the second therapeutic composition comprises at least one of a crystalloid solution, a colloid solution, and a corticosteroid, and the crystalloid solution comprises at least one of saline, D5W, and lactated Ringer's.

[0038] In a thirty-first aspect, which can be based on any of the preceding aspects, the container is one of a syringe, a bag, a bottle, and a vial. [Brief explanation of the drawings]

[0039] [Figure 1] FIG. 1 is a diagram of a non-limiting embodiment of an environment in which the devices, systems, and / or methods described herein may be implemented. [Figure 2] FIG. 2 is a diagram of a non-limiting aspect or embodiment of one or more devices and / or components of one or more systems of FIG. 1. [Figure 3] 1 is a flow chart of a non-limiting embodiment of a process for delivering a therapeutic agent to a patient. DETAILED DESCRIPTION OF THE INVENTION

[0040] For purposes of the following description, the terms "end," "upper," "lower," "right," "left," "vertical," "horizontal," "top," "bottom," "transverse," "longitudinal," and derivatives thereof, shall refer to the present disclosure as oriented in the drawings. However, it should be understood that the present disclosure may contemplate various alternative modifications and step sequences unless expressly specified to the contrary. It should also be understood that the specific devices and processes illustrated in the accompanying drawings and described in the following specification are merely exemplary embodiments or aspects of the present disclosure. Accordingly, specific dimensions and other physical characteristics related to the embodiments or aspects of the embodiments disclosed herein are not to be considered limiting, unless otherwise indicated.

[0041] As used herein, aspects, components, elements, structures, operations, steps, functions, instructions, and the like should not be construed as critical or essential unless expressly stated as such. Also, as used herein, the articles "a" and "a" are intended to include one or more items and may be used interchangeably with "one or more" and "at least one." Furthermore, as used herein, the term "set" is intended to include one or more items (e.g., related items, unrelated items, combinations of related and unrelated items, and / or the like) and may be used interchangeably with "one or more" or "at least one." When only one item is intended, the term "a" or similar term is used. Also, as used herein, terms such as "having" are intended to be open-ended terms. Furthermore, the phrase "based on" is intended to mean "based at least in part on," unless otherwise specified.

[0042] As used herein, the terms “communication” and “communicating” can refer to receiving, accepting, sending, forwarding, providing, etc., information (e.g., data, signals, messages, instructions, commands, etc.). One unit (e.g., a device, a system, a component of a device or system, a combination thereof, and / or the like) communicating with another unit means that one unit can directly or indirectly receive information from the other unit and / or send (e.g., transmit) information to the other unit. This may refer to a direct or indirect connection that is wired and / or wireless in nature. Furthermore, two units can communicate with each other even if the transmitted information is modified, processed, relayed, and / or routed between the first and second units. For example, a first unit can communicate with a second unit even if the first unit passively receives information and does not actively transmit information to the second unit. As another example, a first unit can communicate with a second unit if at least one intermediate unit (e.g., a third unit located between the first unit and the second unit) processes information received from the first unit and transmits the processed information to the second unit. In some non-limiting embodiments, a message can refer to a network packet containing data (e.g., a data packet, etc.).

[0043] As used herein, the term "computing device" can refer to one or more electronic devices configured to communicate directly or indirectly with one or more networks. In some non-limiting embodiments, a computing device can include a mobile device. A mobile device can include a smartphone, a portable computer, a wearable device (e.g., a watch, eyeglasses, lenses, clothing, etc.), a personal digital assistant (PDA), and / or other similar devices. In some non-limiting embodiments, a computing device can include a server, a desktop computer, etc.

[0044] As used herein, the term "system" can refer to one or more computing devices or combinations of computing devices, such as, but not limited to, a processor, a server, a client device, a software application, and / or other similar components. Additionally, references to a "server" or a "processor" as used herein can refer to a previously listed server and / or processor, a different server and / or processor, and / or a combination of servers and / or processors listed as performing a previous step or function. For example, as used herein and in the claims, a first server and / or a first processor listed as performing a first step or function can refer to the same or a different server and / or processor listed as performing a second step or function.

[0045] Provided herein are devices, systems, and methods for delivering therapeutic agents, such as one or more cells in a suspension, to a patient. The devices, systems, and methods described herein provide technical solutions to problems in the field of therapeutic delivery by integrating multiple sensors and / or data via algorithms executed by a processor, which account for numerous issues that may be experienced during therapeutic delivery and currently cannot be adequately accounted for simultaneously. The devices, systems, and methods described herein improve the functionality of existing delivery devices, such as cell delivery devices, and improve clinical outcomes.

[0046] Referring to FIG. 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. While the delivery device 120 and the container 110 are shown as separate components connected by a fluid line 115, they may be integrated. The system 100 further includes a powered drive 122 configured to deliver the therapeutic composition to a patient P. Again, while shown as part of the delivery device 120, the powered drive 122 may be disposed within the container 110. In a non-limiting embodiment, the powered drive 122 includes a pump system or other type of fluid pressurization system. Such a pump system may include an infusion system, a gravity-fed system, and / or any combination of components. The delivery device 120 may further include a processor 124, a memory 126 for storing programming instructions 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 FIG. 2. System 100 further includes one or more sensors 140. While multiple sensors 140 are shown in a particular arrangement and orientation in Figure 1, one 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. Sensors 140 may be in communication with processor 124 such that data detected by sensors 140 may be received and analyzed by processor 124 based on programming instructions communicated and / or stored in memory 126, for example.

[0047] Container 110 may be a syringe 110a, an intravenous bag 100b, a vial 110c, a bottle, or any other container 110n capable of holding a therapeutic composition for delivery to patient P. Container 110 may be lined with one or more suitable coatings to reduce adhesion of the therapeutic composition to one or more surfaces within container 110. In non-limiting embodiments, container 110 may include or be associated with one or more sensors 140 to monitor the status of the therapeutic composition received within container 110, e.g., during loading, transport, and use, e.g., via system 100. 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 enable analysis of one or more cells received within container 110, e.g., by detection of one or more tracking devices (e.g., radioactive labels, iron oxide nanoparticles, gallium), cell morphology, and / or digital pathology. Noninvasive cell-tracking methods are known to those skilled in the art, for example, as disclosed in Kircher et al., "Noninvasive cell-tracking methods," Nature Reviews Clinical Oncology 2011, 8:677-688.

[0048] A processor associated with the system 100 described herein can utilize data received from the sensors 140 to control delivery of a therapeutic composition received within the container 110, as described herein. In a non-limiting embodiment, the processor associated with the system 100 can receive data from one or more sensors 140 and determine whether delivery of the therapeutic composition within the container 110 should be initiated based on data collected by the sensors 140 during loading and / or transport. For example, if the therapeutic composition contained within the container 110 is exposed to a force, chemical condition (pH), temperature, mean kinetic temperature, etc. outside of a predetermined range of acceptable parameters (e.g., between about 40°C and about 50°C, above about 50°C, and / or between 43°C and 50°C, etc., including all values ​​and subranges therebetween), e.g., exceeds a particular threshold for a period of time, and therefore the therapeutic composition should not be delivered to the patient, the processor 124 can provide an alert, e.g., an audible, visual, and / or tactile alert, indicating that delivery of the therapeutic composition should not be initiated. In a non-limiting embodiment, upon determining that the therapeutic composition should not be delivered to the patient, the processor 124 may prevent delivery of the therapeutic composition from initiating, and in a non-limiting embodiment, the prevention of delivery may or may not be overridden by, for example, entry of a password or other authentication.

[0049] In non-limiting embodiments, the container 110 may include one or more ports to allow for the 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 fluorescent and / or dye tests (including those described in Kim et al., “Application of a non-hazardous vital dye for cell counting with automated cell counters,” Analy. Biochem. 2016, 492(2):8-12), visual inspection using a camera, and / or other analyses suitable for determining the status of the therapeutic composition, e.g., one or more cells, as known to those of skill in the art.

[0050] In non-limiting embodiments, fluid line 115 may be flexible and / or rigid and may include one or more lumens therein. In non-limiting embodiments, container 110 and / or fluid line 115 may include one or more flow regulators 141, such as valves, and / or one or more agitators, such as those described in U.S. Pat. No. 6,575,930, the contents of which are incorporated herein by reference in their entirety. In non-limiting embodiments, fluid line 115 includes one or more needles disposed at its end to assist in delivery of the therapeutic composition to patient P. Suitable needles are known to those skilled in the art and may include any useful features depending on the therapeutic composition being delivered, including various bevels.

[0051] In a non-limiting embodiment, the therapeutic composition is one or more cells in suspension. Suitable suspensions for maintaining cell viability are known to those skilled in the art. In a non-limiting embodiment, the suspension includes one or more ultrasound contrast agents to enable detection of extravasation, as described below. In a non-limiting embodiment, extravasation is monitored acoustically by measuring the sound from gas bubbles injected into tissue near the injection site due to the cell suspension breaking up, e.g., by popping. In a non-limiting embodiment, extravasation is monitored based on the lack of an ultrasound return signal from the breaking up of gas bubbles at or near the injection site. In addition to extravasation, other parameters can be monitored by ultrasound, such as blood pH as a measure of inflammation (e.g., Walker et al., "Dynamic solid-state ultrasound contrast agent for monitoring pH fluctuations in vivo," ACS Sens. 2020, vol. 5, no. 4, pp. 1190-1197). In non-limiting embodiments, the therapeutic composition comprises 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 comprises autologous cells, allogeneic cells, a combination of autologous and allogeneic cells, a mixture of autologous and allogeneic cells in which at least one of the cells has been modified, genetically engineered cells, and / or CAR-T cells.

[0052] 1 , in a non-limiting embodiment, the sensors 140 include one or more of a counting sensor 140a configured to count intact cells and / or ruptured cells, a pressure sensor 140b configured to detect pressure within the vessel 110 and / or one or more fluid lines 115, a flow sensor 140c configured to detect flow rate within the one or more fluid lines 115, a site 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 a non-limiting embodiment, the cell counter, pressure, and / or flow sensor may be disposed within or on the vessel 110 and / or fluid lines 115. As used herein, the term “ruptured cells” refers to cells that are damaged, non-viable, destroyed, or otherwise unable to contribute to a desired therapeutic response in a patient.

[0053] Suitable sensors for counting intact and / or ruptured cells are known to those skilled in the art and can include those described at https: / / www.nist.gov / programs-projects / cell-counting-cell-therapies. In a non-limiting embodiment, sensors suitable for counting include those that measure hemolysis as an indirect measure of cell viability, optionally by measuring the conductivity of a cell suspension (e.g., Van Buren et al., "A simple method to monitor hemolysis in real time", Sci Rep. 2020; 10, 5101; e.g., Zhuo et al., "Optofluidic sensor for inline hemolysis detection on whole blood", ACS Sens. 2018, vol. 3, no. 4, pp. 784-791).

[0054] Sensors 140 configured to detect flow rate, viscosity, and / or pressure can be useful in determining the microenvironment to which the therapeutic composition is exposed, which can be useful in various analyses and processes described herein for determining forces, such as shear forces, applied to the therapeutic composition that may negatively affect the therapeutic composition (e.g., by causing an unacceptably high degree of cell rupture). In a non-limiting embodiment, one or more sensors 140 may measure one or more parameters of the therapeutic composition exiting container 110 and / or passing through fluid line 115, and processor 124 may 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 upon receiving data from sensors 140 (and, in a non-limiting embodiment, based at least in part on the diameter of fluid line 115). In a non-limiting embodiment, one or more sensors 140 can measure the viscosity of the therapeutic composition exiting container 110 and / or passing through fluid line 115, and upon receiving viscosity data from sensor 140, processor 124 can adjust the viscosity of the therapeutic composition, for example, by adding or removing less viscous fluids (e.g., buffer and / or saline) from container 110 and / or fluid line 115. In a non-limiting embodiment, a siphon line (e.g., to separate fluid from the cell-containing fluid) can be used to adjust the viscosity.

[0055] In a non-limiting embodiment, one or more sensors 140, e.g., physiological sensors, may be placed in or on the patient P. In a non-limiting embodiment, the sensor 140 may be a site sensor (e.g., a sensor configured to be placed at or near the site of introduction of a therapeutic composition into a patient) and a sensor configured to detect extravasation. Sensors and systems for detecting extravasation are known to those skilled 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 may include ultrasound, optical sensors, microbubbles, etc. In a non-limiting embodiment, the sensor 140 configured to detect extravasation is an ultrasound transducer, and optionally, the delivered therapeutic composition includes an ultrasound contrast agent. In a non-limiting embodiment, the sensor 140 configured to detect extravasation is an optical sensor (e.g., a sensor sold by ivWatch LLC, Newport News, VA). In a non-limiting embodiment, one or more of the sensors 140 are sensors configured to detect surface tension and / or stiffness at the patient's injection site, which can be used to assess extravasation.

[0056] In non-limiting embodiments, the one or more physiological sensors are one or more of sensors for detecting the 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., Boston, MA), brain activity (including EEG), pupil dilation, respiratory rate, vocalizations (e.g., microphone), movement, and / or temperature (including sweating and / or skin flushing). Those skilled in the art will understand that delivery of any therapeutic composition, such as a cell therapy such as a CAR-T therapeutic, may be accompanied by adverse events that can trigger an immune response, such as an allergic reaction, a cytokine storm (also known as cytokine release syndrome), and / or anaphylaxis, and that any suitable sensor 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-dimers, and growth factors. In a non-limiting embodiment, the chemical sensor is an electrochemical sensor. Suitable sensors for detecting an immune response include those described in Xu, et al., "Real-Time Monitoring and Early Warning of a Cytokine Storm In Vivo Using a Wearable Noninvasive Skin Microneedle Patch," Advanced Healthcare Materials 2023, 12(18):e2203133.

[0057] In a non-limiting embodiment, system 100 includes a communications network 160 to provide connectivity between various components of the system, e.g., between sensor 140, flow regulator 141, and delivery device 120. Communications network 160 may include one or more wired and / or wireless networks. For example, communications network 160 may include a cellular network (e.g., a long-term evolution (LTE) network, a third-generation (3G) network, a fourth-generation (4G) network, a fifth-generation (5G) network, a sixth-generation (6G) network, a 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., a public switched telephone network (PSTN)), a private network, an ad hoc network, an intranet, the Internet, an optical fiber-based network, a cloud computing network, etc., and / or a combination of some or all of these or other types of networks.

[0058] The number and arrangement of systems and / or devices shown in Figure 1 are provided as an example. Additional, fewer, different, or differently arranged systems and / or devices may be present. Furthermore, two or more systems and / or devices shown in Figure 1 may be implemented within a single system or device, or a single system or device shown in Figure 1 may be implemented as multiple distributed systems or devices. Additionally or alternatively, a set of systems or devices (e.g., one or more systems, one or more devices) of system 100 may perform one or more functions described as being performed by another set of systems or another set of devices of system 100.

[0059] 2, a diagram of exemplary 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 shown in FIG. 2, device 200 may include a bus 202, a processor 204, a memory 206, a storage component 208, an input component 210, an output component 212, and / or a communication interface 214.

[0060] Bus 202 may include components that enable communication between 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), and / or the like), a microprocessor, a digital signal processor (DSP), and / or any processing component that can be programmed to perform a function (e.g., a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), and / or the like). Memory 206 may include random access memory (RAM), read-only memory (ROM), and / or another type of dynamic or static storage device (e.g., flash memory, magnetic memory, optical memory, and / or the like) that stores information and / or instructions for use by processor 204.

[0061] The storage component 208 may store information and / or software related to the operation and use of the device 200. For example, the storage component 208 may include a hard disk (e.g., a magnetic disk, optical disk, magneto-optical disk, solid-state disk, etc.), a compact disk (CD), a digital versatile disk (DVD), a floppy disk, a cartridge, a magnetic tape, and / or another type of computer-readable medium along with a corresponding drive.

[0062] Input components 210 may include components that enable device 200 to receive information via user input (e.g., a touchscreen display, a keyboard, a keypad, a mouse, buttons, switches, a microphone, a camera, etc.), etc. Additionally or alternatively, input components 210 may include sensors for sensing information (e.g., a global positioning system (GPS) component, an accelerometer, a gyroscope, an actuator, etc.). Output components 212 may include components that provide output information from device 200 (e.g., a display, a speaker, one or more light-emitting diodes (LEDs), etc.).

[0063] Communications interface 214 may include transceiver-like components (e.g., a walkie-talkie, a separate receiver and transmitter, and / or the like) that enable device 200 to communicate with other devices via a wired connection, a wireless connection, a combination of wired and wireless connections, etc. Communications interface 214 may enable device 200 to receive information from another device and / or provide information to another device. For example, communications interface 214 may include an Ethernet interface, an optical interface, a coaxial interface, an infrared interface, a radio frequency (RF) interface, a universal serial bus (USB) interface, a Wi-Fi interface, a cellular network interface, etc.

[0064] The device 200 may perform one or more processes described herein. The device 200 may perform these processes based on the processor 204 executing software instructions stored by a computer-readable medium, such as the memory 206 and / or the storage component 208. A computer-readable medium (e.g., a 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 spread across multiple physical storage devices.

[0065] Software instructions may be loaded into memory 206 and / or storage component 208 from another computer-readable medium or from another device via communications interface 214. When executed, the software instructions stored in memory 206 and / or storage component 208 can cause processor 204 to perform one or more 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 processes described herein. Thus, the embodiments or aspects described herein are not limited to any specific combination of hardware circuitry and software.

[0066] The memory 206 and / or storage component 208 may include data storage or one or more data structures (e.g., databases, etc.). The device 200 may retrieve information from, store information, or retrieve information stored in the data storage or one or more data structures in the memory 206 and / or storage component 208. For example, the information may include encrypted data, input data, output data, transaction data, account data, or any combination thereof.

[0067] The number and arrangement of components shown in Figure 2 are provided as an example. In some non-limiting embodiments or aspects, device 200 may include additional, fewer, different, or differently arranged components 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.

[0068] 1 and 3, in a non-limiting embodiment, the delivery device 120 controls the delivery of a therapeutic composition (FIG. 3, 300) via a processor 124. In a non-limiting embodiment, the delivery device 120 controls the powered drive 122 to deliver the therapeutic composition at a first flow rate (FIG. 3, 302), which may be a desired flow rate. The delivery device 120 can adjust the flow rate, pressure, viscosity, etc. based on data received from sensors (FIG. 3, 306) via communication between the processor 124 and one or more sensors 140 (FIG. 3, 304) and between the processor 124 and the powered drive 122. Adjustments in the operation of system 100 can be based on, but are 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 fluid line 115 is greater than a predetermined flow rate threshold, determining that the number of cells in the ruptured therapeutic composition is greater than a predetermined rupture threshold, determining that extravasation is occurring or is threatening around the injection site, determining that the temperature of the therapeutic composition in fluid line 115 is outside a predetermined temperature range, determining that an immune response is occurring or may occur in the patient, and / or determining that the patient is or may occur in the patient. For example, if there is data suggesting that the number of ruptured cells exceeds a predetermined threshold (optionally stored in memory 126), that the pressure in container 110 or fluid line 115 is too great, that the flow rate in fluid line 115 is too high, that the therapeutic composition is leaking from the injection site (extravasation), and / or that patient P is experiencing an adverse event such as an immune response, the flow rate may be reduced to a second flow rate ( FIG. 3 , 308), which may be a desired flow rate; in a non-limiting embodiment, the second flow rate may be zero (e.g., cessation of delivery of the therapeutic composition). Those skilled in the art will appreciate that various algorithms may be utilized to determine whether to reduce the flow rate, including, for example, but not limited to, the application of various weighting factors and / or various thresholds.In non-limiting embodiments, one or more useful algorithms may relate to shear force and / or any parameter described herein with respect to cell viability, delivery, patient monitoring, and / or patient behavior.

[0069] While cell rupture is exemplified above, in non-limiting embodiments, a sensor can provide predetermined thresholds and / or ranges for any parameter provided, and the ranges / thresholds are stored in memory 126. In non-limiting embodiments, if data received from one or more sensors 140 is within the appropriate range, delivery of the therapeutic composition may continue at the first flow rate while data collection continues (FIG. 3, 304). If the therapeutic composition is below the expected or desired concentration, for example, if a slightly increased but unsafe level of ruptured cells is sensed before or during infusion, the total volume and / or flow rate can be increased so that a total dose sufficient to achieve the desired therapeutic delivery and, therefore, therapeutic response is delivered. In this example, the second flow rate is often higher than the first flow rate. In non-limiting embodiments, the flow rate can be decreased (e.g., the second flow rate may be lower than the first flow rate), but an increased volume of the therapeutic composition can be delivered (e.g., as described below), for example, by delivering the therapeutic composition for a longer period of time.

[0070] In a non-limiting embodiment, in addition to adjusting the flow rate, the delivery device 120 can trigger an alarm if the flow rate exceeds any predetermined threshold, such that the flow rate is reduced. Suitable alarms can be audible, visual, and / or tactile. The alarm can be presented on the delivery device 120 (which can have a user interface such as a display) and / or transmitted by the delivery device 120, which includes a communications interface 128, to a device associated with a healthcare professional, such as a nurse, technician, or doctor.

[0071] In non-limiting embodiments, as a supplement or alternative to adjusting the flow rate, system 100 may be configured to adjust the volume of the therapeutic composition based on processor 124. In non-limiting embodiments, the system may be configured to divert a portion of the therapeutic composition from fluid line 115 for testing and / or disposal, and / or to add buffers and / or diluents to fluid line 115. For example, and without limitation, as shown in FIG. 1 , system 100 may be configured to position flow regulators 141 at one or more locations along fluid line 115, and the flow regulators may be configured to have an open state (e.g., fluid may pass through flow regulator 141 and continue along fluid line 115) and a closed state (e.g., fluid may not pass through flow regulator 141). In non-limiting embodiments, such flow regulator 141 can allow for the withdrawal of fluid from fluid line 115 (e.g., to decrease volume, increase viscosity, and / or decrease viscosity) and / or the addition of fluid to fluid line 115 (e.g., to increase volume, increase viscosity, and / or decrease viscosity). In non-limiting embodiments, the amount of fluid in fluid line 115 can be adjusted to allow, for example, the concentration or separation of cells in fluid line 115.

[0072] In non-limiting embodiments, one or more sensors 140 can be coextensively positioned with such flow regulators 141 so that one or more parameters of the therapeutic composition can be analyzed prior to continued delivery through the fluid lines 115. For example, in non-limiting embodiments, one or more sensors 140 can be positioned at or near the flow regulators 141 and configured, using the processor 124, to detect cell rupture in the therapeutic composition (e.g., based on the forces to which the therapeutic composition is exposed during delivery through any needle-containing fluid line 115, as described in Wahlberg et al., “Ex vivo biomechanical characterization of syringe-needle ejections for intracerebral cell delivery,” Scientific Reports 2018, 8:9194). If the number of ruptured cells reaches a certain threshold, one or more of the flow regulators 141 can be opened to allow the flow of the cell-containing therapeutic composition to be diverted to a separate fluid line 116 for further analysis and / or disposal. Although FIG. 1 shows a particular orientation and placement of the sensor 140 and flow regulator 141, one skilled in the art will recognize that variations are possible.

[0073] In non-limiting embodiments, fluid line 115 may include one or more filtration and / or microfluidic mechanisms for separating debris from the therapeutic composition and / or concentrating the therapeutic composition. For example, fluid line 115 may include one or more filters configured to restrict the flow of debris from ruptured cells from being introduced into the patient. Suitable non-limiting embodiments of concentration and / or filtration mechanisms include microfluidics (e.g., as described in Martel et al., "Continuous Flow Microfluidic Bioparticle Concentrator," Scientific Reports 2015, 5:11300), fluorescence-activated cell sorting (FACS), flow-through cell concentrators, corrugations in fluid line 115, use of siphon lines (e.g., to separate fluid from cell-containing fluid), magnetic bead sorting, centrifugation, and / or microbubble sorting (e.g., available from Akadeum Life Sciences, Inc., Ann Arbor, MI). In a non-limiting embodiment, fluid line 115 can be a dual lumen catheter that can be used to concentrate the therapeutic composition during delivery and / or to deliver the therapeutic composition and / or a second therapeutic composition, as described herein. In a non-limiting embodiment, the dual lumen of fluid line 115 extends to a delivery needle that is in fluid communication with fluid line 115.

[0074] In a non-limiting embodiment, in which the data received from sensor 140 indicates an adverse event, delivery device 120, via processor 124, may cause powered driver 122 or a second driver to deliver a second therapeutic composition, e.g., a composition that treats the adverse event. In a non-limiting embodiment, the data received from sensor 140 may indicate that an immune response, such as a cytokine storm, may be occurring or is occurring in patient P. Non-limiting examples of suitable sensors 140 for determining that an immune response, such as a cytokine storm, is occurring in a patient include those described in Xu et al., “Real-time Monitoring and Early Warning of a Cytokine Storm In Vivo Using a Wearable Noninvasive Skin Microneedle Patch,” Adv. Healthcare Materials 2023, 12(18):2203-133.

[0075] In a non-limiting embodiment, if the data received from the sensor 140 indicates that a cytokine storm may occur or is occurring, the processor 124 may initiate a flush or delivery of a second therapeutic composition, such as, for example, a crystalloid solution, a colloid solution, saline, an immunosuppressant, a beta-agonist, epinephrine (or other adrenergic agent), a cytokine and / or cytokine inhibitor (e.g., an IL-7 inhibitor), D5W (dextrose in water), lactated Ringer's solution, and / or a corticosteroid. In non-limiting embodiments, powered drive 122 or second drive can include a fluid line (or one or more additional lumens within fluid line 115) coextensive with fluid line 115, and flow regulator 141 can be configured to allow multiple configurations, such as a closed position of fluid line 115, an open position of fluid line 115, a closed position of the additional fluid line (and / or lumen) connected to the flush / delivery reservoir, and / or an open position of the additional fluid line (and / or lumen) connected to the flush / delivery reservoir. Delivery of the second therapeutic composition can occur as an alternative to and / or in parallel with the continuous delivery of the therapeutic composition from reservoir 110.

[0076] In a non-limiting embodiment, processor 124 suspends delivery of the therapeutic composition in response to determining that an immune response, such as a cytokine storm, may or has occurred in the patient and / or in response to a received signal indicating that a patient call button has been activated. In a non-limiting embodiment, processor 124 automatically suspends delivery of the therapeutic composition and / or triggers delivery of a second therapeutic composition described herein via system 100 and / or via a different system with which system 100 may communicate. In a non-limiting embodiment, processor 124 causes a display and / or speaker to provide an indication that delivery of the therapeutic composition should be suspended and / or stopped and / or delivery of a second therapeutic composition described herein should be initiated in response to determining that a cytokine storm may or has occurred in the patient and / or in response to a received signal indicating that a patient call button has been activated. Processor 124 can also provide one or more alternative mitigation strategies, for example, via the display and / or speaker.

[0077] In a non-limiting embodiment, system 100 can communicate with a database storing one or more records of a patient, e.g., one or more records of previous treatment with a therapeutic composition, including identification of the therapeutic composition, one or more side effects, one or more thresholds for delivery of the therapeutic composition that result in the side effects (e.g., pressure, flow rate, number of ruptured cells, and / or concentration of debris), and / or identification of one or more second therapeutic compositions effective in mitigating one or more side effects in the patient. In a non-limiting embodiment, system 100 is configured to deliver one or more second therapeutic agents described herein prior to delivery of the therapeutic composition. In a non-limiting embodiment, system 100 is configured to provide a warning that one or more second therapeutic agents should be delivered.

[0078] While the above-described devices, systems, and methods have been described in detail for purposes of illustration based on what are presently considered to be the most practical and preferred embodiments or aspects, it should be understood that such detail is for that purpose only, and that the disclosure is not limited to the described embodiments or aspects, but on the contrary, is intended to cover modifications and equivalent arrangements within the spirit and scope of the appended claims. For example, it should be understood that the disclosure contemplates that, to the extent possible, one or more features of any embodiment or aspect can be combined with one or more features of any other embodiment or aspect. [Explanation of symbols]

[0079] 100 systems 100b intravenous bag 110 Container 110a syringe 110c vial 110n container 115 Fluid Line 116 Fluid Line 120 Cell Delivery Device 122 Power Drive Unit 124 processors 126 memory 128 communication interface 140 sensors 140a Counting sensor 140b pressure sensor 140c flow sensor 140d Body Part Sensor 140e Physiological Sensors 140n sensor 141 Flow regulator 160 Communication Network 200 equipment 202 Bus 204 processors 206 memory 208 Memory Components 210 Input Components 212 Output Components 214 Communication Interface

Claims

1. 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 powered driver operatively connected to the container, the powered driver configured to pressurize the therapeutic composition in the container and at least one fluid line in communication with the container; a control system having a plurality of sensors and at least one processor programmed or configured to receive data from the plurality of sensors and, based at least in part on the data, control the at least one powered driver to pressurize the therapeutic composition in the container and in the at least one fluid line, thereby infusing the therapeutic composition into the patient at a first flow rate; Including, the plurality of sensors a pressure sensor for measuring and providing data indicative of pressure within the vessel and within the at least one fluid line; a flow sensor for measuring and providing data indicative of an actual flow rate of the suspension in the at least one fluid line; a counting sensor for providing data indicative of a count in the suspension flowing through the at least one fluid line of at least one of (i) a number of the one or more cells that remain intact and (ii) a number of the one or more cells that have ruptured; a site sensor disposed about a site of injection of the suspension into the patient for providing data indicative of one of the occurrence or non-occurrence of extravasation at the site of injection; a temperature sensor for measuring and providing data indicative of a temperature of the suspension in the at least one fluid line; a chemical sensor for detecting and providing data indicative of the development of an immune response in the patient; at least one physiological sensor for measuring and providing data indicative of at least one parameter of the patient; and The at least one processor may further select a signal from the plurality of sensors, the signal being: the pressure within at least one of the vessel and the at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension in the at least one fluid line is greater than a predetermined flow rate threshold; the number of the one or more ruptured cells in the suspension is greater than a predetermined rupture threshold; and the occurrence of a risk of extravasation around the injection site; the temperature of the suspension in the at least one fluid line is outside a predetermined temperature range; and the occurrence of an immune response in the patient as evidenced by the 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 the data received from the at least one physiological sensor; and and, upon determining that the at least one powered driver indicates at least one of: system.

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

3. 2. The system of claim 1, wherein the one or more cells comprise at least one of: (i) autologous cells; (ii) allogeneic cells; (iii) a combination of the autologous cells and the allogeneic cells; (iv) a mixture of at least one of the autologous cells and the allogeneic cells, wherein 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 of claim 1 , wherein one of the plurality of sensors is an ultrasound sensor and the suspension includes an ultrasound contrast agent.

5. The system of claim 1 , wherein the at least one powered drive device is a pump system including an injector system.

6. The system of claim 1 , wherein the second flow rate is one of a stop flow and a decrease in flow.

7. The system of claim 1 , 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.

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

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

10. The at least one processor may further select a signal from the plurality of sensors, the signal being: the pressure within at least one of the vessel 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 the one or more cells in the suspension that have ruptured is greater than the predetermined rupture threshold; and the occurrence of extravasation around the injection site; and the temperature of the suspension in the at least one fluid line is outside a predetermined temperature range; and the occurrence of an immune response in the patient as evidenced by the 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 the data received from the at least one physiological sensor; and 10. The system of claim 1, further programmed or configured to trigger at least one of an alarm and a warning upon determining that the system is indicative of any of the following:

11. further comprising at least one flow regulator disposed in the at least one fluid line, each of the at least one flow regulator configured to be switchable between an open state and a closed state; upon determining that the volume of the therapeutic composition needs to be increased, 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; upon determining 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 fluid within the suspension to be removed from the suspension via the at least one fluid line; upon detecting that the number of the one or more ruptured cells 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 diverting the suspension to a separate one of the at least one fluid line for at least one of analysis and disposal. The system of claim 1 .

12. 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 powered driver operatively connected to the container, the powered driver configured to pressurize the therapeutic composition in the container and at least one fluid line in communication with the container; a plurality of sensors including at least two of: (i) a pressure sensor for measuring and providing data indicative of pressure within the container and within the at least one fluid line; (ii) a flow sensor for measuring and providing data indicative of an actual flow rate of the suspension within the at least one fluid line; (iii) a count sensor for providing data indicative of at least one of (i) a number of the one or more cells that remain intact and (ii) a number of the one or more cells that have ruptured within the suspension flowing through the at least one fluid line; (iv) a site sensor disposed around a site of injection of the suspension into the patient, the site being indicative of one of the occurrence or non-occurrence of extravasation at the injection site; (v) a temperature sensor for measuring and providing data indicative of a 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. at least one processor programmed or configured to receive the data from the plurality of sensors and, based at least in part on the data, control the at least one powered driver to pressurize the therapeutic composition in the container and in the at least one fluid line, thereby infusing the therapeutic composition into the patient at a desired flow rate sized according to the data received from the plurality of sensors; Including, the system.

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

14. 13. The system of claim 12, wherein the one or more cells comprise at least one of: (i) autologous cells; (ii) allogeneic cells; (iii) a combination of the autologous cells and the allogeneic cells; (iv) a mixture of at least one of the autologous cells and the allogeneic cells, wherein 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 of claim 12 , wherein one of the plurality of sensors is an ultrasound sensor and the suspension includes an ultrasound contrast agent.

16. The system of claim 12 , wherein the at least one powered drive is a pump system including an injector system.

17. The system of claim 12 , wherein the second flow rate is one of a stop flow and a decrease in flow.

18. The system of 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. 13. The system of claim 12, wherein upon determining that the patient is experiencing an adverse reaction, the at least one processor is programmed or configured to cause the at least one powered driver to deliver a second therapeutic composition to the patient.

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

21. The at least one processor may further select a signal from the plurality of sensors, the signal being: the pressure within at least one of the vessel and the at least one fluid line is greater than a predetermined pressure threshold; the flow rate of the suspension in the at least one fluid line is greater than a predetermined flow rate threshold; the number of the one or more ruptured cells in the suspension is greater than a predetermined rupture threshold; and the occurrence of extravasation around the injection site; and the temperature of the suspension in the at least one fluid line is outside a predetermined temperature range; and the occurrence of an immune response in the patient as evidenced by the 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 the data received from the at least one physiological sensor; and 13. The system of claim 12, further programmed or configured to trigger at least one of an alarm and a warning upon determining that the system is indicative of any of the following:

22. further comprising at least one flow regulator disposed in the at least one fluid line, each of the at least one flow regulator configured to be switchable between an open state and a closed state; upon determining that the volume of the therapeutic composition needs to be increased, 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; upon determining 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 fluid within the suspension to be removed from the suspension via the at least one fluid line; upon detecting that the number of the one or more ruptured cells 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 diverting the suspension to a separate one of the at least one fluid line for at least one of analysis and disposal. The system of claim 12.

23. 1. A system for delivering cell therapy to a patient, comprising: a container configured to hold a 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; a plurality of sensors in communication with the at least one processor, the plurality of sensors comprising at least: a counting sensor configured to collect cell data, the cell data including a number of intact cells and / or ruptured cells; and a pressure sensor configured to collect pressure data, the pressure data including measurements of pressure within the container and / or one or more fluid lines between the container and the patient; and a flow sensor configured to collect flow data, the flow data including measurements of flow in one or more fluid lines between the container and the patient; an ultrasound transducer positioned around an injection site of the therapeutic composition into the patient and configured to collect extravasation data, the extravasation data indicating one of the occurrence and non-occurrence of extravasation at the injection site; 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; Multiple sensors, including Including, the at least one processor: controlling the pump to pressurize the therapeutic composition and deliver the therapeutic composition at a first flow rate; based at least in part on the cellular data, the pressure data, the flow data, the extravasation data, and the physiological data; the therapeutic composition is to be delivered at the first flow rate; or determining whether the therapeutic composition should be delivered at a second flow rate; programmed or configured to system.

24. The determination includes at least determining, based at least in part on the pressure data and / or the flow rate data, that the pressure and / or the flow rate is too high; a determination that a risk of extravasation is occurring based at least in part on the extravasation data; a determination, based at least in part on the cell data, that cells exceeding a predetermined threshold have ruptured; and / or a determination that the patient is experiencing an adverse reaction based at least in part on the physiological data; The system of claim 23, wherein the system is based on

25. At least one of the flow rate and the pressure is too high; There is a risk of extravasation A threshold number of cells have ruptured, and / or the patient is experiencing an adverse reaction; If we determine that, the at least one processor is further programmed or configured to control the pump to deliver the therapeutic composition at the second flow rate.

25. The system of claim 24.

26. 26. The system of claim 25, wherein the second flow rate is one of a stop flow and a decrease in flow.

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

28. 28. The system of claim 27, wherein the alarm is an audible alarm, a visual alarm, and / or a tactile alarm.

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

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

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

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