Patent Description:
It is an objective of organ perfusion apparatuses to mimic the conditions of the human body such that the organ remains viable before being used for research, diagnosis, treatment, or transplantation. Often the organ must be stored and/or transported between facilities. A goal of sustaining and restoring organs during perfusion is to reduce ischemia and reperfusion injury. The increase in storage periods in a normal or near normal functioning state also provides certain advantages. For example, organs can be transported greater distances and there is increased time for testing, treatment, and evaluation of the organs.

Various organ perfusion apparatuses are known. <CIT>; <CIT>; and <CIT> disclose, for example, a perfusion apparatus that employs a disposable perfusion circuit within which the organ may be stored during perfusion. This circuit comprises a basin that may serve as a receptacle for an organ cradle on which the organ may be placed and for a perfusate bath that may be formed around the organ. Inner and outer lids may be used to close the basin during perfusion, and the basin may fit within a coolant container so that both the perfusate bath and the organ are brought to hypothermic temperatures.

<CIT> relates to an apparatus for perfusing an organ or tissue comprising a perfusion circuit for perfusing the organ or tissue with liquid perfusate; and an oxygenation system for oxygenating perfusate that recirculates through the perfusion circuit. The oxygenation system includes an oxygen circuit for delivering oxygen to the liquid perfusate and an air circuit for delivering ambient air to the liquid perfusate.

<CIT>, on which the preamble of claim <NUM> is based, relates to a tissue or organ preservation system for circulating perfusate in contact with a tissue or organ, comprising an organ chamber for containing an organ or tissue; a perfusate reservoir at the base of the organ chamber for collecting perfusate exiting an organ or flowing past tissue, said perfusate reservoir in communication with a perfusion circuit; and an oxygenator mechanism disposed within the perfusate reservoir.

<CIT> relates to an in-vitro animal organ perfusion device which comprises a liquid storage component, a temperature control component, an oxygenation component and a perfusion component, wherein the liquid storage component is used for storing a perfusion solution.

Although the use of hypothermic temperatures during transportation and perfusion greatly improves organ preservation by decreasing oxygen demands and metabolic activity of the organ, it does not completely eliminate them. A corresponding lack of oxygen can drive the cells of the organ to anaerobic activity, which causes a buildup of lactate and mitochondrial uncoupling and depleted adenosine triphosphate ("ATP") stores, and thereby leads to the release of toxic molecules such as radical oxygen species, inflammatory cytokines, and lactate. These toxic molecules and mitochondrial activity increase the production of reactive oxygen molecules, which may in turn lead to adverse ischemia and reperfusion injury.

Given that a lack of oxygen drives the cells to anaerobic activity and worsens ischemia and reperfusion injury, there has been great interest in the benefits associated with increasing oxygen to a hypothermic perfused organ by, say, introducing additional oxygen into the perfusate solution. <CIT> discloses an oxygen generator or concentrator that preferably produces oxygen in real time to provide oxygenation to the perfusate, for example.

However, there are at least two difficulties associated with prior oxygenation devices and methods. The first is the amount of time required to adequately oxygenate the perfusate solution. Time during organ transplantation is at a premium, so an oxygenator device should be able to rapidly oxygenate the perfusate solution. Further, hospitals and clinics may have also acquired or purchased a substantial amount of disposables to be used during perfusion, and may be hesitant to discard these likely expensive disposables to oxygenate the perfusate solution. There is thus also a need for an oxygenator device that works with existing equipment and disposables to oxygenate the perfusate solution.

Thus disclosed herein is an oxygenator device for oxygenating a perfusate solution to be perfused through an organ or tissue. This device comprises an inlet configured to receive oxygen from an oxygen supply, and it also comprises tubing connected to the inlet, the tubing including a plurality of holes by which the received oxygen may exit the tubing.

In combination with the above features, the oxygenator device also comprises a top portion from which the inlet extends, and it further includes a plurality of holders extending below the top portion so as to secure the tubing below the top portion.

Each of the plurality of holders includes (i) a vertical portion extending substantially perpendicular to the top portion and (ii) an angled portion extending at an outward angle relative to the vertical portion. The tubing is secured by the angled portions of the plurality of holders.

In combination with any of the above or below features, the plurality of holders may secure the tubing in a loop having a circumference sufficient to encircle the organ or tissue in use, and a majority of this loop may be substantially parallel to a virtual plane formed by the top portion.

In combination with any of the above or below features, the oxygenator device may be configured to be attached to an organ perfusion circuit, and a top portion of the oxygenator device, from which the inlet extends, may constitute a lid for a basin of the organ perfusion circuit that is configured to hold the organ or tissue during perfusion.

In combination with any of the above or below features, the tubing may be fixed below the top portion so that, when the oxygenator device is placed on the basin, the tubing and the plurality of holes therein may be submerged in a bath of the perfusate solution in the basin.

In combination with any of the above or below features, the tubing may be secured in position by a plurality of holders so that, when the oxygenator device is placed on the basin, the tubing does not interfere with an organ cradle locatable within the basin.

In combination with any of the above or below features, the oxygenator device may further comprise a hydrophobic vent in the top portion, the vent being configured to limit pressure increase within the basin when the oxygenator device is placed on the basin and oxygen flows from the plurality of holes in the tubing to the perfusate solution.

In combination with any of the above or below features, the holes may be arranged in a plurality of groupings spaced apart along a length of the tubing.

In combination with any of the above or below features, each of the groupings may comprise a plurality of the holes spaced apart around a circumference of the tubing.

In combination with any of the above or below features, each pair of the plurality of groupings may be spaced apart by <NUM> of the tubing, and an average diameter of the plurality of holes may be between <NUM> and <NUM>.

Also disclosed herein is a method as defined in claim <NUM>.

The method may also include a step of administering the oxygen from the oxygen source at a rate of about <NUM> liters per minute for at least <NUM> minutes.

The method includes, prior to the placing step, removing a lid of the basin. The placing step thus replaces the lid of the basin with the oxygenator device.

The method may yet further include steps of discontinuing administration of the oxygen from the oxygen supply, and then placing the organ or tissue in the basin of the organ perfusion circuit.

And the oxygen may alternatively be administered while the organ or tissue is being perfused in the organ perfusion circuit.

These and other aspects of the present disclosure will be described with reference to the attached drawings and following detailed description.

<FIG> and <FIG> show an exemplary perfusion apparatus <NUM> for an organ. The organ may preferably be a liver, kidney, heart, lung, or intestine, but it may be any human or animal, natural or engineered, healthy, injured, or diseased organ or tissue. The apparatus <NUM> may include a basin <NUM> (see <FIG>) in which the organ may be placed. The basin <NUM> may hold a removable cradle <NUM>, which may preferably include a surface 60a on which the organ may be disposed when the organ is in the apparatus <NUM>. The basin <NUM> and/or the cradle <NUM> may preferably be configured to allow a perfusate bath of perfusate solution such as VASOSOL® to be contained around the organ.

The basin <NUM> may preferably be disposed within an insulating coolant container <NUM> that may contain cold materials such as ice, ice water, brine, or the like. Coolant container <NUM> may be permanently or removably attached to, or an integral, monolithic part of, apparatus <NUM>. Thus, in use, the organ may be disposed within the cradle <NUM>, which may be disposed within the basin <NUM>, which may be disposed within the coolant container <NUM>, as shown in <FIG>. The arrangement of the coolant container <NUM>, basin <NUM>, and cradle <NUM> preferably provides a configuration that provides cooling for the organ without the contents of coolant container <NUM> contacting the organ or the cradle <NUM>. Although the coolant container <NUM> is described herein as containing ice or ice water, any suitable cooling medium can be used.

As further shown in <FIG>, an inner lid <NUM> and an outer lid <NUM> may be provided on an upper surface of the basin <NUM>. The inner lid <NUM> may be sized to come into close proximity to the perimeter top surface of the cradle <NUM> to help maintain stability of the organ in the event of mechanical impact and shock during transport. More specifically, the inner lid <NUM> may have a downwardly protruding extension 66a that matches a circumferential shape of a peripheral ridge 60b of the cradle <NUM> and is configured to contact the peripheral ridge 60b and help hold the cradle <NUM> in position. The lids <NUM> and <NUM> may create a substantially fluid-tight seal with the basin <NUM>, and they can prevent contamination. The lids <NUM> and <NUM> may also provide for a redundant airtight seal should the seal from either lid <NUM> or <NUM> fail. Both the inner lid <NUM> and the outer lid <NUM> may preferably contain an air vent, e.g., a porous hydrophobic membrane, that allows for gas transfer in order to maintain pressure equilibrium.

Preferably, all components of the apparatus <NUM> that come into contact with perfusate solution and/or the organ are disposable and/or easily replaced. These components may include the basin <NUM>, the organ cradle <NUM>, and the lids <NUM> and <NUM>, which may constitute parts of a disposable organ perfusion circuit. In use, this disposable organ perfusion circuit may be placed within the non-disposable portion of the apparatus <NUM>, and the organ may be placed on the organ cradle <NUM> within the basin <NUM>. Because of the presence of the coolant container <NUM>, both the organ and the perfusate bath within the basin <NUM> are subjected to hypothermic temperatures. The perfusate solution may then be circulated through the disposable perfusion circuit and the organ.

<FIG> and <FIG> show an oxygenator device <NUM> in accordance with one or more aspects of the present disclosure. The device <NUM> may be designed to work with the perfusion apparatus <NUM> to increase the oxygen concentration of the perfusate bath within the basin <NUM>. This device <NUM> may generally be constituted by a main body <NUM> and oxygenation components <NUM>. The main body <NUM> may in turn include a top portion <NUM> including, as shown in <FIG>, radially inner and outer portions <NUM> and <NUM>. The main body <NUM> may also include, as shown in <FIG>, a bottom portion <NUM> projecting downward from the top portion <NUM>. The main body <NUM> may be formed, for example, from clear polycarbonate plastic resin.

The top portion <NUM> may be, like the inner lid <NUM>, sized to correspond to the basin <NUM>. More specifically, a lower lip <NUM> (see <FIG>) of the radially outer portion <NUM> of the top portion <NUM> may be sized so as to be received by an indentation <NUM> (see <FIG>) in an upper surface of the basin <NUM> and thereby allow the oxygenator device <NUM> to constitute a lid for that basin in place of the inner lid <NUM>. Latches (not shown) on the basin <NUM> may be used to lock the oxygenator device <NUM> in place relative to the basin <NUM>. As shown in <FIG> and <FIG>, the top portion <NUM> may be substantially planar. That is, although the surface of at least one of the radially inner and outer portions <NUM> and <NUM> may be slightly inclined, the overall shape of the top portion <NUM> forms a virtual plane projecting into the pages of <FIG> and <FIG>. For example, the outer portion <NUM> may be flat, whereas the inner portion <NUM> may be convex outward. Also provided within the top portion <NUM> may be a vent <NUM> (see <FIG> and <FIG>). Like the air vents of the lids <NUM> and <NUM>, the vent <NUM> may include a porous hydrophobic membrane, which allows for gas transfer in order to maintain pressure equilibrium. More specifically, the membrane of the vent <NUM> may be an acrylic copolymer treated to render it hydrophobic and oleophobic, and the membrane may be attached and bonded to a non-woven nylon substrate. The membrane itself may have an average porosity of <NUM> microns, and it may repel and be resistant to oil, water, and organic solvents and be non-wettable by most low-surface-tension liquids. This stands in contrast to, say, a hydrophilic membrane that has a tendency to mix with or be wettable by such liquids. Around the perimeter of the vent <NUM> may be provided an adhesive to secure the vent <NUM> to the remainder of the top portion <NUM> and thereby ensure that it remains attached thereto with a tight seal.

The bottom portion <NUM> may be formed in the space between the radially inner and outer portions <NUM> and <NUM> of the top portion <NUM>, and it may have a substantially triangular shape in cross-section. More specifically, a radially outer wall <NUM> (see <FIG>) of the bottom portion <NUM> may extend downward substantially perpendicular to the virtual plane of the top portion <NUM>, and a radially inner wall <NUM> of the bottom portion <NUM> may extend downward from the top portion <NUM> at an angle inclined relative to the outer wall <NUM>. The walls <NUM> and <NUM> may meet at a vertex <NUM>, thereby ensuring that the main body <NUM> is able to create a substantially fluid-tight seal with the basin <NUM> and thereby prevent contamination. Finally, the bottom portion <NUM> (and particularly the vertex <NUM>) may, like the downwardly protruding extension 66a of the inner lid <NUM>, also match the circumferential shape of the peripheral ridge 60b of the cradle <NUM>, and it may thus likewise be configured to contact that peripheral ridge and help hold the cradle <NUM> and any organ thereon in position.

The oxygenation components <NUM> may in turn include, as shown in <FIG>, an oxygen inlet <NUM>, a T-fitting <NUM>, holders <NUM>, and tubing <NUM>. The oxygen inlet <NUM> may be an oxygen barb projecting from a bridge portion <NUM> (see <FIG>) that connects the radially inner and outer portions <NUM> and <NUM> of the top portion <NUM>. The oxygen inlet <NUM> may be angled substantially perpendicular to the virtual plane of the top portion <NUM> to facilitate ease of use and to reduce the risk of kinking of the tube delivering oxygen to the inlet. The T-fitting <NUM> may in turn be fluidly connected to the oxygen inlet <NUM>, and it may be formed below the bridge portion <NUM> in a gap <NUM> formed in the bottom portion <NUM>.

The tubing <NUM> may be fluidly connected to the T-fitting <NUM>, and it may be secured in position by the plurality of holders <NUM>. As shown in <FIG>, each of these holders <NUM> may include an upper, vertical portion <NUM> secured to the bottom portion <NUM> of the main body <NUM> and projecting from the top portion <NUM> in a direction substantially perpendicular to the virtual vertical plane of the top portion <NUM>. The holders <NUM> may secure the tubing <NUM> below the bottom portion <NUM>, and each of the holders <NUM> may also include an angled portion <NUM> that is angled outward relative to the vertical portion <NUM>. The angled portion <NUM> may be angled relative to the vertical portion <NUM> by, say, <NUM> degrees, although other angles are possible. The angled portion <NUM> of each of the holders <NUM> may include a hole through which the tubing <NUM> may pass. As discussed below, angling the angled portions <NUM> relative to the vertical portions <NUM> may help ensure that neither the holders <NUM> nor the tubing <NUM> interferes in use with the organ cradle <NUM>, any organ or vasculature thereon, or cannula that may be disposed within the basin <NUM>. The rounded ends of the angled portions <NUM>, at which the holes are located, may also ensure that there is no crashing or interference with the basin <NUM> during use.

The tubing <NUM> may be formed of aromatic polyether-based polyurethane, and it may be of sufficient length to encircle the bottom portion <NUM> and thus to encircle a perfused organ when the oxygenator device <NUM> serves as the lid for the basin <NUM>. Preferably, the total length of the tubing <NUM> may be equal to or about <NUM>,<NUM>, although other lengths are possible. <FIG> shows an enlarged view of the portion IX of the tubing <NUM> shown in <FIG>. , and as shown in this Figure, the tubing <NUM> may include a plurality of groupings <NUM> of holes <NUM> that may be spaced apart along the length of the tubing <NUM> by a distance <NUM>. Preferably, the distance <NUM> may be equal to or about <NUM>, although other distances are possible. <NUM> groupings <NUM> may be formed in the tubing <NUM>, and as shown in <FIG>, which shows a cross-section of the tubing <NUM> at one of the groupings <NUM>, each grouping may include <NUM> holes <NUM> equally spaced around the circumference of the tubing <NUM>. The tubing <NUM> may thus include a total of <NUM> holes <NUM>. Each of the holes <NUM> may be formed in the tubing <NUM> by way of laser ablation. And each hole <NUM> may have a diameter of <NUM> to <NUM>, which has been shown to be well within the capability of the laser ablation process and repeatable. Instead of the tubing <NUM>, hollow fiber filters may be used to provide oxygen to the perfusate solution. Hollow fiber filters may prevent bubbling of the perfusate solution during the oxygenation process. But if the perfusate solution is not whole blood, this potential difference may be insufficient to justify the substantial increase in cost of hollow fiber filters relative to the tubing <NUM>.

The above-described arrangement of the holes <NUM>, and particularly their number and diameter, achieves a sufficiently short time to "bubble" and therefore saturate the perfusate solution of the perfusate bath with oxygen while maintaining a suitable cost. Preferably, at an oxygen flow rate of, say, <NUM> liters per minute, the holes <NUM> ensure that the perfusate solution of the bath will be saturated within a timeframe of <NUM>-<NUM> minutes, which is acceptable for most clinics as surgical procedures taking place concurrently may take substantially longer. Other numbers of holes <NUM> and other sizes of those holes are possible; however, various considerations should be taken into account. More holes <NUM> of the same diameter, for example, may reduce the time required to fully saturate the perfusate solution. But cost of the tubing <NUM> is directly proportional to the number of holes <NUM>, so increasing their number may result in increased cost of the tubing. Substantially less holes <NUM>, on the other hand, may unsatisfactorily increase the time required to saturate the perfusate solution of the bath.

Other arrangements of the holes <NUM> are also possible. They could be positioned linearly along the length of the tubing <NUM>, for example. However, the above-described arrangement with the groupings <NUM>, in which five holes <NUM> are spaced around the circumference of the tubing <NUM>, helps ensure that at least most of the holes <NUM> are placed below the surface of the perfusate in use. Equally spacing the groupings <NUM> by the distance <NUM> across the length of the tubing <NUM> may also help ensure that most of the perfusate solution is evenly exposed to oxygen gas, thereby preventing one region from being under-concentrated.

<FIG> shows a method by which the oxygenator device <NUM> may be used with a perfusion apparatus, e.g., the perfusion apparatus <NUM>, to increase the dissolved oxygen content in the perfusate solution constituting a perfusate bath. In a first step <NUM>, the oxygenator device <NUM> may be placed on the basin <NUM>. This arrangement is shown by cross-section in <FIG>. As shown in this Figure, the lower lip <NUM> of the oxygenator device <NUM> may be sized so as to correspond to the depression <NUM> in the top surface of the basin <NUM>. The holders <NUM> may also secure the tubing <NUM> and the holes <NUM> therein low enough within the basin <NUM> to be submerged within the perfusate bath, a possible level of which is shown by <NUM> in <FIG>. And also by virtue of the angled portions <NUM> of the holders <NUM>, the tubing <NUM> may be located outside so as not to interfere with the organ cradle <NUM>, any organ or vasculature thereon, or any cannula in the assembled position shown in <FIG>. The oxygenator device <NUM> may be secured to the basin <NUM> by way of the aforementioned latches.

In a next step <NUM> the oxygenator device <NUM> may be connected to an external oxygen source. Other than preferably providing regulated, medical-grade oxygen, the oxygen source is not particularly limited. It may be, for example, an oxygen cylinder or a wall valve in a hospital or clinic setting. To connect the oxygenator device <NUM> and the oxygen source, a user or users of the device <NUM> may attach one end of an extension tube to the oxygen inlet <NUM> and another end of that tube to the oxygen source.

Following step <NUM>, oxygen may be administered in a step <NUM>. Preferably, oxygen may be administered from the oxygen source at a rate at or about <NUM> liters per minute for at least <NUM> minutes, more preferably for at least <NUM> minutes, and even more preferably for at least <NUM> minutes. Other rates of oxygen flow are possible, however. For example, the oxygen could be administered from the oxygen source at a rate of <NUM>, <NUM>, or <NUM> liters per minute. But this may unacceptably lengthen the period of time required to fully saturate the perfusate solution of the perfusate bath. On the other hand, oxygen flow rates up to <NUM> liters per minute or more are conceived. However, flow rates greater than <NUM> liters per minute may create a risk of high back pressure on the connections between the tubing <NUM> and the T-fitting <NUM>, which could prevent the perfusate bath from being fully saturated with oxygen due to leaks caused by the high pressure. Administering oxygen at the above preferred rate for the preferred duration may result in dissolved oxygen levels within the perfusate solution of <NUM>-<NUM> mmHg, which is believed to be desirable for perfusion of the organ. Despite the additional oxygen introduced into the basin <NUM> by way of the tubing <NUM> and the holes <NUM> therein, the vent <NUM> may prevent substantial increases in pressure of the atmosphere within the basin <NUM> and above the perfusate bath by venting most of the introduced oxygen to atmosphere. Indeed, the increase in atmosphere pressure within the basin <NUM> may be less than <NUM> mmHg. Once administration of oxygen is discontinued, the pressure within the basin <NUM> may equilibrate to that of the external atmosphere due to the vent <NUM>.

Once desirable oxygenation levels have been reached, the oxygen administration may be discontinued and the oxygenator device <NUM> may be removed from the basin <NUM>. Because the oxygenated perfusate is then open to atmosphere, the inner lid <NUM> may then preferably be placed on the basin <NUM> as soon as possible. The organ may then be placed within the basin <NUM> and perfused with the oxygenated perfusate solution. It is also conceivable that, once the administration of oxygen has been discontinued, there may be some delay in placing the organ within the basin <NUM> and beginning perfusion. It may therefore be necessary to oxygenate the perfusate solution again after a period of time so that the desirable oxygenation level can be maintained. Preferably this re-administration occurs prior to removal of the oxygenator device <NUM> from the basin <NUM>, as the device's sterility may become compromised once removed from the basin.

The process <NUM> shown in <FIG> thus provides a means by which to precharge with oxygen a perfusate solution prior to placement of an organ within the perfusion circuit and subsequent perfusion of that organ. However, various modifications are envisioned. For example, the oxygenator device <NUM> may not be removed from the basin <NUM> once pre-charging is complete, and it could thus serve as the lid of the basin during perfusion of the organ. The oxygenator device <NUM> could also continue to oxygenate the perfusate during perfusion and/or transport of the organ. This oxygenation during perfusion could help maintain elevated oxygen levels in the perfusate throughout transport. Of course, a portable oxygen source would likely be beneficial for this modification. The step <NUM> of the process <NUM> may also be preceded by steps <NUM> and <NUM>. In step <NUM>, following priming and cooling of the perfusion circuit, the inner lid <NUM> of the perfusion circuit may be removed to make space for the oxygenator device <NUM>. And in step <NUM>, the perfusate solution may be decanted into the basin <NUM> so as to form the perfusate bath.

As explained above, the oxygenator device <NUM> thus provides a mechanism by which to rapidly oxygenate a perfusate solution, thereby providing the above-described benefits of oxygen while avoiding the hazards associated with delays in the transplantation process. It also works with existing perfusion circuits, ensuring that these costly disposables need not be replaced by a clinic or hospital to obtain the benefits of oxygenation.

Claim 1:
An oxygenator device (<NUM>) for oxygenating a perfusate solution to be perfused through an organ or tissue, the device comprising:
an inlet (<NUM>) configured to receive oxygen from an oxygen supply;
tubing (<NUM>) connected to the inlet;
a top portion (<NUM>) from which the inlet extends; and
a plurality of holders (<NUM>) extending below the top portion so as to secure the tubing below the top portion,
the oxygenator device being characterized in that:
the tubing includes a plurality of holes (<NUM>) by which the received oxygen may exit the tubing;
each of the plurality of holders includes (i) a vertical portion (<NUM>) extending substantially perpendicular to the top portion and (ii) an angled portion (<NUM>) extending at an outward angle relative to the vertical portion; and
the tubing is secured by the angled portions of the plurality of holders.