JPS6210663B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an artificial organ that can be heat sterilized. More specifically, the present invention provides an artificial organ that can be subjected to desired heat sterilization, such as a heat-sterilized hollow fiber artificial kidney. 2. Description of the Related Art In recent years, artificial organs that substitute or assist the functions of human organs have developed significantly, and in particular, artificial kidneys, artificial lungs, etc. have become widespread. Artificial kidneys replace the functions of living kidneys by removing waste products from the blood into a treatment solution through dialysis and by ultrafiltration of excess water. Hollow fiber artificial kidneys, which are small and easy to use in relation to their effective membrane area, are considered to be the mainstream model in the future. Artificial organs, such as hollow fiber artificial kidneys, must satisfy the following conditions in order to be connected to a living body through an extracorporeal blood circulation circuit. That is, first, it must not contain toxic substances or pyrogens. Second, it must be sterile. Third, leakage into the blood flow path and processing liquid flow path;
No blockages or backlogs will occur. Fourth, it must have the desired performance, such as the ability to remove waste products and water. Fifth, cleaning preparations are easy when replacing blood in the blood flow path. etc. Conventional artificial kidneys are sterilized with formalin, ethylene oxide gas, or radiation. Formalin sterilization is performed by filling an artificial kidney with a 1-5% formaldehyde aqueous solution, but while it has strong sterilizing power, its residual toxicity is a problem, and the disadvantage is that it requires a lot of physiological saline solution to prepare for cleaning, which is time-consuming. . Ethylene oxide gas sterilization is 10-27%
Although the artificial kidney is placed in an ethylene oxide gas atmosphere, there are problems with residual toxicity of ethylene oxide and its derivatives, air bubble removal during cleaning from a dry state, and reproducibility of performance. Radiation sterilization is performed by irradiating the artificial kidney with gamma rays of 0.5 to 5 Mrad, and there is no concern about residual toxicity, but there are problems with deterioration of the artificial kidney components, especially membranes, and cleaning problems similar to gas sterilization. Other sterilization methods include heat sterilization, and the 9th edition of the Japanese Pharmacopoeia states that high-pressure steam sterilization at 115℃,
Specifies a method for killing microorganisms by heating in saturated steam for 30 minutes: 121℃ for 20 minutes and 126℃ for 15 minutes. Furthermore, in water at 80-100℃ or under flowing steam
An intermittent sterilization method in which heating is performed three to five times for 30 to 60 minutes each time every 24 hours is also prescribed. Heat sterilization has the advantage of no residual toxicity and easy cleaning. However, heat-sterilized artificial kidneys and organs have not been developed to date. The main reason why development is difficult is that the artificial organ components themselves cannot withstand heat sterilization, and the blood flow path and treatment liquid flow path cannot be maintained due to deformation, destruction, and poor sealing of the components. The second reason is thermal deterioration of performance. As a result of intensive research to develop an artificial organ that can be heat sterilized, the inventor of the present invention has developed an artificial organ that can maintain the blood flow path without deforming or destroying the parts due to heat during sterilization. The present invention was achieved through the development of this method. That is, firstly, materials that are substantially heat resistant within the range of 40 to 130° C. were selected for each member used in the artificial organ. The heat resistance in the present invention is substantial, and as described later, it is higher than the heat resistance in the literature, especially the heat distortion temperature. Second, heat sterilization heat treatment is performed under hydrostatic pressure to substantially increase heat resistance, so that local stress is not applied even if the component begins to soften; and third, thermal expansion during heating between each component. After considering the interaction between the two, we devised a configuration that completely maintains the seals of the blood flow path and processing liquid flow path after heating. That is, the present invention provides a hollow fiber type artificial organ composed of a hollow fiber, a partition wall, and a container, wherein the hollow fiber, the partition wall, and the container have substantially heat resistance in the range of 40 to 130°C; Linear expansion coefficient a of the member
[1/°C] is in the range of 40 to 130°C, and the coefficient b [1/°C] and temperature t [°C] of the container member have the following relationship: (4.13×10 ^-5 ) ^{The present} invention is an artificial organ for use in heat sterilization, characterized in that e 0 . The artificial organ of the present invention is composed of a hollow fiber 1 container 2 and a partition wall 3 as shown in FIG. Note that in the container, the blood distribution part 4 and the collection part 5 may be made of different members from the container member depending on their compatibility with blood. In the example of FIG. 2, if the distribution and gathering parts are not significantly affected by the interaction between other members due to thermal expansion during heating, the above configuration conditions do not apply to the distribution and gathering parts. In the artificial organ of the present invention, the hollow fibers can be made of cellulose, cellulose ester, polyacrylonitrile, polyvinyl alcohol, polyaromatic acid amide, polycarbonate, polyether, or the like. In either case, it is necessary to form a rigid network structure in the hollow fiber membrane forming process to strengthen the membrane's resistance to densification during heating.
In other words, it is to provide heat resistance that minimizes thermal deterioration of membrane performance. Regarding cellulose hollow fibers, the present inventors have developed hollow fiber membranes with excellent circularity and permeability through hydrothermal treatment and high-temperature saponification regeneration of cellulose ester in Japanese Patent Application Laid-open Nos. 50-46921 and 1977-70611. discloses how to obtain it. This hollow fiber is heated at 65 to 98℃ during the membrane forming process.
It has undergone a thermal history of Other polymer hollow fibers are formed by wet spinning, but heat resistance can be imparted by raising the temperature of the coagulation bath and/or washing and scouring bath. When hollow fibers are heated to around 130°C, membrane performance deteriorates, but if it can be assembled to the desired performance as an artificial organ, use one that is substantially heat resistant. The performance retention rate of the heat-resistant cellulose hollow fibers at 130°C was 90-98%. In particular, hollow fiber materials such as cellulose, polyacrylonitrile and polyaromatic acid amide,
For example, polyamide benzhydrazide isophthalamide has excellent heat resistance and is preferred as a hollow fiber membrane. In the artificial organ of the present invention, the container members include polycarbonate, poly-4-methylpentene-1, polyvinylidene fluoride, and polyacetal shown in Table 1, which have substantial heat resistance in the range of 40 to 130°C. be. Other examples include polysulfone and polyarylate. For comparison, styrene/acrylonitrile copolymer, polymethyl methacrylate, etc. have substantially no heat resistance. In particular, highly transparent polycarbonate, poly-4-methylpentene
1 is preferable as a member of an artificial organ that processes blood. Further, the specific volumes of polycarbonate and poly-4-methylpentene-1 at 40 to 130°C were measured, and the coefficients of linear expansion determined therefrom are shown in Table 2. These measurements were carried out in accordance with ASTM D864 according to Polymer Experimental Science Course 7, "Polymer Materials Testing Methods", Kyoritsu Shuppan (1961). In the artificial organ device shown in FIG. 1, the seal between the hollow fiber and the septum, ie, the seal of the blood flow path, is maintained during and after heating due to the flexibility of both and the tendency of the hollow fiber to expand due to moisture. On the other hand, the seal between the container and the partition wall, that is, the seal of the processing liquid flow path, is caused by interaction due to thermal expansion between the two during heating.
greatly affected. Ideally, the container member and the partition wall member should exhibit the same thermal expansion behavior, but
As shown in Table 2, the coefficient of thermal expansion of the container depends on the temperature, and is larger at higher temperatures. It is extremely difficult to find a partition wall member that exhibits exactly the same thermal expansion behavior. As a result of intensive research, the present inventors discovered the following facts and came to solve the problem mentioned above. First, in the range of 40 to 130°C, the thermal expansion of the partition member is at most twice the thermal expansion of the container member, and is approximately the same or even smaller. This fact was surprising and went against our common sense that ``If the inner partition wall expands more thermally and comes into close contact with the outer container, the seal between the two will be better maintained.'' The fact is that if the thermal expansion of the partition wall member is larger than that of the container, the partition wall member will receive stress from the container during heating to suppress the expansion, and will creep, and after the temperature cools down, a gap will be created by the amount of creep, and the seal will fail. The result was that it was not maintained. Alternatively, the container was subjected to stress due to the expansion of the partition wall, leading to its destruction. On the other hand, if the thermal expansion of the partition wall member is smaller than that of the container, even if a slight gap is created during heating due to temperature rise, both will thermally expand freely, and after the temperature cools down, they will fit again and restore the seal. As a result, the blood flow path etc. can be maintained. Secondly, the partition wall member has a temperature of 5×10 ^-5 to 25 to 130°C.
It has a linear expansion coefficient of about 1.1×10 ^-4 [1/°C] or more; if it is less than this, it is difficult to maintain engagement with the container. Thirdly, the partition wall member does not undergo secondary transition in the temperature range of 50 to 120°C. During the secondary transition, the coefficient of thermal expansion changes discontinuously, and the above two conditions may not be satisfied.Furthermore, undergoing the transition twice when the temperature is raised and lowered greatly impedes the dimensional reproducibility of the partition wall. . However, the secondary transition occurs at 40–49 °C and 121 °C.
If it occurs at ~130°C, the effect is small and can be tolerated. The specific volumes of the urethane resin and epoxy resin used for the partition walls in the examples were measured. The latter underwent a secondary transition at 124°C. These resins satisfy the above three conditions for polycarbonate and poly-4-methylpentene-1 containers. Table 2 shows the heat resistance and linear expansion coefficient of these resins, which are 40
Substantially heat resistant in the range of ~130°C. The material that can be used as the partition member is preferably a high molecular weight polymer. Among high-molecular polymers, preferred are polymers that are polymerized and crosslinked by addition polymerization from two or more components, ie, one or more prepolymers, a curing agent, etc., and whose total mass does not substantially change. This is because no by-products are generated when the partition wall is injected with a prepolymer or the like and molded during assembly, and because it does not contain a diluent or solvent, there is no risk of volumetric shrinkage due to evaporation during heating. Such polymers include urethane resins and epoxy resins. Among urethane resins, poly(ester type urethane) is preferable, which is obtained by addition polymerizing a prepolymer whose terminal end is an isocyanate, a polyol consisting of a fatty acid having a hydroxyl group, and an ester of glycerin, or the like. Poly(ester urethane) has excellent mechanical strength, hardness and heat resistance. On the other hand, epoxy resins that are produced by addition polymerization of a prepolymer whose terminal end is an epoxy group and an amine curing agent or an acid anhydride curing agent whose terminal end is an amino group are superior in terms of mechanical strength, hardness, and heat resistance. . When we heat-treated a polycarbonate container using a low-expansion partition member, such as a polyester resin containing an inorganic filler (a = 3 x 10 ^-5 /°C), we were unable to maintain engagement with the container, resulting in a seal failure. . A heat-sterilized artificial organ can be manufactured by assembling the artificial organ constructed as in the present invention by a known method and performing heat sterilization treatment. That is, high-pressure steam sterilization is applied to types filled with water or physiological saline and types not filled. The effect of the present invention is that the heat sterilization heating does not cause deformation, destruction, or seal failure of members, and the blood flow path and processing liquid flow path can be maintained. As a result, combined with the heat resistance of the hollow fibers, excellent performance can be achieved. Overall, heat-sterilized artificial organs are sterile;
There is no risk of residual toxicity, easy preparation for cleaning,
This will greatly contribute to treatments such as artificial fluoroscopy. The artificial organ of the present invention is not limited to an artificial kidney, but may include an artificial lung (oxygen supply), an artificial liver (poison removal), an artificial pancreas (insulin supply according to blood sugar concentration), and the like. It goes without saying that even in artificial organs that do not use hollow fibers, such as flat membrane type and adsorption type, which have a container and a partition, improvements as heat sterilized artificial organs similar to the present invention can be made.

【table】

[Table] (Note 1) Yujiro Sakurauchi, “Plastic Material Reader” Kogyo Kenkyukai (1973), ASTM D696 (Note 2) Actual value ASTM D864 (Note 3) Heat resistance 88-121℃ (Note 4) Heat resistance 121 -149°C The present invention will be explained in more detail with reference to Examples and Comparative Examples. Example 1 A hollow fiber type artificial organ having the structure shown in the right half of Fig.
30μ) and stored in a container made of polycarbonate [Panlite (registered trademark) L-1250], and both ends were embedded in poly(ester-type urethane) resin [Hysol (registered trademark) ES4003] with a partition wall. A mold was made, blood distribution and collection plates were attached, and the assembly was carried out under a sterilizing air stream. A predetermined heat sterilization process was performed under hydrostatic pressure by filling the blood chamber and the dialysate chamber with distilled water to buffer the thermal expansion of the water. As shown in Table 3, the artificial organ of the present invention had good appearance and sealing performance, no leakage from the hollow fibers, and excellent performance. All sterility test results were negative, and the biological test was also passed.
The device could be used clinically as an artificial kidney. Furthermore, 50 products were subjected to similar heat sterilization to check for leakage from the hollow fibers, but no leakage occurred.

[Table] Example 2 A hollow fiber artificial organ having the structure shown in the right half of Figure 2 was fabricated using heat-resistant polyacrylonitrile hollow fibers (inner diameter
450μ, film thickness 75μ), and stored in a polycarbonate container, and in the same manner as in Example 1, epoxy resin [base material: Mitsui Kanebo Epoxy R-130, curing agent: UCC ZZL-0803; mixing ratio 6C: 40], the bulkhead was molded and assembled. Filling and heat sterilization were performed in the same manner as in Example 1, and the appearance, sealing performance, hollow fiber leakage, performance, and sterility tests all passed. Comparative Example 1 An artificial organ prototype as shown in Figure 1 was made by bundling 8000 heat-resistant cellulose hollow fibers into a container made of rust-free steel (linear expansion coefficient 1 x 10 ^-5 /℃) and Pyrex glass (linear expansion coefficient 0.3×10 ⁻⁵ /° C.), partition walls were molded using the resin used in Examples 1 and 2, and three prototypes of each of four combinations were fabricated. When filling and heat sterilization were performed in the same manner as in Example 1, seven of the prototypes had poor sealing. Example 3 Twenty products were assembled in a container made of poly-4-methylpentene-1 [TPX (registered trademark)] under the same conditions as in Example 1 except for the container. Appearance after heat sterilization,
It passed all sealability, performance, and sterility tests. There were no leaks from the hollow fibers out of 20. Example 4 An artificial organ prototype having the configuration shown in FIG. 1 was assembled by molding an epoxy resin partition wall inside a container made of poly-4-methylpentene-1. I performed heat sterilization and checked the seal, but no leakage was found. Example 5 When assembling a hollow fiber artificial kidney in the same manner as in Example 1, the septum was molded using Vorite 689 (registered trademark) as the prepolymer and Polycin 936 as the polyol as the polyester urethane. did. The linear thermal expansion coefficient of this polyurethane was 2.5×10 ⁻⁴ /°C. Heat sterilization treatment using high-pressure steam was applied to both types of artificial organs filled with physiological saline and types not filled with this liquid. Both artificial organs have hollow fibers and septa,
The sealing property between the partition wall and the container was good.

[Brief explanation of the drawing]

1 and 2 are longitudinal sectional views of an embodiment of the invention. In FIG. 2, the right half and left half show different aspects. 1 to 9 in each figure represent the following, respectively. 1... Hollow fiber, 2... Container, 3... Partition wall, 4...
... blood distribution (or collection) site, 5 ... blood collection (or distribution) site, 6 ... blood conduit, 7 ... processing liquid (or processing fluid) conduit, 8 ... blood chamber, 9
...Processing liquid (or processing fluid) chamber.

Claims (1)

[Claims] 1. A hollow fiber type artificial organ composed of a hollow fiber, a partition wall, and a container, wherein the hollow fiber, the partition wall, and the container have substantially heat resistance in the range of 40 to 130°C; The linear expansion coefficient a [1/℃] of the partition wall member is 40~
The coefficient b [1/°C] of the container member in the range of 130°C
and temperature t [°C], (4.13×10 ^-5 ) ^{e 0} . An artificial organ that uses heat sterilization. 2. The artificial organ according to claim 1, wherein the hollow fibers are cellulose. 3. The artificial organ according to claim 1, wherein the hollow fibers are polyacrylonitrile. 4. The artificial organ according to claim 1, wherein the container member is made of polycarbonate. 5. The artificial organ according to claim 1, wherein the container member is poly-4-methylpentene-1. 6. The artificial organ according to claim 1, wherein the partition member is made of a high molecular weight polymer. 7. The artificial organ according to claim 6, wherein the high molecular weight polymer is a polymer that is polymerized and crosslinked by addition polymerization from two or more components and whose total mass does not substantially change. 8. The artificial organ according to claim 7, wherein the high molecular weight polymer is a urethane resin. 9 Urethane resin is poly(ester type urethane)
The artificial organ according to claim 8. 10. The artificial organ according to claim 7, wherein the high molecular weight polymer is an epoxy resin.