Aqueous solution for preserving tissues and organs

Details Aqueous solution for preserving tissues and organs Aqueous solution for preserving tissues and organs

2001-11-19

2003-11-04

Lankford, Jr., Leon B. (Department: 1651)

Chemistry: molecular biology and microbiology

Differentiated tissue or organ other than blood, per se, or...

Including freezing; composition therefor

C435S002000, C435S325000, C435S374000, C436S018000

Reexamination Certificate

active

06641992

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to an aqueous solution for preserving tissues and organs.
BACKGROUND OF THE INVENTION
After removal from a donor and before transplantation into a recipient, the organ(s) or tissues are subjected to an unavoidable period of ischemia. Thus the liquid solutions used to preserve the organ(s) and tissues have to:
wash the graft free of residual blood,
cool down the organ,
ensure effective prevention and protection against the lesions caused by ischemia.
The liquid solutions currently used do not ensure the preservation of all organs and tissues. Thus there exists a need for a single solution that preserves any tissue and organ.
The method generally used for preserving organs is static hypothermic preservation where the removed organ or tissue is rinsed with a cold preservation solution and maintained in the cold preservation solution. The problem with the cold preservation solutions currently available is that the organs or tissues are preserved for only a limited time, i.e. generally about 24 hours for the kidney, 12 to 18 hours for the liver, and 4 to 6 hours for the heart.
Further, the solutions used to preserve the organ(s) and tissues have different compositions according to the organ(s) and tissues that must be preserved.
For example, the solution EURO COLLINS marketed by FRESENIUS and the BELZER-VIASPAN liquid also known by the name UW (University of Wisconsin) marketed by DUPONT, are recommended for the preservation of the kidney. These solutions are so called “intracellular” type ionic mixtures, in which the potassium concentration is greater than the sodium concentration.
For hepatic preservation, the BELZER-VIASPAN solution may be used.
For cardiac graft preservation, the SAINT THOMAS solution may be used. This solution is a so called “extracellular”-type ionic mixture, in which the sodium concentration is greater than the potassium concentration. Further, this solution is free of any macromolecule. SAINT THOMAS is marketed by Laboratoires AGUETTANT.
The composition of EURO COLLINS, BELZER-VIASPAN, and SAINT THOMAS is set forth in Table 1 below.
TABLE 1
SAINT-
EURO
THOMAS
COLLINS
BELZER
Sodium (mM)
120
30
Potassium (mM)
16
125
Raffinose (mM)
30
Lactobionate (mM)
100
Glutathione (mM)
3
Adenosine (mM)
5
Allopurinol (mg/l)
1
HEA (g/l)
50
hydroxyethyl starch
MW: 250 000
MgSO
4
(mM)
5
H
2
PO
4
(mM)
25
KH
2
PO
4
(g/l)
2.0
Glucose (g/l)
25
HCO
3
(mM)
10
Cl (mM)
160
Mg (mM)
16
CaCl
2
(mM)
1.2
K
2
HPO
4
3H
2
O (g/l)
9.70
KCl (g/l)
1.12
MgSO
4
7H
2
O (g/l)
7.38
NaHCO
3
(g/l)
0.86
Osmolarity (mOsm/kg)
290
320
300
As already stated and as shown in the summary table above, the solution selected for the cardiac preservation is of the extracellular type (rich in sodium), whereas the preservation solution for preserving the kidney and the liver is of the intracellular type (rich in potassium).
One of the disadvantages of these solutions is that they do not preserve all organs and tissues.
The subject invention relates to novel compositions and methods used to preserve a wider variety of organs and tissues for a longer time and in better functional condition than previously possible.
SUMMARY OF THE INVENTION
As used herein, the term “tissues” may include without limitation veins, arteries, valves, and vessels.
One aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising calcium ions, polyethylene glycol having a molecular weight of about 35,000, and from 30 to 250 millimolar sodium ions.
Another aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising calcium ions, polyethylene glycol having a molecular weight of about 35,000, from 30 to 250 millimolar sodium ions, and wherein the polyethylene glycol is substantially free of polyethylene glycol having a molecular weight below 15,000.
An additional or alternative aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising calcium ions, polyethylene glycol having a molecular weight of about 35,000, and wherein the concentration of sodium ions is 125 millimolar.
A further aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising from 0.1 to 2 millimolar calcium ions, polyethylene glycol having a molecular weight of about 35,000, and from 30 to 250 millimolar sodium ions.
Another aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising calcium ions, polyethylene glycol having a molecular weight of about 35,000, from 30 to 250 millimolar sodium ions, and from 0.01 to 5 millimolar polyethylene glycol.
An alternative aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising calcium ions, polyethylene glycol having a molecular weight of about 35,000, from 30 to 250 millimolar sodium ions, impermeant anion, a sugar, a membrane-stabilizing agent, a buffer solution, an anti-free radical agent, and an energy source.
A further aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising polyethylene glycol having a molecular weight of about 35,000 and wherein the polyethylene glycol is substantially free of polyethylene glycol having a molecular weight below 15,000, the concentration of sodium ions is from 30 to 250 millimolar, the concentration of calcium ions is from 0.1 to 2 millimolar, and the concentration of polyethylene glycol is from 0.01 to 5 millimolar.
Another aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising polyethylene glycol having a molecular weight of about 35,000 and wherein the polyethylene glycol is substantially free of polyethylene glycol having a molecular weight below 15,000, the concentration of sodium ions is from 30 to 250 millimolar, the concentration of calcium ions is from 0.1 to 2 millimolar, the concentration of polyethylene glycol is from 0.01 to 5 millimolar, the pH of the aqueous solution is from 6.5 to 8, the osmolarity of the aqueous solution is from 290 to 320 millimoles/kg, and the aqueous solution additionally comprises raffinose, MgSO
4
, H
2
PO
4
−
, glutathione, adenosine, allopurinol, and potassium ions.
Another aspect of the present invention relates to an aqueous solution for the preservation of tissues and organs comprising polyethylene glycol having a molecular weight of about 35,000 and wherein the polyethylene glycol is substantially free of polyethylene glycol having a molecular weight below 15,000, the concentration of sodium ions is from 30 to 250 millimolar, the concentration of calcium ions is from 0.1 to 2 millimolar, the concentration of polyethylene glycol is from 0.01 to 5 millimolar, the pH of the aqueous solution is from 6.5 to 8, the osmolarity of the aqueous solution is from 290 to 320 millimoles/kg, and the aqueous solution additionally comprises raffinose, MgSO
4
, H
2
PO
4
−
glutathione, adenosine, allopurinol, potassium ions, and lactobionic acid.
Generally, the concentration of raffinose may be from 20 to 40 millimolar, the concentration of MgSO
4
may be from 1 to 10 millimolar, the concentration of H
2
PO
4
−
may be from 10 to 40 millimolar, the concentration of glutathione may be from 1 to 6 millimolar, the concentration of adenosine may be from 1 to 10 millimolar, the concentration of allopurinol may be from 0.5 to 5 millimolar, the concentration of potassium ions may be from 10 to 40 millimolar, and the concentration of lactobionic acid may be from 70 to 140 millimolar.
More preferably, the concentration of raffinose is 30 millimolar, the concentration of MgSO
4
is 5 millimolar, the concentration of H
2
PO
4
−
is 25 millimolar, the concentration of glutathione is 3 millimolar, the concentration of adenosine is 5 millimolar, the concentration of allopurinol is 1.0 millimolar, the concentration of potassium ions is 25 millimolar, t

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