CN107281572A - Blood purification system - Google Patents

Blood purification system Download PDF

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Publication number
CN107281572A
CN107281572A CN201610471829.9A CN201610471829A CN107281572A CN 107281572 A CN107281572 A CN 107281572A CN 201610471829 A CN201610471829 A CN 201610471829A CN 107281572 A CN107281572 A CN 107281572A
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China
Prior art keywords
blood
plasma
cytohormone
purification system
absorber
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Inventor
赖文雅
蔡佩宜
郭正亮
黄志杰
温奕泓
范玮伦
杨国义
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Fiberpure Technology Co ltd
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Fiberpure Technology Co ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3607Regulation parameters
    • A61M1/3609Physical characteristics of the blood, e.g. haematocrit, urea
    • A61M1/3612Physical characteristics of the blood, e.g. haematocrit, urea after treatment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621Extra-corporeal blood circuits
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621Extra-corporeal blood circuits
    • A61M1/3627Degassing devices; Buffer reservoirs; Drip chambers; Blood filters
    • A61M1/3633Blood component filters, e.g. leukocyte filters
    • A61M1/3635Constructional details
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3621Extra-corporeal blood circuits
    • A61M1/3643Priming, rinsing before or after use
    • A61M1/3644Mode of operation
    • A61M1/3649Mode of operation using dialysate as priming or rinsing liquid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3687Chemical treatment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/36Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3692Washing or rinsing blood or blood constituents
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26Synthetic macromolecular compounds
    • B01J20/261Synthetic macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00Special media to be introduced, removed or treated
    • A61M2202/04Liquids
    • A61M2202/0413Blood
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2220/00Aspects relating to sorbent materials
    • B01J2220/40Aspects relating to the composition of sorbent or filter aid materials
    • B01J2220/44Materials comprising a mixture of organic materials
    • B01J2220/445Materials comprising a mixture of organic materials comprising a mixture of polymers

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  • Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Anesthesiology (AREA)
  • Hematology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Cardiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Organic Chemistry (AREA)
  • External Artificial Organs (AREA)

Abstract

A blood purification system comprises a plasma separator, a cytokine adsorber and a hemodialyzer, wherein the plasma separator is provided with a first column and a plurality of hollow fiber bundles filled in the column and is used for separating plasma from a plurality of blood cells in blood extracted from a human body; the cytokine adsorber is provided with a second column and a composite adsorption material arranged in the second column, and the composite adsorption material is used for adsorbing part of pathogenic cytokine in the plasma to obtain purified plasma; and a hemodialyzer for dialyzing the mixed blood (purified plasma and blood cells) to obtain clean blood.

Description

Blood purification system
Technical field
The present invention is to disclose a kind of blood purification system, in particular to being used to adsorb blood using compound sorbing material Pathogenic cell hormone or excessive cytohormone in slurry, with the blood after being purified, and by blood circulation the Huis' body of purification Internal blood purification system.
Background technology
According to statistics, septicemia causes serious multiple organ's exhaustion (Multiple organ failure, MOF) fatal rate Up to 30%-60%.In the U.S., septicemia patient year in 2011 has exceeded a million people, and with year multiple growth rate 2.42% speed increase, and each year, because the dead number of septicemia is more than 210,000 5 thousand people, the medical institutions in the U.S. are every Spend within 1 year and look after nearly 17,000,000,000 dollars of septicemia sufferer, be similarly up in the market of European Union's septicaemia treatment in each year 7600000000 Euros, therefore septicemia turns into one of disease for the treatment of cost most expensive.According to statistics, the whole world has up to 1 within each year, 8000000 people suffer from septicemia, and the death rate is up to 28%-50%.In TaiWan, China, the statistics of Department of Health's (now claiming ministry of Health and Welfare) Report, consultation rate of being in hospital in 2006 years is every 100,000 368 people, and convert the people of sufferer about 70,000 6 thousand, dead in 2008 years TaiWan, Chinas Be up to 3,534 people in septicemic cemia sufferer, wherein women die ranking has reached the 9th, many counties and cities final ranking all Discharge into top 10.Go all out to put into the research and development of septicaemia treatment invariably in huge medical treatment and the market demand just because of this, countries in the world.
Septicemia is looked after medical association (ACCP/SCCM) by U.S.'s chest medicine meeting/severe and is defined as because of infection (bacterium, disease Poison, mould or parasitic animal and plant) caused by systemic inflammatory reaction syndrome (Systemic Inflammatory Response Syndrome,SIRS).Septicemia (Sepsis) is clinically the reason for causing patient's quick death.Its feature is simultaneously There are infective micro-organisms (bacterium, virus or fungi) and the reaction of systemic inflammation disease.About 25%-30% septicemia is suffered from Person can develop into serious multiple organ's exhaustion (Multiple organ failure, MOF), and fatal rate reaches 30%-60%.Work as body Body declines to antimicrobial ability, will easily be infected, and easily occurs immunologic dysfunction, for example aging, AIDS, Cytotoxic drug and immunosuppressive drug, malnutrition, excessive drinking, malignant tumour, diabetes are taken, exposed to resistance to the action of a drug cause of disease In the environment of increase and the situation such as aggressive diagnosis and treatment.
After occurring systemic inflammation reaction syndrome (SIRS), the anti-inflammatory for triggering compensatory is reacted.This mistake Exotic mediums stimulate cell to journey before this, disengage a variety of different cytohormones (Cytokine) and cause excessive buildup interleukins 6 (hereinafter referred to as IL-6), interleukin 10 (hereinafter referred to as IL-10) and tumor necrosis factor-alpha (hereinafter referred to as TNF-α) phenomenon.This Phenomenon triggers successional violent inflammatory response:, ischemic/reperfusion not enough from primary cellular damage to tissue perfusion damage to Disseminated intravascular coagulation triggers periphery blood vessel dilatation, diffusivity blood vessel to/immune/inflammation/adventitious agents reciprocation is circulated Intravascular coagulation (DIC) etc., finally results in systemic multiple organ's exhaustion.Clinically also confirm that in septic shock (Septic Shock) IL-6 numerical value is up to 7,500 times of normal person unexpectedly with patient.Therefore, how effectively to be removed in the circulatory system The cytohormone of amount exactly clinically compels to be essential at present come the immunologic mechanism reformed Homeostatic mechanism and recover normal physiological The problem of solving.
Correlative study is had at present and removes cytohormone using absorber or dialyzer, can slow down organ failure's Situation.In prior art, WiwatChancharoenthana uses the mode of hemodiafiltration (Hemodiafiltration, HDF), with high penetration haemodialysis (High flux hemodialysis) Randomized treatment 28 Septicemia Associated Acute injury of kidney (sepsis-related acute kidney injury) sufferer, as a result shows that HDF can be bright It is aobvious remove VEGF (vascular endothelial growth factor, VEGF, hereinafter referred to as VEGF), The cytohormone such as IL-6, IL-10 and TNF-α, renal function recovers preferable.Separately there is prior art, HP Shun are acute for 6 Impaired renal patient, has carried out clinic using the patient of Blood index filter and 24 historical control groups and has compared, be as a result shown in leather In acute injury of kidney patient caused by gram-negative bacteria infection, after 48 hours treat, patient organ's exhaustion scoring substantially subtracts Few 37%, relatively conventional continuity Venous Hemofiltration, endotoxin and cell factor absorption blood filtration are not only safe, can more add It is fast to improve organ dysfunction.
The content of the invention
For prior art, because the selectivity polymeric adsorbent cost of single cell hormone (Cytokine) is too high, and carefully Intracellular hormone species is various, and indivedual exploitation selectivity resins do not meet economic benefit.For this situation.Due to cytohormone molecular weight About slightly 8KDa-30KDa protein or glycoprotein, it is a primary object of the present invention to non-specific and with quite selection Property polymeric adsorbent be target, research and develop adsorbable various kinds of cell hormone and avoid adsorbing other albumen or a variety of useful simultaneously The resin of material, can be effectively reduced medical treatment cost, the replacement therapy method of such acute severe is easy to popularization and add favour needs Sufferer.
Another object of the present invention is to provide a kind of compound sorbing material, swash for the pathogenic cell in adsorbed plasma Plain or excessive cytohormone, with the blood plasma after being purified.
A further object of the present invention is using uncharged resin and electrically charged anion exchange resin with ratio Compound sorbing material is formed after mixing and is inserted in tubing string, is adsorbed and is reached for the pathogenic cell hormone in blood plasma Purify the effect of blood.
According to above-mentioned purpose, the invention discloses a kind of blood purification system, comprising:Plasma separator, cytohormone absorption Device and haemodialyser, wherein plasma separator have first tubing string and the multiple hollow fiber bundles being filled in first tubing string, The purpose of plasma separator is the blood plasma in the blood extracted by human body to be separated with multiple blood cells;Cytohormone is inhaled Adnexa has second tubing string and the compound sorbing material being placed in second tubing string, and cytohormone absorber utilizes compound absorption Material is adsorbed the pathogenic cell hormone of blood plasma partial to be purified blood plasma, wherein compound sorbing material by without The resin of electric charge and electrically charged anion exchange resin composition;And haemodialyser, adsorbed to receive by cytohormone The purification blood plasma that device is conveyed mixes blood with via the separated blood cell of plasma separator is mixed, and utilizes dialyzer pair Mixing blood further gives the waste or medicine remained in blood, thereby obtains clean blood, and will can do In net blood circulation the Huis' body body.
Coordinate disclosed herein blood purification system, the present invention also disclose a kind of blood purification method, include step Have:Blood is provided;Blood is separated to obtain blood plasma and multiple blood cells;Adsorption step is carried out to blood plasma, to remove causing a disease in blood plasma Cytohormone, to be purified blood plasma;Purification blood plasma is mixed with blood cell to form mixing blood;And carry out mixing blood Dialysis, to obtain clean blood.Therefore, either blood purification system or blood purification method can be avoided in existing skill In art, during using drug therapy, due to internal complicated pharmacokinetics and pharmacological mechanism, derivative many side effects.
Brief description of the drawings
Fig. 1 be according to disclosed herein technology, represent blood purification system schematic diagram.
Fig. 2 be according to disclosed herein technology, represent blood purification system block schematic diagram.
Fig. 3 be according to disclosed herein technology, represent blood purification flow chart of steps.
Fig. 4 be according to disclosed herein technology, represent have uncharged resin and electrically charged anion exchange Mixed with resin ratio is 20%:Absorption of 80% (v/v) the compound sorbing material to the Scavenging activity of various cytohormones is bent Line chart.
Fig. 5 be according to disclosed herein technology, represent have uncharged resin and electrically charged anion exchange Mixed with resin ratio is 40%:Absorption of 60% (v/v) the compound sorbing material to the Scavenging activity of various cytohormones is bent Line chart.
Fig. 6 be according to disclosed herein technology, represent have uncharged resin and electrically charged anion exchange Mixed with resin ratio is 60%:Adsorption curve of 40% (v/v) the compound sorbing material to the removing solid capacity of various cytohormones Figure.
Fig. 7 be according to disclosed herein technology, represent have uncharged resin and electrically charged anion exchange Mixed with resin ratio is 80%:Absorption of 20% (v/v) the compound sorbing material to the Scavenging activity of various cytohormones is bent Line chart.
Fig. 8 be according to disclosed herein technology, represent cytohormone absorber to adsorb p-cresol removing energy The adsorption time of power and the adsorption curve figure of clearance rate.
Fig. 9 be according to disclosed herein technology, represent cytohormone absorber to the Scavenging activity of cytohormone Adsorption curve figure.
Figure 10 be according to disclosed herein technology, represent suction of the cytohormone absorber to IL-1 β Scavenging activity Attached curve map.
Figure 11 be according to disclosed herein technology, represent absorption of the cytohormone absorber to IL-6 Scavenging activity Curve map.
Figure 12 be according to disclosed herein technology, represent absorption of the cytohormone absorber to IL-8 Scavenging activity Curve map.
Figure 13 be according to disclosed herein technology, represent suction of the cytohormone absorber to IL-10 Scavenging activity Attached curve map.
Figure 14 be according to disclosed herein technology, represent suction of the cytohormone absorber to the Scavenging activity of TNF-α Attached curve map.
Figure 15 be according to disclosed herein technology, there is shown removing energy of the cytohormone absorber to endotoxin The adsorption curve figure of power.
Figure 16 be according to disclosed herein technology, represent zoopery during synchronously carry out hemodynamic monitoring As a result curve map.
Figure 17 be according to disclosed herein technology, represent non-endotoxin injection and only carry out the animal examination of blood purification Test the curve map of (Hemopurification alone groups) result.
Figure 18 be according to disclosed herein technology, represent TNF-α dialysis initial stage its concentration curve descending slope and Amplitude just has obvious increased curve map.
Figure 19 be according to disclosed herein technology, represent IL-6 in dialysis its concentration curve descending slope and width at initial stage Degree just has obvious increased curve map.
Figure 20 be according to disclosed herein technology, represent the pass of (L+H (new) group) in the test of cytohormone absorber System's figure.
Embodiment
In order that the purpose of the present invention, technical characteristic and advantage, can more correlative technology field personnel understood, and be able to Implement the present invention, appended schema is coordinated herein, the technical characteristic and embodiment of the present invention is specifically illustrated, and enumerates preferable reality Example is applied to further illustrate.With the schema hereinafter compareed, to express the signal relevant with feature of present invention, also need not Completely drawn according to practical situation.And it is related to technology well-known to those skilled in the art in the explanation on this case embodiment Content, is also no longer stated.
Blood purification system applies the removal of uremic in blood, that is, " the washing kidney " being widely known by the people.Its principle is will Blood extracts external out, after material harmful in the program removal blood such as dialysis or absorption, recycles ex vivo It is interior.It is that the small molecule toxins in blood, such as urea or creatine liver are removed using the dialysis function of pellicle for example to wash kidney Etc. (creatinine) with excessive moisture content in removing body.Same concept can be applied to the treatment of septicemia, its operation principle be by After blood is extracted out in vitro, blood cell is separated with blood plasma using plasma separator, cytohormone absorber is recycled by blood plasma Excessive cytohormone (Cytokine) Adsorption, then by treated blood plasma with blood cell mixing Posterior circle ex vivo.By Blood purification system can be with cytohormone excessive in removing body, compared to drug therapy is utilized, due to internal complicated medicine Dynamics and pharmacological mechanism, can often derive many side effects, such as Human Active's albumen c (drotrecogin-alfa (activated), rhAPC) derived from bleeding reaction.But according to disclosed herein blood purification system without by body Intracellular metabolite, therefore without related misgivings.Therefore disclosed herein blood purification system can be shared even with drug therapy Supply drug therapy weak point.Below for disclosed herein blood purification system explain.
Referring first to Fig. 1.Fig. 1 be according to disclosed herein technology, represent blood purification system schematic diagram.In figure In 1, blood purification system 1 includes plasma separator 10, cytohormone absorber 20 and haemodialyser 30, wherein, blood plasma point Communicated with each other respectively with cytohormone absorber 20 and haemodialyser 30 with blood circuit sleeve pipe group 40 from device 10.In addition, Valve member (valve) (the not table in figure is additionally provided between plasma separator 10, cytohormone absorber 20 and haemodialyser 30 Show), this valve member is worked as in fluid (blood, blood plasma or blood cell) in plasma separator 10, cytohormone absorber 20 and blood Opening to close when conveying between dialyzer 30 allows fluid to input or export these devices.
Similarly, please continue to refer to Fig. 1.Plasma separator 10, the separation to separate blood plasma and blood cell in blood is filled Put, plasma separator 10 is mainly made up of tubing string 12 and the multiple hollow fiber bundles 14 being placed in tubing string 12.In this hair It is bright, it is necessary to which accurately control filtering pore size, caliber and pipe thickness, can just efficiently separate blood plasma and blood cell, and accord with Close the stream power demand of the operating process of separation.It is noted that because blood is viscous fluids, can not be caused in operating process Excessive pressure drag, can must on demand control blood to enter the flow of plasma separator 10, and to avoid blood from being separated in blood plasma Blood coagulation phenomenon occurs in device 10.
Cytohormone absorber 20, for adsorbing with remove in blood plasma cause a disease cytohormone adsorbent equipment.Cell swashs Plain absorber 20 is mainly made up of tubing string 22 and compound sorbing material 24, wherein the main mesh of compound sorbing material 24 Be the pathogenic cell hormone or excessive cytohormone that can be adsorbed in blood plasma, and its adsorption capacity is at least greater than 65%, and used compound sorbing material 24 cannot albumen necessary to human body in adsorbed plasma, for example:Albumin (albumin), compound sorbing material 24 is less than 15% to the adsorption capacity of albumin.In addition, for adherent cell hormone Compound sorbing material 24 there is high specific surface area, to provide enough adsorption areas, and with appropriate particle diameter with Intensity, with the pressure produced by resisting in operation, can thereby be avoided in cytohormone absorber 20 because excessive is carried Boosting resistance, and cause the damaged or whole cytohormone absorber 20 of compound sorbing material 24 to be damaged because pressure is excessive, and It can not operate.
In the present invention, cause a disease as absorption or excessive cytohormone compound sorbing material 24 at least by two kinds Resin is constituted, including uncharged resin and electrically charged anion exchange resin, wherein, uncharged resin be styrene- Divinylbenzene resins (poly (styrene-divinylbenzene, PS-DVB)), chemical structural formula isThe physical characteristics of materials of styrene-divinyl benzene resin:Particle diameter is 75um- 106um, specific surface area are 560m2/ g, porosity (pore size) areOperation temperature is 130 DEG C and electrically charged Anion exchange resin is styrene-divinyl benzene resin level Four ammonium, Cl types (poly (styrene-divinylbenzene) four Level ammonium, Cl types), its chemical structural formula is
The physical characteristics of materials of electrically charged anion exchange resin: Particle diameter is more than or is more than at least equal to 450um, exchange capacity or at least equal to 80 DEG C of 0.85 (meq/ml-R), operation temperature. In embodiments of the invention, uncharged resin and electrically charged anion exchange resin are mixed with shape in varing proportions Into composite resin, such as uncharged resin:Electrically charged anion exchange resin can mixing ratio be 20%:80% (v/ V), 40%:60 (v/v), 60%:40% (v/v) or 80%:20% (v/v).
Then, first isolated by-the blood plasma that is purified by cytohormone absorber 20 and in plasma separator 10 Haemodialyser 30 is entered back into after blood cell mixing and carries out haemodialysis step, to obtain clean blood and be recycled back to human body It is interior.Haemodialyser 30 mainly contains the multiple small hollow fibres (being represented not in figure) made by artificial pellicle, And allow liquid (blood) to be flowed between these small hollow fibres, and have clean dialyzate outside hollow fibre (not Represented in figure) enter via the dialyzate entrance 302 of haemodialyser 30, and the waste or medicine allowed in blood via The mode of dialysis and separate out, it is and 304 the dialyzate containing waste or medicine is defeated by the dialyzate outlet of haemodialyser 30 Go out, to reach using haemodialyser 30 come the toxin expelling work of temporary transient or permanent substitution patient renal.
Then, it please also refer to Fig. 2 and Fig. 3.Fig. 2 according to disclosed herein technology, represent blood purification system Block schematic diagram and Fig. 3 according to disclosed herein technology, represent blood purification flow chart of steps.First, coordinate Fig. 2's Blood purification system, the present invention also discloses blood purification method, has comprising step:Blood is provided;Separate blood with blood plasma and Multiple blood cells;Adsorption step is carried out to blood plasma, to remove the pathogenic cell hormone in blood plasma, to be purified blood plasma;Will purification Blood plasma mixes to form mixing blood with blood cell;And mixing blood is dialysed, to obtain clean blood.Detailed step is such as Step 60 to step 70, wherein step 60 is to extract blood out in human body 50 using blood side Pu (pump) 5 in Fig. 3, specific next Say it is by human body 50 using blood side Pu 5 via syringe needle (being represented not in figure) and blood circuit pipeline 40 (as shown in Figure 1) Artery in extract blood out.Then, step 62, blood is delivered to plasma separator 10, using plasma separator 10 by blood In blood cell and blood plasma separation.In this step 62, the blood extracted out in the artery of human body 50 can be via blood circuit pipe Line 40 delivers into plasma separator 10, and using the hollow fiber bundle 12 (as shown in Figure 1) in plasma separator 10 by blood Blood plasma and blood cell in liquid are separated from each other.Step 64, cytohormone absorber 20 will be delivered to by the blood plasma of separation, using thin Excessive cytohormone and/or cause in compound sorbing material 24 (as shown in Figure 1) adsorbed plasma in intracellular hormone absorber 20 Sick cytohormone, to be purified blood plasma.In this step 64, due to the material property of compound sorbing material 24, Jin Jinzhen Pathogenic cell hormone and/or excessive cytohormone in blood plasma is adsorbed, without being carried out to the albumin in blood plasma Absorption, therefore the purification blood plasma still presence containing albumin produced by after absorption.
Then, such as step 66, the blood cell after purifying blood plasma and being separated through plasma separator 10 is mixed to form mixing blood After liquid (purification blood plasma and blood cell mixed liquor), haemodialyser 30 is delivered into.In this step, it will be inhaled by cytohormone After adnexa 20 is adsorbed, resulting purification blood plasma is with passing through the blood cell after plasma separator 10 is separated in blood to be delivered into Before liquid dialyzer 30, first mixed to form mixing blood (purification blood plasma and blood cell mixed liquor), blood is then inputted again Dialyzer 30, this blend step can be mixed in the blood circuit pipeline 40 before entering haemodialyser 30, or Mixing arrangement (being represented not in figure) is set to mix purification blood plasma and blood cell in addition, it is unlimited to this in the present invention System.And then, step 68 is carried out, will mix blood (purification blood plasma and blood cell mixed liquor) using haemodialyser 30 is carried out thoroughly Analysis.In this step, due to still remaining some wastes or medicine in mixing blood (purification blood plasma and blood cell mixed liquor), it is This mixing blood (purification blood plasma and blood cell mixed liquor) of further purification, therefore in whole extracorporeal circulation system, utilize blood Liquid dialyzer 30, and dialyzate (is represented) not in figure in injection haemodialyser 30, for mixing blood (purification blood plasma With blood cell mixed liquor) carry out dialysis step, allow in mixing blood (purification blood plasma with blood cell mixed liquor) may residual medicine or It is that waste is separated out via dialyzate and discharged by haemodialyser 30, to obtain clean blood.Finally, step 70, it will pass through Clean blood output after dialysis, then via in venous circulation the Huis' body of human body.
Therefore, for disclosed herein compound sorbing material, in varing proportions, such as 20%:80% (v/v), 40%:60 (v/v), 60%:40% (v/v) or 80%:20% (v/v) uncharged resin and electrically charged anion are handed over Change mixed with resin and form compound sorbing material, to carry out the composition and cytohormone adsorption effect of compound sorbing material Experiment, wherein table 1 are to represent that mixing ratio is 20%:80% (v/v) compound sorptive material to the clearance rate of cytohormone, Table 2 is to represent that mixing ratio is 40%:60% (v/v) compound sorptive material is to represent to the clearance rate of cytohormone, table 3 Mixing ratio is 60%:40% (v/v) compound sorptive material is to represent mixing ratio to the clearance rate and table 4 of cytohormone For 80%:Clearance rate of 20% (v/v) the compound sorptive material to cytohormone.
Table 1 (20%:80% (v/v))
TNF-α IL-1β IL-6 IL-8 IL-10
0h 0 0 0 0 0
0.5h 76.72 74.42 68.23 56.65 58.67
1h 78.85 74.80 71.18 63.34 62.97
2h 77.90 75.26 71.80 59.99 62.06
3h 78.77 73.56 71.20 62.75 59.08
4h 79.79 75.75 70.56 64.16 60.77
5h 79.79 69.89 67.80 63.34 59.31
Table 2 (40%:60% (v/v))
TNF-α IL-1β IL-6 IL-8 IL-10
0h 0 0 0 0 0
0.5h 9.06 25.33 28.90 -27.74 43.11
1h 15.75 19.61 50.87 20.88 42.60
2h 19.87 37.35 52.71 25.23 49.23
3h 15.37 41.11 43.95 18.02 48.78
4h 20.08 39.22 55.64 20.09 48.14
5h 21.79 38.69 60.63 6.86 47.81
Table 3 (60%:40% (v/v))
Table 4 (80%:20% (v/v))
TNF-α IL-1β IL-6 IL-8 IL-10
0h 0 0 0 0 0
0.5h 53.33 42.04 55.94 40.13 49.00
1h 59.93 49.75 55.98 48.32 57.68
2h 58.67 49.12 64.25 53.70 57.55
3h 57.40 50.34 64.33 50.21 52.38
4h 57.76 50.60 61.76 47.56 55.40
5h 56.44 45.87 58.35 50.64 53.40
And Fig. 4 to Fig. 7 represents the compound sorbing material of different mixing proportion for the clear of various cytohormones respectively The curve map of removing solid capacity.It can be obtained, be handed in uncharged resin and electrically charged anion from table 1-4 Fig. 4 with to Fig. 7 The mixing ratio for changing resin is 60%:When 40%, come for the Scavenging activity of various cytohormones than other mixed proportions It is high.
Therefore, in order to prove disclosed herein blood purification system 1 for current medical industries, particularly blood Dialysis has suitable contribution, for blood purification system 1 to TNF-α, IL-1 β, IL-6, IL-10, endotoxin, p-cresol Adsorption capacity, absorption albumin (albumin) carry out adsorption test and cell toxicant test with removing thing total amount etc., and according to upper State using the data obtained by the uncharged resin of different mixing proportion and electrically charged anion exchange resin, in following reality In testing, the mixed proportion with preferable Scavenging activity is used for 60%:40% (v/v) (uncharged resin:It is electrically charged it is cloudy from Sub-exchange resin) compound sorbing material 24 be filled in the tubing string 22 of cytohormone absorber 20, carry out absorption test.
Experiment one:Test compound type polymeric adsorbent is directed to p-cresol adsorption capacity:
Experimental method:P-cresol method of testings are adsorbed using extracorporal circulatory system:
Testing procedure:
I. filling 100mL resins are preserved in cytohormone absorption tubing string with ethanol (EtOH).
Ii. by ethanol replacement into phosphate buffer solution (PBS, Phosphate-buffered saline).
Iii. solution will be tested with test condition containing p-cresol and help Pu 5 (as schemed using the blood in above-mentioned Fig. 8 Shown in 2) input circulation absorption is carried out into cytohormone absorber 20.
Iv. the 0.5th, be sampled within 1,2,3,4,5 hours.
V. entered using high-effect liquid chromatograph (HPLC, high performance liquid chromatography) Row analysis sample p-cresol concentration.
Vi. test condition, as shown in table 5:
Table 5
As a result with discussion:According to experimental result, by disclosed herein the cytohormone with compound sorbing material 24 Absorber 20 is 87.29% for p-cresol adsorption rate, more than 65%.In addition, being then to represent that cytohormone is adsorbed in table 6 The result of clearance rate of the device 20 for absorption p-cresol obtained by different sample times.
Table 6
Meanwhile, it can also be obtained in Fig. 8, when the adsorption time increase of cytohormone absorber 20, cytohormone is inhaled Adnexa 20 is higher for p-cresol clearance rate.
Experiment two:Cytohormone, endotoxin (endotoxin), albumin (albumin) absorption test.The mesh of this experiment Be adsorption capacity of the test cell hormone absorber 20 for various materials to be tested is come with cardiopulmonary Bypass.
Experimental method:The compound sorbing materials 24 (as shown in Figure 1) of 100mL are filled in the pipe of cytohormone absorber 20 In post 22 (as shown in Figure 1), substances will be added in advance with side Pu (not represented in figure) of wriggling, such as temperature is 37 DEG C of pig blood Slurry, in the tubing string 22 of circulation conveying to cytohormone absorber 20 so that compound polymeric adsorbent 24 in tubing string 22 is inhaled Adhesion test material (temperature is 37 DEG C of Swine plasma).Wherein, circulation time is not less than 2 hours, and test pig blood is sampled afterwards The change in concentration of substances in slurry.
I. cardiopulmonary Bypass:
The situation of Clinical practice is copied, extracorporeal circulation apparatus is set, to emulate the situation that cytohormone is adsorbed in blood plasma. Wherein, the setting of each condition such as flow velocity, plasma volume, resin demand etc. of extracorporeal circulation apparatus, according to Clinical practice Situation is set.
Experimental procedure:
A. prepared by Swine plasma:
1. take addition 1mL heparin sodium injections (heparin sodium) (5000i.u./ml- in every 400mL pigs whole blood Heparin sodium) as anticoagulant.
2. the speed by pig whole blood using rotating speed as 3500rpm is centrifuged at least 20 minutes, wait to take out after standing Supernatant liquid, and in 4 DEG C of preservations.Herein it is noted that before the experiment, adding after cytohormone, being heated To 37 DEG C ± 2 DEG C, and insulation is used.
B. vitro Adsorption is tested:
I. the compound polymeric adsorbents of 100mL are filled in cytohormone absorption tubing string, and carried out clearly with 300mL ethanol Wash.
Ii. by ethanol replacement into phosphate buffer solution.
Iii. by the 1000mL prepared Swine plasma according to experimental design, predetermined concentration (as listed by table 7 concentration model is added Enclose) substances.
Iv. the Swine plasma added in advance is carried out with water proof mode of heating being heated to 37 DEG C, and keeps constant temperature.
V. substances will be added in advance with side Pu of wriggling, and temperature is inhaled for 37 DEG C of Swine plasma circulation conveying to cytohormone Adnexa, the flow velocity of the Swine plasma now inputted is 25mL/min.
Vi. the 0.5th, sampling in 1,2,3,4,5 hours.
Vii. each substances concentration is detected.
Table 7
Substances TNF-α IL-1b IL-6 IL-8 IL-10 LPS albumin
Experimental concentration pg/ml 8000 1600 2000 500 3333 10000 3.5g/L
II. analysis method:
Analyze point-score step as follows:
1. cytohormone ((TNF-α, IL-1 β, IL-6, IL-8, IL-10) concentration analysis:
Cytohormone (TNF-α, IL-1 β, IL-6, IL-8, IL-10) concentration analysis is used into R&DSYSTEM ELISA Kit(Catalog No.:DY210、DY201、DY206、DY208、DY217)。
I. by the reagent and standard appended by R&D SYSTEM (TNF-α, IL-1 β, IL-6, IL-8, IL-10) ELISA Kit Reagent is diluted to use ratio using being preceding placed at room temperature by product with pure water.
Ii. standard items (TNF-α, IL-1 β, IL-6, IL-8, IL-10standard) are configured to debita spissitudo gradient.
Iii. the 100 tested samples of μ l and (TNF-α, IL-1 β, IL-6, IL-8, IL-10standard) standard are separately added into Product, are placed in and react 2 hours at room temperature.
Iv. after tested sample and (TNF-α, IL-1 β, IL-6, IL-8, IL-10standard) standard items being removed, with 200 μ l cleaning solution (Wash buffer) is rinsed 4 times.100 μ l detection antibody (Detection antibody) is added, It is placed in and reacts 2 hours at room temperature.
V. after detecting that antibody is removed, then with 200 μ l cleaning solutions flushing 4 times.Add 100 μ l horseradish peroxidase marks Remember Streptavidin (Streptavidin-HRP, hereinafter referred to as Streptavidin-HRP) reaction solution, be placed in and react at room temperature 20 minutes.
Vi. after Streptavidin-HRP reaction solutions are removed, rinsed 4 times with 200 μ l cleaning solution.Add 100 μ l Chromogenic substrate (Chromogen Substrate, hereinafter referred to as Chromogen Substrate) reaction solution, juxtaposition is at room temperature Reaction 20 minutes, after the stop bath (STOP Solution, hereinafter referred to as STOP Solution) for adding 50 μ l, using wavelength as 450nm light absorption values analyze cytohormone (TNF-α, IL-1 β, IL-6, IL-8, IL-10) concentration.
2. adsorbate total amount is determined:
Take and added cytohormone but not yet carried out the Swine plasma about 5g of adsorption test and carried out after adsorption test Swine plasma about 5g.Then, 105 DEG C are heated to infrared heater progress respectively, and carry out drying until weight no longer becomes Turn to only, the part by weight change of solid content before and after record absorption.
Endotoxin 3. (endotoxin) detection method:Utilize endotoxin from E.coli-SIGMA.
Albumin 4. (Albumin) detection method:
Albumin (Albumin) concentration analysis uses Innovative Research, Inc.ELISA Kit (Catalog No:IRAPKT011)。
I. by Innovative Research, reagent and standard items appended by Inc.ELISA Kit are using being preceding placed in At room temperature, and by reagent with pure water it is diluted to use ratio.
Ii. albumin standard (Albumin standard) is configured to debita spissitudo gradient.
Iii. the 100 tested samples of μ l and albumin standard (Albumin standard) are separately added into, is placed at room temperature Reaction 2 hours.
Iv. after removing tested sample and albumin standard, rinsed 4 times with 200 μ l cleaning solutions.Add 100 μ l inspections Antibody is surveyed, is placed in and reacts 2 hours at room temperature.
V. after detecting that antibody is removed, rinsed 4 times with 200 μ l cleaning solutions.Add 100 μ l Streptavidin-HRP Reaction solution, is placed in and reacts 20 minutes at room temperature.
Vi. after Streptavidin-HRP reaction solutions are removed, rinsed 4 times with 200 μ l cleaning solutions.Add 100 μ l Chromogen Substrate reaction solutions, be placed at room temperature react 20 minutes, add 50 μ l STOP Solution it Afterwards, albumin concentration is analyzed with wavelength 450nm light absorption values.
III. result is with discussing:
1. cytohormone absorber is to the absorption result of each cytohormone:
Below be disclosed herein cytohormone absorber for each cytohormone absorption result, it is bright in result Aobvious learns that adsorption rate is all higher than 65%, because disclosed herein the cytohormone absorber with compound sorbing material 24 20 can effectively adsorb for septicemia relevant cell hormone.Table 8 represents cytohormone absorber to various cytohormones Clearance rate %.
Table 8
In addition, it is further by the clearance rate listed by table 8, by various cytohormones in different sample times
And clearance rate is represented with adsorption curve figure respectively, wherein Fig. 9 represents that cytohormone absorber swashs to each cell Adsorption curve figure, Figure 10 of the Scavenging activity of element represent cytohormone absorber to the adsorption curve figure of IL-1 β Scavenging activity, Figure 11 represents that cytohormone absorber represents cytohormone absorber pair to adsorption curve figure, Figure 12 of IL-6 Scavenging activity Adsorption curve figure, Figure 13 of IL-8 Scavenging activity represent adsorption curve of the cytohormone absorber to IL-10 Scavenging activity Figure and Figure 14 represent adsorption curve figure of the cytohormone absorber to the Scavenging activity of TNF-α.
2. the absorption result of cytohormone absorber induced by endotoxin (endotoxin):
Cytohormone absorber for endotoxin absorption clearance rate up to 43.57%, its result such as table 9, and Adsorption curve figure of the cytohormone absorber to endotoxin Scavenging activity is represented in Figure 15.
Table 9
3. adsorbate total amount measurement result:
Table 10 obtains the front and rear solid content part by weight change of plasma adsorption and is down to 6.20% by 7.06%.
Table 10
Table 11 is then to represent that cytohormone absorber adsorbs albumin result.
Table 11
Therefore, by table 11 it is known that the cytohormone absorber with compound sorbing material for albumin suction Attached rate is 13.39%, less than 15%.
In addition, the present invention has also built the functional pig septicemia animal experiment of septicemia treatment blood purification system Pattern and the septicemia treatment pig septicemia animal examination of blood purification system function and security for completing existing product Test.The purpose of this experiment is:The functional pig sepsis animal experiment pattern of septicemia treatment blood purification system is built, With confirm disclosed herein blood purification system effect and security.
Experimental method includes:Blood purification animal (pig) surgical procedure (SOP-EXP-HEM-001) and 2.
Blood purification is tested:Wash kidney machine instrumentation (SOP-EXP-HEM-002).
Experimental condition is made a summary
Animal:Lanyu miniature pig(♀;35±5Kg);
Chemical inducedsepsis:iv injected with LPS(1μg/kg for2hr);
Product (existing product):(Manufacturer:BellcoSrl,Mirandola,Italy; Material:hydrophobic styrene resin;Surface area:700m2/g);
Blood sampling(per 30min);
Hemodynamic monitoring(per 1hr):Systolic Pressure,Diastolic Pressure, Mean Arterial Pressure,Heartbeat,and SpO2Analysis:Endotoxin;TNF-α;IL-6.
As a result with discussion:
1. hemodynamic monitoring result:
Figure 16 represents synchronously to carry out the result of hemodynamic monitoring during zoopery, in Figure 16 it is known that There is drop in blood pressure and the increased situation of heartbeat after surgery in each group animal, meet septicemia clinic table disease and blood oxygen concentration all Stable state (>=90%) is maintained, Vital status is stable, shows with current LPS dosage (1 μ g/kg) induced animal septicemia Pattern, animal can't be caused to suffer a shock and dead.
2. endotoxin and cytohormone concentration monitor result:
Non- endotoxin injection and animal experiment (the Hemopurification alone groups) result for only carrying out blood purification It has been shown that, as shown in figure 17.Endotoxin is with cytohormone concentration without obvious change in animal body, and display experiment uses existing production The doughnut and resin continous way filtering element (cartridge) system of product do not result in influence to this zootype, and this blood purification system is without safety Doubt.Contained according to document, septicemia is in its process, systemic inflammation reaction syndrome (SIRS;systemic Inflammatory response syndrome) the anti-inflammatory reaction of compensatory, this process exotic mediums before this will be triggered Cell is stimulated, the phenomenon that a variety of different cytohormones cause excessive buildup IL-6, IL-1 β and TNF-α is disengaged, compares this reality Test from the point of view of the data that septicemia (LPS alone groups) is produced with chemical induction animal, endotoxin and cytohormone in animal body Significant increase is all presented in concentration after LPS is given, and TNF-α about peaked at 1.5 to 2 hours, and IL-6 is then small from 1 When after persistently rise, peak within about 5 to 6 hours, this variation tendency is also consistent with the illness of Clinical sepsis, show this move Thing pattern can definitely trigger septicemia.
In the result of existing product adsorption capacity (L+H groups), endotoxin bulk concentration increase after LPS is given, when stopping It can be found that the concentration curve descending slope and amplitude that have absorption group are slightly larger than LPS groups, in addition in cytohormone after only inducing In change, learnt by Figure 18, TNF-α just has obvious increase in dialysis its concentration curve descending slope at initial stage and amplitude, by scheming 19 learn, IL-6 then arrives dialysis later stage bulk concentration and just begun to decline, this trend changed in vivo with TNF-α and IL-6 in itself Relevant, with the display of current data, the septicemia treatment of existing product has endotoxin with blood purification system and cytohormone is inhaled Attached ability, only the adsorption capacity of existing product have no significant difference.
Figure 20 is represented in the cytohormone absorber test according to disclosed by invention (L+H (new) group), at present in dynamic One group of experiment was carried out in object, the cytohormone absorber that this plan of entry evaluation is developed, which has, removes excessive cytohormone Potentiality.It is follow-up by experiment the effect of carrying out formal to confirm its effect.And table 12 is then the knot for representing absorber adsorption Really:
Table 12
In accordance with the above, disclosed herein cytohormone absorber with vitro Adsorption experimental test comprising TNF-α, IL-1 β, IL-6, IL-8, IL-10 clearance rate are above 65%.It is 43.57% (Ying≤30% to adsorb endotoxin ability), and Adsorbable p-cresol is up to 87.29% (Ying≤65%).In addition, adsorbate total amount result is shown, the absorption of cytohormone absorber Material is down to 6.20% from 7.06% in blood plasma.The cytohormone absorber adsorbs (Ying≤15% of albumin 13.20% simultaneously).
The preferred embodiments of the invention is the foregoing is only, the interest field of the present invention is not limited to;More than simultaneously Description, should can understand and implement for the special personage of correlative technology field, thus other without departing from it is disclosed it The lower equivalent change or modification completed of spirit, should be included in claim.

Claims (10)

1. a kind of blood purification system, it is characterised in that include:
Plasma separator, with first tubing string and the multiple hollow fiber bundles being filled in the first tubing string, the blood plasma point From device to separate the blood plasma in blood and multiple blood cells;And
Cytohormone absorber, with second tubing string and the compound sorbing material being placed in the second tubing string, the cell Hormone absorber utilizes the compound sorbing material absorption to receive the blood plasma conveyed by the plasma separator In the blood plasma partial pathogenic cell hormone to be purified blood plasma.
2. blood purification system as claimed in claim 1, it is characterised in that the blood purification system also includes haemodialysis Device, the haemodialyser to mixing blood to be dialysed to obtain clean blood, and the blood that mixes is by described Obtained by after blood cell mixing after purifying blood plasma and being separated via the plasma separator.
3. blood purification system as claimed in claim 1, it is characterised in that the compound sorbing material is by uncharged Resin and electrically charged anion exchange resin composition.
4. blood purification system as claimed in claim 3, it is characterised in that uncharged resin and electrically charged the moon The mixing ratio of ion exchange resin is by 20%:80%th, 40%:60%th, 60%:40% and 80%:20% (v/v) is constituted Group among select.
5. the blood purification system as described in claim 3 or 4, it is characterised in that uncharged resin is poly- (benzene second Alkene-divinylbenzene) (poly (styrene-divinylbenzene), and chemical structural formula is
6. the blood purification system as described in claim 3 or 4, it is characterised in that the electrically charged anion exchange resin For poly- (styrene-divinylbenzene) level Four ammonium, Cl types, and chemical structural formula are
7. a kind of blood purification method, it is characterised in that include:
Blood is provided;
The blood is separated to obtain blood plasma and multiple blood cells;
Adsorption step is carried out to the blood plasma, to remove at least one pathogenic cytohormone in the blood plasma, to be purified blood Slurry;
The purification blood plasma is mixed with the blood cell to form mixing blood;And
The mixing blood is dialysed, to obtain clean blood.
8. blood purification method as claimed in claim 7, it is characterised in that compound adsorption material is utilized in the adsorption step Material is adsorbed to the blood plasma.
9. blood purification method as claimed in claim 8, it is characterised in that the compound sorbing material includes neutral Resin and electrically charged anion exchange resin.
10. blood purification method as claimed in claim 8 or 9, it is characterised in that the mixed proportion of the compound material is 20%:80%th, 40%:60%th, 60%:40% with or 80%:20% (v/v).
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