JPH01121055A - Cleaning of frozen blood - Google Patents
Cleaning of frozen bloodInfo
- Publication number
- JPH01121055A JPH01121055A JP62277486A JP27748687A JPH01121055A JP H01121055 A JPH01121055 A JP H01121055A JP 62277486 A JP62277486 A JP 62277486A JP 27748687 A JP27748687 A JP 27748687A JP H01121055 A JPH01121055 A JP H01121055A
- Authority
- JP
- Japan
- Prior art keywords
- blood
- fluid
- washing
- hollow fiber
- cleaning
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 210000004369 blood Anatomy 0.000 title claims abstract description 171
- 239000008280 blood Substances 0.000 title claims abstract description 171
- 238000004140 cleaning Methods 0.000 title claims abstract description 80
- 239000012530 fluid Substances 0.000 claims abstract description 105
- 239000012528 membrane Substances 0.000 claims abstract description 57
- 239000012510 hollow fiber Substances 0.000 claims abstract description 51
- 230000004087 circulation Effects 0.000 claims abstract description 47
- 230000017531 blood circulation Effects 0.000 claims abstract description 23
- 238000005406 washing Methods 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 38
- 239000007788 liquid Substances 0.000 claims description 23
- 230000002209 hydrophobic effect Effects 0.000 claims description 16
- 150000002433 hydrophilic molecules Chemical class 0.000 claims description 12
- 239000011148 porous material Substances 0.000 claims description 9
- 238000009826 distribution Methods 0.000 claims description 7
- 230000005484 gravity Effects 0.000 claims description 6
- 238000011282 treatment Methods 0.000 abstract description 3
- 230000002093 peripheral effect Effects 0.000 abstract description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 21
- 235000011187 glycerol Nutrition 0.000 description 19
- 239000000306 component Substances 0.000 description 16
- 239000012503 blood component Substances 0.000 description 10
- 230000001681 protective effect Effects 0.000 description 10
- 238000005119 centrifugation Methods 0.000 description 8
- 210000003743 erythrocyte Anatomy 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 7
- 229930091371 Fructose Natural products 0.000 description 6
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 6
- 239000005715 Fructose Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- -1 polypropylene Polymers 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 230000005251 gamma ray Effects 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 239000004743 Polypropylene Substances 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 3
- 238000005138 cryopreservation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229920001155 polypropylene Polymers 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000008313 sensitization Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 238000010257 thawing Methods 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 241000219095 Vitis Species 0.000 description 2
- 235000009754 Vitis X bourquina Nutrition 0.000 description 2
- 235000012333 Vitis X labruscana Nutrition 0.000 description 2
- 235000014787 Vitis vinifera Nutrition 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 230000037452 priming Effects 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- AFENDNXGAFYKQO-UHFFFAOYSA-N 2-hydroxybutyric acid Chemical compound CCC(O)C(O)=O AFENDNXGAFYKQO-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241000532370 Atla Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- WOWBFOBYOAGEEA-UHFFFAOYSA-N diafenthiuron Chemical compound CC(C)C1=C(NC(=S)NC(C)(C)C)C(C(C)C)=CC(OC=2C=CC=CC=2)=C1 WOWBFOBYOAGEEA-UHFFFAOYSA-N 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000004388 gamma ray sterilization Methods 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 238000001631 haemodialysis Methods 0.000 description 1
- 230000000322 hemodialysis Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920002492 poly(sulfone) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 229920005672 polyolefin resin Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000004382 potting Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000004627 regenerated cellulose Substances 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D2323/00—Details relating to membrane preparation
- B01D2323/38—Graft polymerization
- B01D2323/385—Graft polymerization involving radiation
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は冷凍保存血液洗浄方法に関するものである。詳
しく述べると本発明は、凍結保存される血液中に添加さ
れた保護液を効率よく連続的に除去する冷凍保存血液洗
浄方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a cryopreserved blood washing method. Specifically, the present invention relates to a cryopreserved blood washing method that efficiently and continuously removes a protective solution added to cryopreserved blood.
（従来の技術〉
近年、輸血は献血によって得られた全成分を含む血液、
いわゆる全血を輸血する方式から、患者の必要とする血
液成分のみを他人の血液から分画し、輸血する成分輸血
に移行している。このような成分輸血は、全血輸血に比
救して循環系の負担が少なく免疫学的副作用も回避軽減
できる、必要な成分のみを一度に多量輸血できるため、
たとえ全血中に占める割合が少ない成分でも十分な効果
を期待できる、ある患者に必要でない成分を他の患者に
有効に利用できる「出生・清水、総合臨床ｖｏ１．３５
． Ｎｏ、 １１ （１９８６） ］などの利点を有す
るが、この成分輸血も輸血に伴なう三大副作用である感
染と感作を回避する観点からは十分なものではなく、今
日、輸血による肝炎、ＡＩＤＳ、ＡＴＬＡなどへの感染
、あるいは特に小児における感作などが問題視されてお
り、これらに対する予防策が切望されている。(Prior art) In recent years, blood transfusions involve blood containing all the components obtained through blood donation,
There has been a shift from so-called whole blood transfusions to component transfusions, in which only the blood components needed by the patient are fractionated from someone else's blood and transfused. Compared to whole blood transfusions, such component transfusions place less burden on the circulatory system and avoid and reduce immunological side effects, as only the necessary components can be transfused in large quantities at one time.
Even if the proportion of ingredients in whole blood is small, sufficient effects can be expected, and ingredients that are not necessary for one patient can be effectively used for other patients.
．． No. 11 (1986)], however, this component transfusion is not sufficient from the viewpoint of avoiding infection and sensitization, which are the three major side effects associated with blood transfusion, and today, blood transfusion-induced hepatitis, Infection with AIDS, ATLA, etc., and sensitization, especially in children, are considered problems, and preventive measures against these are desperately needed.
最近、このような問題点を解決し得る方法として、予め
採血された自分の血液を輸血する自家血輸血法が注目を
集めている。自分の血液を使えば上記のごときウィルス
召集や感作などといった問題は本質的に生じず、また極
めて希な血液型の人であっても万一の場合に備えること
ができる。Recently, an autologous blood transfusion method, in which a patient's own blood that has been collected in advance is transfused, has been attracting attention as a method that can solve these problems. If one's own blood is used, the above-mentioned problems such as virus recruitment and sensitization will essentially not occur, and even people with extremely rare blood types can be prepared in case of emergencies.
このような自家血輸血法においては、採血した自分の血
液を成分分離した後冷凍保存することが行なわれる。血
液は現在液体のままであると最高でも４２日間しか保存
できないが、このように冷凍保存することにより半永久
的な保存が可能となるために長期にわたる安全な輸血体
制が確立されることとなる。In such an autologous blood transfusion method, the collected blood is separated into components and then frozen and stored. Currently, blood can only be stored in liquid form for a maximum of 42 days, but by freezing it in this way, it can be stored semi-permanently, establishing a safe blood transfusion system over the long term.
（発明が解決しようとする問題点）
ところで、成分分離した血液をそのまま冷凍保存しよう
とすると、赤血球、白血球、血小板などの各成分は破壊
されてしまうために、冷凍保存を行なうには各血液成分
に対して保護液を添加する必要がある。この保護液は、
現在のところ各研究機関等によって、またもちろん対象
となる血液成分によっても異なるものであるが、その多
くはグリセリン、ジメチルスルフオキシドなどを主成分
とするものであり、このため該保存血を体内に戻す際に
は、解凍後、保存血を希釈・洗浄することにより脱保護
液を図る必要がある。(Problem to be Solved by the Invention) By the way, if you attempt to freeze and preserve component-separated blood as it is, each component such as red blood cells, white blood cells, and platelets will be destroyed. It is necessary to add a protective solution to the This protective liquid is
At present, it differs depending on each research institution and, of course, depending on the target blood component, but most of them have glycerin, dimethyl sulfoxide, etc. as their main components, and for this reason, the stored blood cannot be used in the body. In order to return the blood to the original state, it is necessary to dilute and wash the stored blood after thawing to obtain a deprotection solution.
現在行なわれている希釈・洗浄方法としては、いくつか
実例を挙げると、例えば、赤血球濃厚液にハギンス液（
グリセリン７９％、ブドウＭ８％、果糖１％、ＥＤＴＡ
−２ナトリウム塩０．３％八を加えて緩速凍結しｆ：９
合、５０％ブドウ糖液＋５％果１液で第１回洗浄し、５
％果Ｍ液で第２回洗浄し、さらに５％果ＩＮ液で第３回
洗浄し、生理食塩水で第４回洗浄した後、生理食塩水に
再浮遊させており［ボストン・マサチューセッツ総合病
院＜ｒｌａａａｉｎａ）、国立福岡中央病院（墨出）１
、また赤血球濃Ｎ液にロー液（グリセリン２８％、マン
ニトール３％、塩化ナトリウム０．６５％）加えて急速
凍結した場合、第１回目はそのまま遠沈して上澄を廃棄
、第２回目は１５％マンニトール加０．４５％ＮａＣｌ
液を加えて遠沈後上澄を廃棄、第３回目および第４回目
は０．９％ＮａＣ１液を加えて遠沈後上澄を廃棄し、最
後に生理食塩水に再浮遊させる方法などがとられている
Ｅニューヨーク血液センター（Ｈｏｍｅ） ”Ｊ。Some examples of dilution and washing methods currently in use include Huggins' solution for red blood cell concentrate.
Glycerin 79%, Grape M8%, Fructose 1%, EDTA
-2 Sodium salt 0.3% 8 was added and slowly frozen f: 9
1st wash with 50% glucose solution + 5% fruit juice,
After washing a second time with 5% fruit M solution, a third wash with 5% fruit IN solution, and a fourth wash with physiological saline, they were resuspended in physiological saline [Boston/Massachusetts General Hospital <rlaaaina), National Fukuoka Central Hospital (Sumide) 1
Also, when rapid freezing is performed by adding low solution (glycerin 28%, mannitol 3%, sodium chloride 0.65%) to concentrated red blood cell N solution, the first time is centrifugation and the supernatant is discarded, and the second time is 15% mannitol plus 0.45% NaCl
Add a solution and discard the supernatant after centrifugation, add 0.9% NaCl solution for the third and fourth centrifugation, discard the supernatant after centrifugation, and finally resuspend in physiological saline. Taken by E New York Blood Center (Home) ``J.
このように現在、保存血の希釈・洗浄は、いずｈもバッ
ジ方式で行なわれており、まな遠沈あるいは遠心分離を
必要とするものであり、その揉布が非常に繁雑であるば
かりでなく、血液成分の回収効率−も十分なものとは言
えないものであった。Currently, all dilution and washing of stored blood is done by the badge method, which requires centrifugation or centrifugation, and the rubbing process is extremely complicated. Furthermore, the efficiency of collecting blood components was not sufficient.
従って、本発明は新規な冷凍保存血液洗浄方法を提供す
ることを目的とする。本発明はまた、冷凍保存さｈる血
液「１弓こ添加さｈた保護液を効率よく連続的に除去す
る冷凍保存血液洗浄方法を提供することを目的とするも
のである。本発明はさらに無菌的な洗浄操作を可能とす
る冷凍保存血液洗浄方法を提供することを目的とするも
のである。Therefore, an object of the present invention is to provide a novel cryopreserved blood washing method. Another object of the present invention is to provide a cryopreserved blood washing method that efficiently and continuously removes a protective solution added to cryopreserved blood. The object of the present invention is to provide a cryopreserved blood washing method that enables a sterile washing operation.
本発明はさらに血液成分の回収効率の高い冷凍保存血液
洗浄方法を提供することを目的とするものである。A further object of the present invention is to provide a cryopreserved blood washing method with high blood component recovery efficiency.
（問題点を解決するための手段）
上記諸口的は、ハウジング内に多孔質中空糸膜を多数本
配、し、該中空糸膜の内部空間をハウジングに設けられ
た第１流体導入口および導出口に連通させて第１流体流
通空間を形成し、一方ハウジングの内周面と上記多孔質
中空糸膜の外面とで囲まれる空間にはハウジングに設け
られた第２流体導入口および導出口を連通させて前記第
１流体流通空間とは区画された第２流体流通空間を形成
してなる血液洗浄装置を複数個用い、それぞれの血液洗
浄装置の第１流体流通空間または第２流体流通空間のい
ずれかを直列的に接続して血液流路を形成し、この連続
する血液流路を略直線的に配置して洗浄すべき血液を送
通し、一方それぞれ独立した複数の第２流体流通空間ま
たは第１流体流通空間にはそれぞれ異種または同種の洗
浄液を送通して、数段階にわたる洗浄操作を連続的に行
なうことを特徴とする冷凍保存血液の洗浄方法により達
成される。(Means for Solving the Problems) The above solution includes disposing a large number of porous hollow fiber membranes in a housing, and connecting the internal space of the hollow fiber membranes to a first fluid inlet and a guide provided in the housing. A first fluid circulation space is formed by communicating with the outlet, and a second fluid inlet and an outlet provided in the housing are connected to a space surrounded by the inner peripheral surface of the housing and the outer surface of the porous hollow fiber membrane. A plurality of blood cleaning devices are used in which a plurality of blood cleaning devices are connected to each other to form a second fluid distribution space separated from the first fluid distribution space, and the first fluid distribution space or the second fluid distribution space of each blood cleaning device is Either one is connected in series to form a blood flow path, and the continuous blood flow path is arranged substantially linearly to convey the blood to be washed, while a plurality of independent second fluid flow spaces or This is achieved by a method for washing frozen blood, which is characterized in that washing liquids of different types or of the same type are passed through the first fluid circulation spaces, respectively, and washing operations are continuously performed in several stages.
本発明の冷凍保存血液の洗浄方法において、血液が重力
方向に送通される態様が好ましく示される。In the method for washing cryopreserved blood of the present invention, a preferred mode is shown in which blood is passed in the direction of gravity.
また本発明の冷凍保存血液の洗浄方法において、血液は
重力方向と反方向に送通される態様が好ましく示される
。さらに本発明の冷凍保存血液の製造方法において、血
液洗浄装置内に配される多孔質中空糸膜は、疎水性多孔
質中空糸膜の少なくとも内面および孔内面に親水性化合
物がγ線によりグラフトされてなる親水性薄層が形成さ
れてなるものである態様が好ましく示される。In addition, in the method for washing cryopreserved blood of the present invention, a preferred embodiment is shown in which blood is transported in a direction opposite to the direction of gravity. Furthermore, in the method for producing cryopreserved blood of the present invention, the porous hollow fiber membrane disposed in the blood washing device is such that a hydrophilic compound is grafted onto at least the inner surface of the hydrophobic porous hollow fiber membrane and the inner surface of the pores by γ rays. A preferred embodiment is one in which a hydrophilic thin layer is formed.
（作用）
しかして、本発明の冷凍保存血液洗浄方法は、上記した
ように、多孔質中空糸膜を多数本配してなる複数個の血
液洗浄装置の第１流体流通空間または第２流体流通空間
を直列的に接続して血液流路を形成し、この連続する血
液流路を略直線的に配置して洗浄すべき血液を送通し、
一方それぞれ独立した複数の第２流体流通空間または第
１流体流通空間にはそれぞれ異種または同種の洗浄液を
送通するものである。(Function) Therefore, as described above, the cryopreserved blood washing method of the present invention provides the first fluid circulation space or the second fluid circulation space of a plurality of blood washing devices each having a plurality of porous hollow fiber membranes. The spaces are connected in series to form a blood flow path, and the continuous blood flow path is arranged substantially linearly to allow the blood to be washed to flow therethrough;
On the other hand, different or the same type of cleaning liquid is passed through the plurality of independent second fluid circulation spaces or first fluid circulation spaces, respectively.
このように本発明の洗浄方法においては、血液の冷凍保
存システムにおける解凍後の保存血を、多孔質中空糸膜
を用いて洗浄するものである。すなわち、本発明の洗浄
方法においては、上記のごとき血液洗浄装置中に配され
た多数本の多孔質中空糸膜の内部空間（第１流体流通空
間）に保存血液または洗浄液を送通し、一方、該多孔質
中空糸膜の外面とハウジングの内周面とで形成される空
間（第２流体流通空間）には洗浄液または保存血液を流
して、保存血中に含まれるグリセリンなどの血液保護液
成分を中空糸膜を介して濃度差により洗浄液側に透過除
去するために、遠沈あるいは遠心分離などの繁雑でまた
血液成分に対して悪影響を及ぼす虞れのある処理をゼ・
要とせず、簡単でかつ効率のよい洗浄処理が行なえるこ
ととなるものである。As described above, in the cleaning method of the present invention, stored blood after thawing in a blood cryopreservation system is cleaned using a porous hollow fiber membrane. That is, in the cleaning method of the present invention, stored blood or cleaning fluid is passed through the internal space (first fluid circulation space) of a large number of porous hollow fiber membranes arranged in the blood cleaning device as described above, while: A cleaning solution or stored blood is passed through the space formed by the outer surface of the porous hollow fiber membrane and the inner circumferential surface of the housing (second fluid circulation space) to remove blood protection fluid components such as glycerin contained in the stored blood. In order to remove the blood by permeating it to the washing liquid side through a hollow fiber membrane due to the difference in concentration, we do not use complicated treatments such as centrifugation or centrifugation that may have an adverse effect on blood components.
This makes it possible to perform a simple and efficient cleaning process without the need for cleaning.
さらに血液の冷凍保存システムにおいては、保存血液中
に添加された除去されるべきグリセリン等の保護液成分
の濃度が高くかつ複数種の成分を含むものであるため、
上記したような多孔質中空糸膜を配してなる唾液洗浄装
置を用いたとしても、１つの血液洗浄装置にて一種の洗
浄液を用いるのみでは、洗浄効率が悪いばかりでなく、
血液洗浄装置の有効長を大きくしても十分な洗浄がなさ
れない虞れが生じるが、本発明の冷凍保存血液洗浄方法
においては、複数個の血液洗浄装置の血液の流通する空
間（第１流体流通空間または第２流体流通空間）が、直
列的に接続されているために、第１の血液洗浄装置で処
理された血液は外部環境にさらされることなく連続的に
第２の血液洗浄装置へと送られ、第２の血液洗浄装置に
おいて処理を受けるというように、血液は順次複数個の
血液洗浄装置による数段階にわたる洗浄処理を連続的に
かつクローズドシステムで無菌的に受けることができる
ものである。なお、本発明の冷凍保存血液洗浄方法にお
いては、各血液洗浄装置における洗浄液系はそれぞれ独
立したものであるために、各装置において異なる洗浄液
を用いることが可能（もちろん同種の洗浄液を用いるこ
ともできる。）で効率のよい洗浄処理が行なえるもので
ある。Furthermore, in blood cryopreservation systems, the concentration of protective fluid components such as glycerin that should be removed in the stored blood is high and contains multiple types of components.
Even if a saliva cleaning device including a porous hollow fiber membrane as described above is used, using only one type of cleaning liquid in one blood cleaning device will not only result in poor cleaning efficiency;
Even if the effective length of the blood cleaning device is increased, there is a risk that sufficient cleaning will not be performed. Because the blood circulation spaces or the second fluid circulation spaces are connected in series, the blood processed in the first blood washing device is continuously transferred to the second blood washing device without being exposed to the external environment. The blood is then sent to a second blood washing device for processing, so that the blood can undergo several stages of washing processing by multiple blood washing devices in sequence, in a closed system, and aseptically. be. In addition, in the cryopreserved blood washing method of the present invention, since the washing liquid system in each blood washing device is independent, it is possible to use a different washing liquid in each device (of course, the same type of washing liquid can also be used). ) allows for efficient cleaning.
加えて、本発明の冷凍保存血液洗浄方法において、複数
個の血液洗浄装置の血液の流通する空間は、略直線的に
配置されているために、この洗浄回路を通過する血液の
流れは、はぼ定常的に保たれ血液成分に負担をかける虞
れもなく洗浄処理における血液成分の損傷を最少限に止
めることができるものである。In addition, in the cryopreserved blood washing method of the present invention, since the spaces through which blood flows in the plurality of blood washing devices are arranged approximately linearly, the flow of blood passing through this washing circuit is It is possible to keep damage to blood components to a minimum during the washing process without the risk of putting a burden on the blood components, which is maintained at a constant state.
以下、本発明を実施態様に基づきより詳細に説明する。Hereinafter, the present invention will be explained in more detail based on embodiments.
第１図は本発明の冷凍保存血液洗浄方法における洗浄回
路の一例を示す模式図であり、また第２図は本発明の冷
凍保存血液洗浄方法において用いられる血液洗浄装置の
一例を示す概略断面図である。FIG. 1 is a schematic diagram showing an example of a washing circuit in the cryopreserved blood washing method of the present invention, and FIG. 2 is a schematic sectional view showing an example of a blood washing device used in the cryopreserved blood washing method of the invention. It is.
本発明の冷凍保存血液洗浄方法においては、第２図に示
すように、ハウジング１１内に多孔質中空糸膜１２を多
数本配し、該中空糸膜１２の内部空間をハウジング１１
に設けられた第１流体導入口１３および導出口１４に連
通させて第１流体流通空間１５を形成し、一方ハウジン
グ１１の内周面と上記多孔質中空糸膜１２の外面とで囲
まれる空間にはハウジングに設けられた第２流体導入口
１６および導出口１７を連通させて前記第１流体流通空
間１５とは区画された（この例においてはポツティング
剤により形成される隔壁１９により区画されている。）
第２流体流通空間１８を形成してなる血液洗浄装置１０
を複数個用いるものである。In the cryopreserved blood washing method of the present invention, as shown in FIG.
A space that communicates with the first fluid inlet 13 and outlet 14 provided in the housing to form a first fluid circulation space 15, and is surrounded by the inner circumferential surface of the housing 11 and the outer surface of the porous hollow fiber membrane 12. The second fluid inlet 16 and the outlet 17 provided in the housing are communicated with each other to be separated from the first fluid circulation space 15 (in this example, the space is separated by a partition wall 19 formed of a potting agent). )
Blood cleaning device 10 formed with a second fluid circulation space 18
It uses multiple .
このような血液洗浄装置１０内に配される多孔質中空糸
膜」２としては、従来より血液透析に用いられている銅
アンモニア再生セルロース膜などの親水性多孔質中空糸
膜を用いることもできるが、このような親水性多孔質膜
を用いた場合、プライミング時間を短縮するために使用
時まで血液洗浄装置内に充填される水あるいは５〜１０
％グリセリン水溶液よって、あるいは該親水性多孔質中
空糸膜が保存血ないしは洗浄液と接触することによって
すぐに膨潤し、これによって多孔質膜の細孔が閉塞ない
しは縮小されてしまうために保存血中に含まれるグリセ
リンなどの保護液成分を充分に透過除去することが不可
能となる虞れ、さらにこのような親水性多孔質中空糸膜
は機械的強度などの物性の面においても十分なものでは
ないなめ、好ましくは、疎水性多孔質中空糸膜の少なく
とも内面および孔内面に親水性化合物がγ線によりグラ
フトされてなる親水性薄層が形成されてなる多孔質中空
糸膜が好ましい。As the porous hollow fiber membrane 2 disposed in such a blood cleaning device 10, a hydrophilic porous hollow fiber membrane such as a cuprammonium regenerated cellulose membrane conventionally used in hemodialysis can also be used. However, when such a hydrophilic porous membrane is used, in order to shorten the priming time, water or 5 to 10
% glycerin aqueous solution or when the hydrophilic porous hollow fiber membrane comes into contact with the stored blood or washing solution, it swells immediately, and as a result, the pores of the porous membrane are clogged or reduced. There is a risk that it will be impossible to sufficiently permeate and remove the protective liquid components such as glycerin contained therein, and furthermore, such hydrophilic porous hollow fiber membranes do not have sufficient physical properties such as mechanical strength. Preferably, a porous hollow fiber membrane is formed in which a hydrophilic thin layer is formed by grafting a hydrophilic compound with gamma rays on at least the inner surface and the inner surface of the pores of the hydrophobic porous hollow fiber membrane.
この多孔質中空糸膜において基材として用いられる疎水
性多孔質中空糸膜としては、特に限定はなく、例えばポ
リオレフィン系、ポリエステル系、ポリアミド系、ポリ
ウレタン系、ポリ（メタ）アクリレート系、ポリ（メタ
）アクリロニトリル系、ポリスルホン系、ポリ塩化ビニ
ル系およびこれらのポリマーブレンドなどの各種の疎水
性合成樹脂が用いられ得るが、耐γ線性、機械的強度な
どの面から特にポリオレフィン系のものが好ましく、最
も好ましくはポリプロピレンである。また上記したよう
な疎水性多孔質中空糸膜の少なくとも内面および孔内面
にγ線によりグラフトされる親水性化合物としては十分
な親水性を有し、かつ望ましくは生理的安全性の高いも
のであれば特に限定されず、例えば、メタノール、エタ
ノール、グリセリンなどの水溶性アルコール類、果糖、
ブドウ糖、マンニトールなどの低分子量糖類、アラニン
、アルギニン、システィンおよび水溶性アミンｆｆＦｆ
ｆ、シュウ酸、マロン酸、コハク酸などのジカルボン酸
類、グリオキシル酸、ピルビン酸、アセト酢酸などのケ
ト酸類、グリコール酸、乳酸、α−ヒドロキシ酪酸など
のヒドロキシ酸類、アクリル酸、マレイン酸、メタクリ
ル酸などの不飽和カルボニル化合物およびそのナトリウ
ムあるいはカリウム塩類等が用いられ得るが、特に好ま
しくはグリセリンである。なおグリセリンを用いる場合
は、グリセリン濃厚液を用いてもよいが、例えば５〜１
０％濃度のグリセリン水溶液としてもよい。上記したよ
うな疎水性多孔質中空糸膜の内面および孔内面にこのよ
うな親水性化合物よりなる親水性薄層を形成するには、
例えば疎水性多孔質中空糸膜の内部空間に親水性化合物
を充填し、この状態でγ線を疎水性多孔質中空糸膜に照
射すればよい。The hydrophobic porous hollow fiber membrane used as a base material in this porous hollow fiber membrane is not particularly limited, and examples include polyolefin, polyester, polyamide, polyurethane, poly(meth)acrylate, poly(meth) ) Various hydrophobic synthetic resins such as acrylonitrile-based, polysulfone-based, polyvinyl chloride-based, and polymer blends thereof can be used, but polyolefin-based resins are particularly preferred from the viewpoint of γ-ray resistance and mechanical strength, and the most preferred. Preferred is polypropylene. In addition, the hydrophilic compound to be grafted onto at least the inner surface and the inner surface of the pores of the above-mentioned hydrophobic porous hollow fiber membrane by gamma rays should have sufficient hydrophilicity and preferably be highly physiologically safe. For example, water-soluble alcohols such as methanol, ethanol, glycerin, fructose,
Low molecular weight sugars such as glucose and mannitol, alanine, arginine, cysteine and water-soluble aminesffFf
f, dicarboxylic acids such as oxalic acid, malonic acid, and succinic acid, keto acids such as glyoxylic acid, pyruvic acid, and acetoacetic acid, hydroxy acids such as glycolic acid, lactic acid, and α-hydroxybutyric acid, acrylic acid, maleic acid, and methacrylic acid. Unsaturated carbonyl compounds such as and their sodium or potassium salts can be used, but glycerin is particularly preferred. In addition, when using glycerin, a concentrated glycerin solution may be used, but for example, 5 to 1
It may also be a 0% glycerin aqueous solution. In order to form a hydrophilic thin layer made of such a hydrophilic compound on the inner surface and pore inner surface of the hydrophobic porous hollow fiber membrane as described above,
For example, the internal space of a hydrophobic porous hollow fiber membrane may be filled with a hydrophilic compound, and in this state, the hydrophobic porous hollow fiber membrane may be irradiated with gamma rays.
なおγ線の照射条件としては０．１〜２５Ｍｒ ａｄ、
好ましくは２．５〜１０Ｍｒａｄ程度であることが望ま
れる。そしてγ線照射を行なった後、疎水性多孔質膜の
内部空間より該疎水性多孔質膜にグラフト結合しなかっ
た余分な親水性化合物を排出し、無菌の蒸留水あるいは
生理食塩水などを用いて疎水性多孔質膜の内部空間に付
着残留する親水性化合物を充分に除去することにより所
望の血液洗浄用中空糸膜が得られることとなる。さらに
、このようなγ線照射を、後述するように疎水性多孔質
中空糸膜を血液洗浄装置に組付けた後、上記のように親
水性化合物を充填し、装置全体に対して行なえば、同時
にγ線による血液洗浄装置の滅菌が行なえるために極め
て望ましい。なお、さらに第１図に示すように複数個の
血液洗浄装置を接続した回路を形成した後にこのように
親水性化合物を充填してγ線照射を行なう操作を行なう
と、同時にγ線による該回路の滅菌が行なえるために極
めて望ましい。なお、このようにして形成される親水性
薄層はγ線により疎水性多孔質中空糸膜の内面および孔
内面に上記のごとき親水性化合物がグラフトされてなる
ものであるために、十分な親水性を多孔質中空糸膜に付
与するにも係わらず、極めて薄く、たとえ湿潤状態にあ
ったとしても、実質的に疎水性多孔質膜の有する膜構造
を変化させるものではなく、従って安定した透過性能を
示すものである。Note that the γ-ray irradiation conditions are 0.1 to 25 Mr ad,
Preferably, it is desired that it is about 2.5 to 10 Mrad. After γ-ray irradiation, excess hydrophilic compounds that have not been grafted to the hydrophobic porous membrane are discharged from the internal space of the hydrophobic porous membrane, and sterile distilled water or physiological saline is used to remove the excess hydrophilic compound that has not been grafted to the hydrophobic porous membrane. By sufficiently removing the hydrophilic compound remaining attached to the internal space of the hydrophobic porous membrane, a desired hollow fiber membrane for blood cleaning can be obtained. Furthermore, if such γ-ray irradiation is performed on the entire device by assembling a hydrophobic porous hollow fiber membrane into a blood cleaning device as described below and then filling it with a hydrophilic compound as described above, At the same time, the blood cleaning device can be sterilized using gamma rays, which is extremely desirable. Furthermore, as shown in Fig. 1, if a circuit is formed in which a plurality of blood cleaning devices are connected and then filled with a hydrophilic compound and irradiated with gamma rays, the circuit will be irradiated with gamma rays at the same time. It is highly desirable because it can sterilize the body. Note that the hydrophilic thin layer formed in this way is obtained by grafting the above-mentioned hydrophilic compound onto the inner surface of the hydrophobic porous hollow fiber membrane and the inner surface of the pores using gamma rays, so that it has sufficient hydrophilicity. Despite imparting properties to the porous hollow fiber membrane, it is extremely thin and does not substantially change the membrane structure of the hydrophobic porous membrane even in a wet state, and therefore provides stable permeation. It shows performance.
本発明の冷凍保存血液洗浄方法においては、上記したよ
うな構成を有する複数個の血液洗浄装置１０は、それぞ
れの血液洗浄装置１０の第１流体流通空間１５または第
２流体流通空間】８のいずれかが直列的に接続され、こ
れにより各血液洗浄装置１０に連通ずる血液流路を形成
した一連の洗浄回路が組立てられる。In the cryopreserved blood washing method of the present invention, the plurality of blood washing devices 10 having the above-described configuration are arranged in either the first fluid circulation space 15 or the second fluid circulation space 8 of each blood washing device 10. are connected in series, thereby assembling a series of cleaning circuits forming blood flow paths communicating with each blood cleaning device 10.
例えば第１図に示す洗浄回路においては、第２図に示す
ような構成を有する血液洗浄装置１０を４つ用い、第１
の血液洗浄装置１０ａの第１流ｆ４＜導出口１４ａと第
２の血液洗浄装置１０ｂの第１流体導入口１３ｂとを、
例えばポリプロピレン、ポリ塩化ビニルなどの可撓性面
脂製の接続チューブ２０ａなどを用いて接続し、さらに
第２の血液洗浄装置の第１流体導出口１４ｂと第３の血
液洗浄装置１０ｃの第１流体導入口１３ｃ、第３の血液
洗浄装置の第１流体導出口１４ｃと第４の血液洗浄装置
１０ｄの第１流体導入口１３ｄを同様に接続して、第１
の血液洗浄装置１０ａの第１流体流通空間１５ａ、第２
の血液洗浄装置１０ｂの第１流体流通空間１５ｂ、第３
の血液洗浄装置１０Ｃの第１流体流通空間１５ｃおよび
第４の血液洗浄装置１０ｄの第１流体流通空間１５ｄと
が連通された血液流路が形成されている。一方、各血液
洗浄装置１０ａ、１０ｂ、１０ｃ、１０ｄの第２流体流
通空間１８ａ、１８ｂ、１８ｃ、１８ｄはそれぞれ独立
しており、これらは独立した４つの洗浄液流路となる。For example, in the cleaning circuit shown in FIG. 1, four blood cleaning devices 10 having the configuration shown in FIG.
The first flow f4<outlet 14a of the blood cleaning device 10a and the first fluid inlet 13b of the second blood cleaning device 10b,
For example, a connecting tube 20a made of flexible surface oil such as polypropylene or polyvinyl chloride is used to connect the first fluid outlet 14b of the second blood cleaning device and the first fluid outlet 14b of the third blood cleaning device 10c. The fluid inlet 13c, the first fluid outlet 14c of the third blood cleaning device, and the first fluid inlet 13d of the fourth blood cleaning device 10d are connected in the same manner, and the first
The first fluid circulation space 15a of the blood cleaning device 10a, the second
The first fluid circulation space 15b of the blood cleaning device 10b, the third
A blood flow path is formed in which the first fluid circulation space 15c of the blood washing device 10C and the first fluid circulation space 15d of the fourth blood washing device 10d communicate with each other. On the other hand, the second fluid circulation spaces 18a, 18b, 18c, and 18d of each blood washing device 10a, 10b, 10c, and 10d are independent, and these become four independent washing liquid flow paths.
なお、この第１図に示す態様においては、各血液洗浄装
置１０ａ、１０ｂ、１０ｃ、１０ｄの第１流体流通空間
１５ａ、１５ｂ、１５ｃ、１５ｄが連通され、多孔質中
空糸膜１２ａ、１２ｂ、１２ｃ、１２ｄ内部に血液を送
通するものとなされているが、各血液洗浄装置１０ａ、
１０ｂ、１０ｃ、１０ｄの第２流体流通空間１８ａ、１
８ｂ、１８ｃ、１８ｄを連通し、多孔質中空糸膜外部に
血液を送通するような構成としてもよい。また血液洗浄
装置の数も必要により増減することが画然に可能である
。In the embodiment shown in FIG. 1, the first fluid circulation spaces 15a, 15b, 15c, 15d of each blood cleaning device 10a, 10b, 10c, 10d are communicated with each other, and the porous hollow fiber membranes 12a, 12b, 12c are connected to each other. , 12d, each blood cleaning device 10a,
10b, 10c, 10d second fluid circulation spaces 18a, 1
8b, 18c, and 18d may be connected to each other to allow blood to flow outside the porous hollow fiber membrane. Furthermore, the number of blood washing devices can obviously be increased or decreased as necessary.
本発明の冷凍保存血液洗浄方法においては、このように
組立てられた洗浄回路の連続する血液流路を略直線的に
配置する。しかしながらこれは特に厳密なものではなく
、血液流路がまったく反方向に屈曲するようなことがな
い限り、全体を通してほぼ同方向であるといった程度で
あればよい。In the cryopreserved blood washing method of the present invention, the continuous blood flow paths of the thus assembled washing circuit are arranged substantially linearly. However, this is not particularly strict, and as long as the blood flow path does not bend in completely opposite directions, it is sufficient that the blood flow path is in approximately the same direction throughout.
また、この血液流路は、この血液流路を流れる血液に対
して重力が一定に作用するものであれば、鉛直方向にお
いて上から下へ（血液流は重力方向となる。）、鉛直方
向において下から上へ（血液流は反重力方向となる。）
、あるいは水平方向へ配置する等のいず九であってもよ
い。In addition, if gravity acts constantly on the blood flowing through this blood flow path, the blood flow will be from top to bottom in the vertical direction (blood flow is in the direction of gravity). From the bottom to the top (blood flow is in the anti-gravity direction).
, or horizontally.
そしてこのように配置された洗浄回路の血液流路に洗浄
すべき血液を送通し、一方それぞれ独立した複数の洗浄
液流路（すなわち接続されなかった第２流体流通空間ま
たは第１流体流通空間〉にそれぞれ異種または同種の洗
浄液を送通してやることで、数段階にわたる洗浄操作を
連続的に行なうことができる。例えば、第１図に示され
る態様を例にとりより具体的に述べると、まず洗浄処理
に先立ち、回路全体をオートクレーブ滅菌あるいはγ線
滅菌などにより滅菌し、さらに第１の血液洗浄装置１０
“ａの第１流体導入口１３ａより生理食塩水を流し、回
路全体をプライミングする。続いて、各血液洗浄装置１
０ａ、１０ｂ、１０ｃ、１０ｄの各第２流体導入口１６
ａ、１６ｂ、１６Ｃ１１６ｄから所定の洗浄液を各第２
流体流通空間１８ａ、１８ｂ、１８ｃ、１８ｄに流入し
、各第２流体導出口１７ａ、１７ｂ、１７ｃ、１７ｄよ
り排出し続ける。なお各血液洗浄装置１０ａ、１０ｂ、
１０ｃ、１０ｄにおいて用いられる洗浄液は、必要に応
じてそれぞれ異種のものであってもあるいは同種のもの
であってもよい。そして、このように各血液洗浄装置１
０ａ、１０ｂ、１０Ｃ１１０ｄの第２流体流通空間１８
ａ、１８ｂ、１８ｃ、１８ｄに送通される洗浄液の流量
が、例えば１０ｍ １〜５０．１！／ｍ ｉ ｎ、より
好ましくは１００ｍ１〜５１／ｍｉｎの範囲内の所定の
流量で一定となったところで、解凍された保存血液を第
１の血液洗浄装置１０ａの第１流体導入口１３ａより、
例えば１０〜２０００ｍ１／ｍｉｎ、より好ましくは２
０〜１５００ｍｌ／ｍｉｎの範囲内の所定の流量で血液
流路に送通する。血液流路に送通された血液は、まず第
１の血液洗浄装置１０ａの第１流体流通空間１５ａ内の
多孔質中空糸Ｍ １２ ａの内部空間を流通する間に、
該多孔質中空糸膜１２ａを介して、第２流体流通空間１
．８ａを流通する第１の洗浄液との濃度差により該血液
中に含まれる所定の保護液成分を所定の割合まで透過除
去された後、連通ずる第２の血液洗浄装置１０ｂの第１
流体流通空間１５ｂへと送られ、この第１流体流通空間
１５ｂ内の多孔質中空糸Ｍ１２ｂの内部空間を流通する
間に、上記と同様に該多孔質中空糸膜１２ｂを介して、
第２流体流通空間１８ｂを流通する第２の洗浄液との濃
度差により該血液中に残存する所定の保護液成分を所定
の割合まで透過除去された後、連通ずる第３の血液洗浄
装置１０ｃの第２流体流通空間１５ｃへと送られる。さ
らに同様にして第３の血液洗浄装置１０Ｃおよび第４の
血液洗浄装置１０ｄにおいて、残存する保護液成分を透
過除去され、このようにして４段階にわたる一連の洗浄
処理を受けて、完全に脱保護液化された血液は、第４の
血液洗浄装置１０ｄの第１流体導出口１４ｄより収出さ
れ、この後輸血の用途に供されることとなる。Then, the blood to be washed is passed through the blood flow path of the washing circuit arranged in this way, while the blood to be washed is passed through the plurality of independent washing liquid flow paths (i.e., the unconnected second fluid circulation space or first fluid circulation space). By feeding different or the same types of cleaning liquids, it is possible to perform a cleaning operation in several stages continuously.For example, to describe the embodiment shown in Fig. First, the entire circuit is sterilized by autoclave sterilization or γ-ray sterilization, and then the first blood cleaning device 10
Physiological saline is flowed through the first fluid introduction port 13a of "a" to prime the entire circuit.Subsequently, each blood cleaning device 1
Each second fluid inlet 16 0a, 10b, 10c, 10d
a, 16b, and 16C116d.
The fluid flows into the fluid circulation spaces 18a, 18b, 18c, and 18d, and continues to be discharged from the respective second fluid outlet ports 17a, 17b, 17c, and 17d. Note that each blood washing device 10a, 10b,
The cleaning liquids used in 10c and 10d may be different types or the same type as required. In this way, each blood cleaning device 1
0a, 10b, 10C110d second fluid circulation space 18
The flow rate of the cleaning liquid sent to a, 18b, 18c, and 18d is, for example, 10 m 1 to 50.1! /min, more preferably at a predetermined flow rate within the range of 100 m1 to 51/min, the thawed stored blood is introduced through the first fluid inlet 13a of the first blood washing device 10a.
For example, 10 to 2000 m1/min, more preferably 2
It is delivered to the blood flow path at a predetermined flow rate within the range of 0 to 1500 ml/min. The blood delivered to the blood flow path first flows through the internal space of the porous hollow fiber M 12 a in the first fluid circulation space 15 a of the first blood cleaning device 10 a.
Through the porous hollow fiber membrane 12a, the second fluid circulation space 1
．． After a predetermined protective fluid component contained in the blood is permeated and removed to a predetermined ratio due to the concentration difference with the first washing fluid flowing through the blood washing device 8a, the first washing fluid of the second blood washing device 10b communicates with
While being sent to the fluid circulation space 15b and flowing through the internal space of the porous hollow fiber M12b in this first fluid circulation space 15b, through the porous hollow fiber membrane 12b in the same manner as above,
After a predetermined protective liquid component remaining in the blood is permeated and removed to a predetermined ratio due to the concentration difference with the second washing liquid flowing through the second fluid circulation space 18b, the third blood washing device 10c is communicated with the third blood washing device 10c. The fluid is sent to the second fluid circulation space 15c. Furthermore, in the third blood cleaning device 10C and the fourth blood cleaning device 10d, the remaining protective liquid components are permeated and removed, and in this way, they undergo a series of four-stage cleaning treatment to completely remove the protection. The liquefied blood is extracted from the first fluid outlet 14d of the fourth blood cleaning device 10d, and is then used for blood transfusion.
本発明の冷凍保存血液洗浄方法は以上のようにして実施
されるが、保存される血液成分の種類、および添加され
る保護液成分に応じて、用いられる洗浄液および多孔質
中空糸膜の細孔特性等を変更することにより、各種の方
法によって冷凍保存された、赤血球分画、血小板分画、
白血球分画（あるいはリンパ球分画および顆粒球分画）
、および骨髄分画などの各種成分血液の解凍後の洗浄方
法に適用することが可能である。The cryopreserved blood cleaning method of the present invention is carried out as described above, but depending on the type of blood component to be stored and the protective liquid component added, the cleaning solution used and the pore size of the porous hollow fiber membrane may be adjusted. Red blood cell fraction, platelet fraction, cryopreserved by various methods by changing the characteristics etc.
Leukocyte differential (or lymphocyte differential and granulocyte differential)
The present invention can be applied to washing methods after thawing various blood components such as bone marrow fractions and bone marrow fractions.
（実施例） 以下、本発明を実施例によりさらに具体的に説明する。(Example) Hereinafter, the present invention will be explained in more detail with reference to Examples.
実施例１
内径２００μｍ、肉厚１０μｍのポリプロピレン製多孔
質中空糸膜（平均空孔径１．０μｍ、空孔率７０％）１
００００本を、第２図に示すような血液洗浄装置１０の
の円筒状のハウジング１１内に配置し、両端部をポリウ
レタンボッティング材により固定してハウジング１１内
に上記多孔質中空糸膜１２を組付け、有効長２３０ｍｍ
、有効膜面積１゜６ｍ２の血液洗浄装置１０を作成した
。Example 1 Porous hollow fiber membrane made of polypropylene with an inner diameter of 200 μm and a wall thickness of 10 μm (average pore diameter 1.0 μm, porosity 70%) 1
The porous hollow fiber membrane 12 was placed inside the cylindrical housing 11 of the blood cleaning device 10 as shown in FIG. Assembled, effective length 230mm
A blood cleaning device 10 with an effective membrane area of 1°6 m2 was prepared.
このようにして同様の構成を有する血液洗浄装置１０を
４つ作成し、続いて、第１図に示すように、ひとつの装
置の第１流体導出口１４ａ、１４ｂ、１４ｃに次の装置
の第１流体導入口１３ｂ、１３Ｃ１１３ｄをポリエチレ
ン製の接続チューブ２０ａ、２０ｂ、２０ｃを用いて連
結することで４つの血液洗浄装置１０ａ、１０ｂ、１０
ｃ、１０ｄの第１流体流通空間１５ａ、１５ｂ、１５ｃ
、］５ｄが直列的に接続された洗浄回路を作成しな。In this way, four blood cleaning devices 10 having the same configuration are created, and then, as shown in FIG. 1 fluid inlet 13b, 13C113d using polyethylene connection tubes 20a, 20b, 20c, four blood cleaning devices 10a, 10b, 10
c, 10d first fluid circulation spaces 15a, 15b, 15c
, ]5d are connected in series.
この回路の第１の血液洗浄装置１０ａの第１流体導入口
１３ａよりグリセリンを流し、各血液洗浄装置１０ａ、
１０ｂ、１０ｃ、１０ｄ内の多孔質中空糸１２の内部空
間にグリセリンを充填した。Glycerin is flowed through the first fluid inlet 13a of the first blood cleaning device 10a of this circuit, and each blood cleaning device 10a,
The internal spaces of the porous hollow fibers 12 in 10b, 10c, and 10d were filled with glycerin.
この状態で回路全体に対しγ線を照射強度８ Ｍ ｒａ
ｄで照射しな。γ線を照射した後、系内よりグリセリン
を排除し、さらに無菌の生理食塩水を用いて充分に洗浄
し、中空糸膜に付着残留するグリセリンを除去した。（
あるいは各血液洗浄装置１０ａ、１０ｂ、１０ｃ、１０
ｄにグリセリンを充填し、第１流体導入口１３ａ、１３
ｂ、１３ｃ、］、 ３ ｄおよび導出口１４ａ、１４ｂ
、１４ｃ、１４ｄ、ならびに第２流体導入ロ１６ａ、１
６ｂ、１６ｃ、１６ｄおよび第２流体導出ロ１７ａ、１
７ｂ、１７ｃ、１７ｄを夫々キャップでシールし、各血
液洗浄装置１０ａ、１０ｂ、１０ｃ、１０ｄにγ線を照
射強度８ Ｍ ｒ ａ ｄで照射して、親水化した後、
無菌的に、第１図に示すように組付けることも可能であ
る。）
このように処理された回路を用いて保存血の洗浄処理を
行なった。まず洗浄すべき保存血として、等容量のハギ
ンス液（グリセリン７９％、ブドウ′Ｎ８％、果糖１％
、ＥＤＴＡ−２ナトリウム塩０゜３％〉を添加され一８
５℃で保存された保存赤血球濃厚液を用意し、これを４
０℃で解凍した。−方、上記回路をまず、第１の血液洗
浄装置１０ａから第４の血液洗浄装置１０ｄが略直線的
に鉛直方向において上から下へと位置するように、配置
した。次いで回路全体を無菌の生理食塩水でプライミン
グした後、上記回路のそれぞれの血液洗浄装置１０ａ、
１０ｂ、１０ｃ、１０ｄの第２流体導入ロ１６ａ、１６
ｂ、１６ｃ、１６ｄより５００ｍ１／ｍｉｎの流速で第
１表に示す洗浄液を各第２流体流通空間１８ａ、１８ｂ
、１８ｃ、１８ｄに流入し第２流体導出ロ１７ａ、１７
ｂ、１７Ｃ１１７ｄより排出し続けた。洗浄液の流速が
一定となったところで、上記のごとく解凍された保存血
４００ｍ１を上記回路中に１００ｍ１／ｍｉｎの流速で
第１の血液洗浄装置１０ａの第１流体導入口１３ａより
送通した。回路内を流れて第４の血液洗浄装置１０ｄの
第１流体導出口１４ｄより流出する洗浄された血液を収
集した。この洗浄処理に要した時間は４．５分間であっ
た。また洗浄処理前後の赤血球数を測定することにより
赤血球の回収率を求めたところ９５％であり、また洗浄
処理後の血液中に含まれるグリセリンは０．ｌｐｐｍで
あり、実質的に完全に除去されていた。In this state, the entire circuit is irradiated with gamma rays at an intensity of 8 M ra
Do not irradiate with d. After irradiation with γ-rays, glycerin was removed from the system, and the system was thoroughly washed with sterile physiological saline to remove glycerin remaining on the hollow fiber membrane. (
Or each blood washing device 10a, 10b, 10c, 10
d is filled with glycerin, and the first fluid introduction ports 13a, 13
b, 13c,], 3d and outlet ports 14a, 14b
, 14c, 14d, and second fluid introduction holes 16a, 1
6b, 16c, 16d and second fluid outlet 17a, 1
7b, 17c, and 17d are each sealed with a cap, and each blood washing device 10a, 10b, 10c, and 10d is irradiated with gamma rays at an irradiation intensity of 8 M r a d to make it hydrophilic.
It is also possible to assemble aseptically as shown in FIG. ) Using the circuit processed in this way, stored blood was washed. First, as the preserved blood to be washed, prepare an equal volume of Huggins solution (79% glycerin, 8% grape'N, 1% fructose).
, EDTA-2 sodium salt 0°3%> was added.
Prepare a preserved red blood cell concentrate stored at 5°C and incubate it for 4
It was thawed at 0°C. - On the other hand, the above circuit was first arranged so that the first blood washing device 10a to the fourth blood washing device 10d were positioned substantially linearly from top to bottom in the vertical direction. After priming the entire circuit with sterile saline, each blood cleaning device 10a of said circuit;
10b, 10c, 10d second fluid introduction holes 16a, 16
The cleaning liquid shown in Table 1 is applied to each second fluid circulation space 18a, 18b at a flow rate of 500 m1/min from b, 16c, 16d.
, 18c, 18d and the second fluid outlet holes 17a, 17.
b, continued to be discharged from 17C117d. When the flow rate of the washing liquid became constant, 400 ml of stored blood thawed as described above was passed through the first fluid inlet 13a of the first blood washing device 10a at a flow rate of 100 ml/min into the circuit. The washed blood flowing through the circuit and flowing out from the first fluid outlet 14d of the fourth blood washing device 10d was collected. The time required for this cleaning process was 4.5 minutes. Furthermore, the recovery rate of red blood cells was determined to be 95% by measuring the number of red blood cells before and after the washing process, and the glycerin content in the blood after the washing process was 0. lppm, and was virtually completely removed.
第１表
一洗一蓮一韮一
第１血液処理装置 ５０％ブドウ糖＋５％果糖
液
第２血液処理装置 ５％果糖液第３血液処理装
置 ５％果糖液第４血液処理装置 生
理食塩液（発明の効果）
以上述べたように、本発明は、ハウジング内に多孔質中
空糸膜を多数本配し、該中空糸ｊ摸の内部空間をハウジ
ングに設けられた第１流体導入口および導出口に連通さ
せて第１流体流通空間を形成し、一方ハウジングの内周
面と上記多孔質中空糸５Ｍの外面とで囲まれる空間には
ハウジングに設けられな第２流体導入口および導出口を
連通させて前記第１流体流通空間とは区画された第２流
体流通空間を形成してなる血液洗浄装置を複数個用い、
それぞれの血液洗浄装置の第１流体流通空間または第２
流体流通空間のいずれかを直列的に接続して血液流路を
形成し、この連°続する血液流路を略直線的に配置して
洗浄すべき血液を送通し、一方それぞれ独立した複数の
第２流体流通空間または第１流体流通空間にはそれぞれ
異種または同種の洗浄液を送通して、数段階にわたる洗
浄操作を連続的に行なうことを特徴する冷凍保存血液の
洗浄方法であるので、高い洗浄効率および高い血液成分
回収率をもって、数段階にわたる冷凍保存血液の洗浄操
作を連続的にクローズドシステムで無菌的にかつ容易に
行なうことができ、血液の冷凍保存システムを大きく発
展させることとなるものである。Table 1 Issai Ichiren Ichi Niiichi 1st blood processing device 50% glucose + 5% fructose solution 2nd blood processing device 5% fructose solution 3rd blood processing device 5% fructose solution 4th blood processing device Physiological saline solution (invention As described above, the present invention provides a method in which a large number of porous hollow fiber membranes are disposed within a housing, and the internal space of the hollow fiber membranes is connected to the first fluid inlet and outlet provided in the housing. A second fluid inlet and an outlet not provided in the housing are communicated with each other to form a first fluid circulation space, and a second fluid inlet and an outlet not provided in the housing are communicated with a space surrounded by the inner circumferential surface of the housing and the outer surface of the porous hollow fiber 5M. using a plurality of blood cleaning devices each forming a second fluid circulation space separated from the first fluid circulation space;
The first fluid flow space or the second fluid flow space of each blood cleaning device.
One of the fluid circulation spaces is connected in series to form a blood flow path, and the continuous blood flow path is arranged approximately linearly to allow the blood to be washed to flow therethrough. This method of cleaning cryopreserved blood is characterized by passing different or the same type of cleaning liquid through the second fluid circulation space or the first fluid circulation space, respectively, and continuously performing several stages of cleaning operations, so that it has a high degree of cleaning. With efficiency and a high blood component recovery rate, cryopreserved blood can be washed in several stages in a continuous, sterile, and easy closed system, resulting in a major development in blood cryopreservation systems. be.
第１図は本発明の冷凍保存血液洗浄方法における戦場回
路の一例を示す模式図であり、第２図は本発明の冷凍保
存血液洗浄方法において用いられる血液洗浄装置の一例
を示す概略断面図である。
１０．１０ａ、１０ｂ、１０ｃ、１０ｄ・・・血液洗浄
装置、１．１．ｌｌａ、ｌｌｂ、ｌｌｃ、１１ｄ−・・
ハウジング、１２．１２ａ、１２ｂ、１２ｃ。
１２ｄ−＝多孔質中空糸膜、１５．１５ａ、１５ｂ。FIG. 1 is a schematic diagram showing an example of a battlefield circuit in the cryopreserved blood washing method of the present invention, and FIG. 2 is a schematic sectional view showing an example of a blood washing device used in the cryopreserved blood washing method of the invention. be. 10.10a, 10b, 10c, 10d... blood cleaning device, 1.1. lla, llb, llc, 11d-...
Housing, 12.12a, 12b, 12c. 12d-=porous hollow fiber membrane, 15.15a, 15b.
Claims (4)
中空糸膜の内部空間をハウジングに設けられた第１流体
導入口および導出口に連通させて第１流体流通空間を形
成し、一方ハウジングの内周面と上記多孔質中空糸膜の
外面とで囲まれる空間にはハウジングに設けられた第２
流体導入口および導出口を連通させて前記第１流体流通
空間とは区画された第２流体流通空間を形成してなる血
液洗浄装置を複数個用い、それぞれの血液洗浄装置の第
１流体流通空間または第２流体流通空間のいずれかを直
列的に接続して血液流路を形成し、この連続する血液流
路を略直線的に配置して洗浄すべき血液を送通し、一方
それぞれ独立した複数の第２流体流通空間または第１流
体流通空間にはそれぞれ異種または同種の洗浄液を送通
して、数段階にわたる洗浄操作を連続的に行なうことを
特徴とする冷凍保存血液の洗浄方法。(1) A plurality of porous hollow fiber membranes are disposed within the housing, and the internal space of the hollow fiber membranes is communicated with a first fluid inlet and an outlet provided in the housing to form a first fluid circulation space. On the other hand, in the space surrounded by the inner circumferential surface of the housing and the outer surface of the porous hollow fiber membrane, there is a second tube provided in the housing.
A plurality of blood cleaning devices each having a fluid inlet and an outlet communicating with each other to form a second fluid distribution space separated from the first fluid distribution space are used, and a first fluid distribution space of each blood cleaning device is used. Alternatively, either one of the second fluid circulation spaces may be connected in series to form a blood flow path, and the continuous blood flow path may be arranged substantially linearly to allow the blood to be washed to flow therethrough, while a plurality of A method for washing cryopreserved blood, characterized in that washing liquids of different types or of the same type are passed through the second fluid circulation space or the first fluid circulation space, respectively, to continuously perform a washing operation in several stages.
の範囲第１項に記載の冷凍保存血液の洗浄方法。(2) The method for washing cryopreserved blood according to claim 1, wherein the blood is passed in the direction of gravity.
特許請求の範囲第１項に記載の冷凍保存血液の洗浄方法
。(3) The method for washing cryopreserved blood according to claim 1, wherein the blood is passed in a direction opposite to the direction of gravity.
水性多孔質中空糸膜の少なくとも内面および孔内面に親
水性化合物がγ線によりグラフトされてなる親水性薄層
が形成されてなるものである特許請求の範囲第１項〜第
３項のいずれかに記載の冷凍保存血液の洗浄方法。(4) The porous hollow fiber membrane disposed in the blood cleaning device has a hydrophilic thin layer formed by grafting a hydrophilic compound with gamma rays on at least the inner surface of the hydrophobic porous hollow fiber membrane and the inner surface of the pores. 3. A method for washing frozen blood according to any one of claims 1 to 3, which comprises:
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62277486A JP2545556B2 (en) | 1987-11-04 | 1987-11-04 | Frozen preservation blood washing method |
| US07/265,822 US4940541A (en) | 1987-02-11 | 1988-11-01 | Blood cleaning hollow fiber membrane, method for cleaning blood, and apparatus therefor |
| FI885009A FI885009A (en) | 1987-11-02 | 1988-11-01 | FIBERMEMBRAN SAMT FOERFARANDE OCH ANORDNING FOER RENGOERING AV BLOD. |
| CA000581857A CA1328843C (en) | 1987-11-02 | 1988-11-01 | Blood cleaning hollow fiber membrane, method for cleaning blood, and apparatus therefor |
| NO884853A NO173366C (en) | 1987-11-02 | 1988-11-01 | Hollow fiber membrane for blood purification, blood purification process, and blood purification apparatus |
| CN88108821A CN1024629C (en) | 1987-11-02 | 1988-11-02 | Blood cleaning hollow fiber membrane, method for cleaning blood and apparatus therefor |
| KR1019880014403A KR890007758A (en) | 1987-11-02 | 1988-11-02 | Hollow fiber membrane for blood cleaning, blood cleaning method and device |
| DK611088A DK611088A (en) | 1987-11-02 | 1988-11-02 | BLOOD CLEANING, HOLE FIBER MEMBRANE, PROCEDURE FOR CLEANING BLOOD AND APPLICATION FOR EXERCISING THE PROCEDURE |
| AT88310283T ATE148370T1 (en) | 1987-11-02 | 1988-11-02 | METHOD FOR PRODUCING A HOLLOW FIBER MEMBRANE DEVICE FOR PURIFYING BLOOD |
| AU24606/88A AU617702B2 (en) | 1987-11-02 | 1988-11-02 | Blood cleaning hollow fiber membrane, method for cleaning blood, and apparatus therefor |
| EP88310283A EP0315420B1 (en) | 1987-11-02 | 1988-11-02 | Process for producing an apparatus with hollow fiber membrane for cleaning blood |
| EP19930201474 EP0564053A3 (en) | 1987-11-02 | 1988-11-02 | Blood cleaning method |
| DE3855776T DE3855776T2 (en) | 1987-11-02 | 1988-11-02 | Process for the manufacture of a device with a hollow fiber membrane for the purification of blood |
| US07/521,141 US5075003A (en) | 1987-11-02 | 1990-05-28 | Blood cleaning hollow fiber membrane method for cleaning blood, and apparatus therefor |
| CN93103169A CN1079913A (en) | 1987-11-02 | 1993-03-13 | Blood cleans with hollow cortina, method for cleaning blood and device thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62277486A JP2545556B2 (en) | 1987-11-04 | 1987-11-04 | Frozen preservation blood washing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01121055A true JPH01121055A (en) | 1989-05-12 |
| JP2545556B2 JP2545556B2 (en) | 1996-10-23 |
Family
ID=17584264
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62277486A Expired - Lifetime JP2545556B2 (en) | 1987-02-11 | 1987-11-04 | Frozen preservation blood washing method |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2545556B2 (en) |
-
1987
- 1987-11-04 JP JP62277486A patent/JP2545556B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2545556B2 (en) | 1996-10-23 |
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