Patent Application
20230413805
The invention relates generally to organ perfusion. In various illustrated embodiments the invention provides for systems, methods, compositions and solutions for perfusing an organ.
Many patients need organ transplants but are unable to obtain suitable organs. One of the primary reasons is that organs that are otherwise viable when harvested from a donor are not preserved for long enough periods of time to allow them to be transported to appropriate recipients. With current preservation techniques, transplantable organs remain viable for about three to four hours and, beyond that time, suffer ischemia and tissue injury, which renders them unviable for transplant.
Current preservation techniques include cryopreservative methods, which involve the cooling of the transplantable organ to temperatures well below physiological temperatures (e.g., below 25° C.). Such techniques typically use preservation solutions that do not replenish energy sources within the organ during transplant or maintain the organ in a functioning state and therefore are largely ineffective in preventing ischemia and other injuries to the organ. The solutions also often rely on the use of high molecular weight impermeants to maintain the organ at these temperatures prior to transplantation, and such components are in many cases harmful to the organ.
Although improvements to solutions have been made over the last several years, particularly as disclosed in U.S. Pat. Nos. 6,100,082, 6,046,046, and PCT Application No. PCT/US98/19912, further improvements are still needed.
The invention addresses deficiencies in the art by providing, in various embodiments, improved systems, methods, compositions and solutions for perfusing an organ prior to transplantation. According to one aspect, the solutions include components adapted to preserving and maintaining a harvested organ ex-vivo in its functioning state under physiologic or near physiologic conditions prior to its transplantation, while minimizing reperfusion injury and ischemia to the organ while awaiting transplantation.
According to another feature, the solutions include energy sources for the organ while it is being prepared for and undergoing transplantation. Energy sources include, for example, one or more of carbohydrate sources, components for synthesis of energy-rich molecules, such as phosphate sources, and other components. According to one embodiment, the solutions provide for amino acids for assisting the organ in cellular protein synthesis during perfusion. According to one embodiment, the solutions also provide components that help maintain the organ's normal functionality during perfusion, such as cardio stimulants, insulin and other hormones, electrolytes, etc. The solutions may also be adapted to include drugs or other therapeutics for preservation of the organ and/or patient care.
In another aspect, the invention provides for systems and methods for improved preservation. In certain embodiments the solutions are combined with blood products for perfusion. The solutions, systems and methods are also adaptable to drug delivery systems. In certain embodiments, the solutions are combined with additional additives at the point of use.
In one embodiment, a composition for use in a solution for perfusing an organ, such as a heart, is provided comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids that do not include asparagine, glutamine, or cysteine.
In another embodiment, a system for perfusing an organ, such as a heart, is provided comprising an organ and a substantially cell-free composition, where the composition comprises one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids that do not include asparagine, glutamine, or cysteine.
The foregoing and other objects and advantages of the invention will be appreciated more fully from the following further description thereof, with reference to the accompanying figures wherein:
The invention addresses deficiencies in the prior art by providing in various illustrated embodiments systems, methods, compositions, and solutions for maintaining an organ in a functioning state ex vivo under physiological or near physiological conditions. In one embodiment, the organ is a heart and is maintained in a beating state at a physiologic or near physiologic temperature during perfusion of a perfusion fluid, which may include one or more of the solutions described herein. According to certain embodiments, solutions with particular solutes and concentrations are selected and proportioned to enable the organ to function at physiologic or near physiologic conditions. For example, such conditions include maintaining organ function at or near a physiological temperature and/or preserving an organ in a state that permits normal cellular metabolism, such as protein synthesis.
In certain embodiments, solutions are formed from compositions by combining components with a fluid, from more concentrated solutions by dilution, or from more dilute solutions by concentration. In exemplary embodiments, suitable solutions include one or more energy sources, one or more stimulants to assist the organ in continuing its normal physiologic function prior to and during transplantation, and one or more amino acids selected and proportioned so that the organ continues its cellular metabolism during perfusion. Cellular metabolism includes, for example, conducting protein synthesis while functioning during perfusion. Some illustrative solutions are aqueous based, while other illustrative solutions are non-aqueous, for example organic solvent-based, ionic-liquid-based, or fatty-acid-based.
The solutions may include one or more energy-rich components to assist the organ in conducting its normal physiologic function. These components may include energy rich materials that are metabolizable, and/or components of such materials that an organ can use to synthesize energy sources during perfusion. Exemplary sources of energy-rich molecules include, for example, one or more carbohydrates. Examples of carbohydrates include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or combinations thereof, or precursors or metabolites thereof. While not meant to be limiting, examples of monosaccharides suitable for the solutions include octoses; heptoses; hexoses, such as fructose, allose, altrose, glucose, mannose, gulose, idose, galactose, and talose; pentoses such as ribose, arabinose, xylose, and lyxose; tetroses such as erythrose and threose; and trioses such as glyceraldehyde. While not meant to be limiting, examples of disaccharides suitable for the solutions include (+)-maltose (4-O-(α-D-glucopyranosyl)-α-D-glucopyranose), (+)-cellobiose (4-O-(β-D-glucopyranosyl)-D-glucopyranose), (+)-lactose (4-O-(β-D-galactopyranosyl-β-D-glucopyranose), sucrose (2-O-(α-D-glucopyranosyl-β-D-fructofuranoside). While not meant to be limiting, examples of polysaccharides suitable for the solutions include cellulose, starch, amylose, amylopectin, sulfomucopolysaccharides (such as dermatane sulfate, chondroitin sulfate, sulodexide, mesoglycans, heparan sulfates, idosanes, heparins and heparinoids), and glycogen. In some embodiments, monossacharides, disaccharides, and polysaccharides of both aldoses, ketoses, or a combination thereof are used. One or more isomers, including enantiomers, diastereomers, and/or tautomers of monosaccharides, disaccharides, and/or polysaccharides, including those described and not described herein, may be employed in the solutions described herein. In some embodiments, one or more monosaccharides, disaccharides, and/or polysaccharides may have been chemically modified, for example, by derivatization and/or protection (with protecting groups) of one or more functional groups. In certain embodiments, carbohydrates, such as dextrose or other forms of glucose, are preferred.
Other possible energy sources include adenosine triphosphate (ATP), co-enzyme A, pyruvate, flavin adenine dinucleotide (FAD), thiamine pyrophosphate chloride (co-carboxylase), β-nicotinamide adenine dinucleotide (NAD), β-nicotinamide adenine dinucleotide phosphate (NADPH), and phosphate derivatives of nucleosides, e.g., nucleotides, including mono-, di-, and tri-phosphates (e.g., UTP, GTP, GDP, and UDP), coenzymes, or other bio-molecules having similar cellular metabolic functions, and/or metabolites or precursors thereof. For example, phosphate derivatives of adenosine, guanosine, thymidine (5-Me-uridine), cytidine, and uridine, as well as other naturally and chemically modified nucleosides are contemplated.
In certain embodiments, one or more carbohydrates is provided along with a phosphate source, such as a nucleotide. The carbohydrate helps enable the organ to produce ATP or other energy sources during perfusion. The phosphate source may be provided directly through ATP, ADP, AMP, or other sources. In other illustrative embodiments, a phosphate is provided through a phosphate salt, such as glycerophosphate, sodium phosphate or other phosphate ions. A phosphate may include any form thereof in any ionic state, including protonated forms and forms with one or more counter ions.
The solutions may include one or more organ stimulants for assisting the organ's normal physiologic function during perfusion. In some illustrative embodiments, where the transplanted organ is a heart, cardio stimulants are provided to enable the heart to continue functioning (e.g., continue beating) during perfusion and transplantation. Such stimulants may include, for example, catecholamines, such as epinephrine and/or norepinephrine, which facilitate beating of the heart. Other cardio stimulants may be used, such as certain forms of peptides and/or polypeptides (e.g., vasopressin, Anthropleurin-A and Anthropleurin-B), and/or β1/β2 —adrenoreceptor blocking agents (such as CGP 12177), bupranolol, pindolol, alprenolol, and cardiac glycosides. One or more natural products may also be used, such as digitalis (digoxin), palustrin, and/or ferulic acid. Stimulants such as those mentioned above can be included with the solutions or added at the point of use by the user.
In some instances, additional components are provided to assist the organ in conducting its metabolism during perfusion. These components include, for example, forms or derivatives of adenine and/or adenosine, which may be used for ATP synthesis, for maintaining endothelial function, and/or for attenuating ischemia and/or reperfusion injury. According to certain implementations, a magnesium ion source is provided with a phosphate, and in certain embodiments, with adenosine to further enhance ATP synthesis within the cells of the perfused organ.
As noted, the solution may include one or more amino acids, preferably a plurality of amino acids, to support protein synthesis by the organ's cells. Suitable amino acids include, for example, any of the naturally-occurring amino acids. The amino acids may be in various enantiomeric or diastereomeric forms. For example, solutions may employ either D- or L-amino acids, or a combination thereof, e.g., solutions enantioenriched in more of the D- or L-isomer or racemic solutions. Suitable amino acids may also be non-naturally occurring or modified amino acids, such as citrulline, ornithine, homocysteine, homoserine, β-amino acids such as β-alanine, amino-caproic acid, or combinations thereof.
Certain exemplary solutions include some but not all naturally-occurring amino acids. In some embodiments, solutions include essential amino acids. For example, a solution may be prepared with one or more or all of the following amino acids:
In certain embodiments, non-essential and/or semi-essential amino acids are not included in the solutions. For example, in some embodiments, asparagine, glutamine, and/or cysteine are not included. In other embodiments, the solution contains one or more non-essential and/or semi-essential amino acids. Accordingly, in other embodiments, asparagine, glutamine, and/or cysteine are included.
The solutions may also contain electrolytes, particularly calcium ions for facilitating enzymatic reactions, cardiac contractility, and/or coagulation within the organ. Other electrolytes may be used, such as sodium, potassium, chloride, sulfate, magnesium and other inorganic and organic charged species or combinations thereof. It should be noted that any component provided hereunder may be provided, where valence and stability permit, in an ionic form, in a protonated or unprotonated form, in salt or free base form, or as ionic or covalent substituents in combination with other components that hydrolyze and make the component available in aqueous solutions, as suitable and appropriate.
In certain embodiments, the solutions contain buffering components. For example, suitable buffer systems include 2-morpholinoethanesulfonic acid monohydrate (IVIES), cacodylic acid, H2CO3/NaHCO3 (pKa1), citric acid (pKa3), bis(2-hydroxyethyl)-imino-tris-(hydroxymethyl)-methane (Bis-Tris), N-(carbamoylmethyl)iminodiacetic acid (ADA), 3-bis[tris(hydroxymethyl)methylamino]propane (Bis-Tris Propane) (pKa1), piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES), N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), imidazole, N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 3-(N-morpholino)propanesulphonic acid (MOPS), NaH2PO4/Na2HPO4 (pKa2), N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (TES), N-(2-hydroxyethyl)-piperazine-N′-2-ethanesulfonic acid (HEPES), N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid) (HEPPSO), triethanolamine, N-[tris(hydroxymethyl)methyl]glycine (Tricine), tris(hydroxymethyl)aminoethane (Tris), glycinamide, N,N-bis(2-hydroxyethyl) glycine (Bicine), glycylglycine (pKa2a2), N-tris(hydroxymethyl)methyl-3-aminopropanesulfonic acid (TAPS), or a combination thereof. In some embodiments, the solutions contain sodium bicarbonate, potassium phosphate, or TRIS buffer.
The solutions may include other components to help maintain the organ and protect it against ischemia, reperfusion injury and other ill effects during perfusion. In certain exemplary embodiments, these components may include hormones (e.g., insulin), vitamins (e.g., an adult multi-vitamin, such as multi-vitamin MVI-Adult™), and/or steroids (e.g., dexamethasone and SoluMedrol™).
In another aspect, a blood product is provided with the solution to support the organ during metabolism. Exemplary suitable blood products may include whole blood and/or one or more components thereof such as blood serum, plasma, albumin, and red blood cells. In embodiments where whole blood is used, the blood may be passed through a leukocyte and platelet depleting filter to reduce pyrogens, antibodies and/or other items that may cause inflammation in the organ. Thus, in some embodiments, the solution employs whole blood that has been at least partially depleted of leukocytes and/or whole blood that has been at least partially depleted of platelets.
The solutions are preferably provided at a physiological temperature and maintained thereabout throughout perfusion and recirculation. As used herein, “physiological temperature” is referred to as temperatures between about 25° C. and about 37° C., for example, between about 30° C. and about 37° C., such as between about 34° C. and about 37° C.
Table 1 sets forth components that may be used in a preservative solution for preserving an organ as described herein.
The solutions described herein may be prepared from compositions having one or more components such as those described above in concentrations such as those described above. An exemplary embodiment of a composition adaptable for use in organ perfusion includes one or more components selected from Table 2. The amounts provided describe preferred amounts relative to other components in the table and may be scaled to provide compositions of sufficient quantity. In some embodiments, the amounts listed in Table 2 can vary by±about 10% and still be used in the solutions described herein.
A solution may be prepared combining components selected by a user with an aqueous fluid to form a preservative solution. In an illustrative embodiment, one or more components from Table 2 are combined in the relative amounts listed therein per about 1000 mL of aqueous fluid to form a preservative solution for perfusing an organ, such as a heart. In some embodiments the quantity of aqueous fluid can vary±about 10%.
In another aspect, solutions may be administered in combinations as desired by a medical operator.
In other illustrative embodiments, the solutions 15 and/or 17 may be provided systematically to optimize the effectiveness of the system. For example, as shown in
In some illustrative embodiments, the solutions described herein are combined with a blood product, such as whole blood or components thereof, which may also be oxygenated, to give a perfusion fluid. Additionally, synthetic blood products may be used as a substitute or in combination with blood products. Such combined solutions may be included in a perfusion circuit, such as those shown in
In other illustrative embodiments, one of the composition or solutions 13, 15, 17, or 19 may include one or more organ stimulants, such as cardio stimulants, and/or other components. The other components may include, for example, adenosine, a magnesium ion source, one or more phosphates, calcium ions, etc. In embodiments utilizing two or more solutions, such as those in
In one embodiment, a maintenance solution is made from the combination of a first solution, substantially formed from one or more amino acids, and a second solution, substantially formed from one or more carbohydrates, such as dextrose or glucose. The maintenance solution may also have additives, such as those described herein, administered at the point of use just prior to infusion into the organ perfusion system. For example, additional additives that can be included with the solution or added at the point of use by the user include hormones and steroids, such as dexamethasone and insulin, as well as vitamins, such as an adult multi-vitamin, for example adult multivitamins for infusion, such as MVI-Adult™. Additional small molecules and large bio-molecules may also be included with the solution or added at the point of use by the user, for example, therapeutics and/or components typically associated with blood or blood plasma, such as albumin.
In some embodiments, therapeutics that may be included in the compositions, solutions, and systems described herein include hormones, such as thyroid hormones, for example T3 and/or T4 thyroid hormones. Further therapeutics that may be included include drugs such as anti-arrhythmic drugs, for example, for heart therapy, and beta blockers. For instance, in certain embodiments, one or more thyroid hormones, one or more anti-arrhythmic drugs, and one or more beta blockers are added to the first solution, the second solution, and/or the maintenance solution either before or during perfusion of the organ. The above therapeutics may also be added directly to the system, for example to the perfusion circuit before or during perfusion of the organ.
Table 3 sets forth an exemplary first solution, comprising a tissue culture media having the components identified in Table 3 and combined with an aqueous fluid, which may be used to perfuse an organ as described herein. The amounts of components listed in Table 3 are relative to each other and to the quantity of aqueous solution used. In some embodiments, about 500 mL of aqueous fluid is used. In other embodiments, about 1 L of aqueous fluid is used. For example, a combination of about 500 mL of first solution with 500 mL of second solution affords a maintenance solution of about 1 L. In some embodiments, the quantity of aqueous solution can vary±about 10%. The component amounts and the quantity of aqueous solution may be scaled as appropriate for use. The pH of the first solution, in this embodiment, may be adjusted to be about 7.0 to about 8.0, for example about 7.3 to about 7.6.
Since amino acids are the building blocks of proteins, the unique characteristics of each amino acid impart certain important properties on a protein such as the ability to provide structure and to catalyze biochemical reactions. The selection and concentrations of the amino acids provided in the first solution provide support of normal physiologic functions such as metabolism of sugars to provide energy, regulation of protein metabolism, transport of minerals, synthesis of nucleic acids (DNA and RNA), regulation of blood sugar and support of electrical activity, in addition to providing protein structure. Additionally, the concentrations of specific amino acids found in the first solution can be used to predictably stabilize the pH of the first solution and/or other solutions and fluids to which the first solution may be added, for example the maintenance solution and/or the perfusion fluid.
Table 4 provides an exemplary second solution 15, comprising a solution which may be used with the systems of
Additional components may be included in the first or second solution, the maintenance solution, and/or the priming solution and may include one or more of those set forth in Table 5. These additional or supplemental components may be added individually, in various combinations, or all at once as a composition. For example, in certain embodiments, the epinephrine, insulin, and MVI-Adult™, listed in Table 5, are added to the maintenance solution. In another example, the SoluMedrol™ and the sodium bicarbonate, listed in Table 5, are added to the priming solution. The additional components may also be combined in one or more combinations or all together and placed in solution before being added to the first or second solution or to the maintenance solution. These additional components may be degraded or otherwise inactivated if subjected to sterilization, and, as such, may be appropriately applied directly to the perfusion circuit or to a first solution 13 or a second solution 15 after sterilization, such as described with regard to the composition or solution 19 of
As described above, in certain illustrative embodiments, solutions are used to perfuse an organ prior to transplantation. In certain embodiments, one or more solutions are applied to maintain the organ, and a separate solution is applied to prime the organ prior to applying one or more maintenance solutions. Certain exemplary components for priming solutions are identified in Table 6. In some embodiments, the priming solutions include one or more carbohydrates. The component amounts in Table 6 are relative to each other and to the amount of aqueous solvent (about 500 mL) and may be scaled as appropriate. In certain embodiments, the quantity of aqueous solvent varies±about 10%.
In some illustrative embodiments, the invention combines solutions as described herein in desired sequences to provide for improved physiological performance of the organ. Although the first and second solutions are shown above and referenced as solutions 13 and 15 in
In some illustrative embodiments, the solutions contemplated herein may be adapted for use with an organ perfusion system such as that described in U.S. Pat. Nos. 6,100,082, 6,046,046, or PCT Application No. PCT/US98/19912, the specifications of which are hereby incorporated by reference in their entireties.
Certain embodiments of the first solution include epinephrine and a plurality of amino acids. In certain embodiments, the first solution includes electrolytes, such as calcium and magnesium. The first solution may also include other components such as adenosine and/or one or more components from Table 3. In certain embodiments a second solution includes one or more carbohydrates and may also include a phosphate source. The second solution is typically maintained at a pH of about 5.0 to about 6.5, for example, about 5.5 to about 6.0.
In certain embodiments, methods for perfusing an organ are provided through the use of solutions described herein, such as through the systems illustrated in
In one illustrative embodiment, the system described in
In one embodiment, a composition for use in a solution for perfusing an organ, such as a heart, is provided comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids that do not include asparagine, glutamine, or cysteine. The composition may also include other substances, such as those used in solutions described herein.
In another embodiment, a system for perfusing an organ, such as a heart, is provided comprising an organ and a substantially cell-free composition, comprising one or more carbohydrates, one or more organ stimulants, and a plurality of amino acids that do not include asparagine, glutamine, or cysteine. Substantially cell-free includes systems that are substantially free from cellular matter; in particular, systems that are not derived from cells. For example, substantially cell-free includes compositions and solutions prepared from non-cellular sources.
In another aspect, the solutions and systems may be provided in the form of a kit that includes one or more organ maintenance solutions. An exemplary maintenance solution may include components identified above in one or more fluid solutions for organ perfusion. In certain embodiments, the maintenance solution may include multiple solutions, such as a first solution and a second solution and/or a supplemental composition or solution, or may include dry components that may be regenerated in a fluid to form one or more solutions for organ perfusion. The kit may also comprise one or more concentrated solutions which, on dilution, provide a first, second, and/or supplemental solution as described herein. The kit may also include a priming solution. In an exemplary embodiment, the maintenance solution includes a first solution and second solution such as those described above, and a priming solution such as that described above.
In certain embodiments, the kit is provided in a single package, wherein the kit includes one or more solutions (or components necessary to formulate the one or more solutions by mixing with an appropriate fluid), and instructions for sterilization, flow and temperature control during perfusion and use and other information necessary or appropriate to apply the kit to organ perfusion. In certain embodiments, a kit is provided with only a single solution (or set of dry components for use in a solution upon mixing with an appropriate fluid), and the single solution (or set of dry components) is provided along with a set of instructions and other information or materials necessary or useful to operate the solution in a perfusion apparatus or system.
In another aspect, the systems, solutions and methods may be used to deliver therapeutics to an organ during perfusion. For example, one or more of the solutions and/or systems described above may include one or more drugs, biologics, gene therapy vectors, or other therapeutics which are delivered to the organ during perfusion. Suitable exemplary therapeutics may include drugs, biologics, or both. Suitable drugs may include, for example, antifungals, anti-microbials or anti-biotics, anti-inflammatories, anti-proliferatives, anti-virals, steroids, retinoids, NSAIDs, vitamin D3 and vitamin D3 analogs, calcium channel blockers, complement neutralizers, ACE inhibitors, immunosuppressants, and other drugs. Suitable biologics may include proteins; suitable biologics may also include vectors loaded with one or more genes for gene therapy application.
For example, suitable steroids include but are not limited to androgenic and estrogenic steroid hormones, androgen receptor antagonists and 5-α-reductase inhibitors, and corticosteroids. Specific examples include but are not limited to alclometasone, clobetasol, fluocinolone, fluocortolone, diflucortolone, fluticasone, halcinonide, mometasone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone, and dexamethasone, and various esters and acetonides thereof.
Suitable retinoids include but are not limited to retinol, retinal, isotretinoin, acitretin, adapalene, tazarotene, and bexarotene.
Suitable NSAIDs include but are not limited to naproxen, suprofen, ketoprofen, ibuprofen, flurbiprofen, diclofenac, indomethacin, celecoxib, and rofecoxib.
Suitable vitamin D3 analogues include but are not limited to doxercalciferol, seocalcitol, calcipotriene, tacalcitol, calcitriol, ergocalciferol, and calcifediol.
Suitable anti-viral agents include but are not limited to trifluridine, cidofovir, acyclovir, penciclovir, famciclovir, valacyclovir, ganciclovir, and docosanol.
Suitable human carbonic anhydrase inhibitors include but are not limited to methazolamide, acetazolamide, and dorzolamide.
Suitable anti-proliferative agents include but are not limited to 5-FU, taxol, daunorubicin, and mitomycin.
Suitable antibiotic (antimicrobial) agents include but are not limited to bacitracin, chlorhexidine, chlorhexidine digluconate, ciprofloxacin, clindamycin, erythromycin, gentamicin, lomefloxacin, metronidazole, minocycline, moxifloxacin, mupirocin, neomycin, ofloxacin, polymyxin B, rifampicin, rufloxacin, tetracycline, tobramycin, triclosan, and vancomycin. The antiviral and antibacterial prodrugs described herein may be used to treat appropriately responsive systemic infections.
Certain experimental data are available to describe certain embodiments of the solutions described herein and their use in organ perfusion. Certain data are set for in
This application incorporates by reference the specification from each of the following applications: U.S. application Ser. No. 09/534,092, filed on Mar. 23, 2000; PCT/US98/19912, filed on Sep. 23, 1998; U.S. application Ser. No. 09/054,698, filed on Apr. 3, 1998; and U.S. application Ser. No. 08/936,062, filed on Sep. 23, 1997.
It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. For example, a variety of systems and/or methods may be implemented based on the disclosure and still fall within the scope of the invention. Other aspects, advantages, and modifications are within the scope of the following claims.
This application is a continuation of U.S. patent application Ser. No. 16/053,206, filed Aug. 2, 2018, which is a continuation of U.S. patent application Ser. No. 14/734,769, filed Jun. 9, 2015, now U.S. Pat. No. 10,039,276, which is a divisional of U.S. patent application Ser. No. 11/246,919, filed Oct. 7, 2005, now U.S. Pat. No. 9,078,428, and claims priority to U.S. Provisional Patent Application No. 60/725,168, filed Oct. 6, 2005, entitled “Systems and Methods for Ex-Vivo Organ Care,” and U.S. Provisional Patent Application No. 60/694,971, filed Jun. 28, 2005, entitled “Systems and Methods for Ex-Vivo Organ Care.” The entire contents of each of the above is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 60725168 | Oct 2005 | US | |
| 60694971 | Jun 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11246919 | Oct 2005 | US |
| Child | 14734769 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 16053206 | Aug 2018 | US |
| Child | 18241286 | US | |
| Parent | 14734769 | Jun 2015 | US |
| Child | 16053206 | US |
