JPS6241738B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to an artificial organ and a method for manufacturing the same. More specifically, the present invention relates to artificial organs such as artificial kidneys, artificial lungs, and blood separation devices that do not substantially cause transient leukopenia, and methods for manufacturing the same. (Prior art) Artificial organs such as artificial kidneys, artificial livers, artificial lungs, and blood separation devices have been used in the past, and in the dialysis site, dialysis membranes such as hollow fiber membrane type and flat membrane type are used. Regenerated cellulose-based materials are widely used because of their excellent dialysis properties, mechanical strength, cost, etc. However, artificial organs using such regenerated cellulose-based membranes, such as regenerated cellulose-based artificial kidneys, suffer from so-called transient leukopenia (hemodialysis), in which the number of white blood cells decreases temporarily and rapidly immediately after the start of dialysis. leukopenia) and other side effects on living organisms, and the impact this has on patients cannot be ignored. (Problems to be Solved by the Invention) On the other hand, synthetic polymer membranes such as polymethyl methacrylate, polyacrylonitrile, ethylene-vinyl alcohol copolymer, and polycarbonate, which have recently been proposed as permeable membranes, have been proposed to prevent transient leukopenia. Although the degree of expression of ) etc. and performance, which not only limits the number of patients who can use it, but also increases cost, causes many pinholes during use, and limits sterilization methods. In order to solve the above-mentioned problems, it has been proposed to modify the surface of the regenerated cellulose membrane using heparin or the like, but no satisfactory results have been obtained. Accordingly, an object of the present invention is to provide an improved artificial organ and a method for manufacturing the same.
Another object of the present invention is to provide an artificial organ and a method for producing the same that have fewer side effects on living organisms. Still another object of the present invention is to provide an artificial organ that does not substantially cause transient leukopenia, and a method for manufacturing the same. (Means for Solving the Problems) These objects are achieved by an artificial organ in which a vitamin E coating is coated on the surface of a region of the artificial organ that can come into contact with the body fluid. The present invention also provides an artificial organ in which at least a portion of the body fluid circulation area is a body fluid permeable membrane. The present invention is an artificial organ in which the regenerated cellulose membrane is a hollow fiber type membrane. Furthermore, the artificial organ according to the invention is, for example, an artificial kidney, an artificial liver, an artificial lung or a blood separation device. In addition, the above objectives are such that the concentration of vitamin E in the organic solvent solution is 0.01 to 10 in the body fluid circulation area in the artificial organ.
After flowing an organic solvent solution of vitamin E in w/v% and thoroughly blending the solution into the contact area, the solution is discharged, and then the organic solvent is removed by drying. This is achieved by a method for producing an artificial organ, characterized in that the surface of a portion of the artificial organ that can come into contact with the body fluid in the body fluid circulation area is coated with a vitamin E coating. The present invention also provides a method for manufacturing an artificial organ in which at least a portion of the body fluid circulation area is a body fluid permeable membrane. The present invention is a method for producing an artificial organ in which the body fluid permeable membrane is a regenerated cellulose membrane. Further, the present invention is a method for producing an artificial organ, in which the regenerated cellulose membrane is a hollow fiber membrane. Furthermore, the present invention is a method for producing an artificial organ, in which the organic solvent is a lower alcohol. Furthermore, the present invention
This is a method for manufacturing an artificial organ, in which drying is performed by passing a gas inert to the vitamin E through the body fluid circulation area at a temperature of 10 to 80°C. (Function) The artificial organ in the present invention is one that has a circulation area for body fluids such as blood, such as an artificial kidney, an artificial liver, an artificial lung, a plasma separation device, a blood circuit, and an artificial blood vessel. It is desirable that at least a portion of this body fluid circulation area is a body fluid permeable membrane. Note that this artificial organ includes not only tubes and connectors that connect the living body to the artificial organ, but also other blood circuits and the like. Next, one embodiment of the present invention will be described with reference to the drawings. FIG. 1 shows an example of an artificial kidney cell, that is, a hollow fiber type dialyzer. This dialyzer 1 is constructed by inserting a hollow fiber bundle 5 made of a large number of hollow fibers into a cylindrical body 4, which has an inlet pipe 2 and an outlet pipe 3 for dialysate near both ends. Both ends of the cylindrical body are sealed with potting agents 6 and 7 such as polyurethane. For example, it has a structure similar to a shell-and-tube type device in a heat exchanger, and headers 10 and 11 each having an inlet 8 and an outlet 9 for blood are provided at both ends of the cylindrical body. touched,
Headers 10 and 11 and cylindrical body 4 are fixed by caps 12 and 13, respectively. Tubes 14 and 15 connected to the human body are connected to the inlet 8 and the outlet 9. The hollow fibers constituting the hollow fiber bundle 5 are dialysis membranes, such as membranes made of regenerated cellulose, polymethyl methacrylate, polyacrylonitrile, ethylene-vinyl alcohol copolymer, polycarbonate, etc., preferably regenerated cellulose membranes. Especially preferred is a cuprammonium regenerated cellulose membrane. According to the present invention, a body fluid of the artificial kidney as described above, for example, a contact site with the blood in the blood circulation area,
For example, the inner surface of the hollow fiber membrane, the inner surface of the space formed by the header 10 and the potting agent 6, the inner surface of the space formed by the header 11 and the potting agent 7, the inner surface of the blood inlet 8, the inner surface of the blood outlet 9,
The inner surfaces of the tubes 14 and 15, particularly the inner surfaces of the hollow fiber membranes, are coated with a vitamin E coating. For example, taking a hollow fiber membrane as an example, as shown in FIG.
It is made by coating. The vitamin E used in the present invention is fat-soluble, and examples include α-tocopherol,
β-tocopherol, γ-tocopherol, δ-
Examples include tocopherols such as tocopherol, tocotrienols such as α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. The thickness of the vitamin E coating is 0.0001 to 0.1 μm, preferably 0.002 to 0.5 μm.
It is. Such vitamin E has a concentration of 0.01 to 10w/v
%, preferably 0.05 to 2.0 w/v%, as an organic solvent solution, flowing into the body fluid circulation area of the artificial organ (in the case of the artificial kidney shown in Figs. 1 and 2, the blood circulation area),
for a predetermined period of time, e.g. 30 seconds to 60 minutes, preferably 1
By contacting for ~10 minutes, the inner surface of the region, such as the tube 14, the space formed between the header 10 and the potting agent 6, the hollow fiber, the space formed between the header 11 and the potting agent 7, and The vitamin E is sufficiently applied to the inner surface of the tube 15. After discharging the solution, a gas inert to the vitamin E, such as air, is then added at a temperature of 10 to 80°C, preferably 15 to 30°C.
A coating of vitamin E is formed on the contact surface by introducing nitrogen, carbon dioxide gas, etc. and evaporating the organic solvent, and washing with water is further performed as necessary. In this case, it goes without saying that the coating operation may be performed without connecting the tubes 14 and 15 to form a vitamin E coating on the main parts, especially the permeable membrane parts.
Particularly in artificial organs using regenerated cellulose membranes that are prone to transient leukopenia, significant effects can be obtained by coating the permeable membrane portion primarily with vitamin E. In addition, in the case of regenerated cellulose, especially cellulose regenerated by cuprammonium method, as the permeable membrane, glycerin can be added to the organic solvent solution of vitamin E, thereby imparting hydrophilicity to the permeable membrane. . Therefore, it is effective in artificial organs that use hydrophilic permeable membranes, such as artificial kidneys and artificial livers. Note that the concentration of the glycerin in the solution is 0.1
-10 w/v%, preferably 1-5 w/v. The organic solvent used in the present invention includes methanol,
Examples include alcohols such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, and 2-ethylhexanol, and diethyl ether, but lower alcohols are preferred, and ethanol is particularly preferred. The above has mainly explained the artificial kidney, which is a dialyzer, but there are also artificial livers, artificial lungs,
It goes without saying that it can be used in artificial blood vessels, blood circuits, blood separation devices, etc., and if the vitamin E coating is formed on areas that have membranes permeable to body fluids, especially blood, remarkable effects can be obtained. Next, the present invention will be explained in more detail by giving examples. (Example) Example 1 Inner diameter approximately 200 μm, outer diameter approximately 220 μm, length 14 to 14.5
Using 368 cuprammonium regenerated cellulose hollow fibers of cm, as shown in FIG.
Then, headers 10 and 11 were attached to both ends, and the caps 12 and 13 were used to secure the dialyzer (artificial kidney) 1. The inner membrane area of this product was 300 cm ² . On the other hand, an ethanol solution of vitamin E was prepared by dissolving 1.0 g of vitamin E (DL-α-tocopherol) in 100 ml of ethanol. A 50 ml syringe was connected to one end of the dialyzer 1, and the other end was immersed in the vitamin E solution. The plunger of the syringe was activated to fill the dialyzer with the vitamin E solution. In this state, it was left at room temperature for about 5 minutes. Then, after pulling up the dialyzer to drain the vitamin E solution,
An aspirator was connected and air was blown to dry at a temperature of 25°C. Furthermore, to ensure complete drying, it was left in an oven at 60°C overnight. The theoretical thickness of the vitamin E coating in the dialyzer thus obtained was estimated to be about 0.05 μm. Example 2 A dialyzer was manufactured in the same manner as in Example 1 except that the concentration of vitamin E in the ethanol solution of vitamin E was changed to 0.1 w/v%. The theoretical thickness of the vitamin E coating in this dialyzer was estimated to be 0.005 μm. Comparative Example For comparison purposes, a dialyzer similar to Example 1, which was not treated with vitamin E in ethanol solution, was simply wetted by autoclaving. Example 3 Vitamin E (DL-α-tocopherol) was dissolved in ethanol at a concentration of 1 w/v%, and a polystyrene plate was immersed in the resulting solution for 3 minutes, then taken out and left at room temperature to completely dry. A sample was obtained. Similarly, a sample was obtained using a 0.1 w/v % ethanol solution of vitamin E. These samples and untreated samples were evaluated by a platelet dilatation test. Evaluation of platelet expansion ability was performed by the following method. In other words, 4.5 ml of venous blood of a healthy person is 3.8
Blood was collected using a polypropylene syringe containing 0.5 ml of sodium citrate, transferred to a polypropylene test tube, and centrifuged at 800 rpm for 5 minutes.
A diluent (saline: 3.8% sodium citrate = 9:1) was added to the obtained PRP to prepare a platelet suspension. This solution was dropped onto a sample (a plate with a thickness of 0.4 mm) and left for a certain period of time to allow platelets to adhere and expand. This was fixed with 2% glutaraldehyde, subjected to stepwise dehydration in an ethanol series, and observed under an electron microscope after drying. The evaluation method looked at the number of platelets attached to 0.11 mm ² and changes in their morphology. Morphological changes were classified into the following three types. Type: The platelet's normal platelet shape, which is a disc, has become spherical and has 3 to 4 pseudopodia, and is thought to have relatively weak adhesion to the material surface. Type: A type with several or more pseudopodia extended and the cell body expanded to half of the pseudopod, which seems to have strongly adhered to the material surface. Type: One with a thin vesicle expanded to more than half the length of the pseudopod, which appears to have expanded to an almost reduced size, exhibiting a circular system, and completely adhered to the material surface.

[Table] Example 4 After measuring the weight of the rabbit, it was fixed in the dorsal position on a Kitajima type fixation table. Next, the hair in the surgical field was trimmed with electric clippers and wiped with alcohol cotton. An incision was made along the midline from submandibular to the clavicle with scissors, the fascia was further opened, and the right (left) common carotid artery was dissected, being careful not to damage nerves, branch vessels, and surrounding tissues. Next, the left (right) facial vein was carefully dissected in the same way, and a Terumo Corporation Surflow (registered trademark of Terumo Corporation) indwelling catheter with a rubber cap for mixed injection filled with 1 IU/ml heparinized saline was inserted. and fixed with a ligature. Similarly,
A catheter was also inserted into the artery and ligated and fixed. The weights of the test rabbits at this time were as shown in Table 2. Table 2 Sample weight (Kg) VE1.0% 2.53 VE0.1% 2.66 No treatment 2.58 Regarding rabbit 20 prepared in this way,
The dialyzers 1 of Examples 1 and 2 and Comparative Example were opened to prepare experimental circuits. i.e. rabbit 2
The catheter 21 connected to the artery of
2, a bypass catheter 23 is connected to the catheter 21, and the bypass catheter 23 is connected to the catheter 21.
was connected to the chamber 24 communicating with the out 25 side of the manometer, and further the chamber 24 and the vein of the rabbit 20 were connected with a catheter 26. The pump 22 and the dialyzer 1 are connected through a tube 27, and the tube 27 communicates with the inlet 28 side of the manometer. Further, the dialyzer 1 and the chamber 24 were connected through a tube 29. On the other hand, the dialysate inlet and outlet of the dialyzer 1 were connected by a tube 30, a pump 31 was installed in the tube 30, and the dialyzer 1 was immersed in a water bath 32 at 37°C.
The thus constructed circuit was subjected to priming cleaning with 1 IU/ml heparinized saline (100 ml). The collected blood was diluted 2 times with 1.5% EDTA-3K saline and calculated using ELT-8 (Ortho Instrument). The resulting white blood cell count (WBC),
Platelet counts (PLT) and hematocrit values (HCT) are shown in Tables 3-5. In addition, white blood cell count,
The platelet count was corrected for the HCT value using the following formula and expressed as the value at the HCT value immediately before the start of circulation. Cx=CoHCTx/HCTo However, the symbols in the formula are as follows. Cx: Correction value Co: Actual measurement calculation value HCTx: Correction standard Hct value = initial Hct value HCTo: Hct value when the Co value is obtained

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[Table] Figure 4 shows the changes over time in the number of white blood cells obtained from the above results. In the figure, curve A shows the case of vitamin E 1.0%, curve B shows the case of vitamin E 0.1%, and curve C shows the case of vitamin E 0%. As is clear from FIG. 4, those coated with vitamin E and glycerin do not cause the transient leukopenia that usually occurs after the start of use, and the increase in white blood cells due to long-term use is extremely small. Furthermore, the change in platelet count over time is shown in FIG. In the same figure, curve D is for vitamin E 1.0%;
Curve E shows the case of vitamin E 0.1%, and curve F shows the case of vitamin E 0%. As is clear from FIG. 5, it is clear that the vitamin E coating does not have any adverse effect on the change in platelet count over time. (Effects of the invention) As described above, the artificial organ according to the present invention has
Since the surface of the body fluid circulation area in the artificial organ that can come into contact with the body fluid is coated with a vitamin E film, the action of the vitamin E can cause side effects on the living body, such as transient leukopenia. It can be reduced. In particular, when the artificial organ is an external circulation artificial organ that has at least a dialysis membrane at least in part, and especially when the dialysis membrane is a regenerated cellulose membrane, transient leukopenia, which has traditionally occurred significantly, can be significantly reduced. Therefore, it is possible to reduce the risk of infection, which conventionally was large due to a decrease in the number of white blood cells at the initial stage of use. Furthermore, vitamin E shows excellent effects on the above-mentioned transient leukopenia and platelet expansion. Therefore, artificial kidney, artificial liver,
It is useful as an artificial lung, blood separation device, blood circuit, artificial blood vessel, etc., and exhibits particularly excellent effects as an artificial kidney. In addition, artificial organs such as artificial kidneys are primed with physiological saline etc. before use.
If the surface-coated substance peels off or dissolves during this operation, it would be difficult to obtain a sufficient effect, but since vitamin E is fat-soluble, such peeling or dissolution does not occur in the artificial organ according to the present invention. In addition, the method for manufacturing an artificial organ according to the present invention includes flowing an organic solvent solution of vitamin E in which the concentration of vitamin E in the organic solvent solution is 0.01 to 10 w/v% into the body fluid circulation area in the artificial organ. The coating process is carried out by sufficiently applying the solution to the contact area, discharging the solution, and then drying to remove the organic solvent. Therefore, the coating process is easy and the cost is low. and does not require a chemical reaction during coating.
There is less possibility of secondary contamination of the artificial organ due to the covering operation. Furthermore, the action of the vitamin E used can reduce side effects on living organisms, such as transient leukopenia, and also exhibits an excellent effect on inhibiting platelet expansion. Furthermore, since vitamin E is used as an organic solvent solution, the fat-soluble vitamin can be efficiently coated extremely thinly.

[Brief explanation of the drawing]

FIG. 1 is a partially cutaway perspective view showing an embodiment of the artificial organ according to the present invention, FIG. 2 is a longitudinal cross-sectional view of a hollow fiber, and FIG. 3 is a perspective view showing an embodiment of the artificial organ according to the present invention. In the experimental circuit, FIG. 4 is a graph showing changes over time in the number of white blood cells, and FIG. 5 is a graph showing changes over time in the number of platelets. DESCRIPTION OF SYMBOLS 1... dialyzer, 4... cylindrical main body, 5... hollow fiber bundle, 6, 7... potting agent, 10, 11... header, 12, 13... cap.

Claims (1)

[Scope of Claims] 1. An artificial organ in which a vitamin E film is coated on the surface of a part of the artificial organ that can come into contact with the body fluid in the body fluid circulation area. 2. The artificial organ according to claim 1, wherein at least a portion of the body fluid flow area is a body fluid permeable membrane. 3. The artificial organ according to claim 2, wherein the body fluid permeable membrane is a regenerated cellulose membrane. 4. The artificial organ according to claim 3, wherein the regenerated cellulose membrane is a hollow fiber membrane. 5. The artificial organ according to any one of claims 1 to 4, wherein the artificial organ is an artificial kidney, an artificial liver, an artificial lung, or a blood separation device. 6. Flow an organic solvent solution of vitamin E in which the concentration of vitamin E in the organic solvent solution is 0.01 to 10 w/v% into the body fluid circulation area in the artificial organ, and thoroughly spread the solution to the contact area with the solution. After that, the solution is drained, and then the organic solvent is removed by drying.A coating of vitamin E is coated on the surface of a part of the body fluid circulation area in the artificial organ that can come into contact with the body fluid. A method for manufacturing artificial organs. 7. The manufacturing method according to claim 6, wherein at least a portion of the body fluid flow area is a body fluid permeable membrane. 8. The manufacturing method according to claim 7, wherein the body fluid permeable membrane is a regenerated cellulose membrane. 9. The manufacturing method according to claim 8, wherein the regenerated cellulose membrane is a hollow fiber membrane. 10. The manufacturing method according to any one of claims 6 to 9, wherein the organic solvent is a lower alcohol. 11. Drying is carried out by passing a gas inert to the vitamin E through the body fluid circulation area at a temperature of 10 to 80°C.
The manufacturing method described in any one of the paragraphs.