METHOD FOR PERFUSION OF AN EX VIVO ORGAN OR TISSUE, AND PERFUSION APPARATUS

Abstract

: An organ perfusion apparatus comprises a pulsatile pump and a bubble trap. The bubble trap includes a chamber having at least one liquid inlet opening, at least one gas outlet opening and at least one liquid outlet opening. The bubble trap is configured to reduce or eliminate pulsatility of the liquid flow and pressure. A minimum volume of gas is maintained in the chamber, which is sufficient to dampen flow rate and pressure fluctuations of the liquid. In particular, the volume of the chamber above the gas outlet opening is at least 0.4 liter or at least 75% of a total volume of the chamber. The bubble trap may further include a liquid level sensor, and a sampling port in a wall of the chamber. ********************************** TRANSLATION OF THE ABSTRACT Patent of Invention: "PERFUSION APPARATUS WITH PRESSURE FLUCTUATIONS REDUCED AND BUBBLE DETECTOR". It is an organ perfusion apparatus comprising a pulsatile pump and a bubble detector. The bubble detector includes a chamber having at least one liquid inlet port, at least one gas outlet port, and at least one liquid outlet port. The bubble detector is configured to reduce or eliminate the pulsatility of liquid flow and pressure. A minimum volume of gas is held in the chamber, which is sufficient to dampen the flow rate and pressure fluctuations of the liquid. Particularly, the volume of the chamber above the gas outlet opening is at least 0.4 liter or at least 75% of a total volume of the chamber. The bubble detector may additionally include a liquid level sensor and a sampling port in a chamber wall. 23532540v1 1 / 1 23532540v1

Description

1 / 28 METHOD FOR PERFUSION OF AN EX VIVO ORGAN OR TISSUE, AND PERFUSION APPARATUS BACKGROUND

[001] Related technical fields include perfusion apparatus capable of monitoring, sustaining and / or restoring the viability of organ(s) and / or tissue, storing and / or transporting organ(s) or tissue, and in particular, apparatus that include bubble collectors and / or devices for removing entrained gas in a perfusion fluid.

[002] Various perfusion devices developed for storing and / or transporting an organ include, for example, a bubble collector or a similar device for separating gas from a liquid path. For example, US Patent No. 8,128,740 (Wright) discloses an example of an organ perfusion apparatus that includes a bubble collector. Wright discloses a bubble collector with an inlet port, a gas outlet port, and a liquid outlet port. In the described embodiments, the gas outlet port is located near the top of the bubble collector. Wright discloses that a sensor associated with both an inlet tube port connector and a liquid outlet tube port connector can be used to detect the presence of bubbles. US Patent Application No. 2006 / 0210959 discloses a hemodynamic simulator that provides independent control of pulsatile flow rate and pulsatile pressure.The designs include a noise filter to dampen high-frequency vibrations created by the movements of a peristaltic pump. The noise filter can also serve as a bubble collector that has a container with fluid inlet and outlet ports and air inlet and outlet ports at or near the top of the container.

[003] It is often desirable to obtain perfusate samples during the perfusion process to monitor the properties of Petition 870260048834, dated 05 / 22 / 2026, p. 39 / 76 2 / 28 perfusate, organ and / or tissue. For example, Wright reveals a sample port in a tube leading to an inlet of a bubble collector. SUMMARY

[004] For ease of reference in this document, the term organ will mean organ and / or tissue, unless otherwise indicated. Also, for ease of reference, the term fluid will mean a gas, a liquid or a combination thereof, unless otherwise indicated.

[005] Perfusion devices can be used for the storage, transport, diagnosis, and / or treatment of organs collected or designed for transplantation or ex vivo use, and one purpose is to maintain the organ in a viable state. In these devices, a pump is often used to pump perfusate through the device. Pumps that can be used in organ perfusion devices include roller pumps, which have the advantage that minimal components come into contact with the perfusate. However, the use of roller pumps and other similar pumps often results in pulsatile flow rates and perfusate pressure, which may be undesirable. Additionally, sample ports in tubing require sensitive and / or specialized handling tools due to the small size of the tubing.

[006] Exemplary embodiments of the invention provide a perfusion apparatus that includes a bubble collector that not only removes bubbles but also dampens perfusate pulsatility through, for example, a configuration in which a minimum volume of gas sufficient to dampen perfusate pulsatility is maintained within the bubble collector. In the embodiments, sensors are arranged in the bubble collector and configured to detect the level of perfusion fluid in the bubble collector, for example, to determine Petition 870260048834, dated 05 / 22 / 2026, page 40 / 76 3 / 28 if a minimum volume of gas is present sufficient to dampen the pulsatility of the perfusate fluid. The same or other exemplary modalities include a sample port within the chamber and configured to allow a clinician to obtain samples of the perfusion fluid directly from the bubble collector, for example, via a standard syringe with a large needle or an inlet tube.

[007] The embodiments include an apparatus for separating gas from a liquid and dampening flow rates and pressure fluctuations in the liquid. The apparatus may include a chamber with an air outlet and liquid outlets, wherein the air outlet and liquid outlets are preferably, but not necessarily, arranged on the same side wall of the chamber in a substantially straight line. The chamber may be configured to release gas from the perfusion fluid while maintaining a minimum volume of gas sufficient to dampen the flow rate and pressure fluctuations of the perfusion fluid.One method for perfusing an organ or tissue includes causing a perfusion fluid to flow into a chamber under fluctuating flow rate and pressure, maintaining at least a minimum volume of gas in the chamber sufficient to dampen the flow rate and pressure fluctuations of the perfusion fluid, allowing the perfusion fluid with reduced flow rate and pressure fluctuations to exit the chamber, and perfusing the organ or tissue with reduced flow rate and pressure fluctuation fluid.

[008] The embodiments include an apparatus for separating gas from a perfusion liquid which includes a bubble collector and a liquid level sensor. The liquid level sensor can be used, for example, to determine and optionally signal a controller when a liquid level in the bubble collector is outside an ideal range.

[009] A method for preparing a perfusion apparatus for Petition 870260048834, dated 05 / 22 / 2026, page 41 / 76 4 / 28 Perfusing an organ or tissue involves causing a perfusion fluid to flow through a chamber and into the organ or tissue and detecting whether the perfusion fluid reaches a preferred operating level. While the perfusion fluid flows in the chamber, the air outlet may be opened; if it is detected that the perfusion fluid reaches the preferred operating level, the device may close the air outlet.

[0010] The embodiments include an apparatus for separating gas from a perfusion fluid for perfusing an organ or tissue, including a chamber that includes an inlet, a fluid outlet, and a sample port configured to allow a fluid sample to be continuously or periodically extracted from the chamber. A method for perfusing an organ or tissue may include causing a perfusion fluid to flow through a bubble collector into the vasculature of the organ or tissue and continuously or periodically extracting a fluid sample directly from the bubble collector. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 is a schematic diagram of an exemplary organ perfusion apparatus, according to an embodiment of the invention.

[0012] Figure 2 is a perspective view of an exemplary cradle and basin that can be used in the perfusion apparatus of Figure 1.

[0013] Figure 3 is a perspective view of external components of an exemplary bubble collector.

[0014] Figure 4 is a cross-sectional perspective view of the internal components of the bubble collector in Figure 3.

[0015] Figures 5A and 5B are diagrams of the liquid and gas paths inside a bubble collector when a first liquid enters the chamber. Figures 5C to 5E are diagrams of the liquid and gas paths inside the bubble collector of Figures 5A and 5B when the liquid Petition 870260048834, dated 05 / 22 / 2026, page 42 / 76 5 / 28 achieves preferential fluid levels as well as upper / lower fluid levels. In Figures 5A to 5E, NO is defined as normally open and NC is defined as normally closed.

[0016] Figure 6A is an idealized representation of a graph comparing the pressure fluctuations of liquid flowing into the chamber and the pressure fluctuations of liquid exiting the chamber of an exemplary bubble collector. Figures 6B and 6C are graphs displaying sample data of inlet pressure fluctuations and outlet pressure fluctuations of the chamber of an exemplary bubble collector. DETAILED DESCRIPTION OF THE MODALITIES

[0017] The following exemplary implementations relate to a perfusion apparatus, a transport apparatus and / or a storage apparatus for an organ. It should be noted that although the exemplary systems and methods according to this disclosure may be used in specific applications, the representations and / or descriptions included in this disclosure are not intended to be limited by any specific application.

[0018] According to the exemplary implementations, a bubble collector for separating gas from a liquid is provided. The bubble collector may include a chamber that has a top wall, a bottom wall, and side walls. The chamber may include an inlet located preferably within or near the bottom wall (e.g., in a bottom or side wall) configured to allow fluid to enter the chamber. The chamber may have an air vent located between the top wall and the bottom wall, for example, in a side wall substantially midway between the top wall and the bottom wall, configured to allow at least gas to exit the chamber. The chamber may have a first liquid vent, again preferably located within or near the bottom wall (e.g., in a bottom or side wall), configured Petition 870260048834, dated 05 / 22 / 2026, page 43 / 76 6 / 28 to allow at least the liquid to exit the chamber. The chamber may have a second liquid opening, also preferably located on or near the bottom wall (e.g., on a bottom or side wall) and configured to allow at least the liquid to exit the chamber. Preferably, the chamber is configured so that no gas and / or liquid outlet opening in the chamber is closer to the top wall than the air opening. The chamber may be structured to allow free fluid communication between the air opening and the first and second liquid openings. The first and second liquid openings may be located on the same wall or on different chamber walls. Preferably, the first and second liquid openings are located below a minimum fluid level.

[0019] In exemplary implementations, a bubble collector may include an air outlet connected to an air conduit and in fluid communication with the air opening. The air outlet may be located on or near the top wall of the chamber (e.g., on a side or top wall) and may be connected to an air conduit. The air conduit may consist of an air tube or any other suitable conduit. A valve (e.g., a check valve or other suitable means of restriction) may be disposed in the air tube. The valve may be manually actuated or a controller may be configured to engage the valve on stopped fluid flow through the air outlet. The valve may be disposed around or in the air tube. The controller may be any suitable controller which may include a processor and other electronic apparatus suitable for operating software and a valve.

[0020] In the exemplary implementations, the bubble collector may include a first liquid outlet, preferably located near the top wall of the chamber (e.g., on a side wall). Petition 870260048834, dated 05 / 22 / 2026, page 44 / 76 7 / 28 or top). The first liquid outlet is connected to a first conduit and is in fluid communication with the first liquid opening. The first liquid outlet may be connected to the first liquid opening via, for example, a first channel or tube running along a side wall. The bubble collector may include a second liquid outlet, also preferably located near the top wall of the chamber (e.g., on a side or top wall). The second liquid outlet is connected to a second conduit and is in fluid communication with the second liquid opening. The second liquid outlet may be connected to the second liquid opening via, for example, a second channel or tube running along a side wall. The outlets may be located on the same wall or on different walls of the chamber.The air outlet and the first and second liquid outlets may preferably, but not necessarily, be arranged on the same side wall of the chamber in a substantially straight line. The chamber may be structured to allow free fluid communication between the air outlet and the first and second liquid outlets.

[0021] In exemplary deployments, a perfusion apparatus may include a chamber, a pulsatile pump, and a conduit configured to allow the perfusion fluid and any gas within the perfusion fluid to flow from the pump into the chamber under fluctuating flow rate and pressure. For example, the inlet pressure may be reduced from a maximum inlet pressure fluctuation (variation) of 350 mmHg peak-to-peak. For example, the maximum outlet pressure fluctuation may be reduced to less than 1.5 mmHg peak-to-peak. A first outlet conduit connected to a first fluid outlet may be connected to a first organ area (e.g., a portal vein of a liver). A second conduit connected to a second fluid outlet may be connected to a second organ area. Petition 870260048834, dated 05 / 22 / 2026, page 45 / 76 8 / 28 organ (e.g., the hepatic artery of a liver). The chamber can be configured to release gas from the perfusion fluid (e.g., the chamber can function to eliminate bubbles that may be extracted in an upstream portion of the tubing) and to maintain a minimum gas volume sufficient to dampen flow rate and fluid pressure fluctuations. The minimum gas volume is defined by at least the volume of the chamber above the air opening.

[0022] One method for perfusing an organ may involve causing a perfusion fluid to flow into a chamber under fluctuating flow rate and pressure, maintaining at least a minimum volume of gas in the chamber sufficient to dampen the flow rate and pressure fluctuations of the perfusion fluid, allowing the perfusion fluid with reduced flow rate and pressure fluctuations to exit the chamber, and perfusing the organ with the fluid at fluctuating pressure and flow rate. For example, a ratio of the pressure fluctuations of the perfusion fluid flowing into the chamber to the pressure fluctuations of the perfusion fluid exiting the chamber may be greater than 10 to 1, for example, 11 to 1, 50 to 1, 100 to 1, 175 to 1, or even more than 200 or 230 to 1, such as 233 to 1.For example, when the liquid is flowing through the chamber between 0.3 and 2.0 liters per minute, the ratio of the pressure fluctuation of the liquid flowing into the chamber to the pressure fluctuation of the liquid exiting the chamber can be at least 233 to 1. For example, when the liquid is flowing into the chamber at about a maximum of 2 liters per minute and the pressure fluctuation of the liquid flowing into the chamber is about 350 mmHg peak-to-peak, the pressure fluctuation of the liquid exiting the chamber is preferably less than or equal to 2.5 mmHg, as well as less than about 2 mmHg, peak-to-peak.

[0023] In exemplary deployments, at least part of the chamber may be transparent to allow visual assessment of the liquid level in the chamber. Petition 870260048834, dated 05 / 22 / 2026, p. 46 / 76 9 / 28

[0024] In exemplary deployments, the chamber is operable when the liquid is at temperatures between 3 and 40, such as between 3 and 10, 3 and 5, 20 and 40, 20 and 30, 35 and 37 degrees Celsius and similar.

[0025] In exemplary implementations, all chamber walls may be composed of rigid materials. For example, the chamber may be composed of injection-molded resin (e.g., SAN (styrene acrylonitrile) which is medical grade, non-toxic and biocompatible), transparent polycarbonate, PMMA, ABS, PVC or any other suitable material.

[0026] In exemplary deployments, an apparatus for separating gas from a perfusion fluid in a perfusion apparatus may include a bubble collector and a fluid level sensor configured to detect the perfusion fluid level in the bubble collector. The perfusion apparatus (as a delivery unit) may include a controller, a valve configured to control the flow of at least gas exiting the chamber, and an organ bath configured to retain the perfusion fluid. The bubble collector may include a chamber to house gas and perfusion fluid and may include an air outlet configured to allow at least gas to exit the chamber.The controller can be configured to control the valve so that, if the liquid level sensor detects that the perfusion fluid level is too high or too low, the controller controls the valve to open or close the air outlet in order to start or stop air from escaping the chamber through the air outlet. For example, if the liquid level sensor detects that the perfusion fluid level is too low for effective bubble release, for example, due to gas buildup released from the perfusion fluid, the sensor can alert the user or a controller to open the air outlet valve to release air from the chamber. During preparation, the liquid level sensor can be used to determine when the liquid level should be... Petition 870260048834, dated 05 / 22 / 2026, p. 47 / 76 10 / 28 approximates a preferred operating level, for example, allowing the valve to be closed when the fluid level is near, just below, or just above the preferred operating level. For example, the preferred operating fluid level in the chamber may be between 1 and 15 mm below the bottom of the air outlet, preferably between 5 and 10 mm below the bottom of the air outlet, and most preferably about 8 to 9 mm below the bottom of the air outlet. When the valves arranged in the tubing connected to the first and second fluid openings are opened, the air valve outlet can be closed. When the air valve outlet is open, only gas can be expelled into the organ basin. The sensor may have a Hall effect sensor that works according to a magnet or any other suitable sensor contemplated by a person skilled in the art. For example, the fluid level sensor system may include a magnet in a float that floats in the perfusion fluid.Whether the air valve outlet is open or closed depends on the location of the magnet relative to the Hall effect sensor.

[0027] One method for preparing a perfusion apparatus for perfusing an organ or tissue may involve causing a perfusion fluid to flow through a chamber and detecting whether the perfusion fluid has reached the preferred operating level in the chamber. When the preferred operating level has been reached, the air valve outlet may close. When the air valve outlet is closed, the valves arranged on the tubing connected to the first and second fluid openings may be opened to allow preparation of the downstream tubing.

[0028] In exemplary deployments, the apparatus may include one or more bubble sensor(s) configured to detect the presence of gas in liquid exiting the chamber. The bubble sensor may be disposed of in at least one conduit downstream of the bubble collector. For example, the bubble sensor may send a signal to the Petition 870260048834, dated 05 / 22 / 2026, p. 48 / 76 11 / 28 controller when an unacceptable size or quantity of bubbles is detected and the controller can stop the fluid perfusion by trimming the pump and / or controlling a valve (e.g., a throttling valve or other suitable valve) located in at least one perfusate conduit, for example, downstream of the bubble collector. Flow can be resumed after the bubbles in the fluid exiting the chamber have been removed.

[0029] Preferably, the bubble sensor is an ultrasonic sensor disposed around the tubing, although any suitable sensor may be used. Ultrasonic sensors can be advantageous because, in normal use, they do not come into contact with the perfusate and therefore do not need replacement and / or cleaning after use. Conversely, ultrasonic sensors may be disposed in contact with, adjacent to, or around an external tubing surface in order to detect bubbles in the tubing.

[0030] In exemplary embodiments, the apparatus for separating gas from perfusion fluid for perfusing an organ may include a chamber to house the gas and perfusion fluid. The chamber may include an inlet configured to allow at least one of the gas or perfusion fluid to flow into the chamber, a fluid outlet, and a sample port configured to allow a fluid sample to be continuously or periodically extracted from the chamber. The sample port may have a first end located on the top wall of the chamber and configured to allow the fluid sample to be extracted. In embodiments, the sample port may extend to a second end on or near the bottom wall of the chamber, and the second end may be configured to allow perfusion fluid to enter the sample port that will be extracted from the first end.The first end of the sample port may include a luer-type fitting, a threaded cap, or a... Petition 870260048834, dated 05 / 22 / 2026, page 49 / 76 12 / 28 septum or other suitable means of closure. A cover may be configured to seal the first end of the sample port. The sample port may be configured not to contact any of the chamber side walls. Alternatively, the sample port may be configured to contact or be integral with one of the chamber side walls. The sample port may be located in other areas of the fluid path besides the chamber.

[0031] One method for perfusing an organ may involve causing a perfusion fluid to flow through the bubble collector, preferably in a recirculation circuit, and extracting a sample of the perfusion fluid at a single time, periodically, or continuously. Preferably, the sample may be extracted from the fluid outlet, such as at or near the bottom of the bubble collector chamber, which will be the most representative of the perfusion fluid that will enter the organ.

[0032] Figure 1 is a schematic diagram of a perfusion apparatus, as a transport and / or storage apparatus, 10 for an organ 20. The organ 20 may preferably be a liver or kidney, but may be any healthy, injured or diseased organ or tissue, natural or modified, human or animal, including heart, lungs, intestine or other organ or tissue. The apparatus shown includes a basin 30 in which the organ 20 may be placed. As shown in Figure 2, the basin 30 may retain a cradle 60 which preferably includes a surface on which the organ 20 is preferably disposed when the organ 20 is in the apparatus 10. The basin 30 may include a first filter which may function as a coarse particulate filter. The basin 30 and / or the cradle 60 are preferably configured to allow a perfusate bath to form around the organ 20.As shown in Figure 1, basin 30 may also include a temperature sensor 40 located in or near the cradle 60. The basin. Petition 870260048834, dated 05 / 22 / 2026, page 50 / 76 13 / 28 may include multiple temperature sensors 40 that may provide redundancy in case of failure and / or may provide temperature measurement at multiple locations. Preferably, the temperature sensor(s) 40 is / are an infrared temperature sensor. The temperature sensor(s) 40 is / are preferably arranged as conveniently as possible to the organ 20 when the organ 20 is arranged in the cradle 60 in order to improve the usefulness and accuracy of the temperature sensor(s) 40, which preferably provide a perfusate temperature measurement that can be correlated with an organ 20 temperature. Alternatively or additionally, the temperature sensor(s) 40 may be used to directly measure the organ 20 temperature.

[0033] Preferably, the basin 30 is disposed within a cooling container 50 which may contain cold materials such as ice, chilled water, brine or the like. The cooling container 50 may be permanently or removablely fixed, or an integral monolithic part, to the apparatus 10. Thus, in use, the organ 20 is disposed within the cradle 60 and / or the basin 30 which is disposed within a compartment defined by the cooling container 50. Preferably, each of the basin 30, cradle 60 and cooling container 50 is configured or adjusted to fit into the corresponding compatibility component in a single orientation. The configuration of the cooling container 50, the basin 30 and the cradle 60 may have a configuration that provides cooling for the organ 20 without the contents of the cooling container 50 coming into contact with the organ 20 or the cradle 60.Although refrigerated container 50 is described in this document as containing ice, any suitable cooling medium may be used. Ice may be preferred because of the ease with which ice can be produced, but one with normal skill in the art would understand that any means of cooling will be used. Petition 870260048834, dated 05 / 22 / 2026, page 51 / 76 14 / 28 Adequate cooling which could be an active cooling medium (such as an electric thermal refrigerator or a refrigerant loop) or a passive cooling medium similar to ice or ice water or a combination thereof may be used. The amount of ice or other refrigerant medium that may be placed inside the refrigerant container 50 should be determined based on the maximum time that cooling must be provided while the organ 20 is in the apparatus 10.

[0034] Cradle 60 may include components configured to securely restrain organ 20 in place. These components may, for example, include a selectable user network that is attached to cradle 60.

[0035] After passing through the first filter, the perfusate flows along a first flow path 70 which includes a suitable fluid conduit 72, such as flexible or rigid tubing, a pump 80, a pressure sensor 90, a second filter, an optional oxygenator 100 and a bubble collector 110, each of which is discussed below.

[0036] The first filter is preferably a relatively coarse filter (compared to the second filter). This coarse filter may be provided to prevent large particles which may, for example, be byproducts of the organ or organ removed from the donor from entering and clogging the fluid paths of the apparatus 10. The first filter may be an integral part of the basin 30 or the first filter may be disposed elsewhere in the first flow path 70 downstream of the basin 30. The first filter may also be a separate component of the basin 30 or may be disposed within the fluid conduit 72.

[0037] The first flow path 70 may also include a pump 80. Pump 80 may be any pump that is suitable in conjunction with organ perfusion. Examples of pumps Petition 870260048834, dated 05 / 22 / 2026, page 52 / 76 Suitable 15 / 28 roller pumps may include manually operated or motor-driven pumps, such as centrifugal pumps or roller pumps. If a roller pump is included, the roller pump may include a single channel or flow path (where only one tube is compressed by the rollers) or the roller pump may include multiple parallel channels or flow paths (where multiple tubes are compressed by the rollers). If multiple channels or parallel flow paths are included, the rollers may preferably be arranged out of phase or offset so that the pulses created by the rollers are out of phase, which may result in a fluid flow rate and pressure outside the roller pump that is relatively less pulsatile than would be the case with a single roller.Such a multi-channel roller pump can achieve a constant flow rate and pressure or a minimally pulsatile flow rate and pressure, which can be advantageous depending on the other components in the flow path and / or the type of organ being perfused.

[0038] Flow path 70 may include a pressure sensor 90. The pressure sensor 90 can preferably be placed after the pump outlet 80 in order to monitor and / or be used to control the pressure produced at the pump outlet by means of a suitable controller 400. The pressure sensor 90 can provide continuous or periodic pressure monitoring.

[0039] The flow path 70 may include an oxygenator 100 as a membrane or oxygenator body to provide oxygenation to the perfusate. Oxygen may be supplied to the oxygenator 100 by suitable means. Suitable oxygen sources may include pure oxygen or mixed gases such as air. The gas may be compressed, as in a high-pressure cylinder, liquefied as it would be stored in a dewar flask, or extracted from the surrounding atmosphere. Preferably, oxygen may be supplied by means of a generator. Petition 870260048834, dated 05 / 22 / 2026, page 53 / 76 16 / 28 of oxygen, which can be separated from apparatus 10 or integrated with apparatus 10. Oxygen can be obtained through any suitable means, some examples of which include through pressure variation adsorption using a molecular sieve, through a ceramic oxygen generator (a solid-state oxygen pump), or through water decomposition.

[0040] The flow path 70 may include a bubble collector 110. The bubble collector 110 preferably separates gas bubbles that may be carried along in the perfusate flow and prevents such bubbles from continuing downstream and entering the organ 20. The bubble collector 110 may also function as an accumulator that reduces or eliminates the pulsatility of the perfusate flow and pressure and / or provides a sampling port. The bubble collector 110 may include a volume of gas, initially or through the accumulation of gas from bubbles that rise and burst to release the gas, so that flow and pressure fluctuations in the perfusate are dampened or eliminated.

[0041] As shown in Figure 3, the bubble collector 110 may comprise a chamber 200 having a top wall 210, a bottom wall 212 and side walls 214, 216, 218, 220. The chamber 200 may have an inlet 230 that allows gas and / or liquid to enter the chamber 200. The inlet 230 may preferably be located on or near the bottom wall. The inlet 230 may be connected to a conduit that is connected to the pump 80.

[0042] The bubble collector 110 can have any number of outlets as needed for a given application of the perfusion apparatus. As shown in Figure 1, a first liquid outlet 260, a second liquid outlet 280 and an air outlet 240 are shown connected to three different flow paths, which may be particularly suitable for perfusing a liver or any other organ or tissue with multiple blood vessels or for the Petition 870260048834, dated 05 / 22 / 2026, page 54 / 76 17 / 28 Perfusion of multiple organs or tissues simultaneously. For example, when performing liver perfusion, the first fluid outlet 260 is connected to the portal flow path 120 (which is connected to the liver portal vein), the second fluid outlet 280 is connected to the hepatic flow path 130 (which is connected to the liver hepatic artery), and the air outlet 240 is connected to the bypass flow path 140 (which provides a return path to the pelvis 30).

[0043] Chamber 200 may have an air opening 250 that allows gas to escape. The air outlet 240 of the bubble collector 110 may allow gas purging through the air opening 250 during a priming or purging process. The air outlet 240 may be connected to or part of the purge flow path 140. The air outlet 240 is preferably opened during a startup process so that any air or other gas may be purged from the perfusate path 70. Once the gas is purged from the perfusate path 70, the air outlet 240 may preferably be closed. The air outlet 240 may be closed manually or may be closed automatically by means of a suitable controller 400.

[0044] The diversion flow path 140 may include a valve 142 and / or sensors such as oxygen sensor 144 and pH sensor 146. Oxygen sensor 144 and pH sensor 146 may alternatively be arranged in portal flow path 120 and / or hepatic flow path 130, or all or any combination of bypass flow path 140, portal flow path 120, and hepatic flow path 130. Preferably, valve 142 is a throttling valve and may be of similar configuration to valves 122 and 132, but any suitable valve may be used. Oxygen sensor 144 and pH sensor 146 may be used to determine the state of the perfusate. Preferably, bypass flow path 140 is only used during a purging or priming process, although Petition 870260048834, dated 05 / 22 / 2026, page 55 / 76 18 / 28 can also be used during continuous perfusion and optionally to monitor perfusate properties in real time. For the former use, the liquid level sensor 112 could be used to allow the user, or controller, to maintain the liquid level in chamber 200 within a predetermined range around the air opening 250.

[0045] The air opening 250 may preferably be located in the side wall 214 of chamber 200 and between the top wall 210 and the bottom wall 212. The air opening 250 may be connected and in fluid communication with the air outlet 240 through an air channel 320, which may preferably extend in a vertical direction.

[0046] Chamber 200 may have a first liquid opening 270 and a second liquid opening 290 that allows liquid to exit the chamber. The first liquid opening 270 and the second liquid opening 290 may preferably be located on the same side wall 214 and on or near the bottom wall 212. The first liquid opening 270 may be connected in fluid communication with the first liquid outlet 260 through a first channel 300. The second liquid opening 290 may be connected in fluid communication with the second liquid outlet 280 through a second channel 310. Chamber 200 may preferably be structured so that there is uninhibited fluid communication between the inlet 230, the air opening 250, the first liquid opening 270 and the second liquid opening 290.

[0047] The chamber 200 may be polygonal and / or curved at the top wall 210. For example, the chamber 200 may be rectangular, square, round, or other suitable shape in cross-section. The chamber 200 may be substantially L-shaped at the top wall 201, where one corner of the rectangular top wall 210 may be folded into the center of the chamber 200. The chamber 200 may have Petition 870260048834, dated 05 / 22 / 2026, pp. 56 / 76 19 / 28 uniform or non-uniform cross-sectional dimensions. For example, it may be wider at the top and narrower at the bottom. The inlet 230 may be arranged on the bottom wall 212 in a position higher than the lowest portion of the chamber 200. The level sensor 112 (described in more detail below) may be arranged on the same or a different side wall from the air opening 250, the first liquid opening 270 and / or the second liquid opening 290. For example, the level sensor 112 may be arranged on the side wall 216 adjacent to the side wall 214 in which the air opening 250, the first liquid opening 270 and the second liquid opening 290 are located. The relative direction (e.g., top / bottom) of the chamber walls 200 is defined when the bubble collector 110 is in a resting position in the perfusion apparatus 10.

[0048] In the modalities, the perfusate is preferably acellular fluid, for example, fluid that is not blood.

[0049] In the embodiments, at least part of chamber 200 may be transparent so that a physician or clinician can visually inspect the fluid level in chamber 200.

[0050] In the embodiments, chamber 200 can be designed to be operable when the fluid is between 3 and 5 and / or between 20 and 30 and / or between 35 and 38 degrees Celsius. This is advantageous due to the fact that such hypothermic, mesothermic and / or normothermic conditions, respectively, can result in better preservation of various organs.

[0051] In embodiments, chamber 200 may be composed of rigid materials. A rigid material is, for example, a material that is inflexible and non-deformable under normal operating conditions. For example, the chamber may be composed of injection-molded resin (e.g., SAN (styrene acrylonitrile), which is medical grade, non-toxic and biocompatible), transparent polycarbonate, PMMA, ABS, PVC or any other suitable material. Petition 870260048834, dated 05 / 22 / 2026, p. 57 / 76 20 / 28

[0052] Bubble sensors 124, 134 may be arranged downstream to detect whether gas bubbles are present in the perfusate flowing out of the first liquid outlet 260 and / or the second liquid outlet 280. Valves may be arranged as a redundancy in the pipes connected to the first liquid outlet 260 and the second liquid outlet 280 and may be used, for example, to prevent fluid from exiting the chamber 200 when a bubble sensor 124, 134 detects gas in the perfusate exiting the bubble collector 110. The valves may be throttling valves or any other suitable valves.

[0053] A level sensor 112 can detect the liquid level in chamber 200 of the bubble collector 110. In addition to its functions described below, the level sensor 112 can be used as a redundant method to further reduce the risk of air bubbles being sent downstream in the portal flow path 120 and the hepatic flow path 130. The level sensor 112 is preferably disposed along a side wall of chamber 200. The level sensor 112 can be an integral component of the bubble collector 110 or alternatively it can be disposed wholly or in part anywhere within the apparatus 10. The controller 400 can receive a signal from the level sensor 112 indicating the liquid level inside chamber 200. The liquid level sensor 302 can include, for example, a magnet in a float that works in concert with a Hall effect sensor or other suitable sensor.The liquid level sensor 302 can be configured, for example, to detect the level of a float in the liquid along the side wall 216 inside the chamber 200. In this configuration, the float can preferably be an integral component of the chamber 200 and a Hall effect sensor can be separated from the bubble collector 110, thus making the float disposable and the Hall effect sensor reusable. Petition 870260048834, dated 05 / 22 / 2026, p. 58 / 76 21 / 28

[0054] The bubble collector 110 may include valves arranged in the tubes connected to the air outlet 240, the first liquid outlet 260, and the second liquid outlet 280. During the priming process, if the liquid level sensor 112 detects that the liquid inside the chamber 200 is below a preferred operating level, the controller 400 may control the valve in the tube connected to the air outlet 240 to allow gas to exit the chamber and may control valves 122, 132 in the tubes connected to the first liquid outlet 260 and the second liquid outlet 280 to shut off the fluid flowing out of the chamber 200. This allows the liquid in the chamber to reach a preferred operating level. The operating level may be when the liquid level reaches a point just below the level of the air opening 250.For example, the preferred operating level of the liquid in the chamber may be between 1 and 15 mm below the bottom of the air outlet, preferably between 5 and 10 mm below the bottom of the air outlet, and most preferably about 8 to 9 mm below the bottom of the air outlet. When the level sensor 112 detects that the liquid in chamber 200 is at or below the preferred operating level, the controller can control the valve in the tube connected to the air outlet 240 to shut off the flow out of chamber 200, resulting in a chamber 200 with at least a minimum predetermined gas volume. Once the priming process is complete (e.g., when the preferred operating level is reached), the controller 400 can shut off the gas and / or liquid flow out of the chamber through the air outlet 240, for example, by engaging a valve (or other suitable means of restriction) disposed in a tube connected to the air outlet 240.

[0055] Alternatively or additionally, the bubble collector 110 can be operated during a priming process by causing the liquid to flow through chamber 200 and into organ 20 and detecting if the liquid is flowing out of the air outlet 240 in chamber 200. Petition 870260048834, dated 05 / 22 / 2026, p. 59 / 76 22 / 28 If liquid is detected flowing out of air outlet 240, controller 400 can shut off the air outlet (for example, by using a suitable valve).

[0056] The level sensor 112 can optionally be used during the purging process to determine when the washing is complete and / or can be used to determine when the purging process needs to be repeated, which may happen after bubbles have been detected, for example, in a downstream pipe.

[0057] The bubble collector 110 can be configured to reduce fluctuations in flow rate and pressure of liquid flowing out of the first liquid outlet 260 and / or the second liquid outlet 280. By using the level sensor 112 and the air outlet 240, the accumulator function of the bubble collector can be adjusted to account for different amplitudes and frequencies of pulsatility in the flow rate and pressure of the perfusate. For example, as shown in Figures 5A to 5E, the bubble collector 110 can be operated by causing the liquid to flow inside the chamber 200 with fluctuating flow and pressure, which maintains at least a minimum gas volume in the chamber 200 sufficient to dampen the flow and pressure fluctuations of the liquid, allowing the liquid with reduced flow and pressure fluctuations to flow out of the chamber 200 and perform perfusion of the organ 20 with the reduced flow and pressure fluctuating liquid.

[0058] The combination of the range of liquid held in chamber 200 (for example, between 0.1 liters and 0.2 liters of fluid, as discussed below in Example 1) and the minimum volume of compressible gas in chamber 200 can result in a damping of the flow and pressure fluctuations of the liquid (caused, for example, by the pulsatile flow generated by pump 80) as the liquid flows into chamber 200 through inlet 230. For example, the ratio of the pressure fluctuation of the liquid flowing into inlet 230 to the fluctuation of Petition 870260048834, dated 05 / 22 / 2026, pp. 60 / 76 23 / 28 The pressure of the liquid flowing out of the first liquid outlet 260 and / or the second liquid outlet 280 may be more than 10 to 1, for example, 11 to 1, 50 to 1, 100 to 1, 150 to 1, 175 to 1, or more than 200 or 230 to 1, such as 233 to 1. For example, as shown in Figures 6A to 6C, when the pressure fluctuation of the liquid flowing into inlet 230 is about 350 mmHg peak-to-peak, the pressure fluctuation of the liquid flowing out of the first liquid outlet may be controlled to be less than or equal to 2 mmHg peak-to-peak by maintaining an adequate volume of air in chamber 200.

[0059] As shown in Figures 3 and 4, the bubble collector 110 may include a sampling port 350, preferably with a first end located on or near the top wall 210 of the chamber 200 and a tube 306 extending to a second end near the bottom wall 212. The sampling port 350 may be configured to allow a liquid sample to be drawn from the chamber, for example, in a single event, periodically, or continuously. The first end of the sampling port 350 may allow the liquid sample to be drawn and may have a Luer fitting, threaded cap, septum, or other suitable fitting to aid in maintaining sterility. This may be useful for a doctor or physician to obtain samples of the perfusate for analysis at any time.The port can also be used by a user to administer substances into the perfusate without opening the basin, which may be a safer and more convenient approach than opening the disposable portion of the apparatus 10 and breaking the sterile barrier. The bubble collector 110 may also include a 360 cap that seals the first end of the sampling port 350. In an organ perfusion method 20, the sampling port can be used to extract a fluid sample from the bubble collector 110. Petition 870260048834, dated 05 / 22 / 2026, pp. 61 / 76 24 / 28, noting that the fluid sample is not used to perfuse the organ.

[0060] As shown in Figure 1, the portal flow path 120 and the hepatic flow path 130 may optionally include similar or different components such as valves 122, 132; bubble sensors 124, 134; flow sensors 126, 136; flow control clamps 127, 137; and pressure sensors 128, 138. Each similar component may function in a similar manner and such component pairs may optionally be identical structurally and / or functionally to reduce manufacturing costs.

[0061] Flow sensors 126, 136 may preferably be ultrasonic sensors arranged around the tubing, although any suitable sensor may be used. Ultrasonic sensors may be advantageous due to the fact that in normal use such sensors do not come into contact with the perfusate and therefore are not in the sterile path. Such deployment of ultrasonic sensors does not require replacement and / or cleaning after use.

[0062] Valves 122 and 132 may be throttling valves that function to tighten the tubing and reduce or shut off the flow, but any suitable valve may be used. Throttling valves may be advantageous because in normal use they do not come into contact with the perfusate and therefore do not require replacement and / or cleaning after use.

[0063] Flow control clamps 127, 137 can be used for fine adjustment of flow rate in one or both of the portal flow path 120 and the hepatic flow path 130. Preferably, the organ provides autoregulation to control a flow amount that is divided between the portal flow path 120 and the hepatic flow path 130. In such autoregulated flow, pressure sensors 128, 138 provide overpressure monitoring. In the event that the flow rate and pressure delivered to the organ in either or both of the Petition 870260048834, dated 05 / 22 / 2026, pp. 62 / 76 25 / 28 portal flow path 120 or hepatic flow path 130 exceeds a predetermined limit, the device 10 may stop manually or automatically and / or reduce the flow rate supplied by the pump 80 to prevent organ damage. Additionally, or alternatively, pressure sensors 128, 138 may be used to generate warning signals to the user and / or to a suitable controller as pressures approach the predetermined limit.

[0064] After exiting one or both of the portal flow path 120 and the hepatic flow path 130, the perfusate flows through the organ and returns to the basin 30 to form an organ bath.

[0065] The organ perfusion apparatus 10 may also include an accelerometer 150. Preferably, the accelerometer 150 is a three-axis geometric accelerometer, although multiple single-axis geometric accelerometers may be used for the same effect. The accelerometer 150 may be used to continuously or periodically monitor and / or record the state of the apparatus 10. Monitoring may include monitoring for excessive shocks as well as the attitude of the apparatus 10.

[0066] By implementing such monitoring, misuse or potentially inappropriate conditions of device 10 can be detected and optionally recorded and / or transmitted to a monitor.

[0067] Apparatus 10 may include storage compartments for items other than organ 20. For example, apparatus 10 may include a document compartment for storing documents and / or charts related to organ 20. Apparatus 10 may include one or more sample compartments. The sample compartment(s) may be configured, for example, to store fluid and / or tissue samples. The sample compartment(s) may be advantageously located close to the coolant container 50 to provide cooling, which may be similar to or Petition 870260048834, dated 05 / 22 / 2026, pp. 63 / 76 26 / 28 equivalent to the cooling provided to organ 20.

[0068] Device 10 may include one or more tamper-evident closures. A tamper-evident closure may be used to alert a user that device 10 has been opened at an unauthorized time and / or location and / or by an unauthorized person. The tamper-evident closure may alert the user to perform additional testing, screening, or similar procedures before using organ 20 and / or device 10.

[0069] The bubble collector 110 and any tubing or other components that come into contact with the perfusate are preferably disposable. Disposable components may preferably be sterilized before use. These sterilized disposable components may be sold in one or more sterilized disposable kits or sterilizable packages as a unit. This allows the sterilized disposable components to be single-use components. That is, once an organ 20 has been placed in position inside the basin 70 and used, such sterilized disposable components may be discarded without being used for another organ. Consequently, the organ perfusion apparatus 10 maintains strict sterility and prevents contamination of an organ 20 being perfused, transported and / or stored in the apparatus 10. Components of the apparatus 10 that are not disposable may be reused indefinitely.Preferably, all components that come into contact with the perfusate and / or organ 10 are disposable. In exemplary deployments, the tubing, filter, oxygenator, and bubble collector are packaged together in a pre-configured manner to be placed in a flow path arrangement of the fixed locating parts in the device 10, and the cradle and basin are packaged individually or together and optionally together with the tubing, filter, oxygenator, and bubble collector. Petition 870260048834, dated 05 / 22 / 2026, pp. 64 / 76 27 / 28 EXAMPLE 1

[0070] Using the apparatus shown in Figure 1, chamber 200 of the bubble collector 110 has a total volume of approximately 0.7 liters. Chamber 200 holds between 0.1 and 0.163 liters of liquid in use. Chamber 200 holds between 0.537 and 0.6 liters of gas in use. The volume of gas above air opening 250 is between 76% and 95% of the total chamber volume. For example, if chamber 200 has 0.1 liters of liquid in use, the volume of gas above air opening 250 will be 86% of the total chamber volume. Alternatively, if chamber 200 has 0.163 liters of liquid in use, the volume of gas above air opening 250 will be 76% of the total chamber volume. The pump operates so that the liquid flows into the chamber at a maximum rate of about 2.0 liters per minute. The inner diameter of the pump tube segment is about 0.795 centimeters (0.313 inches) and the outer diameter is about 1.11 centimeters (0.437 inches).The pump rotor diameter is approximately 10.16 centimeters (4.0 inches) and contains four equally spaced rollers around the circumference of the rotor, wherein each roller is approximately 1.194 centimeters (0.47 inches) in diameter. The pressure fluctuation of the liquid flowing into inlet 230 is dependent on the rotor RPM and at the maximum flow rate of 2.0 liters per minute, the pressure can fluctuate between approximately 230 mmHg and approximately 350 mmHg. At lower RPMs, pressure fluctuations may be lower. The pressure fluctuation of the liquid flowing out of the first liquid outlet 260 and / or the second liquid outlet 280 is equal to or less than 2 mmHg peak-to-peak at the maximum flow rate of 2.0 liters per minute. The chamber is maintained at a temperature between 3 and 5 degrees Celsius during the operation of the perfusion apparatus; This temperature results from the contact of the chamber with the basin 30 in the refrigerant container 50.

[0071] What has been described and illustrated in this document are Petition 870260048834, dated 05 / 22 / 2026, pp. 65 / 76 28 / 28 Preferred exemplary embodiments of the invention together with some variations. The terms, descriptions and Figures used herein are presented for illustrative purposes only and are not intended to signify limitations. Those skilled in the art will recognize that many variations are possible within the spirit and scope of the invention. Petition 870260048834, dated 05 / 22 / 2026, pp. 66 / 76

Claims

1 / 3 CLAIMS 1. Method for perfusing an organ or tissue ex-vivo, comprising the steps of: causing a perfusion fluid to flow inside a chamber (200) of a bubble collector (110) under fluctuating pressure, the chamber including at least one liquid inlet opening (230), at least one gas outlet opening (250) and at least one liquid outlet opening (270, 290); maintaining at least a minimum volume of gas in the chamber (200) sufficient to dampen pressure fluctuations of the perfusion fluid; allowing the perfusion fluid with reduced pressure fluctuations to flow out of the chamber (200); and perfusing the organ or tissue with reduced pressure fluctuation fluid;characterized in that: the minimum gas volume being maintained by the control of at least one valve for the openings to continuously maintain the gas volume in the chamber (200) at about 75% to 95% of the total volume of the chamber (200) while perfusion of the organ or tissue occurs; the minimum gas volume is sufficient to cause a ratio of pressure fluctuations of the perfusion fluid flowing into the chamber (200) and pressure fluctuations of the perfusion fluid flowing out of the chamber (200) to be greater than 10 to 1; said at least one valve being further controlled to maintain a perfusion fluid level in the chamber (200) between 1 and 15 mm below the bottom of at least one gas outlet opening.

2. Method, according to claim 1, characterized in that the ratio is at least 100 to 1, preferably at least 200 to 1.

3. Method according to claim 1, characterized in that: the volume of gas in the chamber (200) is continuously maintained at about 0.5 liters to about 0.6 liters, while perfusing the organ or tissue at a flow rate of about 0.3 to 2.0 liters per minute.

4. Method according to claim 1, characterized in that: the pressure of the liquid flowing inside the chamber fluctuates between about 20 mmHg and about 350 mmHg; and the pressure of the liquid flowing out of the chamber fluctuates by no more than 2.5 mmHg.

5. Perfusion apparatus comprising: a pulsatile pump (80); a bubble collector (110) comprising a chamber (200) having at least one liquid inlet opening (230), at least one gas outlet opening (250), and at least one liquid outlet opening (270, 290); a controller (400) communicating with the pump, the bubble collector (110) and a liquid level sensor (112) configured to detect a perfusion liquid level in the bubble collector (100); a conduit forming a liquid path between the pump and at least one liquid inlet opening (230) of the chamber; and a conduit forming a liquid path between at least one liquid outlet opening (270, 290) and an organ receptacle; characterized by the fact that: a chamber volume above the gas outlet opening (250) is at least 0.4 liters or at least 75% of a total volume of Petition 870260048834, dated 05 / 22 / 2026, page.68 / 76 3 / 3 chamber; the controller (400) configured to control at least one valve for the openings to maintain a perfusion fluid level in the chamber between 1 and 15 mm below the bottom of at least one gas outlet opening (250).

6. Apparatus, according to claim 5, characterized in that said controller is further configured to control at least one valve to maintain a pressure fluctuation ratio of perfusion fluid flowing into an inlet opening to the pressure fluctuation of perfusion fluid flowing out of the liquid outlet opening (270, 290) of more than 10 to 1, preferably at least 100 to 1.

7. Apparatus, according to claim 5, characterized in that: the volume of the chamber above at least one gas outlet opening (250) is at least 0.4 liters; and the volume of the chamber as a whole is about 0.5 to 1 liter.

8. Apparatus, according to claim 5, characterized in that the chamber volume above at least one gas outlet opening (250) is at least 75% of the total chamber volume.

9. Apparatus according to claim 5, characterized in that the bubble collector further comprises a sampling port (350) extending from a top wall of the bubble collector to a sampling port inlet located near a bottom wall of the bubble collector. Petition 870260048834, dated 22 / 05 / 2026, pp. 69 / 76

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