Patent Publication Number: US-2020288701-A1

Title: Oxygenator device

Description:
BACKGROUND 
     Related technical fields include organ or tissue perfusion apparatuses that are capable of sustaining and/or restoring viability of organs or tissue and preserving organs or tissue for diagnosis, treatment, storage, and/or transport. For convenience, the term “organ” as used herein should be understood to mean organ and/or tissue unless otherwise specified. 
     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. U.S. Pat. No. 9,357,767; U.S. Pat. No. 9,357,766; and U.S. Pat. No. 9,723,830 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. The contents of these prior patents are incorporated by reference herein in their entirety. 
     SUMMARY 
     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. U.S. patent application Ser. No. 13/545,514, the entire contents of which are hereby incorporated by reference, 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 may comprise an inlet configured to receive oxygen from an oxygen supply, and it may also comprise tubing connected to the inlet, the tubing including a plurality of holes by which the received oxygen may exit the tubing. 
     In combination with any of the above or below features, the oxygenator device may also comprise a top portion from which the inlet extends, and it may further include a plurality of holders extending below the top portion so as to secure the tubing below the top portion. 
     In combination with any of the above or below features, each of the plurality of holders may also include (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 may be 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 34.79 mm of the tubing, and an average diameter of the plurality of holes may be between 0.10 mm and 0.18 mm. 
     Also disclosed herein is a method of using the oxygenator device in accordance with any of the above features. This method may include placing the oxygenator device on a basin of an organ perfusion circuit so that the tubing and the holes therein are submerged within a bath of the perfusate solution within the basin; connecting the inlet of the oxygenator device to an oxygen supply; and administering oxygen from the oxygen supply, through the inlet, through the holes in the tubing, and into the perfusate bath so as to increase oxygen concentration of the perfusate solution constituting the bath. 
     The method may also include a step of administering the oxygen from the oxygen source at a rate of about 10 liters per minute for at least 10 minutes. 
     It may further include, prior to the placing step, removing a lid of the basin. The placing step may thus replace 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. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a cross-sectional view of an organ perfusion apparatus according to one or more embodiments of the disclosure. 
         FIG. 2  is a cross-sectional view of the combined coolant container, basin, and cradle of the organ perfusion apparatus of  FIG. 1 . 
         FIG. 3  is a top perspective view of an oxygenator device according to one or more embodiments of the disclosure. 
         FIG. 4  is a bottom perspective view of the oxygenator device of  FIG. 3 . 
         FIG. 5  is a top plan view of the oxygenator device of  FIG. 3 . 
         FIG. 6  is a bottom plan view of the oxygenator device of  FIG. 3 . 
         FIG. 7  is a side elevation view of the oxygenator device of  FIG. 3 . 
         FIG. 8  is another side elevation view of the oxygenator device of  FIG. 3 . 
         FIG. 9  is an enlarged view of a portion IX of the tubing shown in  FIG. 8 . 
         FIG. 10  is a cross-sectional view of the tubing taken along line X-X in  FIG. 9 . 
         FIG. 11  shows a process of using the oxygenator device of  FIG. 3 . 
         FIG. 12  is a cross-sectional view of the oxygenator device of  FIG. 3  placed on a basin of an organ perfusion circuit. 
     
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
       FIGS. 1 and 2  show an exemplary perfusion apparatus  10  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  10  may include a basin  30  (see  FIG. 2 ) in which the organ may be placed. The basin  30  may hold a removable cradle  60 , which may preferably include a surface  60   a  on which the organ may be disposed when the organ is in the apparatus  10 . The basin  30  and/or the cradle  60  may preferably be configured to allow a perfusate bath of perfusate solution such as VASOSOL® to be contained around the organ. 
     The basin  30  may preferably be disposed within an insulating coolant container  50  that may contain cold materials such as ice, ice water, brine, or the like. Coolant container  50  may be permanently or removably attached to, or an integral, monolithic part of, apparatus  10 . Thus, in use, the organ may be disposed within the cradle  60 , which may be disposed within the basin  30 , which may be disposed within the coolant container  50 , as shown in  FIG. 2 . The arrangement of the coolant container  50 , basin  30 , and cradle  60  preferably provides a configuration that provides cooling for the organ without the contents of coolant container  50  contacting the organ or the cradle  60 . Although the coolant container  50  is described herein as containing ice or ice water, any suitable cooling medium can be used. 
     As further shown in  FIG. 2 , an inner lid  66  and an outer lid  67  may be provided on an upper surface of the basin  30 . The inner lid  66  may be sized to come into close proximity to the perimeter top surface of the cradle  60  to help maintain stability of the organ in the event of mechanical impact and shock during transport. More specifically, the inner lid  66  may have a downwardly protruding extension  66   a  that matches a circumferential shape of a peripheral ridge  60   b  of the cradle  60  and is configured to contact the peripheral ridge  60   b  and help hold the cradle  60  in position. The lids  66  and  67  may create a substantially fluid-tight seal with the basin  30 , and they can prevent contamination. The lids  66  and  67  may also provide for a redundant airtight seal should the seal from either lid  66  or  67  fail. Both the inner lid  66  and the outer lid  67  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  10  that come into contact with perfusate solution and/or the organ are disposable and/or easily replaced. These components may include the basin  30 , the organ cradle  60 , and the lids  66  and  67 , 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  10 , and the organ may be placed on the organ cradle  60  within the basin  30 . Because of the presence of the coolant container  50 , both the organ and the perfusate bath within the basin  30  are subjected to hypothermic temperatures. The perfusate solution may then be circulated through the disposable perfusion circuit and the organ. 
       FIGS. 3 and 4  show an oxygenator device  100  in accordance with one or more aspects of the present disclosure. The device  100  may be designed to work with the perfusion apparatus  10  to increase the oxygen concentration of the perfusate bath within the basin  30 . This device  100  may generally be constituted by a main body  110  and oxygenation components  150 . The main body  110  may in turn include a top portion  120  including, as shown in  FIG. 5 , radially inner and outer portions  122  and  124 . The main body  110  may also include, as shown in  FIG. 6 , a bottom portion  130  projecting downward from the top portion  120 . The main body  110  may be formed, for example, from clear polycarbonate plastic resin. 
     The top portion  120  may be, like the inner lid  66 , sized to correspond to the basin  30 . More specifically, a lower lip  126  (see  FIG. 4 ) of the radially outer portion  124  of the top portion  120  may be sized so as to be received by an indentation  36  (see  FIG. 2 ) in an upper surface of the basin  30  and thereby allow the oxygenator device  100  to constitute a lid for that basin in place of the inner lid  66 . Latches (not shown) on the basin  30  may be used to lock the oxygenator device  100  in place relative to the basin  30 . As shown in  FIGS. 7 and 8 , the top portion  120  may be substantially planar. That is, although the surface of at least one of the radially inner and outer portions  122  and  124  may be slightly inclined, the overall shape of the top portion  120  forms a virtual plane projecting into the pages of  FIGS. 7 and 8 . For example, the outer portion  124  may be flat, whereas the inner portion  122  may be convex outward. Also provided within the top portion  120  may be a vent  128  (see  FIGS. 5 and 6 ). Like the air vents of the lids  66  and  67 , the vent  128  may include a porous hydrophobic membrane, which allows for gas transfer in order to maintain pressure equilibrium. More specifically, the membrane of the vent  128  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  0 . 45  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  128  may be provided an adhesive to secure the vent  128  to the remainder of the top portion  120  and thereby ensure that it remains attached thereto with a tight seal. 
     The bottom portion  130  may be formed in the space between the radially inner and outer portions  122  and  124  of the top portion  120 , and it may have a substantially triangular shape in cross-section. More specifically, a radially outer wall  132  (see  FIG. 4 ) of the bottom portion  130  may extend downward substantially perpendicular to the virtual plane of the top portion  120 , and a radially inner wall  134  of the bottom portion  130  may extend downward from the top portion  120  at an angle inclined relative to the outer wall  132 . The walls  132  and  134  may meet at a vertex  136 , thereby ensuring that the main body  110  is able to create a substantially fluid-tight seal with the basin  30  and thereby prevent contamination. Finally, the bottom portion  130  (and particularly the vertex  136 ) may, like the downwardly protruding extension  66   a  of the inner lid  66 , also match the circumferential shape of the peripheral ridge  60   b  of the cradle  60 , and it may thus likewise be configured to contact that peripheral ridge and help hold the cradle  60  and any organ thereon in position. 
     The oxygenation components  150  may in turn include, as shown in  FIG. 7 , an oxygen inlet  160 , a T-fitting  162 , holders  170 , and tubing  180 . The oxygen inlet  160  may be an oxygen barb projecting from a bridge portion  129  (see  FIG. 5 ) that connects the radially inner and outer portions  122  and  124  of the top portion  120 . The oxygen inlet  160  may be angled substantially perpendicular to the virtual plane of the top portion  120  to facilitate ease of use and to reduce the risk of kinking of the tube delivering oxygen to the inlet. The T-fitting  162  may in turn be fluidly connected to the oxygen inlet  160 , and it may be formed below the bridge portion  129  in a gap  138  formed in the bottom portion  130 . 
     The tubing  180  may be fluidly connected to the T-fitting  162 , and it may be secured in position by the plurality of holders  170 . As shown in  FIG. 8 , each of these holders  170  may include an upper, vertical portion  172  secured to the bottom portion  130  of the main body  110  and projecting from the top portion  120  in a direction substantially perpendicular to the virtual vertical plane of the top portion  120 . The holders  170  may secure the tubing  180  below the bottom portion  130 , and each of the holders  170  may also include an angled portion  174  that is angled outward relative to the vertical portion  172 . The angled portion  174  may be angled relative to the vertical portion  172  by, say, 2.5 degrees, although other angles are possible. The angled portion  174  of each of the holders  170  may include a hole through which the tubing  180  may pass. As discussed below, angling the angled portions  174  relative to the vertical portions  172  may help ensure that neither the holders  170  nor the tubing  180  interferes in use with the organ cradle  60 , any organ or vasculature thereon, or cannula that may be disposed within the basin  30 . The rounded ends of the angled portions  174 , at which the holes are located, may also ensure that there is no crashing or interference with the basin  30  during use. 
     The tubing  180  may be formed of aromatic polyether-based polyurethane, and it may be of sufficient length to encircle the bottom portion  130  and thus to encircle a perfused organ when the oxygenator device  100  serves as the lid for the basin  30 . Preferably, the total length of the tubing  180  may be equal to or about 1,054.10 mm, although other lengths are possible.  FIG. 9  shows an enlarged view of the portion IX of the tubing  180  shown in  FIG. 8 , and as shown in this Figure, the tubing  180  may include a plurality of groupings  182  of holes  184  that may be spaced apart along the length of the tubing  180  by a distance  186 . Preferably, the distance  186  may be equal to or about 34.79 mm, although other distances are possible. 24 groupings  182  may be formed in the tubing  180 , and as shown in  FIG. 10 , which shows a cross-section of the tubing  180  at one of the groupings  182 , each grouping may include 5 holes  184  equally spaced around the circumference of the tubing  180 . The tubing  180  may thus include a total of  120  holes  184 . Each of the holes  184  may be formed in the tubing  180  by way of laser ablation. And each hole  184  may have a diameter of 0.10 mm to 0.18 mm, which has been shown to be well within the capability of the laser ablation process and repeatable. Instead of the tubing  180 , 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  180 . 
     The above-described arrangement of the holes  184 , 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, 10 liters per minute, the holes  184  ensure that the perfusate solution of the bath will be saturated within a timeframe of 10-15 minutes, which is acceptable for most clinics as surgical procedures taking place concurrently may take substantially longer. Other numbers of holes  184  and other sizes of those holes are possible; however, various considerations should be taken into account. More holes  184  of the same diameter, for example, may reduce the time required to fully saturate the perfusate solution. But cost of the tubing  180  is directly proportional to the number of holes  184 , so increasing their number may result in increased cost of the tubing. Substantially less holes  184 , on the other hand, may unsatisfactorily increase the time required to saturate the perfusate solution of the bath. 
     Other arrangements of the holes  184  are also possible. They could be positioned linearly along the length of the tubing  180 , for example. However, the above-described arrangement with the groupings  182 , in which five holes  184  are spaced around the circumference of the tubing  180 , helps ensure that at least most of the holes  184  are placed below the surface of the perfusate in use. Equally spacing the groupings  182  by the distance  186  across the length of the tubing  182  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. 11  shows a method by which the oxygenator device  100  may be used with a perfusion apparatus, e.g., the perfusion apparatus  10 , to increase the dissolved oxygen content in the perfusate solution constituting a perfusate bath. In a first step  210 , the oxygenator device  100  may be placed on the basin  30 . This arrangement is shown by cross-section in  FIG. 12 . As shown in this Figure, the lower lip  126  of the oxygenator device  100  may be sized so as to correspond to the depression  36  in the top surface of the basin  30 . The holders  170  may also secure the tubing  180  and the holes  184  therein low enough within the basin  30  to be submerged within the perfusate bath, a possible level of which is shown by  190  in  FIG. 12 . And also by virtue of the angled portions  174  of the holders  170 , the tubing  180  may be located outside so as not to interfere with the organ cradle  60 , any organ or vasculature thereon, or any cannula in the assembled position shown in  FIG. 12 . The oxygenator device  100  may be secured to the basin  30  by way of the aforementioned latches. 
     In a next step  220  the oxygenator device  100  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  100  and the oxygen source, a user or users of the device  100  may attach one end of an extension tube to the oxygen inlet  160  and another end of that tube to the oxygen source. 
     Following step  220 , oxygen may be administered in a step  230 . Preferably, oxygen may be administered from the oxygen source at a rate at or about 10 liters per minute for at least 10 minutes, more preferably for at least 15 minutes, and even more preferably for at least 20 minutes. Other rates of oxygen flow are possible, however. For example, the oxygen could be administered from the oxygen source at a rate of 1, 2, or 3 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 20 liters per minute or more are conceived. However, flow rates greater than 20 liters per minute may create a risk of high back pressure on the connections between the tubing  180  and the T-fitting  162 , 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 600-800 mmHg, which is believed to be desirable for perfusion of the organ. Despite the additional oxygen introduced into the basin  30  by way of the tubing  180  and the holes  184  therein, the vent  128  may prevent substantial increases in pressure of the atmosphere within the basin  30  and above the perfusate bath by venting most of the introduced oxygen to atmosphere. Indeed, the increase in atmosphere pressure within the basin  30  may be less than 5 mmHg. Once administration of oxygen is discontinued, the pressure within the basin  30  may equilibrate to that of the external atmosphere due to the vent  128 . 
     Once desirable oxygenation levels have been reached, the oxygen administration may be discontinued and the oxygenator device  100  may be removed from the basin  30 . Because the oxygenated perfusate is then open to atmosphere, the inner lid  66  may then preferably be placed on the basin  30  as soon as possible. The organ may then be placed within the basin  30  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  30  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  100  from the basin  30 , as the device&#39;s sterility may become compromised once removed from the basin. 
     The process  200  shown in  FIG. 11  thus provides a means by which to pre-charge 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  100  may not be removed from the basin  30  once pre-charging is complete, and it could thus serve as the lid of the basin during perfusion of the organ. The oxygenator device  100  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  210  of the process  200  may also be preceded by steps  205  and  207 . In step  205 , following priming and cooling of the perfusion circuit, the inner lid  66  of the perfusion circuit may be removed to make space for the oxygenator device  100 . And in step  207 , the perfusate solution may be decanted into the basin  30  so as to form the perfusate bath. 
     As explained above, the oxygenator device  100  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. 
     What has been described and illustrated herein are embodiments of the invention along with some variations. The terms, descriptions and figures used herein are set forth by way of illustration only and are not meant as limitations. Those skilled in the art will recognize that many variations are possible within the spirit and scope of the invention.