JPH06105902A - Auxiliary artificial heart and its production - Google Patents

Abstract

PURPOSE:To fix heparin to a blood contact surface without changing the properties of a forming material by making the blood contact surface including back flow check preventive valves an antithrombotic surface covalent bonded with functional groups included in the oxide of a base material surface formed by an ozone treatment and amino group of the heparin. CONSTITUTION:This auxiliary artificial heart 1 has housings 2, 3, a flexible diaphragm 10 segmenting the inside of these housings 2, 3 to a blood chamber 21 and a driving fluid inflow chamber 22, a blood inflow port 4 and blood outflow port 5 communicating with the blood chamber 21, a port for driving fluid inflow and outflow communicating with the driving fluid inflow chamber 21 and the synthetic resin back flow check preventive valves 6, 7 provided within the blood inflow port 4 and the blood outflow port 5. The blood contact surface including the back flow check preventive valves 6, 7 is made to become the antithrombotic surface covalent bonded directly or via at least one kind of coupling agents with the functional groups included in the oxide of the base material surface formed by the ozone treatment and the amino groups of the heparin.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention is applied to patients with decreased cardiac function after open heart surgery, patients with decreased cardiac function awaiting heart transplantation, and patients with impaired systemic blood circulation due to acute myocardial infarction. On the other hand, the present invention relates to an auxiliary artificial heart that is used for temporarily replacing or assisting the function of the heart to maintain systemic blood circulation, and a method for manufacturing the same.

[0002]

2. Description of the Related Art Since 1988, an artificial heart assist system has been approved in Japan since 1988, and its clinical use has become possible. Currently used auxiliary artificial hearts are suck-type auxiliary artificial hearts (suck-type blood pumps) that contract and expand the entire blood chamber to inhale and discharge blood, and part of the blood chamber is formed of a flexible thin film. However, there is a diaphragm-type auxiliary artificial heart (diaphragm-type blood pump) that changes the volume of the blood chamber by driving this thin film to inhale and discharge blood. Many studies and clinical applications of the diaphragm type artificial artificial heart have been studied because of its advantages such as less damage to blood and excellent volume efficiency.

The diaphragm type artificial artificial heart has a blood chamber side housing having a blood inflow port and an outflow port, a drive fluid chamber side housing having a drive fluid inflow and outflow port, and an upper peripheral edge of the blood chamber side housing. And a diaphragm made of a flexible material, the bottom surface of which is fixed to the peripheral portion of the driving fluid side housing. A check valve is installed in each of the blood inflow port and the blood outflow port. In this type of auxiliary artificial heart, the diaphragm needs to have flexibility, and the check valve also preferably has flexibility. Furthermore, it is preferable that the housing is also flexible because it is easy to handle and can reduce the pain to the patient when it is fixed to the external skin. As an auxiliary artificial heart satisfying these points, there is a corfu type auxiliary artificial heart in which the housing, the check valve, and the diaphragm are all made of synthetic resin, specifically, polyurethane.

Although this polyurethane corfu type artificial heart has a sufficient function, it is preferable that its blood contact surface is an antithrombogenic surface in view of longer-term and safe use. Therefore, the present inventors have investigated coating and further fixing various antithrombotic materials on the blood contact surface. However, this requires the use of an organic solvent, which causes a decrease in the physical properties of the material forming the auxiliary artificial heart, such as a decrease in strength, flexibility, and elasticity, and in particular, a check valve is synthesized. In the artificial heart made of resin, the deterioration of valve function has been a problem. Therefore, an object of the present invention is to reduce the changes in physical properties of the auxiliary artificial heart having a diaphragm formed of a synthetic resin, a housing, and further a check valve, especially, a decrease in flexibility and elasticity, and Provided is an auxiliary artificial heart in which heparin, which is an antithrombotic material, is fixed to the blood contact surface, and a method for producing the auxiliary artificial heart.

[0005]

To achieve the above object, a housing, a flexible diaphragm for partitioning the inside of the housing into a blood chamber and a driving fluid inflow chamber, and a blood communicating with the blood chamber are provided. A synthetic resin auxiliary artificial heart having an inflow port, a blood outflow port, and a drive fluid inflow / outflow port communicating with the drive fluid inflow chamber, wherein the blood inflow port and the blood outflow port are made of synthetic resin. A blood flow prevention surface of the auxiliary artificial heart, the blood contact surface including the backflow prevention valve, a functional group contained in the oxide of the substrate surface generated by ozone treatment, and an amino group of heparin. Is an artificial heart prosthesis having an antithrombogenic surface covalently bound either directly or via at least one coupling agent. The heparin is preferably covalently bonded to the functional group in the oxide via at least one coupling agent.

In order to achieve the above object, a housing, a flexible diaphragm for partitioning the inside of the housing into a blood chamber and a driving fluid inflow chamber, a blood inflow port communicating with the blood chamber, and a blood outflow. A port and a drive fluid inflow / outflow port communicating with the drive fluid inflow chamber, and further, in the blood inflow port and the blood outflow port,
After forming a synthetic resin auxiliary artificial heart having a synthetic resin check valve, the blood contact surface of the auxiliary artificial heart including the check valve is treated with ozone to oxidize the surface of the base material forming the blood contact surface. After generating a functional group in the product,
This functional group and heparin, using an aqueous solvent, directly,
Alternatively, it is a method for producing an auxiliary artificial heart which is covalently bonded via at least one coupling agent.

The auxiliary artificial heart of the present invention will be described with reference to the drawings. The auxiliary artificial heart 1 of the present invention has a flexible diaphragm 10 that divides the housings 2, 3 into a blood chamber 21 and a driving fluid inflow chamber 22.
A blood inflow port 4 and a blood outflow port 5 that communicate with the blood chamber 21, a drive fluid outflow and outflow port 10 that communicates with the drive fluid inflow chamber 21, and a blood inflow port 4 and a blood outflow port 5 respectively. The synthetic resin backflow preventive valves 6 and 7, and the blood contact surface including the checkback preventive valves 6 and 7 has a functional group contained in the oxide on the surface of the base material generated by the ozone treatment, and heparin. And the amino group thereof are covalently bonded directly or via at least one coupling agent to form an antithrombotic surface.

Therefore, in the auxiliary artificial heart 1, the blood contact surface has an oxide formed on the surface by ozone treatment, and a functional group is generated or introduced into the blood contact surface without using a solvent. Then, using heparin that can use an aqueous solvent as an antithrombotic material, and the functional group in the oxide and the amino group of heparin are directly or through at least one coupling agent, so that Changes in the physical properties of the synthetic resin that forms the auxiliary artificial heart,
In particular, deterioration of the physical properties of the material forming the check valve, especially flexibility, elasticity, without significantly changing the strength, and because the blood contact surface of the auxiliary artificial heart can be a high antithrombogenic surface, It can be used for a long time as an auxiliary artificial heart. Heparin is directly or indirectly bound to the functional group in the oxide formed on the surface of ozone by the ozone treatment, and since the oxide is not substantially released from the base material, heparin at the time of use There are few departures.

FIG. 1 is a plan view of an embodiment of the auxiliary artificial heart of the present invention, FIG. 2 is a right side view of the auxiliary artificial heart of FIG. 1, and FIG. 3 is a left side view. As shown in FIGS. 1, 2 and 3, the auxiliary artificial heart of this embodiment has an upper blood chamber side housing 2, a lower drive fluid chamber side housing 3, and a blood chamber side housing 2. And a diaphragm 10 provided so as to partition the drive fluid chamber side housing 3 and the drive fluid chamber side housing 3.

The blood chamber side housing 2 has a substantially hemispherical shape as shown in FIGS. 2 and 3, and has a blood inflow port 4 and a blood outflow port 5 on the upper part thereof, and a diaphragm. The peripheral portion of 10 is fixed to the peripheral edge of the blood chamber side housing 2, and the blood chamber side housing 2 and the diaphragm 10 form a blood chamber 21. Further, a first check valve 6 is provided in the blood inflow port 4, and the first check valve 6 allows the blood to flow into the blood chamber and substantially prevents the blood from entering the blood chamber. It prevents the outflow of blood. As the first check valve 6, it is preferable to use a bicuspid valve having a small fluid resistance as shown in FIGS. 1 and 2. This check valve is an annular member 6a for fixing in the blood inflow port.
And, it has two movable pieces 6b which are fixed to the lower part of the annular member 6a so as to be hung and which are located in the blood chamber. Each of the two movable pieces has a flat plate-shaped portion whose tip is formed in a substantially linear shape, and a thin piece-shaped tip portion 6c which is continuous with the flat plate-shaped portion at a predetermined angle. Therefore, FIG.
As shown in FIG. 3, the first check valve is configured such that when blood flows in, in other words, when the diaphragm is deformed toward the drive fluid chamber, the two movable pieces 6a are separated from each other. When deforming, allowing the inflow of blood into the blood chamber and allowing the blood to flow out, in other words, when the diaphragm deforms toward the blood chamber, the two movable pieces are deformed in the direction in which they are in close contact with each other. And prevent the blood from flowing out of the blood chamber.

A second backflow prevention valve 7 is provided in the blood outflow port 5, and the first backflow prevention valve allows the outflow of blood from the blood chamber and is substantially in the blood chamber. It prevents the inflow of blood into the. As the second check valve 7, it is preferable to use a tricuspid valve with little backflow of blood as shown in FIG. This check valve 7
Has a tubular portion that forms a blood inflow port and also forms a housing of the check valve, and three movable pieces that are fixed to the tubular portion in a curved state. , Their upper ends are in close contact with the adjacent movable pieces.
Therefore, the second check valve is, as shown in FIG.
When blood flows in, in other words, when the diaphragm is deformed toward the drive fluid chamber, the tips of the three movable pieces are deformed in a direction in which they are in close contact with each other, preventing blood from flowing out of the blood chamber. Further, when the blood is flown out, in other words, when the diaphragm 10 is deformed to the blood chamber side, as shown in FIG. 3, the distal ends of the three movable pieces are deformed in the directions away from each other. Then, the outflow of blood is allowed through the gap between the tips of the three movable pieces formed. Further, in the auxiliary artificial heart 1 of this embodiment, as shown in FIG. 1, the blood inflow side connection tube 8 and the blood outflow side connection tube 9 for connecting to the heart cannula are fixed to the blood inflow port and the blood outflow port. Has been done.

The blood chamber housing 2 and the first and second check valves 4 and 5 are made of flexible synthetic resin. As the flexible synthetic resin, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, vinyl chloride-ethylene copolymer, vinyl chloride-vinylidene chloride copolymer, polyvinyl chloride-urethane copolymer, polyvinyl chloride -Acrylonitrile copolymers, vinyl chloride-methyl methacrylate copolymers, soft polyvinyl chloride modified products comprising the above polymers and plasticizers, and polyurethanes can be used. In particular, thermoplastic polyurethane is suitable. The thermoplastic polyurethane may be either a thermoplastic polyether polyurethane or a thermoplastic polyester polyurethane, more preferably a thermoplastic polyether polyurethane. Particularly preferred is a segmented thermoplastic polyether polyurethane having a soft segment portion and a hard segment portion. The main component of the soft segment is preferably polytetramethylene ether glycol, polyethylene glycol, polypropylene glycol or the like, and the main component of the hard segment is preferably 1,4-butanediol or the like. Further, as the diisocyanate, 4,4-diphenylmethane diisocyanate, tolylene diisocyanate,
Preferred is 1,6-hexamethylene diisocyanate. As a particularly preferable polyurethane material, polytetramethylene ether glycol is used as the main component of the soft segment, and as the main component of the hard segment,
1,4-Butanediol is a thermoplastic segmented polyurethane formed using 4,4-diphenylmethane diisocyanate as the diisocyanate, which is sold by Dow Chemical Japan Co., Ltd. under the trade name Peresen 2363. Has been done.

As shown in FIGS. 2 and 3, the driving fluid chamber side housing 3 has a substantially hemispherical shape, and the driving fluid inflow / outflow port 1 is located at a position closer to the peripheral edge side than the center thereof.
0 is provided, and a tube 11 for connecting to a drive fluid discharge device is connected to the inflow / outflow port 12 thereof. The peripheral edge of the diaphragm is fixed to the peripheral edge of the drive fluid chamber side housing, and the drive fluid chamber 22 is formed by the drive fluid chamber side housing 3 and the diaphragm 10. As shown in FIGS. 2 and 3, the diaphragm 10 is fixed to both housings in a state where the central portion has a space, in other words, in a state where the central portion projects toward the blood chamber side 21 or the driving fluid chamber side 22. Has been done. When the driving fluid flows into the driving fluid chamber 22, the diaphragm is deformed to the blood chamber side, the volume on the blood chamber side is reduced, and the blood in the blood chamber is caused to flow out. When the driving fluid is sucked, the driving fluid is deformed to the driving fluid chamber side, the volume of the blood chamber side is increased, and the blood is allowed to flow into the blood chamber. By repeating this, blood is intermittently sent from the auxiliary artificial heart.

As the material for forming the diaphragm 10 and the driving fluid chamber side housing 3, those described in the above blood chamber side housing can be preferably used. The peripheral edge of the diaphragm 10 and the peripheral edges of the blood chamber side housing 2 and the drive fluid chamber side housing 3 can be fixed by heating, heat fusion by high frequency or ultrasonic waves, adhesive, solvent, etc. In order to reduce the change in the physical properties of the diaphragm in (2), it is preferable to mold them with a thermoplastic synthetic resin and heat-bond them.

On the blood contact surface of the auxiliary artificial heart including the anti-reflux valve, the functional group contained in the oxide on the surface of the base material generated by the ozone treatment and the amino group of heparin are directly or at least. It has an antithrombotic surface covalently bound via a type of coupling agent. Therefore,
Since heparin is fixed on the blood contact surface without using a solvent, changes in the physical properties of the base material forming the blood contact surface,
Specifically, the flexibility, elasticity, strength, etc. are not significantly reduced.

Various functional groups, for example, highly reactive functional groups such as aldehydes, ketones, and epoxies are formed in the oxide formed on the surface of the substrate by the ozone treatment.
And, it is also possible to directly bond a functional group to these functional groups, but there is also a problem such as steric hindrance, a method of introducing a spacer (coupling agent) into these functional groups, and fixing heparin, It is useful from the viewpoint of easy expression of heparin activity on the surface. As the coupling agent, one kind or two or more kinds may be used.
A compound having three or more aldehyde groups or an epoxy group is preferably used. When a plurality of types of coupling agents are used, a coupling agent (spacer coupling agent) composed of a compound having two or more functional groups such as amino groups in the above-mentioned functional groups introduced on the substrate is previously prepared. After binding and introducing an amino acid or the like into the substrate, heparin may be bound to the substrate using a coupling agent (a coupling agent for fixing heparin) composed of a compound having two or more aldehyde groups or epoxy groups. preferable. Furthermore, when binding heparin, it is preferable to add the coupling agent to the reaction system at the same time as heparin or after the introduction of heparin. In particular, when an amino group is introduced by using a spacer coupling agent, it exhibits almost the same reactivity in the reaction system as the amino group of heparin. Therefore, the latter heparin-immobilizing coupling agent can be used more effectively. Can be fixed to the base material.

When the functional group of the coupling agent that directly binds to heparin or the functional group introduced into the base material is an aldehyde group, a part of the N-sulfate group of heparin is desulfurized to obtain heparin. It is preferable to use a primary amination product. The spacer coupling agent is preferably one that binds (covalently bonds) with a functional group obtained by ozone treatment on a substrate and has two or more primary amino groups. As a coupling agent for a spacer having two or more amino groups, polyethyleneimine (PE
I), polyethylene glycol diamine, ethylene diamine, tetramethylene diamine and the like. Aldehyde compounds and epoxy compounds can be preferably used as the coupling agent used for fixing heparin to the substrate. As the aldehyde compound, glutaraldehyde, glyoxal, succindialdehyde, and as the epoxy compound, polyethylene glycol diglycidyl ether, 1,4-butanediol-diglycidyl ether, sorbitol diglycidyl ether, glycerol diglycidyl ether, etc. are preferably used. To be done.

Specifically, Denacol EX-42 in which the epoxy compound is sorbitol diglycidyl ether.
1, 521, 611, 612, 614, 614B), the diepoxy compound is glycerol diglycidyl ether, Denacol EX-313, and the diepoxy compound is polyethylene glycol glycidyl ether, EX-.
810, 811, 851, 821, 830, 832, 8
41, 861 (manufactured by Nagase Kasei Co., Ltd.) and the like. Furthermore, due to the difference in the reactivity of the epoxy, Denacol EX-3
13, 421, 512, 521, 810, 811, 82
1, 851 and the like are more preferable. In the heparin immobilization described above, the bond between polyethyleneimine and glutaraldehyde and the bond between glutaraldehyde and heparin immobilized on the base material are all covalent bonds, and the heparin is less released.

Next, a method for manufacturing the auxiliary artificial heart of the present invention will be described. The manufacturing method of the auxiliary artificial heart of the present invention,
A housing, a flexible diaphragm that divides the interior of the housing into a blood chamber and a driving fluid inflow chamber, a blood inflow port and a blood outflow port that communicate with the blood chamber, and a driving fluid outflow that communicates with the driving fluid inflow chamber. Has an input port,
Further, in the blood inflow port and the blood outflow port, a step of forming a synthetic resin auxiliary artificial heart having a synthetic resin check valve and ozone treatment of a blood contact surface including the check valve of the auxiliary artificial heart. The step of generating a functional group in the oxide of the surface of the base material that forms the blood contact surface by the method, and the generated functional group and heparin, using an aqueous solvent, directly or at least one coupling agent. And a step of covalently binding via.

Therefore, each step will be described. A housing, a flexible diaphragm that divides the interior of the housing into a blood chamber and a driving fluid inflow chamber, a blood inflow port and a blood outflow port that communicate with the blood chamber, and a driving fluid outflow that communicates with the driving fluid inflow chamber. An inlet port, and further, in the blood inflow port and the blood outflow port,
In the step of forming the auxiliary artificial heart having the synthetic resin check valve, the above-mentioned flexible synthetic resin is used to form the auxiliary artificial heart as shown in FIGS. 1 to 3. Specifically, it is formed using a synthetic resin by injection molding, dip molding, a method of heating and deforming a sheet-shaped synthetic resin, or the like. Briefly, for example, a thermoplastic polyurethane is used to form a sheet, which is pressed against a die having the inner surface shape of the target blood chamber side housing and the target drive fluid chamber side housing to form the housing. , Cut off unnecessary parts. Then, it is fixed by an adhesive or heat fusion in the blood inflow port and the blood outflow port of the blood chamber side housing in which the check valve formed in advance by thermoplastic polyurethane or the like is formed. Further, a heart cannula connecting tube formed beforehand of polyurethane, vinyl chloride or the like is fixed to the blood inflow port and the blood outflow port with an adhesive or heat fusion. Similarly, a tube for connecting the driving fluid discharge device, which is previously formed of polyurethane, vinyl chloride or the like, is fixed to the port of the driving fluid chamber side housing by an adhesive or heat fusion. Then, the diaphragm formed of a flexible synthetic resin such as polyurethane is fixed by an adhesive or heat fusion so that it is sandwiched between the peripheral portions of the blood chamber side housing and the driving fluid chamber side housing. In the auxiliary artificial heart, it is preferable that at least the entire base material forming the blood contact surface including the check valve is made of the same material, for example, a polyurethane material. In particular, it is preferable to use the same material. In the present invention, since heparin is fixed on the blood contact surface after the auxiliary artificial heart is assembled, it is preferable to find the optimum condition for fixing heparin. If the auxiliary artificial heart is formed of the same system and the same material, heparin can be fixed to the whole under the optimum conditions found, and variation in the fixed amount of heparin hardly occurs.

Next, the step of forming a functional group in the oxide on the surface of the base material forming the blood contact surface by subjecting the blood contact surface of the auxiliary artificial heart including the check valve to ozone treatment will be described. The ozone treatment may be carried out by bringing O ₃ / O ₂ gas obtained by oxidizing O ₂ with an ozone generator into contact with the substrate. Alternatively, ozone dissolved in an aqueous solvent such as water or acetic acid which is not oxidized by ozone may be used. Further, the treatment conditions of ozone are various depending on the material such as concentration, reaction time, reaction temperature and the like. For example, even under optimal conditions for one material, a functional group cannot be sufficiently introduced into another material, or the reaction is too strong and the material deteriorates too much. As a guide, when contacting in a gaseous state, 1-50 g / m ³
Concentration, flow rate of 50-5000 ml / min, 0-70
It is possible to select the optimum condition suitable for the material from the reaction time of 0.5 to 120 min at the reaction temperature of ° C.

Ozone treatment is the same as that of the auxiliary artificial heart.
The ozone generator tube is connected to one tube, and ozone is introduced from the blood inflow port side. further,
After the inflow of ozone, it is preferable to allow ozone to flow in from the blood outflow port side so that ozone comes into contact with the entire blood contact surface, particularly ozone comes into contact with the front and back surfaces of the check valve. Furthermore, it is preferable that the above-described ozone inflow operation be performed a plurality of times alternately in different directions.
Next, heparin for fixing to the above-mentioned base material having a functional group will be described.

Heparin is widely known as a compound exhibiting antithrombotic properties and has an N-sulfate site. Heparin can be fixed on the surface of the substrate as it is, but if the functional group of the partner that binds to heparin is an amino group originally possessed by heparin, such as an aldehyde group, if it is a functional group that cannot be sufficiently fixed. It is preferable that a part of the N-sulfate site of heparin is desulfated to be primary aminated. In this case, the degree of primary amination is preferably 5 to 25% of the total amount of primary amino groups in heparin. It is more preferably 10 to 20%, further preferably 10 to 15%. Here, the amount of the primary amino group in heparin includes both the primary amino group obtained by desulfating a part of the N-sulfate site and the primary amino group. If the amount of the primary amino group in heparin is less than 5%, it becomes difficult to fix it on the substrate, and if it exceeds 25%, the activity of heparin decreases, so it is preferable to set it to 5 to 25%. Desulfation of a part of the N-sulfate site of heparin can be performed as follows. Commercially available heparin was dissolved in distilled water to prepare a heparin solution. It can be carried out by adding sulfuric acid to this heparin solution, heating and incubating.

The concentration of the heparin solution is 1.0 to 2
About 0% is suitable, and the added sulfuric acid is 5.0
~ 20N, to 10ml heparin solution,
Add about 0.1-1.0 ml and at 50-100 ° C for 2
Incubation for ~ 30 minutes is preferred. And with the incubation time, the first in heparin
The number of primary amino groups increases, but the heparin activity gradually decreases. Therefore, it is preferable to perform the primary amination of the N-sulfate site to such an extent that the heparin activity is not inappropriately reduced. Specifically, the leucine equivalent of heparin is 0.05
˜0.25 (μmol / 10 mg) is preferable. That is, the leucine equivalent is 0.05 to 0.13 (μmo
If it is lower than 1/10 mg), the amount of primary amino groups is insufficient, and the amount of heparin fixed on the surface of the base material is reduced,
When it is higher than 0.25 (μmol / 10 mg), the heparin activity is reduced, which is not preferable.

Next, the step of fixing heparin on the blood contact surface of the auxiliary artificial heart having the functional group obtained as described above will be described. Immobilization of the heparin and the substrate forming the blood contact surface is at least one coupling agent, preferably 2
Compounds having three or more aldehyde groups, epoxy groups, etc. can be used to bond by the reaction of amino groups with these functional groups. As such an aldehyde compound,
Examples thereof include glutaraldehyde. As the coupling agent, polyethylene glycol glycidyl ether which is an epoxy compound may be used in addition to the aldehyde compound. In these cases, it is preferable to previously couple a coupling agent having two or more primary amino groups (coupling agent for spacer) to the functional group obtained by the ozone treatment on the substrate. Explain.

First, a spacer coupling agent solution having two or more primary amino groups is allowed to flow into the blood contact site side of the auxiliary artificial heart to sufficiently contact the blood contact surface to oxidize the blood contact surface. The functional group in the product and the functional group of the coupling agent are covalently bonded to form an amino group-introduced blood contact surface. As the coupling agent solvent, for example, an aqueous solvent such as water or lower alcohol is used, and the contact conditions are preferably pH 4 to 12, temperature 0 to 80 ° C., and reaction time 10 minutes to 24 hours. If the pH is less than 4, the binding property of the coupling agent to the surface of the base material may be lowered, and the base material may be deteriorated depending on the material. If the pH is higher than 12, the deterioration may be caused depending on the base material. It is not preferable because it exists. If the temperature is lower than 0 ° C, the reactivity is lowered, and if it is higher than 80 ° C, the primary amino group may be modified, which is not preferable. Examples of the coupling agent having two or more amino groups include polyethyleneimine (PEI), polyethylene glycol diamine, ethylene diamine and tetramethylene diamine.
After introducing an amino group on the surface of the base material that forms the blood contact surface in this way, the amino group and the amino group of heparin are bound by a heparin-immobilizing coupling agent having two or more aldehyde groups or epoxy groups. Then, heparin is fixed to the base material. As the coupling agent having two or more epoxy groups or aldehyde groups, those mentioned above can be used.

Further, by the above-mentioned method, the reaction method in which the amino group of the covalently bound spacer coupling agent and the amino group of heparin are bound by the heparin-immobilizing coupling agent is the aqueous solution of the above coupling agent. It is preferable to allow a mixture of the aqueous solution of heparin and the aqueous solution of heparin to flow into and fill the blood-contacting surface side of the auxiliary artificial heart to react. Also. Inflow of heparin solution only,
After filling, the amino group on the blood contacting surface and the functional group of heparin are reacted and lightly bonded, a coupling agent aqueous solution may be allowed to flow in to react. When the heparin aqueous solution and the coupling agent aqueous solution are mixed and reacted at the same time, the reaction conditions are preferably pH 2.0 to 10.0, the reaction time is about 1 hour to 200 hours, and the reaction temperature is 1
It is preferably about 5 to 80 ° C. If it is 1 hour or more, the reaction is sufficient, and if it is 200 hours or less, the degradation of heparin and the decrease in the stability of heparin immobilized on the surface due to excessive crosslinking are small. If the reaction temperature is 15 ° C. or lower, the reaction occurs, and if it is 80 ° C. or lower, the stability of heparin is less deteriorated. The concentration of the compound in the aqueous coupling agent solution is preferably 0.01 to 2 mol / l in terms of the content of epoxy groups and aldehyde groups for efficient crosslinking.

First, the amino group on the blood contact surface
When the functional groups of heparin are reacted with each other to form an ionic bond with each other and then a cross-linking reaction with the coupling agent is performed, the reaction condition between the base material and heparin is pH 2.0.
It is good to set it to 5.0. If the pH is 2.0 or less, the stability of heparin is less reduced, and if the pH is 5.0 or less, the positive charge on the surface of the substrate is not reduced, and the amount of bound heparin is sufficient. The reaction temperature is preferably 0 to 80 ° C.
If the temperature is 0 ° C or higher, the ionic bond rate is sufficient,
If the temperature is below ℃, the stability of heparin will not decrease. The reaction time is preferably 10 to 1500 minutes. 1
If it is 0 minutes or more, ionic bond is sufficiently generated, and even if it is performed for 1500 minutes or more, the ionic bond amount is completely saturated,
This is because there is no new connection. Furthermore, when the blood contact surface is cross-linked with the heparin aqueous solution and the coupling agent aqueous solution, the pH may be either alkaline or acidic.
However, in the present invention, the surface having an amino group does not charge to + unless it is acidic, and thus heparin is promptly released from the surface, so that effective crosslinking cannot be achieved unless it is acidic, which is not preferable. The concentration of the compound in the aqueous coupling agent solution is preferably 0.01 to 2 mol / l in terms of the content of epoxy groups and aldehyde groups for efficient crosslinking. The reaction temperature is preferably 15 to 80 ° C. The reaction time is preferably 1 to 200 hours.

[0029]

EXAMPLES The present invention will be specifically described below with reference to examples. A blood chamber side housing, a drive fluid chamber side housing, a diaphragm, and a bicuspid check valve having a structure as shown in FIG. 1, using thermoplastic and flexible segmented polyurethane (Peresen 2363-80AE). A tricuspid valve type check valve having a structure as shown in FIG. 1 and a connection tube were formed, and the diaphragm and each housing were heat-sealed by ultrasonic heating at their peripheral portions. Further, each of the check valves and the connecting tube were fixed to the blood port by using a polyurethane adhesive, and several Corfu-type auxiliary artificial heart assemblies as shown in FIG. 1 were prepared.

An ozone generator (Nippon Ozone Co., Ltd.) was connected to the two connecting tubes, and the concentration was 25 g / m ³ ,
Processing was performed at a flow rate of 0.8 l / min and a temperature of 25 ° C. for 10 minutes.
Ozone treatment is performed by connecting the ozone generator tube to the two tubes of the artificial heart, first by injecting ozone from the blood inflow port side, and after that, inflowing ozone from the blood outflow port side. Then, ozone was surely brought into contact with the blood contact surface of the auxiliary artificial heart, particularly, both the front and back surfaces of the check valve. Dissolve commercially available heparin in distilled water and add 10%
A solution was made. 1 ml of this heparin solution was placed in 0.4 ml of 5.5N sulfuric acid and incubated at 97 ° C. for 10 minutes. The primary amino groups in all the amino groups in the obtained heparin were 11% including those which heparin originally had and those which were primary amination by desulfating the N-sulfate site. .

The blood contact area (including the check valve and the connecting tube) of the ozone-treated auxiliary artificial heart assembly was filled with 0.5% polyethyleneimine aqueous solution (PFI) adjusted to pH 10 (BASF). 45 ° C, 24
Left for hours. Then, the polyethyleneimine aqueous solution was discharged and then washed with water). A 0.2% aqueous solution (pH 4.0 acetate buffer) of partially desulfated heparin prepared as described above was prepared, and this heparin aqueous solution was treated with polyethyleneimine to form a blood contact site (backflow prevention valve). , Including the connecting tube) and left at 45 ° C. for 24 hours. Then, after discharging the heparin aqueous solution, it was dried (is it necessary). Subsequently, a 1.0% glutaraldehyde aqueous solution (pH 4.0 acetic acid buffer) was heparinized into the blood contact site of the artificial heart assembly (backflow prevention valve,
(Including the connecting tube) and left at room temperature for 24 hours. Then, after discharging the glutaraldehyde aqueous solution, it was dried (is it necessary). Then 1% NaBH ₄
An aqueous solution (pH 10 carbonate buffer solution) was filled into the blood contact site (including the check valve and the connecting tube) of the artificial heart assembly treated with glutaraldehyde, left at room temperature for 4 hours, then discharged and dried. It was Thereby, the auxiliary artificial heart of the present invention having a maximum blood chamber volume of 20 ml was prepared.
In addition, a supplemental artificial heart without the heparin fixation treatment after the ozone treatment was used as a comparative example.

[Experiment] (Experiment 1) 0.01 N hydrochloric acid was filled in the blood contacting sites of the artificial hearts of the above Examples and the artificial hearts of Comparative Examples, discharged, and then stained with toluidine blue. In the auxiliary artificial heart of the example, almost the entire blood contact site was stained purple to magenta. In addition, none of the assisted artificial hearts of Comparative Examples stained.

(Experiment 2) Using the artificial artificial hearts of Examples and Comparative Examples, an acute left ventricular assist experiment was conducted on adult sheep.
As an adult sheep, a body weight of 60 kg is used, and the auxiliary artificial heart is driven by an auxiliary artificial heart drive device (trade name: IABP-P).
An AD driving device (manufactured by Zeon Corporation) was used and the driving mode was fixed at 80 bpm. When formation of thrombus was confirmed, formation of thrombus was observed in the peripheral portion of the check valve and the peripheral portion of the diaphragm in the auxiliary artificial heart of the comparative example per day. In addition, in the auxiliary artificial heart of the example, slight thrombus formation was observed in the peripheral portion of the check valve and the peripheral portion of the diaphragm from four days.
Compared to the comparative example, the amount was extremely small.

(Experiment 3) Thermoplastic and flexible segmented polyurethane (Peresene 2363-80A)
Using E), a sheet having a thickness of 0.4 mm was formed. Then, using an ozone generator (Japan Ozone Co., Ltd.), the ozone concentration was 25 g / m ³ , 0.8 l / min O ₂ , and 1 at 5 ° C.
0 minutes (Sample 3), 10 minutes at 25 ° C (Sample 4),
It processed at 45 degreeC for 10 minutes (sample 5). In addition, the untreated sample was designated as sample 2. And the above sample 2
5 was treated in the same manner as in Example to prepare a polyurethane sheet having heparin fixed on both sides. In addition, the sample which was not subjected to the ozone treatment and heparin treatment was sample 1. Samples 1 to 5 were cut into 5 × 20 mm and the physical properties were measured. The results are shown in Table 1.

[0035]

[Table 1]

From the above results, it was found that the initial elastic modulus was slightly lowered and slightly softened by the heparin treatment, but no significant change in physical properties was observed. In addition, no difference in physical properties was observed with or without ozone treatment. Moreover, when ESCA (trade name JPA90SX, manufactured by JEOL Ltd.) was used to analyze the amount of heparin fixed in Samples 1 to 5, the results are shown in Table 2.

[0037]

[Table 2]

Therefore, as compared with the sample 2, the samples 3 to
In No. 5, it was found that a large amount of heparin was fixed.

[0039]

The auxiliary artificial heart of the present invention comprises a housing, a flexible diaphragm for partitioning the interior of the housing into a blood chamber and a driving fluid inflow chamber, a blood inflow port communicating with the blood chamber, and a blood outflow. A synthetic resin auxiliary artificial heart having a port and a drive fluid inflow / outflow port communicating with the drive fluid inflow chamber, wherein a synthetic resin check valve is provided in the blood inflow port and the blood outflow port. In addition, the blood contact surface of the auxiliary artificial heart including the check valve is a functional group contained in the oxide of the substrate surface generated by ozone treatment, and an amino group of heparin, directly or Since it has an antithrombotic surface covalently bonded through at least one coupling agent, the blood contact surface has an oxide formed on its surface by ozone treatment, and a solvent should be used. It is produced or by introducing functional groups to the Ku blood-contacting surface. Then, using heparin that can use an aqueous solvent as an antithrombotic material, and the functional group in the oxide and the amino group of heparin are directly or through at least one coupling agent, so that Changes in the physical properties of the synthetic resin that forms the auxiliary artificial heart, especially deterioration of the physical properties of the material that forms the check valve, especially without changing flexibility and strength so much, and increasing the blood contact surface of the auxiliary artificial heart The antithrombogenic surface allows for long-term use as an auxiliary artificial heart. In addition, since heparin is directly or indirectly bound to the functional group in the oxide on the surface by ozone treatment, and the oxide is not substantially released from the base material, the release of heparin during use is also avoided. Few.

In the method for manufacturing the auxiliary artificial heart according to the present invention, the housing, the flexible diaphragm dividing the inside of the housing into the blood chamber and the driving fluid inflow chamber, and the blood inflow port communicating with the blood chamber. And a blood outflow port, and a drive fluid inflow / outflow port communicating with the drive fluid inflow chamber, and further, in the blood inflow port and the blood outflow port, synthetic resin made of synthetic resin having a check valve. After forming the auxiliary artificial heart, after generating a functional group in the oxide of the substrate surface forming the blood contact surface by ozone treatment of the blood contact surface including the check valve of the auxiliary artificial heart, This functional group and heparin can be easily produced using an aqueous solvent, directly or through a covalent bond via at least one coupling agent.

[Brief description of drawings]

FIG. 1 is a plan view of an auxiliary artificial heart of the present invention.

FIG. 2 is a right side view of the auxiliary artificial heart of the present invention.

FIG. 3 is a left side view of the auxiliary artificial heart of the present invention.

[Explanation of symbols]

 1 Auxiliary artificial heart 2 Blood chamber side housing 3 Drive fluid chamber side housing 4 Blood inflow port 5 Blood outflow port 6 Backflow prevention valve 7 Backflow prevention valve 10 Diaphragm 21 Blood chamber 22 Drive fluid chamber

Claims (2)

[Claims] 1. A housing, a flexible diaphragm dividing the housing into a blood chamber and a drive fluid inflow chamber, a blood inflow port and a blood outflow port communicating with the blood chamber, and the drive fluid inflow chamber. A synthetic resin auxiliary artificial heart having a driving fluid inflow / outflow port communicating with
The blood inflow port and the blood outflow port each have a synthetic resin check valve, and the blood contact surface of the auxiliary artificial heart including the check valve is a substrate surface generated by ozone treatment. An auxiliary artificial heart, wherein the functional group contained in the oxide and the amino group of heparin are covalently bonded to each other directly or through at least one coupling agent to form an antithrombotic surface. 2. A housing, a flexible diaphragm that divides the interior of the housing into a blood chamber and a drive fluid inflow chamber, a blood inflow port and a blood outflow port that communicate with the blood chamber, and the drive fluid inflow chamber. A synthetic resin auxiliary artificial heart having a synthetic fluid check valve in the blood inflow port and the blood outflow port. After generating a functional group in the oxide on the surface of the base material forming the blood contact surface by ozone treatment of the blood contact surface of the heart including the check valve, the functional group and heparin are treated with an aqueous solvent. A method for producing an auxiliary artificial heart, which is characterized in that it is covalently bonded directly or through at least one coupling agent.