Process for producing an apparatus with hollow fiber membrane for cleaning blood

Abstract: The present invention discloses a blood cleaning hollow fiber membrane characterized by comprising a hydrophobic porous hollow fiber membrane and having a hydrophilic thin layer formed at least on the inner surface of said hollow fiber membrane by the grafting of a hydrophilic compound through the agency of a gamma ray, a method for the cleaning blood and an apparatus therefor using the same.

Description: BACKGROUND OF THE INVENTION Field of the Invention: This invention relates to a method for cleaning blood, and an apparatus therefor. More particularly, it relates to a blood cleaning method and apparatus to be used for removing from blood a protective liquid incorporated therein for permitting frozen storage of the blood. Description of the Prior Art: In recent years, the practice of componential transfusion which comprises fractionating a donor's blood so as to choose only elements necessary for a given patient and transfusing the chosen elements into the patient is taking the place of the practice of transfusing the so-called complete blood, i.e. the blood obtained from a donor in the form containing all the elements thereof. The componential transfusion have advantages that the burden on the circulatory system can be repressed and the immunological secondary reaction alleviated as compared with the complete-blood transfusion, that only necessary elements can be transfused in a large amount at a time and, therefore, even elements contained in small proportions in the complete blood can be expected to manifest their effects sufficiently, and that elements unnecessary for one patient may be effectively utilized for some other patient [Tanaka and Shimizu: Sogo Rinsho (comprehensive clinic), Vol. 35, No. 11 (1986)]. It nevertheless is still imperfect with respect to the preclusion of the two major secondary reactions, infection and sensitization, which are entrained by the operation of transfusion. Today, the infection of patients with hepatitis, AIDS, and ATLA or the sensitization particularly of infantile patients due to transfusion of affected blood has been arousing grave anxiety to the general public. The situation is urging perfection of a preventive measure effective in curbing the impact of transfusion of affected blood. Recently, as a prospective way of solving the problem, the autoblood transfusion method which comprises transfusing into a patient the blood collected in advance from the patient himself has been attracting growing attention. The use of the patient's own blood is essentially incapable of causing such problems as infection with virus and sensitization mentioned above. By this method, even persons of very rare blood types can be assured that they have their blood ready for transfusion in case of accident. In accordance with this autoblood transfusion method, the blood taken from a person himself is fractionated into component elements and, as such, put to frozen storage. Even by the latest technical standard, the blood in its liquid state can be safely preserved for 42 days at most. The frozen storage enables such fractionated blood elements to be safely preserved semipermanently and permits establishment of a system of safe transfusion. When the fractionated blood elements are put in their unmodified form to frozen storage, such elements as erythrocytes, leukocytes, and platelets are destined to be destroyed. For these component elements to be safely preserved in the frozen storage, they require incorporation of protective liquids therein. These protective liquids are variable with research organs engaging in the development thereof and of course with particular component elements to be protected. Most of them use glycerol and dimethyl sulfoxide as main components. When they are to be returned to the owner's body, they must be defrosted, diluted, and then cleaned to be freed of the protective liquids. For the dilution and washing, a few methods have been already put to use such as, for example, a method which, in the case of a red blood corpuscle concentrate slowly frozen as mixed with Hagging's solution (containing 79% of glycerol, 8% of dextrose, 1% of fructose, and 0.3% of EDTA-disodium salt), for example, effects the dilution and washing by giving to the frozen concentrate mixture a first washing with 50% dextrose solution + 5% fructose solution, then a second washing with 5% fructose solution, further a third washing again with 5% fructose solution, a fourth washing with a physiological saline solution, and thereafter resuspending the washed concentrate in the phyisological saline solution [Boston Massachusets General Hospital (Hagging) and National Fukuoka Central Hospital (Sumida)] and a method which, in the case of a red blood corpuscle concentrate rapidly frozen as mixed with a Rowe solution (containing 28% of glycerol, 3% of mannitol, and 0.65% of sodium chloride), for example, effects the dilution and washing by subjecting this concentrate in its unmodified form to a first centrifugal sedimentation and discarding the supernatant, subjecting the residue of the first sedimentation to a second centrifugal sedimentation as mixed with 15% of mannitol and 0.45% of NaCl solution and discarding the resultant supernatant, subjecting the residue to a third and a fourth centrifugal sedimentation each as mixed with 0.9% NaCl solution and discarding the resultant supernatant, and finally resuspending the residue in a physiological saline solution [New York Blood Center (Rowe)]. Thus, the methods heretofore employed invariably effect the dilution and washing batchwise and necessitate either centrifugal sedimentation or centrifugal separation and involve a very complicated procedure. Moreover, they recover the component elements of blood with the efficiency hardly deserving any esteem. It is known from JP-A-62179540 to provide a hollow fibre membrane comprising a hydrophobic porous hollow membrane and a hydrophillic layer grafted thereon through the agency of an ionising ray. However such membranes having a hydrophillic layer grafted thereon are difficult to assemble into a housing by use of a potting compound since the presence of the hydrophillic layer prevents adherence of the potting compound to the membrane. According to one aspect of the present invention there is provided a blood cleaning apparatus, produced by arranging inside a housing a multiplicity of blood cleaning hollow fiber membranes each comprising a hydrophobic porous hollow fiber membrane, causing the empty spaces inside said hollow fiber membranes to communicate with a blood inlet and a blood outlet disposed in said housing, causing the outer surface of said porous hollow fiber membranes to communicate with a cleaning liquid inlet and a cleaning liquid outlet disposed in said housing, the inner empty space of the hydrophobic porous hollow fibre membranes being filled with a hydrophillic compound, and irradiated in that state with gamma rays to sterilise the apparatus and forming a hydrophillic thin layer at least on the inner surface of said hollow fiber membrane by the grafting of the hydrophillic compound. This invention discloses a preferred embodiment of the blood cleaning apparatus, which has been sterilized by a gamma ray. This invention discloses a preferred embodiment of the blood cleaning apparatus, wherein the hydrophillic compound is glycerol. This invention also discloses a preferred embodiment of the blood cleaning apparatus, wherein the hydrophobic porous hollow fiber membranes are each formed of one member selected from the group consisting of polyolefin type, polyester type, polyamide type, polyurethane type, poly(meth)acrylate type, poly(meth)acrylonitrile type, polysulfone type, and polyvinyl chloride type compounds and polymer blends thereof, preferably polypropylene. This invention further discloses a preferred embodiment of the blood cleaning apparatus wherein the blood cleaning hollow fiber membranes each possess an inside diameter in the range of 100 to 500 µm and a wall thickness in the range of 5 to 30 µm. This invention discloses a preferred embodiment of the blood cleaning apparatus, wherein the blood cleaning hollow fiber membranes each possess an average pore diameter in the range of 0.01 to 6.5 µm and a void ratio in the range of 30 to 75%. According to another aspect of the present invention there is provided a method for the cleaning of freeze preserved blood, which method is characterised by using a plurality of blood cleaning apparatuses as defined above causing the empty spaces in said hollow fiber membranes to communicate with first fluid inlet and outlet provided in said housing thereby forming a first fluid passing space and causing the empty space defined by the inner surface of said housing and the outer surface of said porous hollow fiber membranes to communicate with second fluid inlet and fluid outlet thereby forming a second fluid passing space partitioned from said first fluid passing space, thereby enabling a plurality of steps of cleaning operation to be carried out continuously by serially connecting either said first fluid passing spaces or said second fluid passing spaces of said blood cleaning apparatuses thereby forming blood flow paths, arranging the connected blood flow paths substantially linearly, passing the blood subjected to cleaning through said linearly arranged blood flow paths, and meanwhile feeding mutually different or similar cleaning liquids through the remaining plurality of second or first fluid passing spaces. This invention discloses a preferred embodiment of the method for cleaning the freeze preserved blood, wherein the blood is fed in the direction of gravity. This invention also discloses a preferred embodiment of the method for cleaning the freeze preserved blood, wherein the blood is fed in a direction opposite the direction of gravity. In one embodiment of the invention some of either the first fluid passing spaces or the second fluid passing spaces of the plurality of blood cleaning apparatuses forming part of the blood flow path are disposed in the direction of gravity and the remainders thereof to be disposed in a direction opposite the direction of gravity in the continued blood flow paths, passing the blood subjected to cleaning through the linearly arranged blood flow paths, and meanwhile feeding mutually different or similar cleaning liquids through the remaining plurality of second or first fluid passing spaces. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a cross section illustrating in model a detailed construction of a blood cleaning hollow fiber membrane of the present invention, Fig. 2 is a schematic cross section illustrating the construction of a typical blood cleaning apparatus of the present invention, Fig. 3 is a model diagram illustrating a typical cleaning circuit for working the method for cleaning freeze preserved blood in accordance with the present invention, and Fig. 4 is a model diagram illustrating another typical cleaning circuit for working the method for cleaning freeze preserved blood in accordance with the present invention. EXPLANATION OF PREFERRED EMBODIMENT The blood cleaning hollow fiber membrane of the present invention is characterized by comprising a hydrophobic porous hollow fiber membrane and having a hydrophilic thin layer formed at least on the inner surface of the hollow fiber membrane and the inner surface of pores in the hollow fiber membrane by the grafting of a hydrophilic compound through the agency of a gamma ray. As a way of enabling the cleaning of freeze preserved blood in the frozen blood storage system to be carried out in a continuous process, we have conceived a method of cleaning by use of a porous hollow fiber membrane of the kind observed in the dialysis of blood with the artificial kidney. To be specific, this method comprises forming a cleaning apparatus having a multiplicity of porous hollow fiber membranes stowed in a housing and effecting the required cleaning of the preserved blood by passing the blood the empty spaces in the multiplicity of porous hollow fiber membranes and meanwhile passing a cleaning liquid in the empty space defined by the outer surfaces of the porous hollow fiber membranes and the inner surface of the housing thereby causing blood protecting liquid components such as glycerol contained the preserved blood to be removed from the preserved blood and passed through the hollow fiber membrane's into the cleaning liquid by virtue of difference in concentration. When a plurality of such cleaning appratuses are serially connected (by joining a blood outlet of one blood cleaning apparatus to a blood inlet of another blood cleaning apparatus thereby forming a continuous conduit through the blood flow paths of the plurality of blood cleaning appratuses), a plurality of steps of cleaning treatment can be carried out continuously in a closed system. When such hydrophilic porous hollow fiber membranes as cuprammonium regenerated celluolose membranes which have heretofore been used for the dialysis of blood are used in the cleaning treatment described above, however, the hydrophilic porous hollow fiber membranes are readily swelled with the water or the aqueous 5 to 10% glycerol solution which is kept filling the blood cleaning apparatuses until use for the purpose of shortening the priming time or upon contact with the preserved blood or the cleaning liquid. Thus, the pores in the porous hollow fiber membranes are occluded or contracted and the protecting liquid components such as glycerol contained in the preserved blood cannot be sufficiently removed by permeation. Further, these hydrophilic porous hollow fiber membranes are not fully satisfactory in terms of physical properties such as mechanical strength. We have drawn a conclusion that the hydrophilic porous hollow fiber membranes are not very suitable as hollow fiber membranes for blood cleaning. After a diligent study, we have found that a hydrophilic thin layer is formed on at least the inner surface of a hydrophobic porous hollow fiber membrane and the inner surfaces of pores in the porous hollow fiber membrane when the hydrophobic porous hollow fiber membrane is filled in the empty space thereof with a hydrophilic compound and irradiated in that state to a gamma ray and that the hydrophilic porous hollow fiber membrane thus obtained possesses sufficient hydrophilicity and mechanical strength and, when used for the purpose of blood cleaning, avoids inducing the aforementioned problem of occlusion or contraction of pores by swelling, and exhibits outstanding permeation characteristics enough to permit thorough and efficient removal of such protecting liquid components as glycerol from the preserved blood. We have drawn thereupon a conclusion that the method which comprises disposing such hydrophobic porous hollow fiber membranes in a housing for a blood cleaning apparatus and subsequently filling the hydrophobic porous hollow fiber membranes in the empty spaces thereof with a hydrophilic compound and irradiating the hydrophobic porous hollow fiber membranes with a gamma ray as described above is highly desirable because the treatment is capable of converting the hydrophobic porous hollow fiber membranes into hydrophilic countertypes and, at the same time, effecting gamma-ray sterilization of the blood cleaning apparatus. This invention has been perfected as the result. The method of this invention for the cleaning of freeze preserved blood comprises serially connecting either first liquid passing spaces or second liquid passing spaces of a plurality of blood cleaning apparatuses each incorporating therein a multiplicity of porous hollow fiber membranes by joining thereby forming continuous blood flow paths and disposing these continuous blood flow paths substantially linearly and effecting the requiring cleaning of blood by passing the blood to be cleaned through the continuous blood flow paths and meantime feeding different or similar cleaning liquids to the plurality of second liquid passing spaces or first liquid passing spaces which are independent of each other. The cleaning method of the present invention gives to the preserved blood which has been retrieved from the frozen blood storage system and then defrosted the required cleaning by use of porous hollow fiber membranes. To be more specific, the cleaning method of this invention comprises passing the preserved blood or the cleaning liquid through the empty spaces in the multiplicity of porous hollow fiber membranes (first liquid passing spaces) disposed in the blood cleaning apparatus of the description given above and meanwhile passing the cleaning liquid or the preserved blood through the empty space defined by the outer surfaces of the porous hollow fiber membranes and the inner surface of the housing (second liquid passing space). Fig. 1 is a diagram illustrating in model the detailed construction of a hollow fiber membrane for cleaning blood in accordance with this invention. As illustrated in Fig. 1, a hollow fiber membrane 1 of this invention for cleaning blood is characterized by the fact that a hydrophilic thin layer 5 is formed on an inner surface 3 of a hydrophobic porous hollow fiber membrane 2 and on an inner surface 4 of pores by having hydrophilic compound grafted thereto through the agency of a gamma ray. The hydrophobic porous hollow membrane 1 to be used as a substrate for the hollow fiber membrane for cleaning blood according to this invention is formed from one member selected from the group consisting of polyolefin type, polyester type, polyamide type, polyurethane type, poly(meth)acrylate type, poly(meth)acrylonitrile type, polysulfone type, and polyvinyl chloride type resins and polymer blends thereof. The inside diameter of the fiber membrane 1 is in the range of 100 to 500µm and the wall thickness is in the range of 5 to 30µm. The hollow membrane 1 possesses an average pore diameter in the range 0.01 to 6.5µm and a void ratio in the range of 30 to 75 %. Fig. 2 is a schematic cross section illustrating the construction of a typical blood cleaning apparatus embodying the present invention. A blood cleaning apparatus 10 of the present embodiment illustrated in Fig. 2 is provided with a housing 13 which is composed of a housing body 11 open at the opposite terminal parts and a lid 12a and a lid 12a' fitted into the opposite terminal open parts of the housing body 11. This housing body 11 is provided near one terminal part thereof with a cleaning liquid inlet 14 and near the other terminal part thereof with a cleaning liquid outlet 15. The lid 12a is provided therein with a blood inlet 16 and the lid 12a' similarly with a blood outlet 17. In the inner empty space of the housing 13, a multiplicity of blood cleaning hollow fiber membranes of the description given above are disposed. The opposite end parts of the blood cleaning hollow fiber membranes 1 are supported in diaphragms 18a, 18a' formed of a potting agent. Further, the diaphragms 18a, 18a' partition the inner empty space of the housing 13 into three portions. Inside the inner empty space of the housing 13, there are consequently formed a blood passing space defined by the inner surface of the housing body 11 and the diaphragm 18a and adapted to communicate with the blood inlet 16 and the inner empty spaces of the blood cleaning hollow membranes 1, a cleaning liquid passing space defined by the inner surface of the housing body 11, the outer surfaces of the blood cleaning hollow fiber membranes 1, and the diaphragms 18a, 18a' and adapted to communicate with the cleaning liquid inlet 14 and the cleaning liquid outlet 15, and a blood passing space 19a' defined by the inner surface of the housing body 11 and the diaphragm 18a' and adapted to communicate with the blood outlet 17 and the inner empty spaces of the blood cleaning hollow fiber membranes 1. The blood cleaning apparatus constructed as described above is produced in accordance with present invention, by arranging inside the housing 13 a multiplicity of blood cleaning hollow fiber membranes 1 each comprising a hydrophobic porous hollow fiber membrane 2, causing the empty spaces inside said hollow fiber membranes to communicate with the blood inlet 16 and a blood outlet 17 disposed in said housing, causing the outer surface of said porous hollow fiber membranes to communicate with a cleaning liquid inlet 14 and a cleaning liquid outlet 15 disposed in said housing, filling the inner empty space of the hydrophobic porous hollow fibre membranes with a hydrophillic compound, and irradiate in that state to sterilise the apparatus and forming a hydrophillic thin layer 5 at least on the inner surface of said hollow fibre membrane by the grafting of the hydrophillic compound through agency of gamma rays. In the method of this invention for cleaning the freeze preserved blood, a plurality of blood apparatuses 10 each constructed as described above are joined in such a manner that the first liquid passing spaced 19 of the individual blood cleaning apparatuses 10 are serially connected to give rise to a continuous cleaning line forming a blood flow path running through the individual blood cleaning apparatuses. In the cleaning line illustrated in Fig. 3, four blood cleaning apparatuses 10 each constructed as illustrated in Fig. 2 are joined by connecting the first liquid outlet 17a of the first blood cleaning apparatus 10a to the first liquid inlet 16b of the second blood cleaning apparatus 10b with a connecting tube 21a, and then similarly connecting the first liquid outlet 17b of the second blood cleaning apparatus to the first liquid inlet 16c of the third blood cleaning apparatus 10c and the first liquid outlet 17c of the third blood cleaning apparatus to the first liquid inlet 16d of the fourth blood cleaning apparatus 10d thereby giving rise to a blood flow path running continuously through the first liquid passing space 19a of the first blood cleaning apparatus 10a, the first liquid passing space 19b of the second blood cleaning apparatus 10b, the first liquid passing space 19c of the third blood cleaning apparatus 10c, and the first liquid passing space 19d of the fourth blood cleaning apparatus 10d. In contrast, the second liquid passing spaces 20a, 20b, 20c, and 20d respectively of the blood apparatuses 10a, 10b, 10c, and 10d are shown as not being connected to one another. As described above, the blood flow line is constituted by connection of the first liquid passing spaces to one another. However, as indicated previously, as an alternative the second liquid passing spaces 20 a 20 b , 20 c and 20 c may be connected in series to define the blood flow line. The apparatuses 10 shown in Fig. 3 may be arranged so that the flow of blood therethrough is in the direction of gravity or alternatively in the direction opposite to gravity. Fig. 4 illustrates an alternative arrangement of apparatuses 10 wherein two apparatus 10a, 10b are arranged so that the blood feed is in the direction of gravity and wherein two apparatuses 10 a , 10 d are arranged so that the blood feed is in the direction opposite to gravity.

Claims: A process for producing a blood cleaning apparatus, the process including arranging inside a housing (13) a multiplicity of blood cleaning hollow fiber membranes (1) each comprising a hydrophobic porous hollow fiber membrane (2), causing the empty spaces inside said hollow fiber membranes to communicate with the blood inlet (16) and a blood outlet (17) disposed in said housing, causing the outer surface of said porous hollow fiber membranes to communicate with a cleaning liquid inlet (14) and a cleaning liquid outlet (15) disposed in said housing, the inner empty space of the hydrophobic porous hollow fibre membranes being filled with a hydrophillic compound and irradiated in that state with gamma rays to sterilise the apparatus and form a hydrophillic thin layer (5) at least on the inner surface of said hollow fibre membrane by the grafting of the hydrophillic compound A process according to claim 1, wherein said hydrophillic compound is glycerol. A process according to claim 1 or 2, wherein said hydrophobic porous hollow fiber membrane is formed of one member selected from the group consisting of polyolefin type, polyester type, polyamide type, polyurethane type, poly(meth)acrylate type, poly(meth)acrylonitrile type, polysulfone type, and polyvinyl chloride type compounds and polymer blends thereof. A process according to claim 3, wherein said hydrophobic porous hollow fiber membrane is made of polypropylene. A process according to claim 1, wherein said blood cleaning hollow fiber membranes each possess an inside diameter the range of 100 to 500µm, and a wall thickness in the range of 5 to 30µm. A process according to claim 1, wherein said blood cleaning hollow fiber membranes each possess an average pore diameter in the range of 0.01 to 6.5µm and a void ratio in the range of 30 to 75%.

Inventors: AOYAGI JUURO, AOYAGI, JUURO
Applicants: TOKYO BI TECH LAB INC, TOKYO BI-TECH LABORATORIES INC
Application year: 1988
Main classification: B01D63
IPC codes: A61M1, B01D69, B01D67, B01D65, B01D61