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Compositions and method for tissue preservation

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Compositions and method for tissue preservation


Methods and compositions for resuscitating, storing, and preserving functional integrity of organs and tissues. Metabolic function is maintained by sustaining ATP levels, mitochondrial function, cardiomyocyte contractility, prevention of acidosis, inhibition of induction of apoptosis, maintaining ionontrophy and lusiotrophy by regulating calcium, sodium, potassium and chloride ions.

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Inventors: Hemant Thatte, Patrick Treanor, Shukri F. Khuri, Randa Khuri, Laki Rousou
USPTO Applicaton #: #20120264103 - Class: 435 12 (USPTO) - 10/18/12 - Class 435 
Chemistry: Molecular Biology And Microbiology > Differentiated Tissue Or Organ Other Than Blood, Per Se, Or Differentiated Tissue Or Organ Maintaining; Composition Therefor >Including Perfusion; Composition Therefor



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The Patent Description & Claims data below is from USPTO Patent Application 20120264103, Compositions and method for tissue preservation.

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RELATED U.S. APPLICATIONS

This application is a continuation of U.S. application Ser. No. 12/527,119, filed Aug. 13, 2009, which claims priority to International Application No. PCT/US2008/002170, filed Feb. 19, 2008, and which claims priority to U.S. Provisional Application No. 60/901,844 filed Feb. 17, 2007, U.S. Provisional Application No. 60/902,587, filed Feb. 20, 2007, and U.S. Provisional Application No. 60/966,511, filed Aug. 27, 2007, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to tissue preservation.

BACKGROUND OF THE INVENTION

The major obstacles in cardiac transplantation are the limited availability of donor hearts and the poor quality of donor hearts due to deterioration during storage. Using current practices and preservation solutions, the limit of preservation time is 4-6 hours, and in the United States, all cardiac allografts are presently obtained from brain-dead, beating heart donors maintained on life support systems. Moreover, current practices result in a significant incidence of accelerated vasculopathy in transplanted hearts. As such, there is a pressing need for long-term storage solutions that preserve the structural and physiological integrity of donor hearts.

SUMMARY

OF THE INVENTION

The invention provides a solution for preserving a human or human-compatible harvested organ in need of preservation or resuscitation during a preservation or evaluation period prior to implantation, including transplantation or reimplantation. The solution of the invention also allows the organ to be transported to alternate geographic locations during the preservation period. The invention provides improved compositions, methods, and devices for organ storage, which preserve the functional integrity of the organ as well as restore the function to a non-functioning or deteriorated organ. Increasing the use of non-beating heart (NBH) donors and storage of donor hearts for a longer period of time would increase the size of the donor pool substantially and allow transport of donor hearts over longer distances to increase availability to recipients. Transplantation of hearts with intact, functioning coronary endothelium as a result of storage in the improved solution minimizes vasculopathy that occurs after cardiac transplantation using current technology.

The invention provides for compositions for preserving or resuscitating a biological tissue. The composition contains a physiological salt solution and at least one, at least two, at least three, at least four, or at least five of the following compositions: a substrate for the production of adenosine tri phosphate (ATP), a substrate for the consumption of ammonia, a reagent that buffers intracellular acidity, a reagent that quenches reactive oxygen species, and/or a reagent that balances tissue edema/dehydration.

In one aspect, the composition contains a physiological salt solution and a substrate for the production of ATP. Optionally, the substrate for the production of ATP is phosphocreatine, creatine ethyl ester, dicreatine malate, creatine gluconate, fructose, sucrose, ribose, hexose or pentose. Alternatively, the substrate for the production of ATP is creatine orotate, creatine monohydrate, adenosine, or dextrose/glucose.

The composition for preserving or resuscitating a biological tissue contains a physiological salt solution and a compound for the consumption of ammonia. Optionally, the compound for the consumption of ammonia is ornithine or carbomyl phosphate. Alternatively, the compound for the consumption of ammonia is L-citrulline malate.

In another aspect, the composition for preserving or resuscitating a biological tissue contains a physiological salt solution and a reagent that buffers intracellular acidity. In one aspect, the reagent that buffers intracellular acidity is Histidine, Glutamine, Tryptophan, Lysine, or Taurine. Alternatively, the reagent that buffers intracellular acidity is sodium bicarbonate, THAM, or L-carnosine.

Optionally, the composition for preserving or resuscitating a biological tissue contains a physiological salt and a reagent that quenches reactive oxygen species. In one aspect, the reagent that quenches reactive oxygen species is dithiothreitol (DTT), beta-Mercaptoethanol, Acetylcysteine, Alpha lipoic acid, Taurine, Reserveratrol, Lutein, Selenium, Methionine, or Tocopherols/Vitamin E.

In yet another aspect, the composition for preserving or resuscitating a biological tissue contains a physiological salt and a reagent that balances tissue water content (edema/dehydration). Reagents that balance tissue water content include Mannitol, urea, glycerine, isosorbide, or raffinose pentahydrate. Optionally, the reagent that balances tissue water content is the penta fraction of raffinose pentahydrate.

The solution is used to resuscitate a living donor heart, a temporally stored living donor heart for transplantation, as well as cadaveric donor heart and permits extended temporal storage of living, stored, or cadaveric organs such as the heart. Cardiomyocyte function in living donor and cadaveric hearts are preserved as well as endothelial function in coronary vasculature and chambers of the living donor and the cadaveric heart. The solution also mediates reversal of metabolic and degenerative changes and inhibition of cell death and progression to cell viability in the hearts (and other organs) when the organ is contacted with and stored in the solution of the invention shortly after death. Metabolic function is maintained by sustaining ATP levels, mitochondrial function, cardiomyocyte contractility, prevention of acidosis, inhibition of induction of apoptosis. Ionontrophy and lusiotrophy are maintained by regulating calcium, sodium, potassium and chloride ions. Buffering capacity of the solution prevent acidosis. The solution preserves calcium mobilization, nitric oxide generation in the organ as well as maintains both endothelium-dependent and independent vasomotor function in the coronary vasculature. Dehydration and subsequent over-hydration (edema) is prevented upon reperfusion by manipulating ionic concentrations and aquaporin channels, and ischemia-reperfusion injury is prevented. The solution and storage system is a self-sustaining regenerative system for production of substrates for ATP and nitric oxide.

The compositions prevent ischemia-reperfusion injury. This function is mediated by ascorbic acid and glutathione, carnitine (by preventing accumulation of long chain acyl-CoA that leads to generation of free radicals-ischemi-reperfusion injury), carnosine and alpha lipoic acid which are free radical, (hydroxyl radical, singlet oxygen, peroxyl radical and superoxide) scavenger. The composition contains calcium chloride, potassium chloride, potassium phosphate, magnesium sulfate, sodium bicarbonate, D-glucose, adenosine, glutathione, insulin, and a reagent to prevent dehydration and/or edema of an organ and/or tissue. The solution also contains other salts such as magnesium chloride, sodium chloride, and/or sodium phosphate dibasic.

Dehydration of the heart (during storage) and over-hydration or edema after reperfusion is controlled by manipulating sodium (less) and potassium ions (more) (i.e., osmolarity). The solution is slightly hypotonic and hyposmolar, hence driving the water into the heart during storage and balancing out during reperfusion. The increase in external KCl concentration counterbalances the K current (close to Nerst potential) and prevents potassium from moving out along with water (shell of hydration of K ion). Dehydration/edema is also controlled by manipulating the aquaporin channels via the ionic currents. Also, external K may delay/decrease the movement of Ca ions into the cell, thus preventing dehydration via Ca activated K channel For example, the solution contains 125 mM sodium and 7 mM potassium. In one aspect, the composition contains calcium chloride, potassium chloride, potassium phosphate, magnesium sulfate, sodium bicarbonate, D-glucose, adenosine, glutathione, insulin, and a substrate for the production of ATP. For example, the substrate for the production of ATP is creatine orotate, creatine monohydrate, adenosine, or dextrose/glucose. Dichloroacetate increases ATP production by inhibiting the kinase enzyme that phosphorylates PDH enzyme making it inactive. Dichloroacetate induces ATP synthesis by facilitating the TCA cycle.

In the citrulline malate-arginine cycle, malate (cleaved from citrulline) enters the TCA cycle to generate more ATP. Also, citrulline malate is converted to arginine and fumarate; fumarate enters the TCA cycle to facilitate more ATP production. Both malate and fumarate in TCA cycle leads to more ATP production.

The composition contains calcium chloride, potassium chloride, potassium phosphate, magnesium sulfate, sodium bicarbonate, D-glucose, adenosine, glutathione, insulin, and a reagent that buffers acidity. A reagent that buffers intracellular acidity is creatine orotate via facilitated synthesis of carnosine. Creatine monohydrate buffers acidity by increasing energy production and decreased lactate accumulaton. Acidity is also buffered by sodium bicarbonate, Tris-hydroxymethyl aminomethane (THAM), and L-carnosine (intracellular acidity). Dichloroacetate controls acidity by lowering lactate levels in the preserved organ, and thus the solution. L-carnitine facilitates a decrease in myocardial lactate production, hence reducing acidity.

The composition contains calcium chloride, potassium chloride, potassium phosphate, magnesium sulfate, sodium bicarbonate, D-glucose, adenosine, glutathione, insulin, and a substrate for the consumption of ammonia. For example, the substrate for the consumption of ammonia is L-citrulline malate Ammonia combines with carbamoyl phosphate to form citrulline malate, which forms a substrate for nitric oxide and ATP.

The composition contains calcium chloride, potassium chloride, potassium phosphate, magnesium sulfate, sodium bicarbonate, D-glucose, adenosine, glutathione, insulin, a reagent to prevent dehydration and/or edema of an organ and/or tissue, a substrate for the production of ATP, a reagent that buffers acidity, and a substrate for the consumption of ammonia. Preferably, the composition includes the following compounds and concentrations:

about 0.147 g/L calcium chloride (1 mM)

about 0.52 g/L potassium chloride (7 mM)

about 0.06 g/L potassium phosphate (monobasic) (0.44 mM)

about 0.11 g/L magnesium chloride (hexahydrate) (0.50 mM)

about 0.125 g/L magnesium sulfate (heptahydrate) (0.50 mM)

about 7.30 g/L sodium chloride (125 mM)

about 0.35 g/L sodium bicarbonate (4.2 mM)

about 0.05 g/L sodium phosphate (dibasic; heptahydrate) (0.19 mM)

about 1.98 g/L dextrose/D-glucose (11 mM)

about 0.27 g/L adenosine (1 mM)

about 0.46 g/L glutathione (reduced; 1.5 mM)

about 0.18 g/L ascorbic acid (1 mM)

about 0.21 g/L L-arginine (1 mM)

about 0.27 g/L creatine orotate (0.5 mM)

about 0.30 g/L creatine monohydrate (2 mM)

about 0.15 g/L L-citrulline malate (1 mM)

about 0.08 g/L dichloroacetate (0.5 mM)

about 2.3 g/L-carnosine (10 mM)

about 2.0 g/L-carnitine (10 mM)

about 0.021 g/LAlpha-Lipoic acid (0.1 mM)

about 0.50 ml/L insulin (10 mg/ml)

THAM (Tris-Hydroxymethyl Aminomethane; 100 mM stock @12.1 gm/L) to adjust

pH (about 1 L distilled water).

The ingredients are mixed together to form a solution. Insulin is optionally added after the other ingredients are mixed. For example, insulin is added minutes, e.g., 0.5, 1, 2, 5, minutes to hours, e.g., 0.5, 1, 2, 3, 4, or 5 hours prior to immersing an organ in the solution.

A preferred composition includes amounts of the compounds in the following ranges to achieve a desired ratio of compositions:

0.1-0.5 g/L calcium chloride

0.25-0.75 g/L potassium chloride (7 mM)

0.01-0.5 g/L potassium phosphate (monobasic)

0.01-0.5 g/L magnesium chloride (hexahydrate)

0.01-0.5 g/L magnesium sulfate (heptahydrate)

5.0-10.0 g/L sodium chloride (125 mM)

0.01-0.5 g/L sodium bicarbonate

0.01-0.5 g/L sodium phosphate (dibasic; heptahydrate)

1.0-5.0 g/L D-dextrose/glucose (11 mM)

0.01-0.5 g/L adenosine (1 mM)

0.01-0.75 g/L glutathione (reduced; 1.5 mM)

0.01-0.5 g/L ascorbic acid (1 mM)

0.01-0.5 g/L L-arginine (1 mM)

0.01-0.5 g/L creatine orotate (0.5 mM).

0.01-0.5 g/L creatine monohydrate (2 mM)

0.01-0.5 g/L L-citrulline malate (1 mM)

0.01-0.5 g/L dichloroacetate (0.5 mM)

0.23-2.3 g/L-carnosine (1-10 mM)

0.20-2.0 g/L-carnitine (1-10 mM)

0.0021-0.21 g/LAlpha-Lipoic acid (0.01-1.0 mM)

0.25-0.75 ml/L insulin (10 mg/ml)

THAM to adjust pH (0.01-3.0 L distilled water).

For example, the solution contains:

about 0.14 g/L calcium chloride

about 0.52 g/L potassium chloride (7 mM)

about 0.06 g/L potassium phosphate (monobasic)

about 0.10 g/L magnesium chloride (hexahydrate)

about 0.10 g/L magnesium sulfate (heptahydrate)

about 7.31 g/L sodium chloride (125 mM)

about 0.35 g/L sodium bicarbonate

about 0.05 g/L sodium phosphate (dibasic; heptahydrate)

about 1.98 g/L dextrose/D-glucose (11 mM)

about 0.27 g/L adenosine (1 mM)

about 0.46 g/L glutathione (reduced; 1.5 mM)

about 0.18 g/L ascorbic acid (1 mM)

about 0.21 g/L L-arginine (1 mM)

about 0.27 g/L creatine orotate (0.5 mM)

about 0.30 g/L creatine monohydrate (2 mM)

about 0.15 g/L L-citrulline malate (1 mM)

about 0.08 g/L dichloroacetate (0.5 mM)

about 2.3 g/L-carnosine (10 mM)

about 2.0 g/L-carnitine (10 mM)

about 0.021 g/LAlpha-Lipoic acid (0.1 mM)

about 0.50 ml/L insulin (10 mg/ml)

THAM to adjust pH (about 1 L distilled water).

The solutions described above are used to maintain the physiological integrity of an organ. The organ or tissue, which is preferably isolated from a human body or the body of an animal, is contacted for a duration of at least 1 hour. Alternatively, the organ or tissue is perfused in situ, i.e., prior to being removed from the body. For example, the organ or tissue is contacted in situ in a cadaver or in a living patient. The organ or tissue is contacted with the solution from a period of about 1-5 hours, e.g., 4 hours up to several days, e.g., 1, 2, 5, 8, days or more.

A variety of different organs and tissue types are favorably stored and resuscitated using the solutions. For example, the organ or tissue is a heart. Other suitable tissues/organs include kidney, liver, stomach, spleen, pancreas, lung, brain, eye, intestines, bladder, skin or dermal tissue, blood vessels such as veins or arteries, heart valves, sperm, and oocyte(s).

The method of maintaining or restoring the physiological integrity of an organ or tissue is carried out by contacting the organ or tissue with the solution(s) described above for a duration of time such that esterase activity is in the range of >150 arbitrary fluorescence photon units, intracellular NO concentration is in the range of >1 nM, and mitochondrial membrane potential ratio of the cells of the organ is >1.00. The solution preserves intact cardiac myocyte contractile proteins (myosin heavy chain (HC), myosin light chain (LC), acitinin, actin, troponinc C); eNOS, caveolin, and vWF, e.g., as assessed with Western and Immunoblots, whereas storage of tissues/organs such as heart in previous solutions led to degradation of such proteins such as myosin heavy chain thereby compromising the integrity and function of the transplanted organ. Absence or fragmentation of these compostions indicate deterioration of the organ. Clinical parameters include Left Ventricular End Diastolic Pressure (LVEDP) 0-30 mm Hg, BP 100-140/60-100, pH>6.8. The solution also inhibits stenosis, plaques, clot formation due to damaged endothelium, as well formation of an atheroma (arterial sclerosis), which is a significant problem in transplant cases.

Also within the invention is a method of evaluating the physiological integrity of an organ or tissue. The organ or tissue is contacted with solution(s) described above (or another solution) and a level of concentration or activity of one or more of the following parameters is detected or evaluated. Biological indices to be evaluated include esterase, nitric oxide, or cellular membrane potential. Esterase activity is in the range of >150 arbitrary (fluorescence photon) units, intracellular NO concentration is in the range of >1 nM, and mitochondrial membrane potential of the cells of said organ is in the range of >1.00 (ratio of polarized versus depolarized, where >1 indicates that the mitochondrial membrane is polarized and the tissue is healthy. The foregoing values indicate that the organ or tissue, e.g., a heart, is suitable for transplantation into a recipient living mammal.

The compositions for making the storage/resuscitation solution are optionally packaged in a kit with the ingredients/amounts listed below or multiples thereof, i.e., scaled up to make 2, 3, 5, 10, 20 times the amount of solution. An exemplary kit contains



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stats Patent Info
Application #
US 20120264103 A1
Publish Date
10/18/2012
Document #
13488749
File Date
06/05/2012
USPTO Class
435/12
Other USPTO Classes
435/11, 435374
International Class
01N1/02
Drawings
17


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Unite States Government As Represented By The Department Of Veterans Affairs Office Of

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Chemistry: Molecular Biology And Microbiology   Differentiated Tissue Or Organ Other Than Blood, Per Se, Or Differentiated Tissue Or Organ Maintaining; Composition Therefor   Including Perfusion; Composition Therefor