JP2013075888A - Organ preservation device - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an organ preservation device for preserving an organ which is taken out from a living body, which can select an optimum preserving condition for the organ by analyzing the condition of the organ during preservation.SOLUTION: The organ preservation device includes: an organ preserving part (19) for preserving an organ (18); a preserving liquid perfusion part (20) for perfusing the organ (18) preserved in the organ preserving part with preserving liquid for preserving organs; a temperature control part for controlling the temperature of the organ preserving part; an introduction part (21) for introducing an active component agent into the preserving liquid circulating through the preserving liquid perfusion part (20); a function-evaluating part for evaluating functions of the organ by measuring the rate of flow of the preserving liquid perfusing the organ (18); and an adjusting part (33) for adjusting the temperature of the temperature control part, the type and the introduction amount of the active component agent introduced from the introduction part (21), and the rate of flow of the preserving liquid based on the data obtained by the function-evaluation.

Description

  The present invention is an organ storage device that can store an organ taken out of a living body of a mammal such as a human and analyze the state of the organ being stored and select an optimal storage state.

Various apparatuses for storing an organ taken out from a living body have been proposed. For example, Patent Document 1 proposes a storage apparatus shown in FIG. A container (2), an arterial perfusion circuit (3), a portal perfusion circuit (5), at least one flow sensor (7), and at least one pressure, storing the liver graft (1) in a preservation solution In order to improve the preservation of liver graft (1) with sensor (8), it was further connected to arterial oxygenator (11) connected to arterial perfusion circuit (3), portal perfusion circuit (5) Temperature conversion configured to maintain the temperature inside the portal oxygenator (12), at least one arterial perfusion pump (9), at least one portal perfusion pump (10), and the container (2) at normal body temperature A device comprising a module (13) and a pressure and flow control device (14) has been proposed.
In such a device, the temperature and the pressure and flow rate of the liquid to be circulated can be adjusted so that the liver or liver graft can be stored under normal body temperature conditions.

Special table 2011-520839 gazette

However, the organ storage device according to the above-mentioned proposal merely performs storage under predetermined conditions. In some cases, the stored organ state is not suitable for transplantation. It was.
In other words, the organ preservation device that has been proposed in the past only preserves the organ, and it is currently unknown whether it is suitable for transplantation. Whether the stored organ is suitable for transplantation or not. There is a need to provide an organ preservation device that can discriminate between them and can maintain a state suitable for transplantation.
Accordingly, an object of the present invention is to provide an organ storage device that can store an organ taken out of a living body and analyze the state of the organ being stored to select an optimal storage state.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have measured the flow rate and pressure of a preservation solution to be perfused into a preserved organ and collated it with a preset database or a programmed control law and evaluation standard. As a result, it was found that the state of the organ can be grasped, and the present invention has been completed.
That is, the present invention provides the following devices.
An organ preservation device for perfusion preservation of an organ separated from a living body,
An organ holding unit for holding the organ;
A preservation solution perfusion section for perfusing an preservation solution for organ preservation to the organ held in the organ holding section;
A temperature management unit for managing the temperature of the organ preservation unit;
An introduction part for introducing an active ingredient into a preservation solution to be distributed to the preservation solution perfusion part;
A function evaluation unit that evaluates the function of the organ by measuring the flow rate and pressure of the preservation solution to be perfused into the organ;
Organ preservation comprising a temperature control part based on data obtained by functional evaluation, and an adjustment part for adjusting the type and amount of active ingredient introduced by the introduction part and the flow rate of the preservation solution Device.
Examples of organs that can be preserved in the present invention include liver, kidney, heart, small intestine, pancreas and the like, and can be preferably applied particularly to the liver.
Further, the present invention is characterized in that the temperature management unit controls the temperature of the preservation solution stored in the organ preservation unit so as to gradually warm and / or cool the temperature of the preservation solution from 4 ° C. to 25 ° C. The organ preservation apparatus is provided.
The present invention also provides an organ preservation method using the above organ preservation device, characterized by gradually heating and / or cooling the temperature of the organ preservation part from 4 ° C. to 25 ° C. .

  According to the organ preservation device of the present invention, an organ taken out from a living body can be preserved, and an optimal preservation state can be selected by analyzing the state of the organ being preserved, so that the organ taken out from the living body is not simply deteriorated. Rather than storing, even if the organ has deteriorated, if the deteriorated portion can be repaired, it can be repaired and the organ can be held in a state suitable for transplantation.

It is the schematic which shows the conventional organ preservation apparatus. It is a perspective view which shows embodiment of this invention. It is a flow of processing of perfusion flow rate information and perfusion pressure information obtained from a flow meter. It is a graph which shows the amount of lactose dehydrogenase (LDH) released | released in the preservation | save liquid in the organ preservation | save performed in Examples 1-3.

18 organ 19 organ holding unit 20 preservation solution perfusion unit 21 introduction unit 22 pump 23 air trap 24 oxygen addition management unit 25 flow meter 26 pressure sensor 27 valve 28 air trap 29 temperature measurement unit 30 heat exchange unit 31 pump 32 filter 33 adjustment unit

  Hereinafter, the present invention will be described in detail with reference to the drawings, but the present invention is not limited thereto.

The organ preservation device of the present embodiment is an organ preservation device for perfusion preservation of an organ separated from a living body, and as shown in FIG.
An organ holding part (19) for holding the organ (18);
A preservation solution perfusion section (20) for perfusing a preservation solution for organ preservation to the organ (18) held in the organ holding section;
A temperature management unit for managing the temperature of the organ preservation unit;
An introduction part (21) for introducing an active ingredient into a preservation solution to be circulated through the preservation solution perfusion part (20);
A function evaluation unit that evaluates the function of the organ by measuring the flow rate of the preservation solution to be perfused into the organ (18);
An adjustment unit (33) for adjusting the temperature of the temperature management unit, the type and amount of the active ingredient introduced by the introduction unit (21), and the flow rate of the preservation solution based on the data obtained by the function evaluation; It has. FIG. 2 specifically shows an organ preservation device that enables circulation of the portal vein and hepatic artery.
In addition, Wisconsin solution [University of Wisconcin]
(UW) solution] (Patent Document 1, JP-A-7-330501).

This will be described in more detail below.
The organ holding part (19) has an opening on one side and is formed of a hollow rectangular box, and an organ (liver (18) in the present embodiment) immersed in a preservation solution is contained therein. It is supposed to be placed. Although the opening is not particularly shown here, a lid that can be freely opened and closed may be provided.
Further, the pH of the solution in the organ holding part (19) is measured by a pH meter, and the dissolved oxygen amount of the solution in the organ holding part (19) is measured by a dissolved oxygen concentration meter (Do meter).

The preservation liquid perfusion section (20) includes an introduction pipe section for introducing the preservation liquid into the organ (18) and a discharge pipe section for discharging the preservation liquid from the organ.
The introduction tube part is a part for introducing the preservation solution injected into the organ preservation unit into the organ, and the transfer pump, one end of which is connected to the transfer pump and the other end is the preservation solution in the organ preservation unit. An extraction tube immersed in the tube, an introduction tube having one end connected to a transfer pump and the other end connected to an organ, an air trap (23, 28) and an oxygenator (24) disposed in the extraction tube, It consists of a flow meter (25), a pressure sensor (26) and a valve (27) arranged in the introduction pipe.
The drainage pipe part is a part for draining the preservation solution injected into the organ to the outside of the organ, a transfer pump, and a drainage pipe having one end connected to the transfer pump and the other end provided in the organ preservation part. A lead-out tube having one end connected to the transfer pump and the other end connected to the organ, an air trap (23, 28), a flow meter (25), a pressure sensor (26), and a valve (27) arranged in the lead-out tube ).
In FIG. 2, a hepatic artery circulation tube and a portal circulation tube are clearly shown. In FIG. 2, the flow of the above-described preservation solution in the hepatic artery circulation tube and the portal vein circulation tube is indicated by arrows.

The temperature management unit includes a temperature measurement unit (29), a heat exchange unit (30) for heating and cooling the storage liquid, and a signal for adjusting the temperature set based on data from the temperature measurement unit to the heat exchange unit. It consists of a central processor (not shown) of the adjusting unit for transmission. The temperature measuring unit (29) can be composed of a normal thermocouple thermometer, and the heat exchanging unit can heat and cool the storage solution through a pipe for circulating the storage solution. A heating mechanism or a cooling mechanism can be used without particular limitation. The pipe is provided with a pump (31) and a filter (32) for removing impurities from the storage solution.
At this time, the temperature management unit (29) performs temperature control so that the temperature of the preservation solution stored in the organ preservation unit (19) is gradually heated and / or cooled to a predetermined temperature.
The predetermined temperature is preferably 4 ° C to 25 ° C.
Temperature control is performed by gradually increasing the temperature from 4 ° C. to 25 ° C. Specifically, the rate of temperature increase of the storage solution is the average rate over the entire temperature control time (total temperature change / total temperature). The control time is 0.15 to 0.25 ° C./min, and the temperature change amount per unit time (temperature change amount per unit minute) is 1.5 ° C./min to 0.01 ° C./min. It is preferable to control the temperature smoothly.
The temperature control can be performed by the adjustment unit (33) issuing an instruction to the temperature management unit, operating the temperature management unit, and appropriately heating and cooling the storage solution by the heat exchange unit (30).
By perfusing the organ with the above temperature-controlled storage solution, the organ tissue can be activated to suppress deterioration, and the deteriorated cells can be activated.

The introduction part (21) is provided with a plurality of tanks (22) so that a plurality of types of drugs (active ingredient agents) can be individually stored, and each tank (22) is an introduction pipe of the introduction piping part. Are connected to each other via a pipe and an injection pump so that various amounts of various drugs can be injected.
Examples of the drug (active ingredient) that can be used at this time include the following.
For example, carbohydrates (glucose, dextrose), oxygen, hydrogen, electrolytes (sodium, potassium, bicarbonate, calcium, magnesium), antibiotics and antimicrobials (gram negative and gram positive bacteria, penicillin), hormones (insulin, Epinephrine), endogenous metabolites or precursors of endogenous metabolites (adenosine, L-arginine), fatty acids (saturated and unsaturated, single chain and long chain), pharmaceutically active agents (vasodilators, heparin, Nitroglycerin, ACE inhibitor, beta blocker, calcium channel blocker, cytoprotective agent, antioxidant, complement, anti-complement, immunosuppressant, non-steroidal anti-inflammatory agent, antifungal agent, antiviral agent, steroids Vitamins, enzymes, coenzymes, etc.), but are not limited thereto. Other components such as adjusting the pH, stabilizing the solution and adjusting the viscosity can also be used.

The function evaluation unit is composed of the above-described flow meter. By collecting data from the flow meter (25), the state of the organ can be grasped. In particular, it is possible to grasp the state from the data of the flow meter (25) arranged in the introduction pipe. Moreover, since the data of a pressure gauge (26) can also be used supplementarily, a pressure gauge (26) can also be used as a component of a function evaluation part.
All the data is input to the central processor of the adjustment unit (33) and checked against a database or program stored in a storage medium (not shown) to evaluate the stored organ state. It will be.

  The adjustment unit (33) includes a central processor (not shown) and a storage medium storing a database or a programmed control law and evaluation standard, and inputs data of a flow meter and a pressure gauge and performs an evaluation. After that, instructions to be performed based on the evaluation are the heat exchange section (30), the pumps of the introduction pipe section and the discharge pipe section (Pump in FIG. 2), the air traps (23, 28) of the introduction pipe section, and oxygen addition An instruction is given to the management unit (24) and the introduction unit to adjust the temperature of the temperature management unit, the type and amount of the active ingredient introduced into the introduction unit, and the flow rate of the preservation solution. .

And the organ preservation apparatus of this embodiment can be used as follows.
First, as shown in FIG. 2, the organ separated from the human body, in this embodiment, the liver (18) is placed inside the organ holder (19) so that the preservation solution can be perfused uniformly. Then, as shown in FIG. 2, the end of the introduction tube of the introduction tube is connected to the hepatic artery or portal vein of the placed liver (18). Moreover, as shown in FIG. 2, the end part of the discharge pipe of the discharge pipe part is connected to the organ holding part (19).
Next, a transfer pump or the like is operated to operate the preservation solution perfusion section (20), and the preservation solution is perfused. At this time, the temperature management unit is also operated, and the storage solution is appropriately heated and cooled by the heat exchange unit to control the storage solution at an appropriate temperature. As described above, the temperature is controlled by heating and / or cooling so as to increase the temperature at a preferable rate of temperature increase, and increasing the temperature to the initial temperature, preferably 4 ° C. to 25 ° C.
In addition, when the function evaluation unit (for example, the flow meter (25) or the pressure sensor (26)) is operated to grasp the response of the organ, and it is determined that the organ has deteriorated, an instruction from the adjustment unit Thus, the temperature of the temperature control unit, the type and amount of the active ingredient introduced into the introduction unit, and the flow rate of the preservation solution are adjusted.
And evaluation of a function evaluation part and adjustment by an adjustment part are performed as follows.
As shown in FIG. 3, the perfusion flow rate information and perfusion pressure information obtained from the flow meter are sent to the central processor. Next, the deterioration of the organ function is evaluated by checking against a database set in advance by the central processor or programmed control rules and evaluation criteria, and if it is judged that transplantation will be hindered, the organ function is improved. Instructions to the transfer pump, introduction part, heat exchanging part, various conditions (liquidity of preservation solution (pH, amount of sugar chain length control component, viscosity, amount of vasodilator, amount of vasoconstrictor) Volume, cellular nutrient components, oxygen addition amount, various ion amounts), preservation solution temperature, flow rate, and pressure.

  An organ taken out from the living body of the present embodiment can be stored, and the state of the organ being stored can be analyzed to select an optimal storage state.

The present invention is not limited to the above-described embodiment, and various modifications can be made without departing from the spirit of the present invention.
For example, the organ storage device of the present invention can be used not only in human organs (eg, liver) but also in mammalian organs (eg, pig liver).

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated more concretely, this invention is not restrict | limited at all to these.

[Example 1] The organ shown in FIG. 2 was used as an organ preservation organ preservation device by perfusion in which the liver after warm ischemia treatment was gradually reheated from a low temperature using an organ preservation device.
First, the organ holding part (19) of the organ preservation device was filled with 1.5 liters of a solution prepared by preparing components based on the University of Wisconsin solution as a preservation solution for organ resuscitation.
Next, the temperature control part was set to 4 ° C. and operated, and the temperature of the preservation solution was set to 4 ° C.
As experimental animals, pigs (large Yorkshire species, Duroc hybrids , body weight 20 kg, 2-3 months old ) were used in the test in accordance with ethical rules.
First, the pig was laparotomized under anesthesia, and the portal vein and the hepatic artery were ligated to remove 600 to 700 g of the liver so that the warm ischemic treatment of the liver was 60 minutes.
Next, the liver was subjected to low-temperature simple cold storage for 2 hours in a preservation solution at 4 ° C. as an operation corresponding to low-temperature simple cold storage used clinically. During the low-temperature simple cooling storage, the storage solution was not refluxed.
After completion of the low-temperature simple cooling storage, the removed liver was placed in the organ holding part (19) into which the storage solution was introduced, and the tubes were connected.
For connection, one end of the hepatic artery introduction tube of the preservation solution perfusion part (20) is inserted into the hepatic artery, and one end of the preservation solution perfusion part (20) of the introduction tube for the hepatic portal vein is connected to the hepatic portal. This was done by inserting into the pulse. Moreover, it installed so that the other end part of each inlet tube might be immersed in a preservation | save liquid.
After completion of the low-temperature simple cooling storage, the preservation solution was perfused into the liver. Perfusion was performed under the following conditions using an organ preservation device.
Perfusion conditions:
Temperature of preservation solution: Heated from 4 ° C. to 22 ° C. at an average rate of 0.2 ° C./minute (heating was performed by circulating the preservation solution through the heat exchanger (30))
Oxygen supply condition in oxygen addition device: Maintain 8 mg / L or more (maintain saturated dissolved oxygen content)
Pump flow rate (for hepatic artery): 0.22 mL / min / g
Pump flow rate (for hepatic portal vein): 0.06 mL / min / g
Time: 2 hours (evaluation of liver condition)
The liver condition was evaluated using the amount of lactose dehydrogenase (LDH) released by the liver into the preservation solution during perfusion as an index.
LDH is an enzyme that is present in the cell and is released outside the cell membrane due to cell damage. Therefore, the degree of cell damage can be grasped by measuring the amount of released LDH.
In order to calculate the amount of LDH released, the amount of LDH in the preservation solution at the start of perfusion and 2 hours after the start of perfusion was measured according to a conventional method.
In addition, the amount of LDH released was calculated by the following formula.
LDH release amount = (LDH amount 2 hours after the start of perfusion-LDH amount at the start of perfusion)
The result of LDH release amount is shown in FIG.

[Example 2] Organ preservation that was perfused at a low temperature using an organ preservation device under conditions without a warm ischemia treatment. A cold preservation treatment was performed in the same manner as in Example 1 without performing a warm ischemia treatment of the liver. The perfusion was carried out at a temperature of 4 ° C., and the amount of LDH released was measured in the same manner as in Example 1. The result is shown in FIG.

[Example 3] Liver ischemic treatment was performed on the liver after organ perfusion was performed at low temperature using an organ preservation device. Liver ischemic treatment was performed in the same manner as in Example 1, and the liver was treated at low temperature as in Example 1. The treatment was performed, and the preservation solution was perfused at a temperature of 4 ° C., and the amount of LDH released was measured in the same manner as in Example 1. The result is shown in FIG.

From the results shown in FIG. 4, it can be seen that any of the examples has a good organ preservation state and is useful as an organ preservation device. In particular, using the organ preservation device of the present invention, Example (Example 1) in which organ preservation by perfusion gradually recovering from a low temperature has a smaller LDH release amount than tissue preservation example (Example 3) in which perfusion was performed at low temperature, and tissue It turns out that there are few obstacles.
In addition, when the temperature is gradually recovered from the low temperature after the warm ischemia treatment by perfusion using the organ preservation apparatus of the present invention (Example 1), the perfusion is performed at a low temperature without performing the warm ischemia treatment (Example 2). Even when compared to, the significant amount of LDH release is not seen, indicating that there is little tissue damage.

Claims (3)

An organ preservation device for perfusion preservation of an organ separated from a living body,
An organ holding unit for holding the organ;
A preservation solution perfusion section for perfusing an preservation solution for organ preservation into an organ held in the organ holding section;
A temperature management unit for managing the temperature of the organ preservation unit;
An introduction part for introducing an active ingredient into a preservation solution to be distributed to the preservation solution perfusion part;
A function evaluation unit that evaluates the function of the organ by measuring the flow rate and pressure of the preservation solution to be perfused into the organ;
Organ preservation comprising a temperature control part based on data obtained by functional evaluation, and an adjustment part for adjusting the type and amount of active ingredient introduced by the introduction part and the flow rate of the preservation solution apparatus. The organ according to claim 1, wherein the temperature management unit controls the temperature of the preservation solution stored in the organ preservation unit so as to gradually warm and / or cool the temperature of the preservation solution from 4 ° C to 25 ° C. Storage device. An organ preservation method using the organ preservation device according to claim 1,
An organ preservation method comprising gradually warming and / or cooling the temperature of an organ preservation part from 4 ° C to 25 ° C.

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