JPS61115569A - Artificial kidney and its production - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] ■8 invention i! BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an artificial kidney and a method for manufacturing the same. More specifically, the present invention relates to an artificial kidney that does not substantially cause transient leukopenia and a method for producing the same.

PRIOR ART Traditionally, artificial kidneys have been used, especially at the dialysis site.
As a hollow fiber model, flat membrane type, etc. dialysis membrane, its excellent dialysis properties, I! l Mechanical strength 9 Regenerated cellulose-based materials are widely used in terms of price and other factors. However, artificial kidneys using such regenerated cellulose membranes suffer from so-called transient leukopenia (hei + odi
lysis keukopenia) and other side effects on living organisms, and the effects this has on patients can be ignored.

On the other hand, recently a permeable membrane'! ``U'r proposed 4''''0゛61
“1'☆Synthetic polymer membranes such as methyl methacrylate, polyacrylonitrile, ethylene-vinyl alcohol copolymer, and polycarbonate are relatively weak in causing transient leukopenia compared to the regenerated cellulose-based membranes. However, these synthetic polymer membranes have a poor balance between physical properties such as mechanical strength, heat resistance, ultrafiltration rate (tJFR), etc., and performance during processing, assembly, or use, which limits the number of patients who can use them. However, there are problems such as high costs, many pinholes during use, and limited 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 definitive results have been obtained yet.

(1) Purpose of the Invention Therefore, the purpose of the present invention is to provide an improved artificial kidney and a method for manufacturing the same.

Another object of the present invention is to provide an artificial kidney with fewer side effects on living organisms and a method for manufacturing the same. Still another object of the present invention is to provide an artificial kidney that does not substantially cause transient leukopenia and a method for manufacturing the same. Another object of the present invention is to provide an artificial kidney with good durability and a method for manufacturing the same. These objectives are to provide an artificial kidney in which a housing and a body fluid selectively permeable membrane are housed in the housing, and to seal the pores of the body fluid selectively permeable membrane so that the surface of the area in contact with the body fluid in the body fluid circulation area is made of silicone. This can be achieved by using an artificial kidney covered with Further, the present invention is an artificial kidney, wherein the body fluid selectively permeable membrane is a hollow fiber membrane. Furthermore, the present invention
The artificial kidney is such that the body fluid permeable membrane is a regenerated cellulose membrane. Further, the present invention provides an artificial kidney in which the silicone is at least one selected from the group consisting of silicone oil, silicone rubber, and silicone resin.

These objectives are also achieved by flowing an organic solvent solution of silicone into a housing and a body fluid flow area in an artificial kidney in which a body fluid permselective membrane is housed in the housing, and sufficiently applying the solution to the contact area with the solution. A method for producing an artificial kidney comprising coating silicone on the surface of a part of the body fluid circulation area in the artificial kidney that comes into contact with the body fluid and is characterized by drying and removing the organic solvent after blending. This is achieved by In addition, the present invention provides that the body fluid selectively permeable membrane is made of regenerated cellulose.
This is a method for manufacturing an artificial kidney. Further, the present invention is a method for manufacturing an artificial kidney in which the body fluid selectively permeable membrane is a hollow fiber membrane. Furthermore, the present invention is a method for producing an artificial kidney, wherein the organic solvent is a chlorofluorinated hydrocarbon or a fluorinated hydrocarbon. The present invention is a method for producing an artificial kidney in which the silicone is at least one selected from the group consisting of silicone oil, silicone rubber, and silicone resin, and particularly silicone rubber. Further, the present invention provides that the chlorofluorinated hydrocarbon solvent is 1.1.2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane and 1.1.2-trichloro-1,2,2-trifluoroethane.
．． This is a method for producing an artificial kidney made of at least one member selected from the group consisting of 1,2,2-tetrachloro-1,2-difluoroethane. The present invention relates to the 'fA of silicone in chlorofluorocarbon or fluorohydrocarbon solvent solution.
degree is 0.05 to 10 W/v%, especially 0.1 to 5. Ow/
This is a method for manufacturing an artificial organ with v%. Furthermore, the present invention is a method for manufacturing an artificial organ, in which drying is performed by flowing a gas inert to the silicone at a temperature of 10 to 60° C. through the body fluid circulation area.

10 Detailed Description of the Invention Next, one embodiment of the invention will be described with reference to the drawings. FIG. 1 shows an example of an artificial kidney, that is, a hollow fiber 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. It has a structure similar to a shell-and-tube type device in a heat exchanger, for example, in which both ends of the cylindrical body are sealed with botting agents 6 and 7 such as polyurethane. A header 10.11 with an inlet 8 and an outlet 9 for blood at each end.
are in contact with each other, and the header 10.11 and the cylindrical body 4 are fixed by the caps 12.13, respectively.The inlet 8 and the outlet 9 are provided with a tube 14 connected to the human body.
．． 15 are connected.

The hollow fibers constituting the hollow fiber bundle 5 are body fluid selective dialysis membranes, such as regenerated cellulose.

The membrane is made of polymethyl methacrylate, polyacrylonitrile, ethylene-vinyl alcohol copolymer, polycarbonate, etc., preferably a regenerated cellulose membrane, particularly preferably a cuprammonium regenerated cellulose membrane.

According to the present invention, a silicone coating is coated on the inner surface of the hollow fiber membrane, which is the contact area with body fluids, such as blood, in the circulation area of the artificial kidney. Furthermore, 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, and the inner surface of the blood outlet 9 are also coated with a silicone coating. It is preferable to do so.

Furthermore, the same applies to the tubes 14, 15 of the blood circuit. Taking a hollow fiber membrane as an example, as shown in FIG. 2, the inner surface of the hollow fiber membrane 16 is coated with a silicone coating [117] without clogging the pores in the side wall of the hollow fiber membrane 16. . However, there is no problem even if some of the pores are blocked. Although it is preferable that the covering 11117 be uniform throughout, it is not necessary to cover the entire inner surface of the hollow fiber 11R16, and the inner surface may be exposed here and there.

The silicone used in the present invention forms a thin film on the surface of the film by dissolving it in a solvent and coming into contact with the film, and includes silicone oil, silicone rubber,
There are silicone resins, etc.

Examples of silicone oil include methyl silicone oil,
Examples include dimethyl silicone oil, methylphenyl silicone oil, and methylchlorophenyl silicone oil. Examples of silicone rubber or silicone resin include dimethylborine 0xane, methylphenylpolysiloxane,
Examples include methylvinylpolysiloxane, methylphenylvinylpolysiloxane, and partially crosslinked silicones, such as aminoalkylsiloxane-dimethylsiloxane copolymers. Among these silicones, silicone rubbers are preferred, and in particular silicone rubbers represented by the following general formula I [wherein R is an alkyl group having 1 to 6 carbon atoms, Y G, t 0f-1 and OH2 (however, R' Q is an alkyl group having 1 to 3 carbon atoms.
is a hydrogen atom, at least one selected from the group consisting of CH3 and CH2-NH2, a is 0 or 1°, b is O or 1 (however, a+b is 0 or 2), , ] and a repeating unit having the general formula ■ CH3R”Si 03 (II
) (wherein, R' is at least one selected from the group consisting of Of-1 and CH3, and C
is 1 or 2. ) repeating unit 95~BOm
It is an at least partially cured organosiloxane copolymer consisting of Ffk%.

The back of the silicone rubber is preferably room temperature vulcanized rubber,
Raw rubber as it is does not have sufficient strength, so it is reinforced by adding a filler such as fine silica powder.

Examples of the vulcanizing agent include organic peroxides such as benzoyl peroxide, bis-2,4-dichlorobenzoyl peroxide, dicumyl peroxide, and ditertiarybutyl peroxide, fatty acid azo compounds, and the like.

Although the treatment of the membrane with the silicone solution can be carried out before assembly, it is best to carry out the treatment after module assembly.

Such silicone has a concentration of 0.05 to 1°W/v%.
, preferably as a 0.1 to 5 W/v% chlorinated fluorinated hydrocarbon or fluorinated hydrocarbon solvent solution, to the body fluid circulation area of the artificial kidney (in the case of the artificial kidney shown in FIGS. 1 and 2, the blood circulation area).
and contact for a predetermined period of time, for example 30 seconds to 60 minutes, preferably 1 to 10 minutes, so that the inner surface of the area, for example tube 14. Between the header 10 and the botting agent 6 1 formation 8F'6''!!1・Medium 9 thread・''15-
11! : *Make sure the silicone is thoroughly applied to the space formed between the botting agent 7 and the inner surface of the tube 15. Then, after discharging the solution, 1
A gas inert to the silicone, such as air, nitrogen, carbon dioxide, etc., is introduced at a temperature of 0 to 60°C, preferably 20 to 30°C, and the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent is removed by evaporation. By doing so, a silicone film is formed on the contact surface, which is further washed with water if necessary. In this case, it is of course possible to carry out the coating operation without connecting the tubes 14, 15 to form a silicone coating on the main parts, especially the permeable membrane parts. Particularly in artificial kidneys using regenerated cellulose membranes that are prone to transient leukopenia, significant effects can be obtained by coating the permeable membrane portion with silicone S. Furthermore, in the case of regenerated cellulose, especially regenerated cellulose produced by cuprammonium method, as the permeable membrane, glycerin or ethylene glycol may be contained in the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent solution of the silicone. This makes it possible to impart hydrophilicity to the permeable membrane. therefore,
In this way, it is effective in an artificial kidney using a hydrophilic permeable membrane. The concentration of glycerin or ethylene glycone in the solution is 0.1 to 10 W/v%, preferably 1 to 5 W/v%. It is also possible to make the permeable membrane of the silicone-coated artificial kidney hydrophilic by flowing an aqueous solution of glycerin or ethylene glycol 4-ol into the membrane. Also, before coating with silicone,
It is also possible to make the permeable membrane of the artificial kidney hydrophilic by flowing an aqueous solution of glycerin or ethylene glycol into contact therewith.

The solvent used in the present invention includes various alcohols such as ethyl alcohol and hexane, but preferred are chlorofluorinated hydrocarbons and fluorinated hydrocarbons, such as 1,1,2-trichloro-1,2 , 2-trifluoroethane, trichlorofluoromethane, 1,1,2.2-
Examples include tetrachloro-1,2-difluoroethane, preferably 1,1,2-trichloro-1,2,2-)-
There is refluoroethane. In addition, examples of fluorinated hydrocarbons include perfluorosyqloalkanes such as methyl fluoride, carbon tetrafluoride, tetrafluoroethane, tetrafluoroethylene, perfluoromethylpropylcyclohexane, perfluorobutylsif-1-cohexibuzane, perfluorodecalin, Examples include perfluoromethyldecalin, perfluoroalkyltetrahydrobylane, and perfluorodecane. These chlorofluorinated hydrocarbons and fluorinated hydrocarbons are most preferred because they have high solubility in silicone and are harmless to the human body. It goes without saying that mixtures of these and alcohols can also be used.

Artificial 1llJR produced in such a temperature range should be sterilized and stored by autoclave sterilization, ethylene oxide sterilization, gamma ray sterilization, etc., or it should be sterilized using silicone as described above before use. Coating treatment is applied.

Also, do something like this! 4. After removing the chlorofluorinated hydrocarbon or the fluorinated hydrocarbon solvent, the constructed artificial kidney is further treated with at least one liquid selected from the group consisting of water, physiological saline, and aqueous glycerin solution, which is harmless to living organisms. The seed liquid may be brought into contact with the side surface of the body fluid circulation area and sterilized using an autoclave.

Note that whether or not the membrane is coated with silicone can be detected by bringing the membrane into contact with a solvent again to elute the silicone.

Next, the present invention will be explained in more detail by giving examples.

Example 1 Inner diameter approximately 200μ, outer diameter 220μ-1 length 14~14
．． Using 368 5 cm copper ammonia regenerated cellulose hollow fibers, insert them into the cylindrical body 1 as shown in FIG.
Fix both ends with polyurethane botting agent 6.7,
Furthermore, attach headers 10 and 11 to both ends, and cap 1.
2. Dialyzer (artificial kidney) 1 fixed by 13
It was created. The internal area of this film was 300,012.

On the other hand, a partially cured organosiloxane copolymer rubber consisting of 10 to 20% by weight of aminoalkylsiloxane and 90 to 80% by weight of dimethylsiloxane (1.0 (solid content equivalent)) 1.1.2-trichloro-1,2, of silicone dissolved in 100 ml of 2-trichloro-1,2,2-trifluoroethane.
A 2-trifluoroethane solution was prepared. 50+11j at one end of the dialyzer-1! A syringe was connected, and the other end was dipped into the silicone solution. The plunger of the syringe was actuated to fill the dialyzer with silicone solution.

In this state, it was left at room temperature for about 5 minutes. Next, the dialyzer was pulled up to discharge the silicone solution, an aspirator was connected, and the dialyzer was dried by blowing air at a temperature of 25°C. Furthermore, to ensure complete drying, the chicken was left in an oven at 30°C overnight. The dialyzer thus produced was sterilized by autoclaving at 115° C. for 30 minutes. The theoretical film layer of the silicone coating in the dialyzer thus obtained was estimated to be approximately 0.05 μm.

Example 2 Example 1 in the method of Example 1 except that the concentration of silicone in the 1.1.2-trichloro-1,2,2-)-lifluoroethane solution of silicone was 0.1 W/v%.
A dialyzer was manufactured in the same manner. The theoretical thickness of the silicone coating inside this dialyzer is 0.
It was estimated to be 0.035μ.

Comparative Example For comparison purposes, a dialyzer similar to Example 1 without silicone treatment in 1.1.2-trichloro-1,2,2-trifluoroethane solution was wetted simply by autoclave treatment.

Example 3 After measuring the weight of the rabbit, it was fixed in the anterior position on a Kitajima fixation table. Next, the hair in the surgical field was trimmed with electric clippers and wiped with alcohol cotton. Using scissors, make an incision along the midline from below the jaw to the clavicle, and roughly open the muscle limb, taking care not to damage the nerves, branching blood vessels, and surrounding tissues.
The common carotid artery was dissected. Next, the left (right > m-plane vein) was dissected deeply in the same way, and a Surf 0-care catheter with a rubber cap filled with IIU/lj! of heparinized saline was inserted and fixed. Similarly, a catheter was inserted into the artery and the knot was fixed.

The weights of the rabbits tested at this time were as shown in Table 1.

Silicone 1.0% 2.35 Silicone
0.1% 2.48 No treatment II
2. 40 Regarding the rabbit 20 thus prepared, the dialyzers 1 of Examples 1 and 2 and Comparative Example were opened to prepare an experimental circuit.

That is, the catheter 2 connected to the artery of the rabbit 20
1 is connected to a pump 22, a bypass catheter 23 is connected to the catheter 21, and the bypass catheter 23 is connected to the pump 22.
is the chamber 24 that communicates with the out 25 side of the manometer.
The chamber 24 was connected to the vein of the rabbit 20 using a catheter 26. The pump 22 and the dialyzer 1 are connected by 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 by 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 circuit constructed in this manner was subjected to briming cleaning with 11 LJ/m, 2 heparinized saline (10011).

The collected blood was diluted 2 times with saline to 1.5% EDTA-3, and then added to an automatic blood cell counting device: ELT-8 (Q rtho
Calculated using Instrument Co., Ltd.).

The white blood cell count (WBC) and platelet (PLT) obtained as a result were
) and hematocrit values ()ICT) are shown in Tables 2-4. In addition, the white blood cell count and platelet count are determined by HC using the following formula.
The T value was corrected and expressed as the HCT value immediately before the start of circulation.

(・ Cx-CoHCTX H.C.T.

However, the symbols in the formula are as follows.

Cx: Correction value CO: Actual measurement value 1-1cTx: Correction reference Hat value = initial HCt value H
CTo: HCt value when Co value is obtained (below the margin)
As shown in the figure. In the figure, curve A shows the case of 1.0% silicone, curve B shows the case of 0.1% silicone, and curve C shows the case of 0% silicone. Furthermore, the change in platelet count over time is shown in FIG. In the same figure, the curve is 1.0% silicone,
Curve E shows the case with 0.1% silicone and curve F shows the case with 0% silicone.

(9) Specific Effects of the Invention As described above, the artificial kidney according to the present invention includes a housing and a body fluid selectively permeable membrane housed in the housing, and the pores of the body fluid selectively permeable membrane are occluded. Since this is an artificial kidney in which the surface of the area that comes into contact with body fluids in the body fluid circulation area is coated with silicone, side effects on the living body, such as transient leukopenia, can be reduced by the action of the silicone used. It also exhibits excellent effects on inhibiting platelet expansion. Further, the method for manufacturing an artificial kidney according to the present invention includes a housing and an organic solvent solution of silicone flowing into a body fluid flow area in the artificial kidney in which a body fluid selectively permeable membrane is housed in the housing, and a silicone organic solvent solution flowing into a body fluid flow area in a body fluid flow region in which a body fluid selectively permeable membrane is housed in the housing. Since the coating process is carried out by blending the solution with the chemical components and then drying to remove the organic solvent, the coating process is easy, and therefore the cost can be reduced, and there is no chemical reaction during coating. Since this method does not require any additional coating, there is less possibility of secondary contamination of the artificial organ due to the covering operation. In particular, in the present invention, when chlorofluorinated hydrocarbon or fluorinated hydrocarbon is used as the medium,
Compared to using organic solvents such as alcohol, this method is not only safer in terms of disaster prevention, but also has stronger silicone coating on the body fluid circulation area within the artificial kidney, making it difficult to peel off and highly durable. There is an advantage.

[Brief explanation of drawings]

FIG. 1 is a partially cutaway perspective view showing a broken embodiment of the artificial kidney according to the present invention; FIG. 2 is a longitudinal cross-sectional view of a hollow fiber;
FIG. 3 is an experimental circuit for evaluating the performance of the artificial organ according to the present invention, 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. 1... dialyzer, 4... cylindrical body, 5...
Hollow fiber bundle, 6,7...botting agent, 10.11.
...Header, 12.13...Cap. Patent applicant Terumo Co., Ltd. No. 3
8 Chiku 4 Dentai Gaikonkan time (min)

Claims (13)

[Claims] (1) In an artificial kidney that includes a housing and a body fluid selectively permeable membrane housed in the housing, silicone is applied to the surface of the body fluid flow area in contact with the body fluid by blocking the pores of the body fluid selectively permeable membrane. An artificial kidney covered with (2) The artificial kidney according to claim 1, wherein the body fluid selectively permeable membrane is a hollow fiber membrane. (3) The artificial kidney according to claim 1 or 2, wherein the body fluid permselective membrane is a regenerated cellulose membrane. (4) The artificial kidney according to claim 1, wherein the silicone is at least one selected from the group consisting of silicone oil, silicone rubber, and silicone resin. (5) After flowing an organic solvent solution of silicone into the housing and the body fluid flow area of the artificial kidney in which the body fluid selectively permeable membrane is housed in the housing, and sufficiently blending the solution into the contact area with the solution, A method for producing an artificial kidney comprising coating a surface of a part of the artificial kidney that can come into contact with the body fluid in a body fluid circulation area with silicone, the method comprising drying to remove the organic solvent. (6) The method for producing an artificial kidney according to claim 5, wherein the body fluid permselective membrane is a regenerated cellulose membrane. (7) The method for producing an artificial kidney according to claim 5 or 6, wherein the body fluid selectively permeable membrane is a hollow fiber membrane. (8) The method for producing an artificial kidney according to claim 5, wherein the organic solvent is a chlorofluorinated hydrocarbon or a fluorinated hydrocarbon. (9) Manufacturing the artificial kidney according to any one of claims 5 to 7, wherein the silicone is at least one selected from the group consisting of silicone oil, silicone rubber, and silicone resin. Method. (10) The method for manufacturing an artificial kidney according to any one of claims 5 to 7, wherein the silicone is silicone rubber. (11) The chlorofluorinated hydrocarbon solvents are 1,1,2-trichloro-1,2,2-trifluoroethane, trichlorofluoromethane and 1,1,2,2-tetrachloro-1,
Claims 8 to 10 are at least one selected from the group consisting of 2-difluoroethane.
A method for producing an artificial kidney according to any one of paragraphs. (12) The concentration of silicone in the chlorofluorinated hydrocarbon or fluorinated hydrocarbon solvent solution is 0.05 to 10 w/v%. Kidney manufacturing method. (13) The drying is performed by flowing a gas inert to the silicone at a temperature of 10 to 60°C through the body fluid circulation area, according to any one of claims 5 to 12. manufacturing method.