System and method for ventilating organ

Abstract

To provide a system and method for ventilating an organ.SOLUTION: Provided are a system and method for maintaining vitality of an organ (1029) ex vivo, such as a lung, through negative pressure ventilation (NPV) and perfusion. The system includes fluidically coupled components: an organ enclosure (107), a diaphragm enclosure (109), an actuator / pump (105), a valve (112), a reservoir (103), and a perfusion system. The actuator can displace a precise amount of a working fluid that displaces a precise amount of a sterile support fluid. The sterile fluid travels between the diaphragm enclosure and the organ enclosure, thereby ventilating the organ within an organ chamber. The perfusion system circulates a perfusion fluid through the organ.SELECTED DRAWING: Figure 1

Description

[Background technology]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application Serial No. 63 / 260,097 (Attorney Docket No. AA648), filed August 9, 2021, and entitled "SYSTEM AND METHOD FOR VENTILATING AN ORGAN," which is incorporated herein by reference in its entirety.

[0002] The present disclosure generally relates to a system for controlling airflow into an organ. To provide airflow to an organ, positive or negative pressure can be used to move air. When positive pressure is applied, air is moved into the organ, forcing it to expand. When negative pressure is applied, the organ expands and drawing air into it. Negative pressure ventilation (NPV) has been used in vivo, for example, as assisted breathing for patients suffering from polio. Certain actions on an organ require the organ to be placed ex vivo and ventilated for a period exceeding a threshold amount of time. These actions include, but are not limited to, organ laboratory research and organ transport / maintenance / monitoring / repair for transplantation. NPV can be performed, for example, by extracting air from a bioreactor holding the organ, forcing the organ to expand and drawing in air, simulating inspiration. This process can be reversed, i.e., providing air to the bioreactor, forcing the organ to contract, and releasing the air, simulating expiration. This two-step process is used as an improvement over using positive pressure alone, which can induce injury to organs. Current NPV systems have limitations including, but not limited to: (1) reacting to changes in hydraulic fluid compressibility or other material properties (temperature dependence, degradation / segregation) during operation; (2) being exposed to air bubbles inside any of the hydraulic fluid chambers during operation as a result of insufficient system priming, system leakage, or bubble generation; (3) experiencing diaphragm membrane elasticity between the hydraulic fluid along the thickness of the material; (4) experiencing scaffold / tissue elasticity (external volume expansion not equal to internal volume expansion); (5) experiencing a lack of elasticity / rigidity in the hydraulic system (chambers, tubing); (6) experiencing leakage from improper seals around the hydraulic piston or system fittings; (7) experiencing looseness in the piston linear actuator; (8) experiencing airway restriction or obstruction; (9) inappropriate or incorrect location of sensors in the hydraulic pathways and airways; and (10) suboptimal methods and assumptions used to determine parameters when direct measurements are not made (tidal volume calculated from airway flow).

[0003] The background described above is intended merely to provide a contextual overview of some existing problems and is not intended to be exhaustive. Summary of the Invention [Means for solving the problem]

[0004] The system of the present teachings generates cyclic ventilation of the organ through a fluidly coupled diaphragm. An NPV system controls airflow into and out of the organ. In certain aspects, the system of the present teachings measures various pressure, tidal volume, and temperature parameters to track and assess organ performance. In certain aspects, the materials and environment in contact with the organ are sterile. The organ is immersed in a sterile support fluid, providing moisture to the outside of the organ. The sterile support fluid is coupled to a working hydraulic fluid via an elastic, impermeable diaphragm membrane. The working hydraulic fluid is actuated using a low-pressure piston in a pumping chamber. A perfusion loop, which supplies blood perfusion solution to the organ, is connected to the organ's arteries and veins. The system can include sensors to measure parameters such as, but not limited to, support fluid temperature, perfusate temperature, pulmonary artery flow rate, pulmonary artery or arterial pressure, inspiratory tidal volume, peak inspiratory pressure (also called peak airway pressure), inspiratory air temperature and humidity, and positive end-expiratory pressure. The system includes the ability to measure these parameters to plot pressure-volume relationships and calculate the dynamic compliance of organ tissue. All components can be sterile, single-use, or there can be a combination of single-use and auto-cleavable components.

[0005] An organ bioreactor of the present teachings can include a reservoir chamber and an organ chamber containing a sterile support fluid, a working fluid chamber containing a working hydraulic fluid, also referred to herein as working fluid, and a diaphragm in the diaphragm chamber that separates the sterile support fluid from the working fluid. The reservoir chamber can be used to prepare the system for operational use, for example, to prime the system. The organ bioreactor and actuator can be used to perform ventilation operations. The diaphragm allows the sterile fluid and working fluid to be coupled. For example, when the working fluid is drawn out of the diaphragm chamber by the actuator, the diaphragm deforms and sterile fluid is drawn into the diaphragm chamber, replacing the working fluid. The system can include a solenoid valve for isolating or connecting portions of the fluid network during operation. The organ chamber can include a mounting plate that can secure and position the organ. The mounting plate is configured with openings that can be used to introduce and exhaust air and circulate perfusion fluid. The loading plate is configured to be removed, the organ attached / detached, and then secured to the organ chamber and sealed prior to operation. A system such as that described in U.S. Patent Application No. 17 / 180,506, filed February 19, 2021, and entitled "System and Method for Organ Maintenance and Transport," can be used to allow circulation of perfusion fluid.

[0006] One or more computer systems can be configured to perform specific operations or actions by having software, firmware, hardware, or a combination thereof installed on the system that, when operated, causes the system to perform the action. One or more computer programs can be configured to perform specific operations or actions by including instructions that, when executed by a data processing device, cause the device to perform the action. One general aspect includes a system for negative pressure ventilation of an organ. The system also includes an actuator configured to displace a first fluid by a first volume. The system also includes a diaphragm enclosure containing a flexible membrane, the flexible membrane having two surfaces, one of which is fluidly coupled to the first fluid and the other of which is fluidly coupled to a second fluid, such that, when the actuator displaces the first fluid, the flexible membrane displaces the second fluid by the first volume. The system also includes an organ enclosure that houses the organ, the organ enclosure fluidly coupled to the diaphragm enclosure, the organ enclosure receiving a second fluid from the diaphragm enclosure when the actuator displaces the first fluid. The system also includes where the displacement of the second fluid enables negative pressure ventilation of air and inhalation / exhalation by the organ. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the method.

[0007] Implementations may include one or more of the following features. The system may include at least one sensor configured to collect sensor data. The at least one sensor may include a tidal volume sensor configured to collect tidal volume sensor data during negative pressure ventilation and a pressure sensor configured to sense the pressure of the second fluid during negative pressure ventilation. The at least one sensor may include an air bubble sensor configured to collect air bubble sensor data during a priming process. The system may include at least one controller configured to execute instructions, the instructions configured to control devices in the system. The instructions may include receiving the sensor data and controlling an actuator based at least on the sensor data. The system may include a reservoir holding the second fluid, the reservoir fluidly coupled to the diaphragm enclosure. The instructions may include receiving bubble sensor data from the bubble sensor, the bubble sensor fluidly coupled to the reservoir and the organ enclosure, and moving a quantity of a second fluid from the reservoir to the organ enclosure, the amount based on the bubble sensor data.The system may include a perfusion system including at least one perfusion pump, a gas management system including an enclosure configured to expose venous fluid to a gas, a thermal management system including a device configured to expose venous fluid exiting the gas management system to a thermal regulation means, and a perfusion fluid reservoir including a fluid enclosure configured to hold venous fluid to be directed to the organ, the perfusion fluid reservoir configured to receive perfusion fluid for mixing with the venous fluid to form a mixed fluid, the perfusion fluid reservoir including a drain configured to release excess venous fluid and / or the mixed fluid. The instructions include controlling a perfusion pump, a gas management system, and a thermal management system, and the instructions are configured to direct the perfusion pump to pump venous fluid from the organ, through the gas management system and the thermal management system, and into the organ. The perfusion system may include at least one venous fluid sample port. The perfusion system may include at least one venous sensor.The perfusion system may include at least one arterial fluid sample port. The perfusion system may include at least one arterial sensor. The perfusion fluid may include a blood-based fluid. The perfusion fluid may include an oxygen-carrying molecule. The system may include an actuator, a flexible membrane, an organ enclosure, and a portable enclosure enclosing the perfusion system, and a portable power source. The instructions may include maintaining a gas concentration in the venous fluid at a preselected level. The instructions may include maintaining a dissolved gas concentration in the venous fluid at a user-input level. The instructions may include maintaining a dissolved gas concentration in the venous fluid at a dynamically determined level. The device may include valves controlling flow to / from the reservoir and the organ enclosure, at least one sensor, an actuator, a gas management system providing gas to the venous fluid, and a perfusion pump moving the venous fluid from a venous sinus in the organ to an arterial sinus in the organ. The instructions may include maintaining a dissolved gas concentration in the perfusion fluid at a preselected level. The instructions may include dynamically modifying ventilation and perfusion parameters based at least on data from at least one sensor. The instructions may include dynamically modifying properties of the perfusion fluid, venous fluid, and second fluid based at least on data from the at least one sensor, and assessing the status of the organ, venous fluid, and perfusion fluid based at least on data from the at least one sensor. The instructions may include calculating measurements by measuring pressure in the organ enclosure, actuator stroke, and air properties, and controlling a state of negative pressure ventilation based on the measurements. The instructions may include controlling perfusion of the mixed fluid and properties of the perfusion fluid based at least on flow rates of the perfusion fluid and mixed fluid, pressure of the perfusion fluid and mixed fluid in the arterial sinus, temperature of the perfusion fluid and mixed fluid, and chemical composition of the perfusion fluid and mixed fluid. The instructions may include assessing the perfusion fluid and mixed fluid, and automatically adjusting properties of the perfusion fluid and mixed fluid based at least on the assessment.The instructions may include assessing the perfusion fluid and the mixed fluid and automatically adjusting properties of the perfusion fluid and the mixed fluid based at least on the assessment, the adjusting being based on the balance of gases provided to the gas management system, the balance being based at least on the assessment. The instructions may include assessing organ compliance based at least on the organ tidal volume and pressure. The instructions may include assessing organ compliance based at least on the oxygen flow rate. The instructions may include managing the flow rates of the perfusion fluid and the mixed fluid and independently adjusting delivery and filling pressures to achieve desired pressures of the perfusion fluid and the mixed fluid. The instructions may include adjusting the flow rates and pressures of the perfusion fluid and the mixed fluid as they enter the organ. The instructions may include measuring resistance in the organ and adjusting the flow rates and pressures of the perfusion fluid and the mixed fluid as they enter the organ based on the resistance. The perfusion fluid may include a formulation designed to repair defects within the organ. The perfusion fluid may include a formulation designed to maintain the organ in a preselected state for a preselected amount of time. The perfusion fluid may include a formulation designed to control an immune response in the organ recipient. The thermal management system may include maintaining the temperature of the venous fluid and the mixed fluid within a preselected temperature range. The system may include a perfusion fluid exchange system that enables replacement of the perfusion fluid with a substitution solution. The system may include a filter between at least one perfusion pump and the perfusion fluid reservoir, the filter capturing particles. The organ enclosure may include four sides and a lid. The organ enclosure may include a cylinder and a lid. The organ enclosure may include transparent sides. The organ enclosure may include a transparent lid. The organ enclosure may include a platform for placing the organ. The organ enclosure may include a platform for placing the organ and a mounting plate operably coupled to the platform. The mounting plate may include at least one tube cavity configured to enable perfusion and ventilation of the organ. The organ enclosure may include at least one interface that allows for fluid exchange.The instructions may include opening and closing a valve that enables coupled filling and draining of the reservoir and the organ enclosure. The diaphragm enclosure may include at least one outer shell. The system may include a portable enclosure enclosing the actuator, the flexible membrane, and the organ enclosure, and a portable power source. The second fluid may include a medium formulated to support organ tissue. The second fluid may include a sterile fluid. The second fluid may include an isotonic fluid. The second fluid may include a water-based fluid. The second fluid may include a mineral-based hydraulic fluid. The system may include a valve that controls movement of the second fluid into / out of the organ enclosure. The second fluid may include a protein. The second fluid may include a clotting factor. Implementations of the described techniques may include hardware, methods or processes, or computer software on a computer-accessible medium.

[0008] One general aspect includes a method of ventilating an organ using negative pressure ventilation. The method also includes displacing a first fluid by a first volume with an actuated pump, the first fluid fluid being fluidly coupled to a first surface of a flexible membrane, the flexible membrane being contained within a diaphragm enclosure, the diaphragm enclosure being fluidly coupled to an organ enclosure, the flexible membrane displacing a second fluid by the first volume as the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the second fluid moving in and out of the organ enclosure causing the organ to expand and contract, forcing air in and out of the organ. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the method.

[0009] Implementations may include one or more of the following features. The method may include sensing a tidal volume of air. The method may include pumping perfusion fluid out of the organ, collecting data associated with the perfusion fluid, adjusting properties of the perfusion fluid to form a conditioned perfusion fluid based at least on the collected data, and pumping the conditioned perfusion fluid into the organ. The method may include forming a mixed fluid by mixing fresh perfusion fluid with the conditioned perfusion fluid based on the collected data. The method may include controlling perfusion of the mixed fluid and properties of the perfusion fluid based at least on flow rates of the perfusion fluid and the mixed fluid, pressures of the perfusion fluid and the mixed fluid at the arterial sinus, temperatures of the perfusion fluid and the mixed fluid, and chemical compositions of the perfusion fluid and the mixed fluid. The method may include assessing the perfusion fluid and the mixed fluid and automatically adjusting properties of the perfusion fluid and the mixed fluid based at least on the assessment. The method may include assessing the perfusion fluid and the mixed fluid and automatically adjusting the properties of the perfusion fluid and the mixed fluid based at least on the assessment, the adjusting being based on the balance of gases provided to the gas management system, the balance being based at least on the assessment. The method may include managing the flow rates of the perfusion fluid and the mixed fluid and independently adjusting the delivery pressure and the fill pressure to achieve a desired pressure of the perfusion fluid and the mixed fluid. The method may include adjusting the flow rate and flow pressure of the perfusion fluid as it enters the organ. The method may include measuring resistance in the organ and adjusting the flow rate and flow pressure of the perfusion fluid as it enters the organ based on the resistance. The method may include maintaining the temperature of the venous fluid and the mixed fluid within a preselected temperature range. The method may include draining the adjusted perfusion fluid based on the collected data. The method may include filtering air. The method may include perfusing the organ at a normothermia. The method may include perfusing the organ at a non-normothermia. The method may include assessing a characteristic of the organ during negative pressure ventilation and perfusing and / or ventilating an agent into the organ based on the characteristic. The second fluid may include a medium formulated to support organ tissue. The second fluid may include a sterile fluid.The second fluid may include an isotonic fluid. The second fluid may include a water-based fluid. The second fluid may include a mineral-based hydraulic fluid. The method may include controlling movement of the second fluid to / from the organ enclosure by a valve. The method may include maintaining a dissolved gas concentration in the venous fluid at a preselected level. The method may include maintaining a dissolved gas concentration in the venous fluid at a user-input level. The method may include maintaining a dissolved gas concentration in the venous fluid at a dynamically determined level. The method may include controlling flow to / from a reservoir and the organ enclosure by a valve, the reservoir being fluidly coupled to the diaphragm enclosure; providing gas to the venous fluid by a gas management system; and moving the venous fluid from a venous sinus in the organ to an arterial sinus in the organ by a perfusion pump. The method may include maintaining a dissolved gas concentration in the perfusate at a preselected level. The method may include dynamically modifying ventilation and perfusion parameters based on at least data from at least one sensor. The method may include dynamically modifying properties of the perfusion fluid, venous fluid, and second fluid based on at least data from the at least one sensor, and assessing the status of the organ, venous fluid, and perfusion fluid based on at least data from the at least one sensor. The perfusion fluid may include a formulation designed to repair defects in the organ. The perfusion fluid may include a formulation designed to maintain the organ in a preselected state for a preselected amount of time. The perfusion fluid may include a formulation designed to control an immune response in the organ recipient. The method may include enabling replacement of the perfusion fluid with a substitution solution by a perfusion fluid exchange system. The method may include calculating measurements by measuring pressure, actuator stroke, and air properties within the organ enclosure, and controlling a state of negative pressure ventilation based on the measurements. The method may include assessing organ compliance based on at least the organ tidal volume and pressure. The method may include assessing organ compliance based at least on oxygen flow.The method may include trapping particles between at least one perfusion pump and the perfusion fluid reservoir with a filter. The organ enclosure may include four sides and a lid. The organ enclosure may include a cylinder and a lid. The organ enclosure may include transparent sides. The organ enclosure may include a transparent lid. The organ enclosure may include a platform for mounting the organ. The organ enclosure may include a platform for mounting the organ and a mounting plate operably coupled to the platform. The mounting plate may include at least one tube cavity configured to enable perfusion and ventilation of the organ. The organ enclosure may include at least one interface that enables fluid exchange. The method may include opening and closing valves that enable coupled filling and draining of the reservoir and the organ enclosure. The diaphragm enclosure may include at least one outer shell. The second fluid may include a protein. The second fluid may include a clotting factor. Implementations of the described techniques may include hardware, a method or process, or computer software on a computer-accessible medium.

[0010] One general aspect includes a method for priming an organ enclosure. The method includes displacing a first fluid by a first volume with an actuated pump, the first fluid fluid being fluidly coupled to a first surface of a flexible membrane contained within a diaphragm enclosure, the diaphragm enclosure being fluidly coupled to the organ enclosure and a reservoir, the flexible membrane displacing a second fluid by the first volume as the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the second fluid moving from the reservoir to the organ enclosure. The method also includes detecting, with a sensor, when the organ enclosure is filled. The method also includes closing a fluid connection between the reservoir and the organ enclosure when the organ enclosure is filled. Other embodiments of this aspect include corresponding computer systems, apparatus, and computer programs recorded on one or more computer storage devices, each configured to perform the actions of the method. [Brief explanation of the drawings]

[0011] Non-limiting and non-exhaustive aspects of the present disclosure are described with reference to the following figures, in which like reference numerals refer to like parts throughout the various views unless otherwise specified.

[0012] [Figure 1] FIG. 1 is a schematic block diagram of a ventilation and perfusion system of the present teachings.

[0013] [Figure 2] FIG. 2 is a schematic block diagram of a ventilation system of the present teachings.

[0014] [Figure 3] FIG. 3 is a schematic perspective view of one configuration of a ventilation system of the present teachings.

[0015] [Figure 4] FIG. 4 is a pictorial diagram of the configuration of FIG. 3 including exemplary fluid connections.

[0016] [Figure 5] 5 is an elevational view of the chamber and actuator of the configuration of FIG. 3 including an organ to be loaded, and a cross-sectional view of the diaphragm of the configuration of FIG. 3.

[0017] [Figure 6] FIG. 6 is a schematic bottom perspective view of the configuration of FIG.

[0018] [Figure 7] FIG. 7 is a schematic bottom exploded view of the configuration of FIG.

[0019] [Figure 8] FIG. 8 is a schematic top exploded view of the configuration of FIG.

[0020] [Figure 9] FIG. 9 is a cross-sectional view of the configuration of FIG.

[0021] [Figure 10] FIG. 10 is a cross-sectional view of the diaphragm of the configuration of FIG. 3 in two positions.

[0022] [Figure 11] FIG. 11 is a flowchart of a first exemplary method of the present teachings.

[0023] [Figure 12] FIG. 12 is a flowchart of a second exemplary method of the present teachings. DETAILED DESCRIPTION OF THE INVENTION

[0024] The system of the present teachings applies negative pressure and perfusion to an organ to simulate the function of an organ in the body. For example, if the organ is a lung, in one aspect, the system of the present teachings induces inspiration of air into the lung by withdrawing sterile support fluid from the organ chamber housing the lung. In one aspect, the system induces expiration by adding sterile support fluid to the organ chamber. A controller issues commands to an actuator, which enables movement of sterile support fluid into / from the organ chamber. A sterile boundary is maintained between the working fluid in the actuator and the sterile support fluid in the organ chamber by the inclusion of a flexible membrane, which separates and combines the fluids. The diaphragm chamber consists of two outer shells and a flexible membrane. Fluid can flow in and out of each cavity through connection ports on each side of the diaphragm chamber. One port is connected to the actuator / syringe pump, and the second port is connected to the organ chamber and reservoir. The inside of the diaphragm chamber is separated into two cavities by an elastic membrane, which also separates the system's working fluid from the sterile fluid. The intent of this fluid separation is to improve the sterility and disposability of the device. By separating the working fluid in the actuator / syringe pump from the sterile support fluid in the organ chamber, the elastic membrane acts as a separation between the durable / non-disposable and disposable portions of the system. The elastic membrane provides a dynamic connection between the system's working fluid and the sterile support fluid. When the actuator is extended and working fluid is drawn into the syringe, the elastic membrane responds by pulling toward the syringe. Similarly, when the actuator is retracted and working fluid is pushed out of the syringe, the membrane is pushed away from the syringe. This equal exchange of fluids allows the actuator / syringe pump to precisely displace volumes of sterile support fluid into and out of the organ chamber.

[0025] Referring now to FIG. 1 , in one aspect, the fluid driving organ ventilation is stored in reservoir 103 and actuator 105. The sterile support fluid can include any type of medium, e.g., a sterile and isotonic medium, formulated to support organ tissue. The working fluid can include water or a mineral-based hydraulic fluid intended to sufficiently lubricate the actuator, reduce wear, and sustain a high number of cycles during operation. The orientation (open or closed) of valve 112, along with the position of diaphragm 122, allows for movement of sterile support fluid into / out of organ chamber 107. Perfusion of the organ allows for maintenance of a normothermic or non-normo-ther ... To properly mimic in vivo behavior, the dissolved gas concentration and temperature of the venous fluid are maintained at levels that may be preselected, manually entered, or dynamically determined, for example. The venous fluid circulates in a loop that carries the venous fluid from the organ 1029 through the venous port, past the sensor and sample port 1026, through the gas exchange mechanism 1025 and thermal management 1013, and into the organ 1029 through the arterial port, possibly mixing / exchanging with the perfusate along the way to form a mixed fluid.

[0026] Continuing to refer to FIG. 1 , in one aspect, system operation is enabled by a controller (not shown) that processes data, a gas supply (not shown) that receives and supplies gases such as air, and a pneumatic system (not shown) that moves fluids through the system. Sensors 1024 are positioned throughout the perfusion and ventilation loops to collect sensed parameters. The exemplary configurations described herein do not limit the types or locations of sensors 1024 that may be added to a system of the present teachings. The controller processes these sensed parameters and metrics to dynamically modify ventilation and perfusion parameters as well as the properties of the perfusate and sterile support fluids to assess not only fluid status but also organ status. For example, organ chamber pressure, actuator stroke / tidal volume, and organ air conditions (pressure, humidity, temperature) can be measured and used to control ventilation status during operation. Arterial pressure, perfusate flow rate, perfusate temperature, and perfusate chemical composition (lactate, glucose, oxygen saturation, dissolved oxygen, and pH) can be measured and used to control the perfusion system and perfusate characteristics. A sample port allows for withdrawal of perfusate within the perfusion loop to assess organ viability. Perfusate assessment drives manual and / or automatic changes in numerous adjustments that can be made to ensure organ viability. For example, if oxygen saturation falls below a preselected threshold, the gas exchange mechanism 1025 adjusts the gas balance, thus correcting the shortfall in oxygen saturation. In certain aspects, the perfusate can include a blood-based fluid. In certain aspects, the perfusate can include oxygen-carrying molecules. Assessing organ health can be accomplished using the same suite of sensors. For example, for the lungs, dynamic compliance (based on tidal volume, lung pressure at full inspiration, and lung pressure at full expiration) is an organ assessment metric. Oxygen flow is another organ assessment metric. It is based on removing oxygen and carbon dioxide, measuring oxygen and carbon dioxide before and after inspiration / expiration, and calculating the mass change and flow of oxygen and carbon dioxide.

[0027] Continuing with FIG. 1 , the perfusion pump 1001 can include features such as those described in U.S. Patent No. 8,273,049, issued September 25, 2012, entitled “Pumping Cassette,” which is incorporated herein by reference in its entirety. The perfusion pump 1001's perfusion fluid fill pressure and combined fluid (venous fluid and perfusion fluid) delivery pressure are configured to be independently adjusted to manage flow rate and achieve a desired pressure. The perfusion pump 1001 regulates the combined fluid flow rate and flow pressure entering the organ 1029. As resistance within the organ 1029 changes, the perfusion pump 1001 varies the pumping pressure and flow rate to accommodate the changed resistance. The perfusion pump 1001, when controlled by a control and pneumatic system (not shown), enables low hemolysis, and the control and pneumatic system can be driven by preselected, default, user-defined, dynamically determined, or other criteria. In certain aspects, the organ's environment is configured to be adjusted to improve the organ's condition. For example, if the organ reaches a compromised state, the perfusion fluid can be formulated to repair defects within the organ. Medications can be administered to improve the organ's health. In certain aspects, the perfusion fluid can include a growth medium to both grow and stimulate the organ. In certain aspects, the system ensures that the organ remains functional, possibly for a period of time, after the perfusion / growth medium is administered. In certain aspects, the formulation of the perfusion fluid is targeted to determine the optimal time for transplant scheduling. Additionally, the air being exchanged during ventilation can be modified, for example, to add medications. If the organ is to be used as a transplant, the perfusion fluid and air modifier can be formulated to reduce a potential adverse immune response by the recipient.

[0028] Continuing to refer to FIG. 1 , a gas exchange mechanism (gas management) 1025 regulates gases in the perfusate as the perfusion pump 1001 pumps the perfusate through the gas management system 1025. The gas management system 1025 regulates gas being depleted or added as the perfusate progresses through the organ 1029. The thermal management 1013 maintains the temperature of the perfusate within a preselected temperature range by the thermal management system 1013. Perfusate exiting the organ 1029 through a vein can be directed to the perfusion pump 1001 to create a closed-loop circulation, potentially reducing hemolysis. In certain aspects, the exiting perfusate can be directed to a perfusate reservoir 1027 or other components (not shown) to manage the circulated perfusate. For some types of organs, flowing the output into the perfusate reservoir 1027 can create an environment that can resemble the human body as closely as possible. In some configurations, output can be pumped from the perfusate exchange system 1030 to a perfusate drain 1031, and substitution solution from a perfusate source 1033 can be infused into the system at a flow rate that matches the output flow rate. In some configurations, the exiting perfusate (output) is metered to ensure that the output volume is replaced by substitution solution. The perfusate reservoir 1027 thus allows complete circulation of perfusate through the organ 1029. In some configurations, a filter (not shown) is placed between the perfusate reservoir 1027 and the perfusion pump 1001. The filter captures particles, such as tissue chunks or contaminants, from being pumped into the organ. The organ chamber 107 can take any shape and size, depending on the type of tissue being stored. For example, the organ chamber 107 may include, for example, four sides and a lid, or a cylinder and a lid. In some configurations, the sides and lid may be transparent to allow visualization of the enclosed tissue. In one aspect, the filter 1004 establishes an exit pressure from the organ 1029. The organ 1029 rests within the organ chamber 107, possibly on a platform (or coupled to a mounting plate). The organ chamber 107 includes features that are universal for several organ types.The organ chamber 107 includes various interfaces to allow for the input and output of fluids.

[0029] Continuing to refer to FIG. 1 , in one aspect, the system of the present teachings can be portable, allowing for movement of an organ from one location to another, for example, from a harvesting location to a transplanting location. A portable power source allows the actuator to continue to move the working fluid, thereby moving the sterile support fluid. The portable power source powers the controller and the perfusion pump and other devices requiring power. In one aspect, the portable system, including the actuator, diaphragm, organ enclosure, and portable power source, is configured to be contained within an enclosure, the footprint of which can fit through a standard doorway. In one aspect, the portable system, including the actuator, diaphragm, organ enclosure, perfusion system, and portable power source, is configured to be contained within an enclosure, the footprint of which can fit through a standard doorway.

[0030] 2, in one aspect, a ventilation system of the present teachings includes a controller 101. The controller 101 can drive both the ventilation system and the perfusion system of the present teachings, but will be described herein with reference to the ventilation system. The controller 101 is configured to send commands to open and close valves, which may allow for coupled filling and draining of the reservoir 103 and the organ chamber 107. The controller 101 is configured to command the actuator 105, which allows for fluid movement to (and from) the actuator 105 at a preselected volume and rate.

[0031] Continuing with and still further referring to FIG. 2 , diaphragm chamber 109 includes at least one outer shell and at least one membrane 122. Diaphragm chamber 109 is separated into two cavities by membrane 122, which further separates the working fluid from the sterile fluid. The intent of this fluid separation is to improve the sterility and disposability of the device. By separating the working fluid controlled by actuator 105 from the sterile fluid in organ chamber 107, diaphragm membrane 122 can function as a separation between the durable / non-disposable and disposable portions of the system. Diaphragm membrane 122 provides a dynamic connection between the working fluid and the sterile fluid of the system. When actuator 105 moves the syringe in one direction and working fluid is drawn into the syringe, membrane 122 is pulled toward the syringe in response. Similarly, when the actuator 105 moves the syringe in another direction, forcing working fluid into the actuator cavity 121, the membrane 122 is forced away from the syringe. This controlled exchange of fluids allows the actuator 105 to precisely displace sterile fluid volumes into and out of the organ chamber 107. Fluid can flow into and out of the sterile cavity 119 through connecting ports / valves 113 / 111 on each side of the membrane 122. Fluid valve 111 is fluidly connected to the organ chamber 107, and fluid valve 113 is fluidly connected to the reservoir 103. In one aspect, ports 111 / 113 can include individual two-way valves. In one aspect, a single three-way valve can be used to meter flow to both ports 111 / 113.

[0032] 2 , in one aspect, the ventilation system prepares the system of the present teachings for ventilating an organ through the use of a priming process. In one aspect, the priming process can include, but is not limited to, draining the organ chamber 107, filling the reservoir 103 with a sterile support fluid, and opening the valve 113 connecting the reservoir 103 with the diaphragm chamber 109. When the reservoir 103 is full, the organ chamber 107 can be drained and the priming operation can begin. The controller 101 commands the valve 113 to open, commands the valve 111 to close, and commands the actuator 105 to draw working fluid into the syringe and out of the actuator cavity 121. The syringe is configured to be mechanically coupled to the actuator 105. Sterile support fluid from reservoir 103 fills chamber 119, which is formed by the movement of diaphragm 122 in response to the withdrawal of working fluid from actuator cavity 121. Controller 101 commands valve 113 to close, valve 111 to open, and actuator 105 to force working fluid out of the syringe, forcing the working fluid in cavity 121 through diaphragm 122 into fill chamber 119 and sterile support fluid into organ chamber 107. Controller 101 closes valve 111 and opens valve 113, following the described process until organ chamber 107 is filled. In one aspect, to determine whether organ chamber 107 is filled with fluid, organ chamber 107 includes a priming line 118 through which air and fluid pass. Prime line 118 is operably coupled to, for example, air bubble sensor 116 and configured to be opened and closed by operation of priming valve 91. When the air bubble sensor 116 no longer detects air or bubbles, the organ chamber 107 is configured to fill. At this point, the priming process is complete. The controller 101 opens valve 113 and closes valves 111 and 91.

[0033] Continuing with and still further referring to FIG. 2 , following the priming operation, the organ can undergo general operation. General operation addresses modes of use, including, but not limited to, testing of the acellular scaffold, cell maturation where cells can respond to motility signals, cell maintenance using media, and organ / lung ventilation using vascular perfusion. The organ is immersed in fluid within the organ chamber 107. The organ is coupled with a mounting plate, which is attached to the organ chamber 107 and sealed in place. Sealing can be accomplished, for example, but not limited to, by an O-ring. When operation is complete, the organ is removed, and the organ chamber is evacuated following the reverse of the filling process described herein until a predetermined volume has circulated. Pressure sensor 93 monitors the pressure (peak inspiratory pressure and positive end-expiratory pressure) of the sterile fluid exerted on the organ within the organ chamber 107 during ventilation. The pressure, along with the tidal volume measured / calculated by actuator 105, contributes to the pressure-volume relationship. The pressure-volume relationship can allow for the measurement of the dynamic compliance of tissue materials.

[0034] Continuing with reference to FIG. 2, organs can leak in several ways, including, but not limited to, leakage of blood into the surrounding sterile support fluid, leakage of blood into air pathways within the organ, leakage of air into the surrounding sterile support fluid, and leakage of sterile support fluid into air pathways within the organ. Methods of detection can include, but are not limited to, monitoring the pressure profile of the organ chamber inflation / deflation and perfusion loop, detecting changes, and characterizing them. In one aspect, methods of detection can include optical / ultrasonic sensors to indicate changes in level height and detect added gas or liquid, and optical sensors to monitor conductivity.

[0035] Referring now to Figures 3-6, various orientations of ventilation system configurations are shown. Other configurations are possible. The ventilation system in the illustrated configuration includes four main components: a reservoir, an organ chamber, a diaphragm chamber, and a working fluid actuator. The organ chamber holds the organ being ventilated and possibly perfused. The reservoir holds a sterile support fluid, which is used to fill the organ chamber during priming and to enable ventilation during operational use. The working fluid actuator forces the working fluid toward and away from a flexible diaphragm held by the diaphragm chamber. The ventilation system components form a hydraulically actuated, mechanically coupled diaphragm pump that moves the sterile support fluid into the organ chamber and applies pressure and compression to the outside of the organ as the working fluid is forced against the flexible diaphragm. The compression force on the organ serves to expel air from the organ. As working fluid is withdrawn from the diaphragm, sterile support fluid is withdrawn from the organ chamber, filling the empty space within the diaphragm chamber. As sterile support fluid is withdrawn from the organ chamber, the organ experiences a lower or negative pressure relative to atmospheric / ambient conditions in the air supply, causing the organ to expand. The expansion draws air into the organ.

[0036] Continuing with reference to FIGS. 3-6, the priming process begins when reservoir 103 is filled with sterile support fluid. Reservoir 103 can be filled by any means: automatically upon system startup, controlled by controller 101 (FIG. 1), manually, or by a combination of automatic and manual control. Fill / drain cavity 245 (FIG. 6) is configured to be appropriately adapted to allow filling or draining of reservoir 103. The composition of the sterile support fluid can be, for example, sterile and isotonic. In certain aspects, additional agents, such as proteins and clotting factors, can be included in the support fluid.

[0037] Continuing with reference to FIGS. 3-6 , in one aspect, the reservoir 103 is covered by a reservoir cap 233, which can be leak-tightly sealed (gas and liquid) by conventional means, such as, but not limited to, an O-ring or gasket. The reservoir cap 233 can include a sealed mounting cavity for, for example, but not limited to, a tubing fitting and a sensor. In one aspect, the reservoir cap 233 can include a mounting portion, a tubing fitting, and a sensor to allow for determining whether the sterile support has been fully pumped from the reservoir 103 into the organ chamber 107 during the priming operation. In one aspect, the organ chamber filling operation terminates when the organ chamber 107 contains no more gas. Whether the organ chamber 107 contains gas can be determined, for example, by exposing the vented effluent from the organ chamber 107 to an air bubble sensor. In one aspect, the air bubble sensor 231 interrogates the effluent from the priming line arriving in tubing 301 ( FIG. 4 ). The effluent of the priming line is configured to enter the reservoir 103 through the barbed tubing fitting 235. When the air bubble sensor 231 does not detect air or bubbles in the tubing 301 (FIG. 4), a valve, such as a solenoid valve, is configured to close and effluent exiting the barbed tubing fitting 213 and passing from the organ chamber 107 through the tubing 202 (FIG. 4) is discontinued. Other methods of determining that the priming operation is complete are also contemplated by the present teachings.

[0038] Continuing with reference to FIGS. 3-6 , the organ chamber 107 is used to hold an organ undergoing ventilation and possibly perfusion. To maintain a sterile environment, the organ chamber 107 can be covered by, for example, a chamber cap 217 and leak-tight sealed therewith. In one aspect, the chamber cap 217 is permanently attached to the organ chamber 107. The organ is itself held in place by a loading plate 215. The loading plate 215 can be leak-tight sealed with and removable from the chamber cap 217. In one aspect, the loading plate 215 can be integral with the chamber cap 217, and the combination can be disengaged from the organ chamber 107 to load and remove the organ. The loading plate 215 includes a means by which the organ is perfused and a means by which gases flow into and out of the organ. In one aspect, the loading plate 215 includes tubing cavities for perfusion and ventilation. In one aspect, the duct cavities can include a cavity for venous flow, a cavity for arterial flow, and at least one cavity for gas flow. In one configuration, an arterial line 255 ( FIG. 5 ) allows arterial flow from the perfusion system, and a venous line 253 ( FIG. 5 ) allows venous flow to the perfusion system. The perfusion system described herein with reference to FIG. 1 can be used. Other configurations of the perfusion system are also contemplated by the present teachings. In one configuration, a gas line 123 ( FIG. 5 ) provides a pathway for the organ to expel gas and inhale gas, as described herein. Exhaled and inhaled gases are monitored, as described herein with reference to FIG. 1. The venous line 253 ( FIG. 5 ), the arterial line 255 ( FIG. 5 ), and the gas line 123 ( FIG. 5 ) can pass through the mounting plate 215 and the chamber cap 217 (if they are separate components) and cannulate the organ at anatomically appropriate points.

[0039] Continuing with reference to FIGS. 3-6 , in the exemplary configuration shown, priming and ventilation are enabled by the combination of the actuator 211, syringe 225, plunger 219, diaphragm membrane 122, reservoir valve 204, organ chamber valve 203, and tubing 303. The priming operation involves steadily moving sterile support fluid from the reservoir 103 to the organ chamber 107. The process begins with the reservoir 103 filled with sterile support fluid and the organ chamber empty of sterile support fluid. An organ can be loaded into the organ chamber 107 before the priming operation is performed. As described herein, the first step in the priming process involves opening the reservoir valve 204 and priming line valve 227 and closing the organ chamber valve 203. In one aspect, each of the reservoir valve 204 and organ chamber valve 203 can be held in place by a valve mount 205. The second step in the priming process occurs when the pumping arrangement acts on the working fluid. In one aspect, the pumping arrangement can include a precision syringe coupled to a linear actuator motor. In one aspect, the linear actuator is connected to the syringe plunger, thus controlling the position and movement of the plunger. The arrangement shown includes a linear actuator 211, a syringe plunger 219, and a syringe barrel 225, which together draw the working fluid out of the diaphragm working fluid section 121.

[0040] 3-6 , the working fluid pulls the diaphragm 122 toward the syringe barrel 225, thereby drawing sterile support fluid into the tubing 303 through the barbed tubing fitting 257 and into the diaphragm sterile support fluid section 119. The third step in the priming process involves closing the reservoir valve 204 and opening the organ chamber valve 203. At this point, the sterile support fluid occupies the diaphragm sterile support fluid section 119 and the working fluid occupies the syringe 225. When the organ chamber valve 203 is open, a fourth step is performed in which the actuator 211 commands the plunger 219 to expel the working fluid in the syringe 225 into the diaphragm working fluid section 121. The working fluid pushes the membrane 122 away from the actuator 211, thus forcing the sterile support fluid through the valve 203, tubing 303, and barbed fitting and into the organ chamber 107. Steps 1-4 are repeated until the bubble sensor 231 detects no more air or bubbles in the priming tubing 301. At this point, the fifth step involves closing the bubble chamber valve 227 and the organ chamber valve 203.

[0041] Continuing with reference to Figures 3-6, ventilation begins when the organ chamber 107 fills with sterile support fluid surrounding the organ. Negative pressure ventilation involves the absence of a step that forces gas into the organ. Instead, the organ's geometry is modified by changes in the volume of the surrounding sterile support fluid, which causes the organ to expand and contract. During the contraction phase, as a volume of sterile support fluid is displaced into the organ chamber 107, the relatively high pressure on the organ causes it to contract, which will expel gas out the gas line 123. During the expansion phase, as a volume of sterile support fluid is displaced into the diaphragm chamber 119, the relatively low pressure on the organ causes it to expand, which will draw gas into the gas line 123. The first step in the ventilation process is to open the organ chamber valve 203 and ensure that the reservoir valve 204 and bubble chamber valve 227 are closed. The second step in the ventilation process is to enable the actuator 211 to command the syringe pump 219 to draw working fluid into the syringe 225. As described with reference to the priming process, drawing working fluid into the syringe 225 moves the membrane 122 toward the actuator 211. The space in the diaphragm chamber 109 created by the movement of the membrane 122 is filled with sterile support fluid in the organ chamber 107. The pressure on the organ from the sterile support fluid is reduced, causing the organ to expand and "breathe." The third step in the ventilation process is to enable the actuator 211 to command the syringe pump 219 to force working fluid out of the syringe 225 and into the diaphragm chamber 109. The working fluid moves the membrane 122 away from the actuator 211, displacing the sterile support fluid in the diaphragm chamber section 119 into the organ chamber 107. The additional sterile support fluid in the organ chamber 107 forces the organ to contract and "exhale," regardless of whether gas was inhaled during the previous step. Steps 2 and 3 can be repeated as long as required to ventilate the organ. Gases exiting the organ can be examined, and, if necessary, changes can be made in the timing of the ventilation steps.For example, the time between when the working fluid is moved towards the actuator 211 and when the working fluid is moved away from the actuator 211 can be adjusted, for example, if the organ shows signs of reduced tidal volume.

[0042] 7 and 8, exploded perspective views of the ventilation device configuration of the present teachings are shown. A base 259 anchors the ventilation system and provides mounting locations for the reservoir wall 103A and organ chamber wall 107A, as well as the syringe 225, diaphragm chamber 109, and base stand 201. In one aspect, the base stand 201 includes multiple sections that provide a stable base and space for the diaphragm chamber 109 between the sections. The base stand 201 includes a single component with a cavity, if needed, to provide space for the diaphragm chamber 109. The reservoir wall 103A includes an enclosure, which may be a leak-tight seal, that is mounted on the base 259. The base 259 includes a form-fitting pocket molded to the shape of the reservoir wall 103A. A sealing material, for example, can be fitted into the pocket (e.g., an O-ring) or released therein (e.g., an adhesive). The reservoir frame 103A and pocket can take any shape, e.g., cylindrical or cubical. The base 259 includes mounting cavities 241 / 245 for openings that allow fluid flow to and from the reservoir 103 (FIG. 3). As described herein, during the priming process, sterile support fluid exits the reservoir 103 (FIG. 3) at a predetermined rate through a barbed tubing fitting mounted in cavity 241. Cavity 245 similarly accommodates fittings and provides a fill / drain for the sterile support fluid in the reservoir 103 (FIG. 3). The organ chamber frame 107A can fit into a pocket in the base 259, for example, as described with respect to the reservoir frame 103A. The reservoir frame 103A and organ chamber frame 107A can be shaped the same or differently. For example, one frame can be cylindrical, while the other is cubical. The base 259 includes at least one cavity 243 that can house a tubing fitting, which allows tubing to deliver and remove sterile supporting fluids from the organ chamber 107, as described herein.

[0043] 9 and 10, cross-sectional views of exemplary configurations illustrate the positions of diaphragm 122 when (1) syringe 219 draws working fluid into barrel 225 and (2) syringe 219 pushes working fluid into working fluid diaphragm chamber 121. With respect to (1), when working fluid is in barrel 225, sterile support fluid is drawn out of organ chamber 107 and into sterile support fluid diaphragm chamber 119. As sterile support fluid is drawn out of organ chamber 107, the organ has room to expand, and as it expands, air is drawn in, filling the vacuum caused by the expansion. With respect to (2), when working fluid is in working fluid diaphragm chamber 121, sterile support fluid in sterile support fluid diaphragm chamber 119 moves into organ chamber 107, causing the organ to contract. This contraction expels air from the organ. The amount of sterile support fluid moving in and out of the organ chamber 107 can be explicitly controlled, thereby controlling the amount of ventilation experienced by the organ.

[0044] 11 , a method 1100 of priming an organ enclosure can include, but is not limited to, displacing (1102) a first volume of a first fluid by an actuated pump, the first fluid being fluidly coupled to a first surface of a flexible membrane, the flexible membrane being contained within a diaphragm enclosure, the diaphragm enclosure being fluidly coupled to the organ enclosure and a reservoir, the flexible membrane displacing a second fluid by the first volume as the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the second fluid moving from the reservoir to the organ enclosure. The method 1100 also includes detecting (1104) when the organ enclosure is filled by a sensor, and closing (1106) a fluid connection between the reservoir and the organ enclosure when the organ enclosure is filled. After the organ enclosure has been primed, a method of ventilating an organ using negative pressure can include, but is not limited to, displacing a first fluid by a first volume with an actuated pump, the first fluid fluid being fluidly coupled to a first surface of a flexible membrane, the flexible membrane being contained within a diaphragm enclosure, the diaphragm enclosure being fluidly coupled to the organ enclosure, the flexible membrane displacing a second fluid by the first volume as the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the second fluid moving in and out of the organ enclosure, causing the organ to expand and contract and forcing air in and out of the organ. In one aspect, the method includes sensing a tidal volume of air. In another aspect, a method includes pumping perfusion fluid out of an organ, collecting data associated with the perfusion fluid, adjusting properties of the perfusion fluid to form a conditioned perfusion fluid based at least on the collected data, and pumping the conditioned perfusion fluid into the organ. In another aspect, the method includes mixing fresh perfusion fluid with the conditioned perfusion fluid based on the collected data. In another aspect, the method includes draining the conditioned perfusion fluid based on the collected data. In another aspect, the method includes filtering air.In another aspect, the method includes perfusing the organ normothermally. In another aspect, the method includes perfusing the organ sub-normothermally. In another aspect, the method includes assessing a characteristic of the organ during negative pressure ventilation and perfusing and / or ventilating an agent into the organ based on the characteristic.

[0045] Referring now to FIG. 12, a method 1200 of ventilating an organ using negative pressure ventilation can include, but is not limited to, displacing (1202) a first volume of a first fluid by an actuated pump, the first fluid being fluidly coupled to a first surface of a flexible membrane, the flexible membrane being contained within a diaphragm enclosure, the diaphragm enclosure being fluidly coupled to an organ enclosure, the flexible membrane displacing a second fluid by the first volume as the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the second fluid moving in and out of the organ enclosure, causing the organ to expand and contract and forcing air in and out of the organ.

[0046] Those skilled in the art will understand that the methods described within this disclosure may be applied to computer systems configured to perform such methods, and / or computer-readable media containing programs for performing such methods, and / or software and / or firmware and / or hardware (e.g., integrated circuits) designed to perform such methods. Raw data and / or results may be stored for future retrieval and processing, printed, displayed, transferred to another computer, and / or transferred anywhere. Communications links may be wired or wireless, including, by way of non-limiting example, Ethernet, cellular or broadband networks, WiFi or local area networks, military communications systems, and / or satellite communications systems. Portions of the system may run on computers with, for example, varying numbers of CPUs. Other alternative computer platforms may be used.

[0047] As one skilled in the art would understand, the methods described in this disclosure may be implemented, in whole or in part, electronically. Signals representing actions taken by elements of the systems of this disclosure and other disclosed configurations may travel via at least one live communications network. Control and data information may be executed electronically and stored on at least one computer-readable medium. The system may be implemented to execute on at least one computer node within at least one live communications network. Common forms of computer-readable media include, for example, but are not limited to, floppy disks, flexible disks, hard disks, magnetic tape, or any other magnetic medium, compact disk read-only memory or any other optical medium, punch cards, paper tape, or any other physical medium with a pattern of holes, random access memory, programmable read-only memory, erasable programmable read-only memory (EPROM), flash EPROM, or any other memory chip or cartridge, or any other medium from which a computer can read.

[0048] Those skilled in the art will understand that information and signals may be represented using any of a variety of different existing techniques. For example, data, instructions, commands, information, signals, bits, symbols, or chips that may be referred to throughout this description may be represented by voltages, currents, electromagnetic waves, magnetic fields or particles, optical fields or particles, ultrasound, projected capacitance, or any combination thereof.

[0049] Those skilled in the art will further appreciate that the various illustrative logic blocks, modules, circuits, and algorithm steps described in connection with the arrangements disclosed herein can be implemented as electronic hardware, computer software, or a combination of both. To clearly illustrate this interchangeability of hardware and software, the various illustrative components, blocks, modules, circuits, and steps are described in terms of their functionality. Whether such functionality is implemented as hardware or software depends on the particular application and design constraints imposed on the overall system. Those skilled in the art may implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the appended claims.

[0050] The various illustrative logic blocks, modules, and circuits described in connection with the arrangements disclosed herein may be implemented with or implemented using a general-purpose processor, a digital signal processor (DSP), an application-specific integrated circuit (ASIC), a field-programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof, designed to perform the functions described herein. A general-purpose processor may be a microprocessor, but alternatively, the processor may be any conventional processor, controller, microcontroller, or state machine. A processor may also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, multiple microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration.

[0051] The actions of a method or algorithm described in connection with the arrangements disclosed herein may be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. The software module may reside in RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, a hard disk, a removable disk, a CD-ROM, or any other form of storage medium known in the art. The storage medium may be coupled to the processor such that the processor can read information from, and write information to, the storage medium. Alternatively, the storage medium may be integral to the processor. The processor and the storage medium may reside in an ASIC. The ASIC may reside in a functional device, such as a computer, a robot, a user terminal, a mobile phone or tablet, a car, or an IP camera. Alternatively, the processor and the storage medium may reside as separate components within such a functional device.

[0052] The above description is not intended to be exhaustive or to limit features to the precise form disclosed. Various alternatives and modifications can be devised by those skilled in the art without departing from the disclosure, and the generic principles defined herein may be applied to other aspects without departing from the spirit or scope of the appended claims. Therefore, the present disclosure is intended to encompass all such alternatives, modifications, and variations. In addition, while several configurations of the present disclosure are shown in the drawings and / or discussed herein, the disclosure is not intended to be limited thereto, as it is intended that the disclosure be as broad as the art will permit, and that the specification be similarly perused. Therefore, the above description should not be construed as limiting, but merely as examples of particular configurations. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto. Other elements, steps, actions, methods, and techniques that are not substantially different from those described above and / or in the appended claims are also intended to be within the scope of the present disclosure. Thus, the appended claims are not intended to be limited to the arrangements shown and described herein, but are to be accorded the widest scope consistent with the principles and novel features disclosed herein.

[0053] The arrangements shown in the drawings are presented only to demonstrate certain embodiments of the present disclosure. The drawings described are merely illustrative and non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn to a particular scale for illustrative purposes. Additionally, elements shown in drawings with the same number may be the same or similar elements, depending on the context.

[0054] When the term "comprising" is used in the present description and claims, it does not exclude other elements or steps. When an indefinite or definite article, such as "a," "an," or "the," is used when referring to a singular noun, this also includes the plural of that noun unless something is specifically stated otherwise. Thus, the term "comprising" should not be construed as being limited to the items listed thereafter; it does not exclude other elements or steps; thus, the scope of the expression "a device comprising items A and B" should not be limited to devices consisting only of components A and B. Furthermore, to the extent that the terms "includes," "has," "possesses," and equivalents are used in the present description and claims, such terms, when employed as transitional terms in the claims, are intended to be inclusive in a manner similar to the term "comprising," such that they are interpreted as "comprising."

[0055] Additionally, the terms "first," "second," "third," and the like, whether used in the description or the claims, are provided to distinguish between similar elements and not necessarily to describe a sequence or chronology. It is to be understood that the terms so used are interchangeable under appropriate circumstances (unless expressly disclosed otherwise) and that the disclosed embodiments described herein are capable of operation in sequences and / or arrangements other than those described or illustrated herein.

[0056] The claims are as follows:

Claims

1. 1. A system for negative pressure ventilation of an organ, said system comprising: an actuator configured to cause a first fluid to be displaced by a first volume; a diaphragm enclosure containing a flexible membrane, the flexible membrane having two surfaces, one of the two surfaces being fluidly coupled to the first fluid and the other of the two surfaces being fluidly coupled to a second fluid, the flexible membrane displacing the second fluid by the first volume when the actuator causes the first fluid to be displaced; an organ enclosure for housing the organ; Equipped with the organ enclosure is fluidly coupled to the diaphragm enclosure, the organ enclosure receiving the second fluid from the diaphragm enclosure when the actuator causes the first fluid to be displaced; The system, wherein the displacement of the second fluid allows negative pressure ventilation of the air and inspiration / expiration by the organ.

2. further comprising at least one sensor configured to collect sensor data; The system of claim 1 .

3. The at least one sensor a tidal volume sensor configured to collect tidal volume sensor data during said negative pressure ventilation; a pressure sensor configured to sense the pressure of the second fluid during the negative pressure ventilation; and The system of claim 2 , comprising:

4. The system of claim 2 , wherein the at least one sensor comprises an air bubble sensor configured to collect air bubble sensor data during a priming process.

5. The system of claim 2 , further comprising at least one controller configured to execute instructions, the instructions configured to control devices within the system.

6. The instruction: receiving the sensor data; controlling the actuator based at least on the sensor data; The system of claim 5 , comprising:

7. The system of claim 5 , further comprising a reservoir for holding the second fluid, the reservoir being fluidly coupled with the diaphragm enclosure.

8. The instruction: receiving air bubble sensor data from an air bubble sensor, the air bubble sensor being fluidly coupled with the reservoir and the organ enclosure; transferring a quantity of the second fluid from the reservoir to the organ enclosure; 8. The system of claim 7, comprising:

9. further comprising a perfusion system, said perfusion system comprising: at least one perfusion pump; a gas management system including an enclosure configured to expose the intravenous fluid to a gas; a thermal management system including a device configured to expose the intravenous fluid exiting the gas management system to a thermal regulation means; a perfusion fluid reservoir including a fluid enclosure configured to hold the venous fluid to be directed to the organ; Including, 8. The system of claim 7, wherein the perfusion fluid reservoir is configured to receive perfusion fluid for mixing with the venous fluid to form a mixed fluid, and the perfusion fluid reservoir includes a drain configured to release excess amounts of the venous fluid and / or the mixed fluid.

10. The fluid path further comprises: at least one venous sensor configured to determine a characteristic of the venous fluid; at least one arterial sensor configured to determine a characteristic of the arterial fluid; Including, 10. The system of claim 9, wherein the instructions include controlling the perfusion pump, the gas management system, and the thermal management system, and the instructions are configured to instruct the perfusion pump to pump the venous fluid from the organ, through the gas management system and the thermal management system, and into the organ.

11. The system of claim 9 , wherein the perfusion system comprises at least one venous fluid sample port.

12. The system of claim 9 , wherein the perfusion system comprises at least one venous sensor.

13. The system of claim 9 , wherein the perfusion system comprises at least one arterial fluid sample port.

14. The system of claim 9 , wherein the perfusion system comprises at least one arterial sensor.

15. The system of claim 9 , wherein the perfusion fluid comprises a blood-based fluid.

16. The system of claim 9 , wherein the perfusion fluid comprises oxygen-carrying molecules.

17. a portable enclosure surrounding the actuator, the flexible membrane, and the organ enclosure; Portable power supply and The system of claim 1 further comprising:

18. a portable enclosure enclosing the actuator, the flexible membrane, the organ enclosure, and the perfusion system; Portable power supply and The system of claim 9 further comprising:

19. 1. A method of ventilating an organ using negative pressure ventilation, said method comprising: displacing a first volume of a first fluid with an actuated pump; 1. A method of displacing a second fluid by the first volume when the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the flexible membrane being contained within a diaphragm enclosure, the diaphragm enclosure being fluidly coupled to an organ enclosure, the flexible membrane displacing a second fluid by the first volume when the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the second fluid moving in and out of the organ enclosure causing the organ to expand and contract and forcing air in and out of the organ.

20. 20. The method of claim 19, further comprising sensing a tidal volume of the air.

21. pumping perfusion fluid out of the organ; collecting data associated with the perfusate; adjusting a characteristic of the perfusion fluid based at least on the collected data to form an adjusted perfusion fluid; pumping the regulated perfusion fluid into the organ; and 20. The method of claim 19, further comprising:

22. 22. The method of claim 21, further comprising forming a mixed fluid by mixing fresh perfusion fluid with the adjusted perfusion fluid based on the collected data.

23. 22. The method of claim 21, further comprising draining the adjusted perfusion fluid based on the collected data.

24. 20. The method of claim 19, further comprising filtering the air.

25. 20. The method of claim 19, further comprising perfusing the organ normothermally.

26. 20. The method of claim 19, further comprising perfusing the organ at a non-normothermia.

27. assessing a characteristic of the organ during negative pressure ventilation; perfusing and / or ventilating the agent into the organ based on the property; 20. The method of claim 19, further comprising:

28. 1. A method of priming an organ enclosure, said method comprising: displacing a first volume of a first fluid with an actuated pump, the first fluid being fluidly coupled to a first surface of a flexible membrane, the flexible membrane being contained within a diaphragm enclosure, the diaphragm enclosure being fluidly coupled to the organ enclosure and a reservoir, the flexible membrane displacing a second fluid by the first volume as the first fluid is displaced, the second fluid being fluidly coupled to a second surface of the flexible membrane, the second fluid moving from the reservoir to the organ enclosure; detecting, with a sensor, when the organ enclosure is full; closing the fluid connection between the reservoir and the organ enclosure when the organ enclosure is filled; A method comprising:

29. The system of claim 1 , wherein the second fluid comprises a medium formulated to support organ tissue.

30. The system of claim 1 , wherein the second fluid comprises a sterile fluid.

31. The system of claim 1 , wherein the second fluid comprises an isotonic fluid.

32. The system of claim 1 , wherein the second fluid comprises a water-based fluid.

33. The system of claim 1 , wherein the second fluid comprises a mineral-based hydraulic fluid.

34. 10. The system of claim 1, further comprising a valve controlling movement of the second fluid to / from the organ enclosure.

35. 10. The system of claim 9, wherein the instructions include maintaining a dissolved gas concentration in the intravenous fluid at a preselected level.

36. The system of claim 9 , wherein the instructions include maintaining a dissolved gas concentration in the intravenous fluid at a user-input level.

37. 10. The system of claim 9, wherein the instructions include maintaining a dissolved gas concentration in the intravenous fluid at a dynamically determined level.

38. The device comprises: valves controlling flow to / from the reservoir and the organ enclosure; the at least one sensor; the actuator; a gas management system for providing gas to the intravenous fluid; a perfusion pump that moves the venous fluid from a venous sinus in the organ to an arterial sinus in the organ; The system of claim 9, comprising:

39. 10. The system of claim 9, wherein the instructions include maintaining a dissolved gas concentration in the perfusate at a preselected level.

40. 10. The system of claim 9, wherein the instructions include dynamically modifying ventilation and perfusion parameters based at least on data from the at least one sensor.

41. The instruction: dynamically modifying properties of the perfusion fluid, the venous fluid, and the second fluid based at least on data from the at least one sensor; assessing a status of the organ, the venous fluid, and the perfusion fluid based on at least data from the at least one sensor; The system of claim 9 , comprising:

42. The instruction: calculating measurements by measuring the pressure in the organ enclosure, the stroke of the actuator, and the properties of the air; controlling a state of the negative pressure ventilation based on the measured values; The system of claim 9 , comprising:

43. 10. The system of claim 9, wherein the instructions include controlling the perfusion of the mixed fluid and the properties of the perfusion fluid based on at least the flow rates of the perfusion fluid and the mixed fluid, the pressure of the perfusion fluid and the mixed fluid in the arterial sinus, the temperature of the perfusion fluid and the mixed fluid, and the chemical composition of the perfusion fluid and the mixed fluid.

44. The instruction: assessing the perfusate and the mixed fluid; automatically adjusting properties of the perfusion fluid and the mixed fluid based at least on the assessment; The system of claim 9 , comprising:

45. The instruction: assessing the perfusate and the mixed fluid; automatically adjusting properties of the perfusion fluid and the mixed fluid based at least on the assessment; Including, The system of claim 9 , wherein the adjusting is based on a balance of gases provided to the gas management system, the balance being based at least on the assessment.

46. The system of claim 9 , wherein the instructions include assessing compliance of the organ based on at least a tidal volume and a pressure of the organ.

47. The system of claim 9 , wherein the instructions include assessing compliance of the organ based at least on oxygen flow.

48. 10. The system of claim 9, wherein the instructions include managing flow rates of the irrigation fluid and the mixed fluid and independently adjusting delivery and fill pressures to achieve desired pressures of the irrigation fluid and the mixed fluid.

49. 10. The system of claim 9, wherein the instructions include adjusting the flow rate and pressure of the perfusion fluid and the mixed fluid as they enter the organ.

50. The instruction: measuring the resistance in the organ; adjusting the flow rate and flow pressure of the perfusion fluid and the mixed fluid based on the resistance so that the perfusion fluid and the mixed fluid enter the organ; The system of claim 9 , comprising:

51. 10. The system of claim 9, wherein the perfusion fluid comprises a formulation designed to repair defects in the organ.

52. 10. The system of claim 9, wherein the perfusion fluid comprises a formulation designed to maintain the organ in a preselected status for a preselected amount of time.

53. 10. The system of claim 9, wherein the perfusion fluid comprises a formulation designed to control an immune response in the organ recipient.

54. 10. The system of claim 9, wherein the thermal management system includes maintaining the temperature of the intravenous fluid and the mixed fluid within a preselected temperature range.

55. further comprising a perfusion fluid exchange system that allows replacement of the perfusion fluid with a substitution solution. The system of claim 9.

56. 10. The system of claim 9, further comprising a filter between the at least one perfusion pump and the perfusion fluid reservoir, the filter trapping particles.

57. 10. The system of claim 9, wherein the organ enclosure comprises four sides and a lid.

58. 10. The system of claim 9, wherein the organ enclosure comprises a cylinder and a lid.

59. 10. The system of claim 9, wherein the organ enclosure comprises transparent sides.

60. 10. The system of claim 9, wherein the organ enclosure comprises a transparent lid.

61. 10. The system of claim 9, wherein the organ enclosure comprises a platform for placing the organ.

62. The organ enclosure comprises: a platform for placing the organ; a mounting plate operatively coupled to the platform; The system of claim 9, comprising:

63. 10. The system of claim 9, wherein the organ enclosure comprises at least one interface that allows for fluid exchange.

64. 8. The system of claim 7, wherein the instructions include opening and closing valves that allow coupled filling and draining of the reservoir and the organ enclosure.

65. The system of claim 5 , wherein the diaphragm enclosure comprises at least one outer shell.

66. The system of claim 1 , wherein the second fluid comprises a protein.

67. The system of claim 1 , wherein the second fluid comprises a clotting factor.

68. 63. The system of claim 62, wherein the mounting plate comprises at least one ductal cavity configured to allow perfusion and ventilation of the organ.

69. 20. The method of claim 19, wherein the second fluid further comprises a medium formulated to support organ tissue.

70. 20. The method of claim 19, wherein the second fluid comprises a sterile fluid.

71. 20. The method of claim 19, wherein the second fluid comprises an isotonic fluid.

72. 20. The method of claim 19, wherein the second fluid comprises a water-based fluid.

73. 20. The method of claim 19, wherein the second fluid comprises a mineral-based hydraulic fluid.

74. 20. The method of claim 19, further comprising controlling the movement of the second fluid into / out of the organ enclosure by a valve.

75. 20. The method of claim 19, further comprising maintaining a dissolved gas concentration in the intravenous fluid at a preselected level.

76. 20. The method of claim 19, further comprising maintaining the dissolved gas concentration in the intravenous fluid at a user-input level.

77. 20. The method of claim 19, further comprising maintaining a dissolved gas concentration in the intravenous fluid at a dynamically determined level.

78. controlling flow to / from a reservoir and the organ enclosure by a valve, the reservoir being fluidly coupled to the diaphragm enclosure; providing gas to the intravenous fluid via a gas management system; moving the venous fluid from a venous sinus in the organ to an arterial sinus in the organ with a perfusion pump; 20. The method of claim 19, further comprising:

79. 20. The method of claim 19, further comprising maintaining a dissolved gas concentration in the perfusate at a preselected level.

80. 20. The method of claim 19, further comprising dynamically modifying ventilation and perfusion parameters based on at least data from at least one sensor.

81. dynamically modifying properties of the perfusion fluid, the venous fluid, and the second fluid based at least on data from the at least one sensor; assessing the status of the organ, the venous fluid, and the perfusion fluid based on at least data from the at least one sensor; 81. The method of claim 80, further comprising:

82. calculating measurements by measuring the pressure in the organ enclosure, the stroke of an actuator, and the properties of the air; controlling a state of the negative pressure ventilation based on the measured values; 20. The method of claim 19, further comprising:

83. 23. The method of claim 22, further comprising controlling the perfusion of the mixed fluid and the properties of the perfusion fluid based on at least the flow rates of the perfusion fluid and the mixed fluid, the pressure of the perfusion fluid and the mixed fluid in the arterial sinus, the temperature of the perfusion fluid and the mixed fluid, and the chemical composition of the perfusion fluid and the mixed fluid.

84. assessing the perfusate and the mixed fluid; automatically adjusting properties of the perfusion fluid and the mixed fluid based at least on the assessment; 23. The method of claim 22, further comprising:

85. assessing the perfusate and the mixed fluid; automatically adjusting characteristics of the perfusion fluid and the mixed fluid based at least on the assessment; 23. The method of claim 22, wherein the adjusting is based on a balance of gases provided to a gas management system, the balance being based at least on the assessment.

86. further comprising assessing compliance of the organ based at least on the tidal volume and pressure of the organ.

20. The method of claim 19.

87. further comprising assessing compliance of the organ based at least on oxygen flow.

20. The method of claim 19.

88. 23. The method of claim 22, further comprising independently adjusting delivery and fill pressures to manage the flow rates of the perfusion fluid and the mixed fluid and achieve desired pressures of the perfusion fluid and the mixed fluid.

89. 23. The method of claim 22, further comprising adjusting the flow rate and pressure of the perfusion fluid and the mixed fluid as they enter the organ.

90. measuring the resistance in the organ; adjusting the flow rate and flow pressure of the perfusion fluid and the mixed fluid based on the resistance so that the perfusion fluid and the mixed fluid enter the organ; 23. The method of claim 22, further comprising:

91. 82. The method of claim 81, wherein the perfusion solution comprises a formulation designed to repair defects in the organ.

92. 82. The method of claim 81, wherein the perfusion fluid comprises a formulation designed to maintain the organ in a preselected status for a preselected amount of time.

93. 82. The method of claim 81, wherein the perfusion solution comprises a formulation designed to control an immune response in the organ recipient.

94. 23. The method of claim 22, further comprising maintaining the temperature of the intravenous fluid and the combined fluid within a preselected temperature range.

95. 82. The method of claim 81, further comprising allowing replacement of the perfusion fluid with a substitution solution by a perfusion fluid exchange system.

96. 20. The method of claim 19, further comprising trapping particles between the at least one perfusion pump and the perfusion fluid reservoir with a filter.

97. 20. The method of claim 19, wherein the organ enclosure comprises four sides and a lid.

98. 20. The method of claim 19, wherein the organ enclosure comprises a cylinder and a lid.

99. 20. The method of claim 19, wherein the organ enclosure comprises transparent sides.

100. 20. The method of claim 19, wherein the organ enclosure comprises a transparent lid.

101. 20. The method of claim 19, wherein the organ enclosure comprises a platform for placing the organ.

102. The organ enclosure comprises: a platform for placing the organ; a mounting plate operatively coupled to the platform; 20. The method of claim 19, comprising:

103. 20. The method of claim 19, wherein the organ enclosure comprises at least one interface that allows for fluid exchange.

104. 20. The method of claim 19, further comprising opening and closing valves to allow coupled filling and draining of a reservoir and the organ enclosure.

105. 20. The method of claim 19, wherein the diaphragm enclosure comprises at least one outer shell.

106. 20. The method of claim 19, wherein the second fluid comprises a protein.

107. 20. The method of claim 19, wherein the second fluid comprises a clotting factor.

108. 103. The method of claim 102, wherein the mounting plate comprises at least one ductal cavity configured to allow perfusion and ventilation of the organ.

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