Patent Description:
Organ perfusion is a useful technique, particularly for preserving, testing and assessing donated organs for transplantation. For example, different perfusion apparatus, system and methods have been developed for ex vivo maintenance and transportation of harvested organs. After an organ for transplantation is harvested from an organ donor, it is usually maintained ex vivo by perfusion for a period of time before it is transplanted into a recipient. For ex vivo maintenance of an excised organ, a perfusion solution may be used to supply oxygen and nutrients to the cells and tissues within the harvested organ, and to remove carbon dioxide and wastes, through the organ's endogenous vasculature. The perfusate may be formed of whole blood, a blood fraction mixed with a dilutant such as PERFADEX™, or an appropriate substitute for blood such as STEEN Solution™, and which has the appropriate temperature, gas composition, solute concentrations and pH. The perfusate may be supplied into the organ's primary artery or arteries, passed through capillary beds in the organ and into the veins, and then excreted from the organ's primary vein or veins. <CIT> discloses an apparatus that supplies perfusate to an excised organ held in the container and returns perfusate to a liquid circuit that includes an oxygenator and a heat exchanger. The flow of perfusate in the liquid circuit is controlled by a plurality of valves. <CIT> discloses an apparatus for perfusing an excised lung, in which perfusate is pumped into the lung via a pulmonary artery interface. The perfusate exits the lungs through the left atrial cuff and flows into a cup-shaped interface provided with a plurality of openings that are in fluid communication with a selector valve and an outlet conduit. The selector valve is used to control the openings and maintain a desired level of perfusate in the cup-shaped interface. Further examples of prior art perfusion apparatuses and methods can be found in <CIT>, <CIT> and <CIT>.

Despite advancement in perfusion technology to date, a large percentage of donated organs have not been used for transplantation due to a number of reasons. For example, the functionality of some harvested organs were not adequately preserved or restored, rendering them unsuitable for transplantation. Some harvested organs were discarded as unsuitable based on visual inspection, which were in fact good candidates for transplantation. It has been reported that currently only about <NUM>-<NUM>% of donated lungs and hearts were found suitable and used for transplantation.

Further improvement in perfusion techniques is thus desirable.

The present disclosure provides an apparatus according to claim <NUM> and a method according to claim <NUM>. The following discussion is provided for understanding the claims, but the scope of protection is only defined by the claims. In particular, the use of the word "embodiment" or "aspect" does not indicate that protection is sought beyond the scope of the claims.

In accordance with an aspect of the present disclosure, there is provide an apparatus for perfusion of organs, comprising a base unit configured to removably couple with a perfusion module for perfusing an organ, and a first module, the base unit comprising conduits for connecting a source of a perfusate to the organ to circulate the perfusate through the organ; first and second pumps coupled to the conduits for driving circulation of the perfusate in the conduits; and a controller configured and connected for controlling the first and second pumps to regulate the circulation of the perfusate through the organ; wherein the perfusion module is one of a plurality of organ-specific modules each configured to couple with the base unit, the organ-specific modules comprising the first module configured for perfusing a lung. The base unit and the first module may be configured such that when the base unit is coupled to the module for perfusing the lung, a first one of the conduits is connectable to a pulmonary artery of the lung for supplying the perfusate into the lung, a second one of the conduits is connectable to a pulmonary vein of the lung for returning perfusate egressed from the lung to the source, and the controller is operable to control the first and second pumps to apply a first pressure in the first conduit to drive flow of the perfusate into the pulmonary artery and to maintain a second pressure in the second conduit to resist the flow of the perfusate out of the atrium attached to the lung. The first module may comprise a ventilator for ventilating the lung, or may comprise a connector for connecting the lung to an external ventilator. The organ-specific modules may include a second module configured for perfusing a heart. The base unit and the second module may be configured such that when the base unit is coupled to the second module, the conduits are connectable to the heart to circulate the perfusate through the aorta, right atrium, left atrium and a pulmonary artery of the heart, and the controller is operable to control the first and second pumps to apply a first pressure at the right atrium and left atrium with the first pump and a second pressure at the aorta with the second pump. The apparatus may be configured to be operable to perfuse the heart in a resting condition or in a working condition. The second module may comprise connectors for connecting the heart to at least one of a pacemaker, an electrocardiogram monitor, and a defibrillator. The organ-specific modules may comprise a module configured for perfusing a liver. The base unit and the module for perfusing the liver may be configured such that when the base unit is coupled to the module for perfusing the liver, the conduits are connectable to the liver to supply the perfusate to the liver through a portal vein and a hepatic artery of the liver, and the controller is operable to control the first and second pumps to regulate flow of the perfusate through each one of the portal vein and the hepatic artery. The module for perfusing the liver may comprise a bile collector for collecting bile from the liver. The organ-specific modules may comprise a module configured for perfusing a kidney. The apparatus may comprise one or more of the organ-specific modules. The base unit may comprise a conditioning system coupled to the conduits for conditioning the perfusate. The conditioning system may comprise a heat exchanger for controlling a temperature of the perfusate, and a gas exchanger for selectively oxygenating or deoxygenating the perfusate. The controller may be operable to control the heat exchanger to regulate the temperature of the perfusate, and to control the gas exchanger to oxygenate or deoxygenate the perfusate. The apparatus may comprise a plurality of pressure sensors and flow rate sensors for detecting signals indicative of pressures and flow rates at selected locations in selected ones of the conduits, and a temperature sensor for detecting a signal indicative of a temperature of the perfusate or the organ. The controller may be operable to control a perfusate flow property based on, at least in part, the detected signals from at least one of the pressure sensors and the flow rate sensors. The perfusate flow property may include at least one of a pressure at a selected location in the conduits, or a flow rate in a selected one of the plurality of the conduits. The base unit may comprise a user interface for receiving a user input, and controls circulation or condition of the perfusate based on, at least in part, the user input. The user input may include an indication of a desired pressure at a selected location, or a desired flow rate in a selected conduit. The base unit may comprise a container for receiving and storing the perfusate to provide the source of the perfusate. The pumps may comprise centrifugal pumps. The conduits may comprise a bypass conduit for returning a portion of the perfusate from the conduits or the perfusion module to the source without passing through the organ. The perfusion module may comprise an organ-specific perfusion chamber.

In a further aspect, there is provided an apparatus for perfusion of organs, comprising a plurality of organ-specific perfusion modules each comprising a perfusion chamber for perfusing a respective specific organ and a set of fluid conduits configured for connecting the specific organ to a source of a perfusate; and a base unit comprising a receptacle for removably mounting a selected one of the organ-specific modules onto the base unit, conduits connecting the source of the perfusate to the fluid conduits of the each organ-specific perfusion module, to allow circulation of the perfusate through the respective specific organ, first and second pumps coupled to the conduits for regulating circulation of the perfusate through the specific organ, a heat exchanger for controlling a temperature of the perfusate, a gas exchanger for oxygenating or deoxygenating the perfusate, and a controller for controlling the pumps and the heat exchanger to regulate circulation of the perfusate through the specific organ and to regulate a property or condition of the perfusate, the controller configurable to regulate circulation of the perfusate based on a specific set of control settings associated with each one of the organ-specific modules.

In another aspect, there is provided a method of perfusing a lung, comprising circulating a perfusate through the lung by supplying the perfusate into the lung through a pulmonary artery and withdraw the perfusate from the lung through a pulmonary vein; applying a first pressure in the pulmonary artery to drive flow of the perfusate through the lung; applying a second pressure in the pulmonary vein to resist the flow of the perfusate through the lung. The second pressure may be regulated to maintain the second pressure substantially constant.

In a further aspect, there is provided an apparatus for perfusion of multiple types of organs, comprising a base unit configured to removably couple with a perfusion module for perfusing an organ, the base unit comprising conduits for connecting a source of a perfusate to the organ to circulate the perfusate through the organ; first and second pumps coupled to the conduits for driving circulation of the perfusate in the conduits; and a controller configured and connected for controlling the first and second pumps to regulate the circulation of the perfusate through the organ; wherein the controller is operable to control the first and second pumps to perfuse the organ in accordance with organ specific perfusion parameters, and wherein the organ specific perfusions parameters are selected based on the type of the organ and may be selected by an operator for at least two organ types selected from the group of heart, liver, kidney and lung.

In another aspect, there is provided an apparatus for perfusing lungs, comprising conduits for connecting a source of a perfusate to a lung to circulate the perfusate through the lung, the conduits comprising a first conduit connectable to supply the perfusate into the lung through a pulmonary artery of the lung and a second conduit connectable to return perfusate egressed from the lung to the source through a pulmonary vein of the lung; a first pump coupled to the first conduit for driving flow of the perfusate into the lung; a second pump coupled to the second conduit for resisting flow of the perfusate out of the lung; and a controller for controlling the first and second pumps to regulate circulation of the perfusate through the lung. The apparatus may further comprise a ventilator for ventilating the lung.

Other aspects, features, and embodiments of the present disclosure will become apparent to those of ordinary skill in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.

In the figures, which illustrate, by way of example only, embodiments of the present disclosure,.

In overview, it has been realized that multiple pumps can be conveniently used in ex vivo perfusion devices, not only for heart perfusion but also for lung perfusion or perfusion of other organs, to achieve improved flow control to allow better simulation of blood circulation in intact organs, and assessment of organ conditions. A fluid subsystem with pumps and a control subsystem may be conveniently provided in a base unit that can be coupled to different organ-specific modules. The inclusion of multiple pumps allows the base unit to be conveniently configured and adapted to work with multiple organ-specific modules for perfusing different types of organs, such as heart, lung, liver, or kidney.

For example, to perfuse an excised lung, a first pump may be used to apply a preload pressure to drive flow of a perfusate into a pulmonary artery of the lung, and a second pump may be used to maintain an afterload pressure to resist the flow of the perfusate out of a pulmonary vein of the lung. As the first and second pumps can be individually controlled, such as by a controller, the preload pressure, the flow rate, and the afterload pressure can be conveniently controlled and regulated. For example, while the afterload pressure is maintained at a constant level, the preload pressure and flow rate may be adjusted as desired.

In another example, to perfuse an excised liver, a first pump may be used to drive flow of a perfusate into a hepatic artery of the liver, and a second pump may be used to drive flow of a perfusate into a portal vein of the liver. As the first and second pumps can be individually controlled, the flow properties of perfusate flows into the hepatic artery and the portal vein can be separately or independently adjusted and regulated.

In a further example, multiple pumps may be used to perfuse a heart, as described herein, or as described in <CIT>, and in <CIT>.

<FIG> illustrates an example apparatus <NUM> for perfusion of different organ types. Apparatus <NUM> includes a base unit <NUM> and a perfusion module <NUM> removably coupled to the base unit <NUM>.

Perfusion module <NUM> is selected from a number of selectable organ-specific modules each for perfusing a specific type of organ. Each perfusion module <NUM> may include a perfusion chamber (not shown in <FIG>) for supporting the organ to be perfused. The perfusion module <NUM> may also be configured to provide an environment that sustains the function or health of an excised organ ex vivo, such as maintenance of humidity, gas composition, and temperature.

The base unit <NUM> includes a fluid subsystem <NUM> for connecting a perfusate source <NUM> to the organ supported on a perfusion module <NUM> in order to circulate the perfusate through the organ. Base unit <NUM> also includes a conditioning subsystem <NUM> for conditioning the perfusate, and a control subsystem <NUM> for controlling perfusate circulation through the organ.

Fluid subsystem <NUM> may include any number of conduits (not separately shown in <FIG>) configured to supply fluids to the organ and return fluids from the organ or any selected location in the fluid subsystem <NUM> back to the perfusate source <NUM>. The conduits may be provided in any suitable form, shape or size, as will be further described below. The number of conduits and their configuration may be selected depending on the types of organs to be perfused with the apparatus <NUM>, as can be understood by those skilled in the art. Sufficient conduits are provided and configured so as to accommodate all selectable organ-specific perfusion modules <NUM> and different modes of operation for perfusion of multiple types of excised organs The fluid subsystem <NUM> may include multiple pumps, such as first pump <NUM> and second pump <NUM>.

The perfusion module <NUM> may be configured to position the organ for connection to conduits in the fluid subsystem <NUM>. The perfusion module <NUM> may also optionally include its own conduits for such connection. The base unit <NUM> and the perfusion module <NUM> may include coupling structures (not shown) for quick coupling and connection of conduits there between.

The perfusate source <NUM> may be mounted on base unit <NUM>, or may be attached or connected to base unit <NUM>. It is not necessary that the perfusate source <NUM> be included in base unit <NUM> but it may be convenient to provide a perfusate storage or container in base unit <NUM>. In some embodiments, it may be convenient to provide the perfusate source within the perfusion module <NUM>.

The conditioning subsystem <NUM> may include any necessary or optional conditioning devices or equipment for conditioning the perfusate, such as its composition, temperature, pH, or the like. In an embodiment, conditioning subsystem <NUM> may include a heat exchanger (not shown in <FIG>, but see below and other figures) for controlling and regulating the temperature of the perfusate or the organ. The heat exchanger may be replaced with a heater, or separate heater and cooler. Conditioning subsystem <NUM> may also include a gas exchanger (not shown in <FIG>, but see below and other figures) for adjusting a gas content in the perfusate. Typically, the gas exchanger may include an oxygenator for oxygenating or deoxygenating the perfusate, depending on the application. Other perfusate conditioning devices may be provided as understood by those skilled in the art.

As depicted, conditioning subsystem <NUM> may be coupled to conduits in fluid subsystem <NUM> for conditioning the perfusate, at one or more selected locations in the fluid subsystem <NUM>. In different embodiments, conditioning subsystem <NUM> may be coupled to the perfusate source <NUM> to condition the perfusate stored in perfusate source <NUM>.

In an embodiment, the control subsystem <NUM> includes a controller <NUM>, for controlling the operation of the apparatus <NUM>, and any additional necessary or optional control components or devices such flow sensors <NUM>, pressure sensors <NUM>, communication lines or the like (not all shown in <FIG>, but see below and other figures). The controller <NUM> is configured and connected for controlling pumps <NUM>, <NUM> to regulate circulation of the perfusate through the organ. The pumps <NUM>, <NUM> are coupled to selected conduits in fluid subsystem <NUM> for driving circulation of the perfusate through the conduits.

As will be appreciated by those skilled in the art, controller <NUM> may be a digital controller such as a general or specifically-designed microcontroller, or an analog controller, or a combination thereof. A suitable controller may include hardware such as a processor or electronic circuit, and software which may be stored in a memory. A controller or any of its components may also be implemented by hardware only.

Conveniently, different types of organs may be perfused and assessed using the apparatus <NUM>, by coupling the corresponding organ-specific perfusion module <NUM> to the base unit <NUM>. To this end, control subsystem <NUM> may be configured and adapted to allow customized, organ-specific control settings and control parameters to be used with respective organ-specific module.

<FIG> illustrates a base unit <NUM>, which is a particular embodiment of base unit <NUM>. As depicted, the base unit <NUM> can removably couple with the organ-specific perfusion module <NUM>.

Perfusate that collects in the perfusion module <NUM> can flow to the perfusate source <NUM> through a drainage conduit <NUM>.

The perfusion module <NUM> may include one or more sensors (not shown), which may be connected with the controller <NUM>, for monitoring the level of a pool of perfusate, if any, in the perfusion module <NUM>. Other sensors (not shown) may also be provided and connected with the controller <NUM> for monitoring other aspects of the environment surrounding an organ in the perfusion module <NUM>, as would be understood by persons skilled in the art. The perfusion module <NUM> may include connectors, such as a tubing connector or a cannula, for connecting a blood vessel or a chamber of an organ to a conduit of the fluid subsystem <NUM>. Suitable, commercially-available cannulae may include those available from XVIVO™ Perfusion.

The perfusate source <NUM> may be provided in the form of a container, chamber, or the like, and is alternatively referred to as a reservoir. The perfusate source <NUM> can have different forms, shapes, and sizes and may be pressurized or unpressurized.

The fluid subsystem <NUM> in the base unit <NUM>, as illustrated in <FIG>, may include conduits <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, and <NUM>, depicted as thick lines in <FIG>; centrifugal pumps <NUM> and <NUM>; Y-connectors <NUM> and <NUM>; and pressure ports <NUM>, <NUM>, <NUM>, and <NUM>. A conduit may be formed of a tubing, a channel, a chamber, a pipe, or the like, or a combination thereof. A conduit may also include a cannula that connects another conduit to a blood vessel of an organ. A conduit may have any suitable diameter and flexibility, and may be formed of any suitable material. Some conduits in a base unit may be rigid. End connection conduits may be flexible to easy handling. Examples of suitable conduit materials include PVC perfusion tubing as may be utilized in cardiopulmonary bypass surgery, including those available from Sorin Group, Maquet Getinge Group, or Medtronic; silicone tubing; or other suitable inert, durable plastic tubing.

Connections between conduits and other components of the fluid subsystem <NUM> (e.g., pumps, pressure ports, heat exchanger, gas exchanger) or components of the control subsystem <NUM> (e.g. pressure sensors, flow sensors), perfusate source <NUM>, and conditioning subsystem <NUM> may be sealed, such that the base unit <NUM> and the perfusion module <NUM> form a closed fluid circuit.

As noted above the conditioning subsystem <NUM> in base unit <NUM> includes heat exchanger <NUM> and gas exchanger <NUM>, which are configured and adapted to condition the perfusate supplied to the organ. The temperature, gas composition, pH, concentrations of solutes (e.g., [Na+], [K+], [Cl-], [Ca<NUM>+], lactate concentration, or glucose concentration), and other parameters of the perfusate can be monitored and modulated in manners or with techniques known to persons of skill in the art. In particular, the perfusate can be heated or cooled to a desired temperature, such as a normothermic temperature from the range of about <NUM> to about <NUM>, by the heat exchanger <NUM>, as depicted in <FIG>. The heat exchanger <NUM> is typically connected to a power source, such an electrical socket or battery (not shown). Further, the gas composition of the perfusate can be modulated or maintained by the gas exchanger <NUM>, as depicted in <FIG>. The gas exchanger <NUM> may be connected to a gas source, such as a pressurized gas tank (not shown), where the gas may be oxygen. The gas exchanger <NUM> may be titrated to maintain a pH of <NUM> to <NUM>, partial pressure of arterial oxygen of <NUM> to <NUM> millimeters of mercury ("mmHg"), and partial pressure of arterial carbon dioxide of <NUM> to <NUM> mmHg.

It is noted that different organs may require different gas compositions in the perfusate. For instance, while for heart perfusion the perfusate may be oxygenated to increase its oxygen content, a perfusate to be pumped into a pulmonary artery of a lung may be conditioned to have comparatively lower concentrations of oxygen and comparatively higher concentrations of carbon dioxide. In some embodiments, gas treatment or mixing may not be necessary. For different organs, the requirements may also vary. For example, a standard gas mix may be suitable for perfusion of heart, liver and kidney, and a separate, unique gas mix may be provided for lung perfusion.

The heat exchanger <NUM>, gas exchanger <NUM>, and other components of the conditioning subsystem <NUM> may communicate with the controller <NUM>, through either wired or wireless communication. The controller <NUM> may control, possibly through feedback control using information from selected sensors such as temperature sensors, the conditioning of the perfusate. The location of the heat exchanger <NUM> and the gas exchanger <NUM> depicted in <FIG> should not be understood as limiting, as alternative positions in the apparatus may be suitable in different embodiments. Moreover, multiple heat exchangers and gas exchangers may be used in the apparatus <NUM>. The heat exchanger <NUM> and the gas exchanger <NUM> may be combined in a single device. For instance, the Affinity NT™ oxygenation system available from Medtronic modulates the temperature and the gas composition of a perfusate.

The control subsystem <NUM>, as specifically embodied in the base unit <NUM> depicted in <FIG>, includes a controller <NUM> in communication, either by wired or wireless connection, with the following components: flow sensors <NUM>, <NUM>, <NUM>, and <NUM>; pressure sensors <NUM>, <NUM>, <NUM>, and <NUM>; and valve <NUM>. As can be appreciated, a valve may include or be replaced by a clamp. The controller <NUM> depicted in <FIG> also communicates with components of the fluid subsystem <NUM>, including the centrifugal pumps <NUM> and <NUM>, and components of the conditioning subsystem <NUM>, including a heat exchanger <NUM> and a gas exchanger <NUM>. The controller <NUM> depicted in <FIG> may also communicate with components of the perfusion module <NUM>, such as organ-specific devices that monitor or control the organ (not shown in <FIG>, but see other figures). More specifically, controller <NUM> controls the pump speeds of the pumps <NUM> and <NUM>, as well as the occlusion of a passage between two conduits by the valve (or clamp) <NUM>, in response to information provided by the flow sensors <NUM>, <NUM>, <NUM>, and <NUM> and information provided by the pressure sensors <NUM>, <NUM>, <NUM>, and <NUM>.

The pump <NUM> and <NUM> in base unit <NUM> can each apply a fluid pressure to a perfusate in conduit <NUM> or <NUM> respectively. Such pressure can drive flow of the perfusate, or provide resistance to the flow as retrograde flow through a centrifugal pump is possible. Suitable, commercially-available centrifugal pumps may include ROTAFLOW™ pumps, which are available from Maquet Getinge Group; BIO-PUMP ™ pumps, which are available from Medtronic; and RevOlution <NUM>™ pumps, which are available from Sorin Group.

The pressure sensors <NUM>, <NUM>, <NUM>, and <NUM> in base unit <NUM> can detect pressures in the interior of the respective conduit via the respective pressure port <NUM>, <NUM>, <NUM>, and <NUM> respectively. The pressure ports form junctions between conduits through which perfusate can pass. The pressure ports also include a channel into which a pressure sensor can be inserted.

The flow sensors <NUM>, <NUM>, <NUM>, and <NUM> in base unit <NUM> may be attached to the exterior of the respective conduit. Suitable, commercially-available flow sensors may include a TX40 or TX50 Bio-Probe™ Flow Transducer, which is available from Medtronic, and PXL series flow probes, which are available from Transonic Systems.

The valve or clamp <NUM> connecting two conduits can control or regulate the flow of perfusate between the two conduits by occluding a passage between the conduits.

The valve or clamp <NUM> may be a servo-actuated partial occlusion clamp with variable clamping positions that enable regulation of flow. Examples of suitable valves or clamps may include an electrical remote-controlled tubing clamp available from Sorin Group, an electrical venous occluder available from Sorin Group or a venous line clamp.

The fluid subsystem <NUM> may include three sections of conduits and associated components, as depicted in <FIG>. Many of the associated components communicate with the controller <NUM> as indicated by dotted lines in <FIG>.

The first section of fluid subsystem <NUM> connects to the reservoir <NUM> via a conduit <NUM>. The conduit <NUM> is connected to the centrifugal pump <NUM>. The centrifugal pump <NUM> is connected to the heat exchanger <NUM> and the gas exchanger <NUM> via conduit <NUM>. The gas exchanger <NUM> connects to a Y-connector <NUM> via conduit <NUM>. One branch of the Y-connector <NUM> connects to a purge line <NUM>.

The purge line <NUM>, which may also be referred to herein as a bypass line, connects to the reservoir <NUM>. Purge line <NUM> can be used to remove air from conduits in the fluid subsystem <NUM>. For example, for pursing a heart or another organ, it may be important to remove air pockets or air bubbles from the perfusate stream before the perfusate is supplied to the heart. While not specifically shown, a bypass or purge line may be provided for each one of the arteries that are cannulated in each organ to allow easier de-airing of the fluid subsystem at the startup phase of perfusion, or for handling air entrained in the fluid circuit. While not specifically depicted in <FIG>, it can be appreciated that a top portion of purge line <NUM> can be raised to be higher than the upstream conduit connected thereto, so that an air bubble or pocket in the conduit can rise to the top portion of the purge line <NUM> and be removed through the purge line <NUM>, to prevent the air from entering the arterial system of the organ.

The other branch of the Y-connector <NUM> connects to conduit <NUM>. Flow sensor <NUM> is attached to the conduit <NUM>. The conduit <NUM> is connected to a pressure port <NUM>, which is associated with a pressure sensor <NUM>. The pressure port <NUM> is also connected to a conduit <NUM>. When the base unit <NUM> is not coupled with a perfusion module <NUM>, the conduit <NUM> is not connected on one end, and a cap may be inserted into the free end of the conduit <NUM>, in a manner that is known to the skilled person, for instance to stop leakage from or maintain sterility of the fluid subsystem <NUM>.

The second section of the fluid subsystem <NUM> includes a conduit <NUM> that connects the reservoir <NUM> to the centrifugal pump <NUM>. The centrifugal pump <NUM> is connected to a Y-connector <NUM> via a conduit <NUM>. One branch from the Y-connector <NUM> is a conduit <NUM>, to which is attached a valve or clamp <NUM> and a flow sensor <NUM>. The conduit <NUM> connects to pressure port <NUM>, which is associated with a pressure sensor <NUM>. Pressure port <NUM> also connects with a conduit <NUM>. The other branch from the Y-connector <NUM> connects to a conduit <NUM>, to which a flow sensor <NUM> is attached. The conduit <NUM> connects to a pressure port <NUM>, which is associated with a pressure sensor <NUM>. The pressure port <NUM> also connects with a conduit <NUM>.

The third section of the fluid subsystem <NUM> has a conduit <NUM> that connects to a pressure port <NUM>, which is associated with a pressure sensor <NUM>. The pressure port <NUM> connects to a conduit <NUM>, to which is attached a flow sensor <NUM>. The conduit <NUM> also connects to the reservoir <NUM>. The third section of the fluid subsystem <NUM> may optionally contain a third centrifugal pump (not shown) which can provide back pressure to a blood vessel connected to conduit <NUM>.

When the base unit <NUM> is not coupled with an organ-specific perfusion module <NUM>, the terminal conduits <NUM>, <NUM>, <NUM>, and <NUM> are not connected on one end, and a cap or stopper (not shown in <FIG>) may be inserted into the free end of the conduits, in a manner that is known to persons of skill in the art, for instance to stop leakage from or maintain sterility of the fluid subsystem <NUM>. The base unit <NUM> may include additional components, including bubble detectors, leukocyte filters, additional flow sensors, additional pressure sensors, additional heat exchangers, additional gas exchangers, and additional pumps.

As would be understood by persons of skill in the art, some of the conduits in the fluid subsystem <NUM> can be isolated from the perfusate in other conduits of the fluid subsystem <NUM> through the addition of valves, clamps, or stoppers at appropriate locations (not shown). As one example, when the base unit <NUM> is coupled with a particular organ-specific perfusion module <NUM>, the third section of the fluid subsystem <NUM>, as described, may not be necessary and so can be isolated by placing a cap, stopper or the like (not shown) in the free end of conduit <NUM> and by placing a clamp or the like (not shown) on conduit <NUM>. Similarly, when the base unit <NUM> is coupled with a particular organ-specific perfusion module <NUM>, the purge line <NUM> can be isolated from flows of perfusate through the Y-connector <NUM> by placing a clamp (not shown) or the like on the purge line <NUM>.

Alternatively, in different embodiments, some of the organ-specific conduits of the fluid subsystem <NUM> may be provided on a corresponding organ-specific perfusion module <NUM>, instead of on the base unit <NUM>.

As would be understood by persons of skill in the art, in order to prevent siphoning of perfusate into the reservoir, an additional chamber (not shown) can be added to one or more of the conduit <NUM>, the conduit <NUM>, the drainage conduit <NUM>, and the purge line <NUM>. An example of said additional chamber is a soft shell reservoir, such as the CVR <NUM> or BMR <NUM> available from Sorin Group or the VRB <NUM> from Maquet Getinge Group.

Prior to coupling the base unit <NUM> to an organ-specific perfusion module <NUM>, the fluid subsystem <NUM> may be primed with a fluid, such as a saline or a perfusate, so as to remove air from the conduits prior to coupling with the perfusion module.

<FIG> illustrate different configurations of apparatus <NUM> where the base unit <NUM>, as illustrated in <FIG> and described above, is coupled to different organ-specific perfusion modules for heart <NUM> (<FIG>), lung <NUM> (<FIG>), liver <NUM> (<FIG>), or kidney <NUM> (<FIG>). In each specific configuration shown in <FIG>, the same base unit <NUM> is used, but a different organ-specific module <NUM> is coupled to the base unit <NUM>, including through connection of one or more of conduits <NUM>, <NUM>, <NUM>, and <NUM> to a vein or artery of the organ, which connection may be made by a different type of conduit such as a cannula. In addition, controller <NUM> controls the pump speeds of the centrifugal pumps <NUM> and <NUM>, as well as the occlusion of a passage between two conduits by the valve or clamp <NUM>, in response to organ-specific information in the memory of the controller or inputted by a user. The organ-specific information may include desired flows or pressures at specified points in the conduits of the fluid subsystem <NUM>, which may be achieved or maintained by the controller <NUM> by way of feedback control using information provided by the flow sensors (<NUM>, <NUM>, <NUM>, <NUM>) and the pressure sensors (<NUM>, <NUM>, <NUM>, and <NUM>).

<FIG> illustrates a specific embodiment of an apparatus <NUM> in which a base unit <NUM> is attached to a heart-specific perfusion module <NUM>, such as that of a human or a pig. Blood vessels extending from the heart are connected to a fluid subsystem <NUM>. Heart-specific parameters, such as desired pressures or flow rates in particular locations of fluid subsystem <NUM>, are inputted into the controller <NUM>.

Prior to connection of the heart <NUM> to the fluid subsystem <NUM>, the fluid subsystem <NUM> is primed with a perfusate and one end of a cannula is connected to each of the aorta <NUM>, the pulmonary artery <NUM>, the right atrium <NUM>, and the left atrium <NUM> of the excised heart <NUM>. Cannulae <NUM>, <NUM>, <NUM>, and <NUM> of the heart-specific perfusion module <NUM> act as an interface between the heart <NUM> and the fluid subsystem <NUM> of the base unit <NUM>. A cannula <NUM> connects the aorta <NUM> to the free end of a conduit <NUM>. A cannula <NUM> connects the pulmonary artery <NUM> to the free end of a conduit <NUM>. A cannula <NUM> connects the right atrium <NUM> to the free end of a conduit <NUM>. A cannula <NUM> connects the left atrium <NUM> to the free end of a conduit <NUM>.

Once the heart <NUM> is connected to the fluid subsystem <NUM>, perfusion can begin, so as to drive perfusate through the coronary arteries <NUM>, into the capillaries of the heart <NUM>, and then into the coronary veins <NUM> (perfusion is not illustrated on <FIG>). A number of suitable perfusate solutions are known to those skilled in the art. Suitable perfusion solutions can include whole blood; whole blood with additional calcium, phosphate, or dextrose; modified Krebs solutions; STEEN solution; and the like. One perfusate can be replaced with another in a number of ways that would be known to persons of skill in the art, such as connecting the fluid subsystem <NUM> to a different reservoir <NUM> containing a different perfusate. Any perfusate that accumulates in the heart-specific perfusion module <NUM>, such as perfusate that leaks from the attachment points of the heart's blood vessels to the cannulae, can be returned to the reservoir <NUM> through drainage conduit <NUM>.

Once attached in this manner, the heart can be perfused in either resting mode, as illustrated in <FIG>, or in working mode, as illustrated in <FIG>. The term "resting mode" refers to a method of perfusing a heart with a nutrient-rich oxygenated solution in a reverse fashion via the aorta. The backwards pressure causes the aortic valve to shut thereby forcing the solution into the coronary arteries. "Resting mode" is also known as the preservation mode or the Langendorff perfusion. The term "working mode" refers to coronary perfusion throughout a heart by ventricular filling via the left atrium and ejection from the left ventricle via the aorta driven by the heart's contractile function and regular cardiac rhythm. Arrows in <FIG> and <FIG> indicate the direction of flow of the perfusate in the conduit nearest to and parallel to the arrow.

In resting mode, as illustrated in <FIG>, the first section of fluid subsystem <NUM> directs pressure into the aorta from centrifugal pump <NUM>. As will be apparent to persons skilled in the art, suitable fluid pressure in the aorta <NUM> will lead to flow of conditioned perfusate from conduit <NUM> into the coronary arteries <NUM>, which branch off from the aorta <NUM>. If the pressure in the aorta is sufficient, perfusate will move through the coronary arteries <NUM> into capillary beds <NUM> inside the walls of the heart, thereby providing oxygen and nutrients to the heart muscle. Perfusate will then move from the capillary beds <NUM> into the coronary veins <NUM>, moving carbon dioxide and wastes away from the heart muscle. The coronary veins <NUM> empty into the right atrium <NUM> of the heart <NUM>, leading to a flow of perfusate from the right atrium <NUM>, through the right ventricle <NUM>, and into the pulmonary artery <NUM>. In this manner, perfusate containing carbon dioxide and wastes is moved into the third section of fluid subsystem <NUM> and returned to the reservoir <NUM> via a conduit <NUM>.

In working mode, as illustrated in <FIG>, the second section of fluid subsystem <NUM> supplies perfusate to the right atrium <NUM> and left atrium <NUM> via pumping from the centrifugal pump <NUM>. The relative flow of perfusate delivered to each atrium is controllable through adjustment of valve or clamp <NUM>. Perfusate pumped out of the right ventricle <NUM> and into the pulmonary artery <NUM> is collected by the third section of fluid subsystem <NUM> and returned to the reservoir <NUM> via conduit <NUM>. Perfusate pumped out of the left ventricle <NUM> moves into the aorta <NUM>. In working mode, the centrifugal pump <NUM> applies a back pressure on ejection of perfusate from the left ventricle. Controlling the speed of the centrifugal pump <NUM> can allow the resistance to left ventricular ejection to be controlled, which may allow for an assessment of the heart's contractile performance, as would be understood by persons of skill in the art, and as described in <CIT>. In working mode, perfusate ejected from the left ventricle flows through the conduits <NUM> and <NUM> toward the Y-connector <NUM>. At the Y-connector <NUM>, the flow egressing from the conduit <NUM> will proceed into the reservoir <NUM>, at least in part via the purge line <NUM>, but also through the centrifugal pump <NUM> and the conduit <NUM>, depending on the speed of the centrifugal pump <NUM>. As in resting mode, sufficient pressure in the aorta <NUM> will lead to perfusion of the heart muscle through flow of conditioned perfusate into the coronary arteries <NUM>. Further information in this regard is provided in <CIT>.

Although not depicted in <FIG>, <FIG>, and <FIG>, the base unit <NUM> and the heart-specific perfusion module <NUM> may be configured to connect to, or include, one or more heart-specific devices (not shown), which may be used to monitor or control the activity or function of the heart. As one example, pacemaker connectors, ECG electrodes and defibrillation pads may be built into heart-specific module <NUM>, thereby allowing continuous monitoring and correction of dysrhythmias through delivery of pacing or DC shocks as required.

The controller <NUM> may be configured using different heart-specific parameter settings, which may be entered by a user using a user interface such as a graphical user interface (GUI), or may be loaded from a configuration file stored in a computer memory. The target values of one or more specific parameters may be achieved or maintained by adjusting the speeds of the centrifugal pumps <NUM> and <NUM>, the extent of occlusion by the valve or clamp <NUM>, or settings on heart-specific devices being used to monitor or control the activity of the heart.

The controller <NUM> may comprise one or more proportional-integral-derivative (PID) controllers, which mediate feedback control of components in the fluid subsystem <NUM>. As will be known to persons skilled in the art, a PID controller continuously calculates an error value as the difference between a desired setpoint and a measured variable. The PID controller attempts to minimize the error value or a composite of multiple error values over time by adjustment of a control variable.

In a specific embodiment, the controller <NUM> comprises three PID controllers <NUM>, <NUM>, and <NUM>. Each of the PID controllers can calculate an error rate ("E1") for one pressure input and another error rate ("E2") for one flow input. The setpoint values may be entered by a user or stored in a memory of the controller <NUM>. The two error values are transformed into a single error value through a suitable mathematical operation that would be known to persons skilled in the art. Said mathematical operation can be different for each of the three PID controllers, can be loaded on startup from a configuration file stored in a computer memory or from data entered by a user, and can be adjusted by either software or by a user during perfusion of an organ. The composite error is subjected to a PID calculation so as to generate an adjustment of a component of the fluid subsystem <NUM>.

Feedback control in a specific embodiment of the base unit <NUM> coupled with a heart-specific perfusion module <NUM> in working mode is illustrated in <FIG>. The PID controller <NUM> receives a measurement for aortic pressure from a pressure sensor <NUM>, calculates an error value relative to a setpoint A, and then calculates a speed adjustment of a centrifugal pump <NUM>. The PID controller <NUM> receives no flow input. The PID controller <NUM> receives a measurement for left atrial pressure from a pressure sensor <NUM> and calculates an error value relative to setpoint C. The PID controller <NUM> also receives a measurement of left atrial flow from a flow sensor <NUM>, and calculates an error value relative to setpoint D. The two error values are translated into a single error value through a suitable mathematical operation, and an adjustment of the speed of a centrifugal pump <NUM> is calculated. A PID controller <NUM> receives a measurement for right atrial pressure from a pressure sensor <NUM> and calculates an error value relative to setpoint E. The PID controller <NUM> also receives a measurement for pulmonary artery flow from a flow sensor <NUM> and calculates an error value relative to setpoint F. The two error values are translated into a single error value through a suitable mathematical operation, and an adjustment of a partial occlusion clamp <NUM> is calculated. Table <NUM> provides typical values, as well as a typical range of values, for the setpoint inputs A, B, C, D, E, and F with respect to a heart-specific perfusion module.

<FIG> illustrates a specific embodiment of an apparatus <NUM> in which a base unit <NUM> is attached to a lung-specific perfusion module <NUM> bearing a lung <NUM>. The lung may be a human lung or a pig lung. It should be understood that a lung may refer to a single lung, a pair of lungs, or a portion of a lung such as a lobe of a lung. The lung may include an excised portion of the left atrium of the heart that contains the connection points of one or more pulmonary veins with the left atrium.

Prior to connection of the lung <NUM> to the fluid subsystem <NUM>, the fluid subsystem <NUM> is primed with a perfusate; one end of a cannula is connected to one or more pulmonary arteries <NUM>; and one end of a cannula is connected to one or more pulmonary veins (not shown), for instance through attachment of the cannula to the excised left atrium <NUM> of the heart. Cannulae <NUM> and <NUM> of the lung-specific perfusion module <NUM> act as an interface between the lung <NUM> and the fluid subsystem <NUM> of the base unit <NUM>. Cannula <NUM> connects the pulmonary artery <NUM> with the free end of a conduit <NUM>. Cannula <NUM> connects the left atrium <NUM> of the heart with the free end of a conduit <NUM>.

In <FIG>, <FIG>, and <FIG>, the conduits <NUM>, <NUM>, <NUM>, and <NUM> are closed as indicated by the "X" markings, such as by valves or clamps. Alternatively, these conduits and the components on these conduits between the cross-marks (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) may be detached from a base unit or omitted on a base unit.

When a lung is attached in this manner to the fluid subsystem <NUM>, centrifugal pump <NUM> can apply pressure to the fluid in conduit <NUM> and thereby drive flow into the pulmonary artery <NUM>. The perfusate entering the pulmonary artery <NUM> may have been conditioned by passage through one or more of a heat exchanger <NUM>, so as to warm the perfusate to between <NUM> and <NUM>, and a gas exchanger <NUM>, so as to deoxygenate the perfusate. As would be apparent to persons skilled in the art, with sufficient pressure, perfusate will flow from the pulmonary artery <NUM> into the capillary beds <NUM> of the lung, and from there flow into one or more of the pulmonary veins <NUM> which drain into the left atrium <NUM> of the heart. Centrifugal pump <NUM> can elevate pressure in the left atrium to a physiologic level by pumping against the flow out of the left atrium <NUM>. When centrifugal pumps <NUM> and <NUM> are at particular settings, flow proceeds from the excised left atrium <NUM>, into a conduit <NUM>, and from there is returned to the reservoir <NUM> by passage through the centrifugal pump <NUM> in a direction that is against the direction of pumping in the centrifugal pump <NUM> (see arrows in <FIG> depicting direction of flow of perfusate in conduits nearest to and parallel to each arrow). Such an arrangement can conveniently eliminate the siphon effect in embodiments where a reservoir (source) of the perfusate is located below the lung, as can be understood by those skilled in the art.

Although not depicted in <FIG>, base unit <NUM> coupled with a lung-specific perfusion module <NUM> is compatible with additional lung-specific control devices being used to monitor or control the activity of the lung <NUM>. For instance, the trachea of the lung can be attached to a ventilator or other means can be employed to move air in and out of the lungs.

The controller <NUM> may have lung-specific parameter settings, inputted into it by either software or by a user, that are to be achieved or maintained by adjusting the speed of the centrifugal pumps <NUM> and <NUM>, or settings on lung-specific devices being used to monitor or control the activity of the lung.

Feedback control in a specific embodiment of the base unit <NUM> coupled with a lung-specific perfusion module <NUM> is illustrated in <FIG>. The PID controller <NUM> receives a measurement for pulmonary artery pressure from a pressure sensor <NUM> and calculates an error value relative to a setpoint A. The PID controller <NUM> also receives a measurement for pulmonary artery flow from a flow sensor <NUM> and calculates an error value relative to a setpoint B. The two error values are translated into a single error value through a suitable mathematical operation, and an adjustment of the speed of a centrifugal pump <NUM> is calculated. The PID controller <NUM> receives a measurement for pulmonary venous pressure from a pressure sensor <NUM>, calculates an error value relative to setpoint C, and then calculates an adjustment of the speed of a centrifugal pump <NUM>. No flow input is received by the PID controller <NUM>. The PID controller <NUM> receives no inputs and generates no outputs. Table <NUM> provides typical values, as well as a typical range of values, for the setpoint inputs A, B, C, D, E, and F with respect to a lung-specific perfusion module.

<FIG> illustrates a specific embodiment of an apparatus <NUM> in which a base unit <NUM> is attached to a liver-specific perfusion module <NUM> bearing a liver <NUM>. The liver may be a whole liver or a portion of a liver, such as a liver lobe.

Prior to connection of the liver <NUM> to the fluid subsystem <NUM>, the fluid subsystem <NUM> is primed with a perfusate and one end of a cannula is connected to each of the hepatic artery <NUM> and the portal vein <NUM>. Cannulae <NUM> and <NUM> of the liver-specific perfusion module <NUM> act as an interface between the liver <NUM> and the fluid subsystem <NUM> of the base unit <NUM>. Cannula <NUM> connects the hepatic artery <NUM> with the free end of a conduit <NUM>. Cannula <NUM> connects the portal vein <NUM> with the free end of a conduit <NUM>.

The first section of the fluid subsystem <NUM> can direct fluid pressure and flow of conditioned perfusate from the centrifugal pump <NUM> into the hepatic artery <NUM>. The second section of the fluid subsystem <NUM> can direct fluid pressure and flow of the perfusate from centrifugal pump <NUM> into the portal vein <NUM>. The pressure applied to and the flow rate into the hepatic artery <NUM> and the portal vein <NUM> can be different. As would be apparent to the skilled person, if sufficient pressures are applied, perfusate will flow through the hepatic artery and portal vein respectively and into the capillary beds <NUM> that provide oxygen and nutrients to the liver. Perfusate can then carry carbon dioxide and wastes from the capillary beds <NUM> into the hepatic veins <NUM>. Perfusate emerging from the hepatic veins into the liver-specific perfusion module <NUM> can be returned to the reservoir <NUM> through drainage conduit <NUM>.

Although not depicted in <FIG>, the base unit <NUM> attached to a liver-specific perfusion module <NUM> is compatible with organ-specific control devices that can be used to control or monitor the activity of the liver. For instance, bile output can be measured and collected with a bile collector.

The controller <NUM> may have liver-specific parameter settings, inputted into it by either software or by a user, that are to be achieved or maintained by adjusting the speed of the centrifugal pumps <NUM> and <NUM>, or settings on liver-specific devices being used to monitor or control the activity of the liver.

Feedback control in a specific embodiment of the base unit <NUM> coupled with a liver-specific perfusion module <NUM> is illustrated in <FIG>. The PID controller <NUM> receives a measurement for hepatic artery pressure from a pressure sensor <NUM> and calculates an error value relative to a setpoint A. The PID controller <NUM> also receives a measurement for hepatic artery flow from a flow sensor <NUM> and calculates an error value relative to a setpoint B. The two error values are translated into a single error value through a suitable mathematical operation, and an adjustment of the speed of a centrifugal pump <NUM> is calculated. The PID controller <NUM> receives a measurement for portal vein pressure from a pressure sensor <NUM>, and calculates an error value relative to setpoint C. The PID controller <NUM> also receives a measurement for portal vein flow from a flow sensor <NUM>, and calculates an error value relative to setpoint D. The two error values are translated into a single error value through a suitable mathematical operation, and an adjustment of the speed of a centrifugal pump <NUM> is calculated. The PID controller <NUM> receives no inputs and generates no outputs. Table <NUM> provides typical values, as well as a typical range of values, for the setpoint inputs A, B, C, D, E, and F with respect to a liver-specific perfusion module.

<FIG> illustrates a specific embodiment of an apparatus <NUM> in which a base unit <NUM> is attached to a kidney-specific perfusion module <NUM> bearing a kidney <NUM>. The kidney may refer to a single kidney or to both kidneys of a human, or of an animal such as a pig.

Prior to connection of the kidney <NUM> to the fluid subsystem <NUM>, the fluid subsystem <NUM> is primed with a perfusate and one end of a cannula is connected to each of the renal artery <NUM> and the renal vein <NUM>. Cannulae <NUM> and <NUM> of the kidney-specific perfusion module <NUM> act as an interface between the kidney <NUM> and the fluid subsystem <NUM> of the base unit <NUM>. Cannula <NUM> connects the renal artery <NUM> with the free end of a conduit <NUM>. Cannula <NUM> connects the renal vein <NUM> with the free end of a conduit <NUM>.

The first section of the fluid subsystem <NUM> can direct fluid pressure and flow of conditioned perfusate from centrifugal pump <NUM> into the renal artery <NUM>. As would be apparent to the skilled person, if sufficient pressure is directed into renal artery <NUM>, conditioned perfusate will flow into the capillary beds <NUM> that provide oxygen and nutrients to the cells of the kidney. Perfusate can then carry carbon dioxide and wastes from the capillary beds <NUM> into the renal vein <NUM>. Centrifugal pump <NUM> can elevate pressure in the renal vein <NUM> by pumping against the flow out of the renal vein <NUM>. When centrifugal pumps <NUM> and <NUM> are at particular settings, flow proceeds from the renal vein <NUM>, into a conduit <NUM>, and from there is returned to the reservoir <NUM> by passage through the centrifugal pump <NUM> in a direction that is opposite to that of the pumping by the centrifugal pump <NUM> (see arrows in <FIG> depicting direction of flow of perfusate in conduits nearest to and parallel to each arrow).

Although not depicted in <FIG>, the base unit <NUM> attached to a kidney-specific perfusion module <NUM> is compatible with organ-specific control devices that can be used to control or monitor the activity of the kidney. For instance, urine output can be measured and collected with a urine collector.

The controller <NUM> may have kidney-specific parameter settings, inputted into it by either software or by a user, that are to be achieved or maintained by adjusting the speed of the centrifugal pumps <NUM> and <NUM>, the extent of occlusion by the valve or clamp <NUM>, or settings on kidney-specific devices being used to monitor or control the activity of the kidney.

Feedback control in a specific embodiment of the base unit <NUM> coupled with a kidney-specific perfusion module <NUM> is illustrated in <FIG>. The PID controller <NUM> receives a measurement for renal artery pressure from a pressure sensor <NUM> and calculates an error value relative to a setpoint A. The PID controller <NUM> also receives a measurement for renal artery flow from a flow sensor <NUM> and calculates an error value relative to a setpoint B. The two error values are translated into a single error value through a suitable mathematical operation, and an adjustment of the speed of a centrifugal pump <NUM> is calculated. The PID controller <NUM> receives a measurement for renal vein pressure from a pressure sensor <NUM>, calculates an error value relative to setpoint C, and then calculates an adjustment to the speed of a centrifugal pump <NUM>. The PID controller <NUM> receives no flow input. The PID controller <NUM> receives no inputs and generates no outputs. Table <NUM> provides typical values, as well as a typical range of values, for the setpoint inputs A, B, C, D, E, and F with respect to a kidney-specific perfusion module.

As indicated in <FIG>, many components of fluid subsystem <NUM> can communicate with controller <NUM>, by wire or through wireless connection. The embodiments of the controller <NUM> depicted in <FIG>, <FIG>, <FIG>, and <FIG> are examples of how sensors in the fluid system <NUM> can be used to control other components in the fluid subsystem <NUM>. It will be apparent to persons of skill that other components inside or outside the fluid subsystem <NUM> can similarly be subject to feedback control by a controller <NUM>, at least in part, by information collected from sensors in the fluid subsystem <NUM>, the perfusate source <NUM>, the conditioning subsystem <NUM>, and/or the organ-specific perfusion module <NUM>. As a further example of such feedback control, the temperature of the perfusate in the perfusate source <NUM> may be controlled by measuring the temperature of an organ in an organ-specific perfusion module <NUM> and adjusting the current through an electrical heater (not shown) submerged in perfusate in the perfusate source <NUM>.

<FIG> is a high-level block diagram of a computing device <NUM>, which is an example of controller <NUM>. Computing device <NUM> may include or be part of a portable computing device (e.g., a mobile phone, netbook, laptop, personal data assistant (PDA), or tablet device) or a stationary computer (e.g., a desktop computer, or set-top box). As will become apparent, the computing device <NUM> includes software that allows a user to control and monitor an organ perfusion apparatus, such as apparatus <NUM>.

As illustrated, computing device <NUM> includes one or more processors <NUM>, memory <NUM>, a network interface <NUM> and one or more I/O interfaces <NUM> in communication over a bus <NUM>.

One or more processors <NUM> may be one or more Intel x86, Intel x64, AMD x86-<NUM>, PowerPC, ARM processors or the like.

Memory <NUM> may include random-access memory, read-only memory, or persistent storage such as a hard disk, a solid-state drive or the like. Read-only memory or persistent storage is a computer-readable medium. A computer-readable medium may be organized using a file system, controlled and administered by an operating system governing overall operation of the computing device.

Network interface <NUM> serves as a communication device to interconnect the computing device <NUM> with one or more computer networks such as, for example, a local area network (LAN) or the Internet. Network interface <NUM> may be configured to enable computing device <NUM> to communicate with external devices via one or more networks. Network interface <NUM> may be a network interface card, such as an Ethernet card, an optical transceiver, a radio frequency transceiver, or any other type of device that can send and receive information.

One or more I/O interfaces <NUM> may serve to interconnect the computing device <NUM> with peripheral devices, such as for example, keyboards, mice, video displays, and the like (not shown). Optionally, network interface <NUM> may be accessed via the one or more I/O interfaces <NUM>.

One or more I/O interfaces <NUM> may serve to collect information from and control components of the apparatus of the invention, as exemplified by apparatus <NUM>. For instance, an I/O interface <NUM> may communicate by wire or wirelessly with centrifugal pumps, pressure sensors, flow sensors, heat exchangers, and gas exchangers.

I/O interfaces <NUM> may be configured to receive input from a user. Input from a user may be generated as part of a user running one or more software applications.

Software comprising instructions is executed by one or more processors <NUM> from a computer-readable medium. For example, software may be loaded into random-access memory from persistent storage of memory <NUM> or from one or more devices via I/O interfaces <NUM> for execution by one or more processors <NUM>. As another example, software may be loaded and executed by one or more processors <NUM> directly from read-only memory.

Memory <NUM> stores an operating system <NUM>, applications <NUM>, and a perfusion application <NUM>. Operating system <NUM> may be configured facilitate the interaction of applications, such as an application <NUM> and a perfusion application <NUM>, with processor(s) <NUM>, memory <NUM>, I/O interfaces <NUM>, and network interface <NUM> of computing device <NUM>.

Operating system <NUM> may be an operating system designed to be installed on laptops and desktops. For example, operating system <NUM> may be a Windows operating system, Linux, or Mac OS. In another example, if computing device <NUM> is a mobile device, such as a smartphone or a tablet, operating system <NUM> may be one of Android, iOS or a Windows mobile operating system.

Applications <NUM> may be any applications implemented within or executed by computing device <NUM> and may be implemented or contained within, operable by, executed by, and/or be operatively/communicatively coupled to components of computing device <NUM>. Applications <NUM> may include instructions that may cause processor(s) <NUM> of computing device <NUM> to perform particular functions. Applications <NUM> may include algorithms which are expressed in computer programming statements, such as, for loops, while-loops, if-statements, do-loops, etc. Applications may be developed using a programming language. Examples of programming languages include Hypertext Markup Language (HTML), Dynamic HTML, Extensible Markup Language (XML), Extensible Stylesheet Language (XSL), Document Style Semantics and Specification Language (DSSSL), Cascading Style Sheets (CSS), Synchronized Multimedia Integration Language (SMIL), Wireless Markup Language (WML), JavaTM, JiniTM, C, C++, Perl, Python, UNIX Shell, Visual Basic or Visual Basic Script, Virtual Reality Markup Language (VRML), ColdFusionTM and other compilers, assemblers, and interpreters.

Perfusion application <NUM> is an example of an application configured to perfuse an organ according to the techniques described herein. As described above, base unit <NUM> may include graphical user interfaces that enable a user to monitor and/or control one or more perfusion parameters (e.g., flow). Perfusion application <NUM> may be configured to enable a user to monitor and/or control perfusion parameters using one or more graphical user interfaces. Perfusion application <NUM> may include different organ-specific components. That is, perfusion application <NUM> may be configured to enable a user to monitor and/or control perfusion parameters for specific organs/configurations of apparatus <NUM>.

It should be noted that although example computing device <NUM> is illustrated as having distinct functional blocks, such an illustration is for descriptive purposes and does not limit computing device <NUM> to a particular hardware architecture. Functions of computing device <NUM> may be realized using any combination of hardware, firmware and/or software implementations.

<FIG> is a flow chart of an algorithm <NUM> that can be executed by one or more processors <NUM> to monitor and control an apparatus of the disclosure, such as apparatus <NUM>.

The software is initiated by a signal provided by a user or automated process at block <NUM>. At block <NUM>, one or more processors <NUM> receive initial settings to configure the apparatus for the intended application, including the type of organ to be perfused, monitored, and/or controlled.

At block <NUM>, one or more processors <NUM> communicates with one or more I/O interfaces <NUM> to prime the fluid subsystem <NUM> with fluid, such as a saline or a perfusate, prior to attachment of the organ.

At block <NUM>, one or more processors <NUM> communicates with one or more I/O interfaces <NUM> to control the fluid subsystem <NUM> so as to initiate perfusion of an organ once attached.

At block <NUM>, one or more processors <NUM> communicates with one or more I/O interfaces <NUM> to receive information from sensors (e.g., of flow, pressure, temperature, oxygen, and carbon dioxide) in the fluid subsystem <NUM> or other parts of the apparatus. Some or all of this information from the sensors is displayed at block <NUM>, and the display may be continually or periodically updated with information received from the sensors. The software then determines at block <NUM> whether adjustments are required. If so, at block <NUM> adjustments are made to components of the fluid subsystem <NUM> (e.g., to change centrifugal pump speed), either according to predetermined settings or through live interfacing with a user. The steps at block <NUM> and block <NUM> may include PID calculations, similar to those described above with respect to <FIG>, <FIG>, <FIG>, and <FIG>.

At block <NUM>, the status of the integrated perfusion device is communicated to the user by updating the display, and at block <NUM> the software checks for user input (e.g. to change setpoints for feedback control). At block <NUM>, it is determined whether perfusion is done, either according to predetermined settings or through live interfacing with a user. If perfusion is not done, the software returns to block <NUM> to again sample sensors. If perfusion is done, at block <NUM>, it is determined whether the operation settings should be reconfigured, such as by loading a new configuration file. Reconfiguration may be required when a new organ-specific perfusion module is to be used, or when a different mode of operation is desired. If the settings are to be reconfigured, the software returns to block <NUM> to receive new initial settings. If the settings are not to be reconfigured, perfusion is stopped at block <NUM>.

Another aspect of software <NUM> may be the recording of information from sensors in the apparatus and adjustments <NUM> made by the software. This information may be stored in memory <NUM>.

As now can be appreciated, an example apparatus for perfusion of organs may include a plurality of organ-specific perfusion modules each comprising a perfusion chamber for perfusing a respective specific organ and a set of fluid conduits configured for connecting the specific organ to a source of a perfusate. The apparatus may also include a base unit, which includes a receptacle for removably mounting a selected organ-specific module onto the base unit, conduits connecting the source of the perfusate to the fluid conduits of each organ-specific perfusion module, to allow circulation of the perfusate through the respective specific organ. The base unit also includes first and second pumps coupled to the conduits for regulating circulation of the perfusate through the specific organ, a heat exchanger for controlling a temperature of the perfusate, a gas exchanger for oxygenating or deoxygenating the perfusate, and a controller for controlling the pumps and the heat exchanger to regulate circulation of the perfusate through the specific organ and to regulate a property or condition of the perfusate. The controller is configurable to regulate circulation of the perfusate based on a specific set of control settings associated with each one of the organ-specific modules.

It should also be understood that in some embodiments, in a method of perfusing a lung, a perfusate can be circulated through the lung by supplying the perfusate into the lung through a pulmonary artery and withdrawing the perfusate from the lung through a pulmonary vein. A first pressure is applied in the pulmonary artery to drive flow of the perfusate through the lung. A second pressure is applied in the pulmonary vein to resist the flow of the perfusate through the lung. The second pressure may be regulated to maintain the second pressure substantially constant.

In different embodiments, an apparatus for perfusion of multiple types of organs may include a base unit configured to removably couple with a perfusion module for perfusing an organ. The base unit includes conduits for connecting a source of a perfusate to the organ to circulate the perfusate through the organ. First and second pumps are coupled to the conduits for driving circulation of the perfusate in the conduits. A controller is configured and connected for controlling the first and second pumps to regulate the circulation of the perfusate through the organ. The controller is operable to control the first and second pumps to perfuse the organ in accordance with organ specific perfusion parameters, and wherein the organ specific perfusions parameters are selected based on the type of the organ and may be selected by an operator for at least two organ types selected from the group of heart, liver, kidney and lung.

In yet another embodiment, an apparatus for perfusing lungs may be provided. The apparatus may include conduits for connecting a source of a perfusate to a lung to circulate the perfusate through the lung. The conduits include a first conduit connectable to supply the perfusate into the lung through a pulmonary artery of the lung and a second conduit connectable to return perfusate egressed from the lung to the source through a pulmonary vein of the lung. A first pump is coupled to the first conduit for driving flow of the perfusate into the lung. A second pump is coupled to the second conduit for resisting flow of the perfusate out of the lung. A controller is provided for controlling the first and second pumps to regulate circulation of the perfusate through the lung. The apparatus may include a ventilator for ventilating the lung. Sensors may be provided to monitor the circulation parameters and conditions of the lung, as can be understood by those skilled in the art in view of this disclosure.

The following examples further illustrate embodiments of the present disclosure, or demonstrate functionalities that could be achieved with various configurations or combinations described herein.

An apparatus <NUM> was assembled and configured as depicted in <FIG> and <FIG> for testing perfusion of a heart. Only some of the relevant components of apparatus <NUM> are shown in <FIG> and <FIG>. The conduits in a base unit <NUM> were primed with saline prior to attachment of the conduits to a heart-specific perfusion module 212A.

Standard procurement methods were used to obtain a pig heart <NUM>. Long sections of aorta, pulmonary artery and superior vena cava were excised with the heart to ensure adequate space for cannulation with the ex vivo perfusion system. After excision, a XVIVO™ flexible cone cannula <NUM> was sewn to the left atrium <NUM> and a <NUM>/<NUM> inch polycarbonate tubing connector <NUM> was inserted into the ascending aorta <NUM>. Cannulae with <NUM>/<NUM> inch connectors <NUM> and <NUM> were secured to the superior and inferior vena cava <NUM> and the pulmonary artery <NUM>, respectively.

The excised pig heart <NUM>, with attached cannulae, was mounted onto a removable support that formed part of heart-specific module 212A. The heart <NUM> was suspended within a polycarbonate reservoir. Securing clamps attached to the mast of the rig stabilized all lines, leaving the heart unrestricted on all sides. The saline prime was displaced with swine blood to leave a blood prime with a hematocrit of <NUM>-<NUM>%. Sodium bicarbonate and glucose were added to bring the prime within normal physiological blood ranges. The heart was de-aired by atrial filling and an air-free connection was made to the circuit. Heart-specific module 212A included a reservoir <NUM> for the perfusate.

This heart-specific perfusion module 212A was attached to a base unit <NUM> to form the apparatus <NUM>, as depicted in <FIG>. The tubing connector <NUM> connects the aorta <NUM> to the free end of a conduit <NUM>. The cannula <NUM> connects the pulmonary artery <NUM> to the free end of a conduit <NUM>. The cannula <NUM> connects the right atrium <NUM> to the free end of a conduit <NUM>. The cannula <NUM> connects the left atrium <NUM> to the free end of a conduit <NUM>. Conduit <NUM> was <NUM>/<NUM> inch tubing; conduit <NUM> was <NUM>/<NUM> inch tubing; all other conduits were <NUM>/<NUM> inch tubing.

As depicted in <FIG>, the heart <NUM> was also attached to a dual chamber pacemaker <NUM>, a defibrillator <NUM>, and an ECG monitor <NUM>. The pacemaker <NUM>, the defibrillator <NUM>, and the ECG monitor <NUM> were connected to the controller <NUM>. Heart-specific parameters were entered into the software <NUM> that operated the controller <NUM>.

As depicted in <FIG>, perfusion in resting mode was commenced at <NUM>-<NUM> milliliters per minute (mL/min) with a pressure of <NUM>-<NUM> mmHg from the centrifugal pump <NUM> to achieve coronary blood flow. The venous blood from the coronary sinus was collected from the pulmonary artery <NUM> and flowed through the conduit <NUM> to a soft shell reservoir <NUM>, so that the perfusate could not siphon back to the reservoir. Perfusate in the soft shell reservoir <NUM> flowed to the reservoir <NUM> through the conduit <NUM>.

After <NUM> of stable resting mode perfusion, biventricular preload was instituted gradually to obtain a heart in working mode. The centrifugal pump <NUM> was turned on and the occlusion clamp <NUM> was released, increasing preload on the right and left atrium. As the heart started to eject against the retrograde flow into the aorta from the conduit <NUM>, the speed of the centrifugal pump <NUM> was adjusted to provide afterload to the ejecting left ventricle and maintain aortic diastolic pressure.

When flow probes indicated that the heart was ejecting, a Ventri-Cath multi-segment <NUM>-electrode combined pressure/volume catheter (Millar Instruments Inc. , Houston, Tex. , USA) was inserted along the longitudinal axis of the left ventricle with the proximal electrode at the level of the aortic valve (not shown). In similar fashion, another catheter was inserted into the right ventricle via the pulmonary artery (not shown). Data was collected at a sampling rate of <NUM> with Lab chart <NUM> (AD Instruments, Bella Vista, NSW, Australia) using a Powerlab AD module (not shown).

With the apparatus <NUM>, standard cardiac functional parameters were evaluated through the continuous measurement of left and right ventricular output, stroke volume, and stroke work. With the addition of ventricular pressure catheters, maximal and minimal rate of pressure change over time (dP/dT max and min) and the ventricular relaxation constant (Tau) were evaluated as well. Through the addition of flow probes on the aortic and pulmonary artery cannulas, the change in volume over time (dV/dT max and min) were evaluated. Measurements were obtained using catheters and fluid filled catheters or flow probes that were integrated into the test system.

As disclosed in <FIG> in <CIT>, the attribute of a centrifugal pump providing afterload to the ejecting left ventricle may be demonstrated by increasing pump speed (rpm) resulting in an increase in aortic root pressure with a compensatory rise in left atrial pressure as the heart attempts to accommodate the increased afterload.

Using apparatus <NUM>, which includes a heart-specific module with a pig heart, as depicted in <FIG>, standard cardiac functional parameters were evaluated through the continuous measurement of left and right ventricular output, stroke volume, and stroke work. With the addition of ventricular pressure catheters (not shown), maximal and minimal rate of pressure change over time (dP/dT max and min) and the ventricular relaxation constant (Tau) were evaluated as well. Through the addition of flow probes on the aortic and pulmonary artery cannulas, the change in volume over time (dV/dT max and min) was evaluated. The preload recruitable stroke was estimated through a gradual reduction in the preload pump speed (rpm), while continuously recording stroke work and atrial pressure, as illustrated in the graph of <FIG>.

The circuit was effective during resting and working modes whilst proving to be successful in maintaining cardiac function in excess of five hours.

An apparatus <NUM> was assembled and configured as depicted in <FIG> for testing perfusion of a lung.

The lungs <NUM> of a pig were harvested, mounted in a lung-specific perfusion module <NUM>, and attached to a base unit <NUM> (but only some relevant components thereof are shown in <FIG>) to form the apparatus <NUM>. Lung-specific parameters were entered into the software <NUM> that operated the controller <NUM>.

The trachea of the excised pig lungs <NUM> was connected to a ventilator <NUM>, namely an Evita XL available from Dräger. Ventilator parameters that were measured included peak/plateau pressures and positive end-expiratory pressure ("PEEP"), inspired and expired tidal volume, minute ventilation, airway compliance and resistance.

The dual pump configuration illustrated in <FIG> created a basic resistance to flow against the excised left atrium <NUM> of the heart, providing a constant left arterial pressure ("LAP") compared to typical manually-adjusted systems. Automation of LAP allowed for less inter-/intra-operator variability. In one experiment, the apparatus <NUM> was able to maintain user-specified pulmonary artery (mean ± standard error of the mean: <NUM>±<NUM> mmHg) and left arterial (<NUM>±<NUM> mmHg) pressures constantly during ex vivo lung perfusion for up to <NUM> hours with minimal adjustment required on the part of the user. In another experiment, the apparatus <NUM> was able to detect and respond to changes in pulmonary vascular resistance ("PVR") over time (<NUM>±<NUM> dynes•s•cm-<NUM>).

As illustrated in <FIG>, the apparatus <NUM> provided a closed circuit system with tight regulation of pulmonary artery pressure ("PAP") and flow, in addition to left atrial pressure ("LAP") control. A centrifugal pump <NUM> ("PAP pump") provided flow through a heat exchanger <NUM> and a gas exchanger <NUM> which served to deoxygenate the perfusate and add carbon dioxide. Conditioned perfusate flowed through a conduit <NUM> into the pulmonary artery <NUM>, with either constant pressure or constant flow, depending on user preference. Flow egressed from the excised left atrium <NUM> of the heart and into a conduit <NUM>. A centrifugal pump <NUM> ("LAP pump") provided a constant, physiological back pressure to the left atrium <NUM>. In one example, through a graphical user interface (not shown) for a controller <NUM>, the user could specify the desired perfusion parameters including pump speed, flow and pressure.

The graph in <FIG> illustrates feedback control of pump speed, flow and pressure. The reported parameters are left atrial pressure (mmHg), pulmonary artery pressure (mmHg), pulmonary artery flow in litres per minutes (LPM), centrifugal pump <NUM> speed ("LAP pump rpm"), and centrifugal pump <NUM> speed ("PAP pump rpm").

At point "A" in <FIG>, PAP was set to <NUM> mmHg and LAP was set to <NUM> mmHg. Pressure was maintained while pump speed in rotations per minutes ("rpm") varied. At point "B" in <FIG>, PAP was increased to <NUM> mmHg. The PAP pump <NUM> consequently increased speed, and therefore flow, until the desired PAP was achieved. With the increased flow, less speed was required to maintain LAP and thus the LAP pump <NUM> speed decreased to maintain the set LAP of <NUM> mmHg. At point "C" in <FIG>, PAP was lowered to <NUM> mmHg, and LAP was maintained at <NUM> mmHg. With the decrease in flow, the LAP pump <NUM> increased speed to maintain a constant <NUM> mmHg LAP. At point "D" in <FIG>, the lungs <NUM> were ventilated with air lacking oxygen to induce hypoxic pulmonary vasoconstriction. As vascular resistance increased, if pump speed were to remain constant, pressure would increase. The apparatus <NUM> reacted to the increased resistance by decreasing the speed of the PAP pump <NUM> and therefore flow, to maintain the desired pressure of <NUM> mmHg. Similarly, the LAP pump <NUM> speed varied to maintain the desired pressure of <NUM> mmHg. At point "E" in <FIG>, PAP was set to <NUM> mmHg, and the LAP pump <NUM> was set to a constant <NUM> rpm. As can be clearly seen in <FIG>, after point "E", without the feedback loop being active, LAP is sporadic and uncontrolled.

An apparatus <NUM> was assembled and configured as depicted in <FIG>, for testing perfusion of a liver.

A liver <NUM> was procured from a pig, mounted in a liver-specific perfusion module 412A, and attached to a base unit <NUM> (but only some relevant components thereof are shown in <FIG>) to form the apparatus <NUM>. The perfusion module 412A included a reservoir <NUM> for the perfusate. The liver was also attached to a bile collector <NUM>. The liver was perfused with a whole blood-based perfusate solution by pumping through centrifugal pump <NUM> ("arterial pump") into a conduit <NUM>, which was connected to the hepatic artery <NUM>, and by pumping through centrifugal pump <NUM> ("portal venous pump") into a conduit <NUM>, which was connected to the portal vein <NUM>.

The graph in <FIG> demonstrates certain parameters over the perfusion interval for the apparatus <NUM> depicted in <FIG>. Recorded parameters were the hepatic artery pressure (mmHg), the hepatic artery flow (mL/min), the centrifugal pump <NUM> speed in rpms ("HAP pump rpm"), the portal vein pressure (mmHg), the portal vein flow (mL/min), and the centrifugal pump <NUM> speed in rpms ("PVP pump rpm").

The hepatic artery pressure was set at <NUM> Hg and the pressure remained constant throughout the perfusion interval, with pump speed (in rpms) and therefore flow varying as the hepatic arterial resistance changed over time. The portal venous pressure was initially set to <NUM> Hg, and then lowered to <NUM> Hg at point "A" in <FIG>. The graph <FIG> demonstrates that pressure was held constant while pump speed and therefore flow changed to maintain the desired pressure.

An apparatus <NUM> was assembled as depicted in <FIG> for testing perfusion of kidney.

A kidney <NUM> was procured from a pig, mounted in a kidney-specific module 512A, and attached to an embodiment of base unit <NUM> (but only some relevant components thereof are shown in <FIG>) to form the apparatus <NUM>. The kidney was also attached to a waste collector <NUM>. The kidney was perfused by pumping through the centrifugal pump <NUM> into a conduit <NUM>, which was connected to the renal artery <NUM>. The graph in <FIG> demonstrates certain perfusion parameters over the perfusion interval, including renal artery pressure ("RAP"), renal artery flow (mL/min), and pump <NUM> speed in rpms ("RAP pump rpm").

Selected Embodiments of the present invention may be used in a variety of fields and applications. For example, they may have applications in transplantation surgery and research.

It will be understood that any range of values herein is intended to specifically include any intermediate value or sub-range within the given range, and all such intermediate values and sub-ranges are individually and specifically disclosed.

The word "include" or its variations such as "includes" or "including" will be understood to imply the inclusion of a stated integer or groups of integers but not the exclusion of any other integer or group of integers.

It will also be understood that the word "a" or "an" is intended to mean "one or more" or "at least one", and any singular form is intended to include plurals herein.

It will be further understood that the term "comprise", including any variation thereof, is intended to be open-ended and means "include, but not limited to," unless otherwise specifically indicated to the contrary.

Claim 1:
An apparatus (<NUM>) for perfusion of organs, comprising:
a base unit (<NUM>; <NUM>) configured to removably couple with any one of a plurality of organ-specific modules for perfusing an organ, said base unit comprising
conduits (<NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>,<NUM>, <NUM>, <NUM>, <NUM>) for connecting a source of a perfusate (<NUM>) to the organ to circulate the perfusate through the organ;
first and second pumps (<NUM>, <NUM>) coupled to said conduits for driving circulation of the perfusate in said conduits; and
a controller (<NUM>) configured and connected for controlling said first and second pumps to regulate the circulation of the perfusate through the organ;
wherein the apparatus comprises a first module (<NUM>) of the plurality of organ-specific modules, the first module (<NUM>) being configured for perfusing a lung (<NUM>), wherein the conduits and the controller are configured to connect and control the first pump (<NUM>) to apply a first pressure at a pulmonary artery of the lung to drive flow of the perfusate through the lung and to connect and control the second pump (<NUM>) to apply a second pressure at a left atrium attached to the lung to resist the flow of the perfusate.