CN115245709A - Filter material for selectively removing leukocytes and simultaneously retaining platelets and preparation method thereof - Google Patents
Filter material for selectively removing leukocytes and simultaneously retaining platelets and preparation method thereof Download PDFInfo
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D39/00—Filtering material for liquid or gaseous fluids
- B01D39/14—Other self-supporting filtering material ; Other filtering material
- B01D39/16—Other self-supporting filtering material ; Other filtering material of organic material, e.g. synthetic fibres
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES 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
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/02—Blood transfusion apparatus
- A61M1/0281—Apparatus for treatment of blood or blood constituents prior to transfusion, e.g. washing, filtering or thawing
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Abstract
The invention belongs to the technical field of leukocyte filtration of blood products, and particularly relates to a filter material for selectively removing leukocytes and simultaneously retaining platelets and a preparation method thereof. The filter material is obtained by crosslinking the following raw materials in parts by weight on a non-woven fabric: 4-10 parts of four-arm polyethylene glycol amine compound and 1-4 parts of cross-linking agent; wherein the four-arm polyethylene glycol amine compound is a compound shown as a formula I or a salt thereof. The invention can realize the filtration of the white blood cells in the whole blood product, can simplify the processing flow of the blood product, reduces the processing cost and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of leukocyte filtration of blood products, and particularly relates to a filter material for selectively removing leukocytes and simultaneously retaining platelets and a preparation method thereof.
Background
Blood transfusion is a common medical means in clinical medicine, and the primary purpose is to help some patients with diseases, and wounded persons who bleed blood during operation or are accidentally injured to bleed a large amount of blood, to recover health. The presence of leukocytes in blood products can cause many associated transfusion side effects (e.g., nonhemolytic fever, respiratory distress admission, ineffective platelet infusion, etc.); secondly, leukocytes in the blood are also the main vector for viral transmission. Therefore, it is very important to remove leukocytes from blood products before transfusion.
The development of leukocyte filters has been about half a century ago, and the preparation method and material selection thereof are continuously innovated along with the improvement and development of science and technology. The third generation of leukocyte filters appeared in the last 90 s, which were mainly made by placing non-woven fabric type material in the middle of a resin type support net. Nonwoven materials are typically treated to improve their wettability with blood. Because the third generation leukocyte filter has the advantages of simple preparation process, high leukocyte removal efficiency and the like, the leukocyte in blood is filtered by adopting the filtering method at home and abroad no matter in blood centers or in hospitals clinically at present, but filters produced by different companies and manufacturers have different selection and use of filter core materials.
Although blood products for transfusion require filtration to remove leukocytes, it is undesirable to filter out other cells such as red blood cells and platelets in blood. However, the physiological functions of platelets are: when the blood vessel is ruptured, the hydrodynamics of the blood changes, and the blood platelet can be quickly adhered to the ruptured blood vessel, quickly activates and releases the intracellular substances, quickly activates the blood coagulation system, forms a clot and reduces the loss of the blood. Therefore, platelets have an easy-to-adhere property, and thus, when leukocytes are filtered, the platelets also adhere to the filter medium very easily and are removed.
Therefore, it is an important subject of the art to develop a filter medium capable of selectively filtering leukocytes without filtering platelets. USP5895575 uses water-soluble polysaccharide coated with a nonwoven fabric of polyvinyl acetate and a nitrocellulose film to remove leukocytes and retain platelets, depending on the nature of platelets and leukocytes in blood. USP4936998 describes a method of treating a polyester nonwoven fabric with a HEMA (hydroxyethyl methacrylate) and DHEMA copolymer coating, based on the difference in surface charge density between leukocytes and platelets, so that leukocytes are adsorbed on the filter media and platelets pass through. EP0559086 describes a leukocyte filter, which is prepared by cross-linking glycoside hydroxyethyl methacrylate, dioxane and HEMA (initiator azobisisobutyronitrile, 4 hours at 70 ℃) on the surface of polyester fiber through free radical polymerization, and the filter is used for coating or copolymerization modification of the polyvinyl fiber according to different adsorption performances of platelets and leukocytes in blood, and has good leukocyte removal rate and Platelet recovery rate for Platelet Concentrates (PC).
Although these filter media have a good effect on the filtration of concentrated platelets, they can achieve both a high leukocyte removal rate and a high platelet recovery rate. However, these filter materials can only be applied to concentrate platelet samples, and for whole blood samples, because the content of platelets is relatively low, a high proportion of platelets still can be filtered by the filter material, and the recovery rate of platelets cannot meet the requirements of relevant national standards. Therefore, at present, 2U (400 mL) of whole blood is generally prepared into three components of erythroblasts suspension, plasma and concentrated platelets respectively in the blood center, and then leukocytes are removed respectively. Moreover, 2U of whole blood prepared platelets concentrate cannot be directly filtered, and must be pooled into a therapeutic dose (12U or 6 bags of 400mL of whole blood prepared PC) before the leukocytes can be removed by filtration. Only then, the recovery rate of the blood platelet can be more than 85 percent, which meets the requirements of the relevant national standard.
In the process of processing the blood sample, the problem of limited platelet recovery rate leads to complex processing steps and more filter materials (the three components of blood need to be respectively filtered by leucocyte) are used. Therefore, there is a need in the art for a leukocyte filtering material for whole blood samples, which can filter leukocytes as much as possible and retain platelets in the filtration of whole blood samples.
The four-arm polyethylene glycol and the derivatives thereof are polymers formed by grafting molecular chains of four polyethylene glycols and the derivatives thereof on the same quaternary carbon. In the prior art, the compounds can form gel, micelle and the like through crosslinking and the like, and can be used for drug loading (Liu Donggong and the like, four-arm polyethylene glycol-polylactide three-dimensional composite micelle and drug delivery performance thereof) and the like. At present, no relevant reports on the technology of using the four-arm polyethylene glycol and the derivatives thereof for preparing the blood sample filter material are found.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a filter material for selectively removing leukocytes and simultaneously retaining platelets and a preparation method thereof, and aims to realize the leukocyte filtration of whole blood.
A filter material for selectively removing leucocytes and simultaneously retaining blood platelets is obtained by crosslinking the following raw materials in parts by weight on a non-woven fabric: 4-10 parts of four-arm polyethylene glycol amine compound and 1-4 parts of cross-linking agent;
wherein the four-arm polyethylene glycol amine compound is a compound represented by formula I or a salt thereof:
wherein n is 1 、n 2 、n 3 And n 4 Each independently from 25-75.
Preferably, the number average molecular weight of the four-arm polyethylene glycol amine compound is 5000 to 20000.
Preferably, the number average molecular weight of the four-arm polyethylene glycol amine compound is 9000-11000.
Preferably, the crosslinking agent is selected from among dialdehyde compounds.
Preferably, the dialdehyde compound is one or a combination of two or more of glutaraldehyde, succinaldehyde and hexanedial.
Preferably, the non-woven fabric is a PBT non-woven fabric, a PET non-woven fabric or a PP non-woven fabric.
Preferably, the method comprises the following steps:
step 1, preparing the four-arm polyethylene glycol amine compound into a solution A, and preparing a cross-linking agent into a solution B;
step 2, adding the non-woven fabric into the solution A;
and 3, adding the solution B into the solution A, and performing crosslinking to obtain the polymer.
Preferably, in step 3, the crosslinking reaction is carried out at 25-80 ℃ for 2-12 hours.
The invention also provides the application of the filter material in filtering white blood cells in whole blood.
In the present invention, "% wt" means weight percent and "% v" means volume percent.
The invention forms the hydrogel coating by crosslinking the four-arm polyethylene glycol amine compound and the crosslinking agent on the surface of the non-woven fabric. The material prepared by the method has good filtering effect on leucocytes and weak filtering effect on blood platelets. In particular, in the prior art, the leukocyte filtering material can achieve a good platelet recovery rate only when being used for filtering concentrated platelets with high platelet concentration. The filter material can be directly used for filtering whole blood products, the recovery rate of platelets can reach more than 80%, and the quality of the prepared blood products meets the quality requirements of whole blood and blood components (GB 18469-2012). Therefore, the invention can simplify the processing steps of blood products, reduce the processing cost and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a scanning electron microscope image of a filter material, wherein A: original PBT non-woven fabric; b: the filter prepared in example 1; c: the filter prepared in example 2; d: the filter prepared in example 3; e: the filter prepared in example 4.
Detailed Description
In the following examples and experimental examples, reagents and materials not specifically described are commercially available. In the following examples, the four-arm polyethylene glycol amine compound is referred to by the abbreviation "4 armPEG". The structural formula of the four-arm polyethylene glycol amine compound is as follows:
wherein n is 1 、n 2 、n 3 And n 4 Each independently from 25-75.
Example 1 Filter Material for selectively removing leukocytes while retaining platelets
1.000g of 4ARM PEG (Kekeshi technology, 4ARM-PEG-NH2HCl, number average molecular weight 2000 Da) was accurately weighed using an electronic balance, and dissolved in 50mL of an aqueous solution to obtain a 2% by weight 4ARM PEG solution. 20g of PBT nonwoven fabric was immersed in 100mL of the solution, 0.5mL of a glutaraldehyde solution (containing 0.25g of glutaraldehyde) 50% v was added, the mixture was placed in a 60 ℃ drying oven and crosslinked for 3 hours, and after the reaction was completed, the PBT nonwoven fabric was washed with distilled water to obtain a glutaraldehyde-crosslinked 4armPEG PBT nonwoven fabric film for future use.
Example 2 Filter for Selective leukocyte removal while retaining platelets
1.000g of 4armPEG (KeyKa technology, 4ARM-PEG-NH2HCl, number average molecular weight 5000 Da) was accurately weighed using an electronic balance, dissolved in 50mL of an aqueous solution, to obtain a 4armPEG solution, 2% by weight. 20g of PBT nonwoven fabric was immersed in 100mL of the solution, 0.5mL of a glutaraldehyde solution (containing 0.25g of glutaraldehyde) 50% v was added, the mixture was placed in a 60 ℃ drying oven and crosslinked for 3 hours, and after the reaction was completed, the PBT nonwoven fabric was washed with distilled water to obtain a glutaraldehyde-crosslinked 4armPEG PBT nonwoven fabric film for future use.
Example 3 Filter Material for selectively removing leukocytes while retaining platelets
1.000g of 4armPEG (Kekeka technology, 4ARM-PEG-NH2HCl, number average molecular weight 10000 Da) was accurately weighed using an electronic balance, and dissolved in 50mL of an aqueous solution to obtain a 2% by weight 4armPEG solution. 20g of PBT nonwoven fabric was immersed in 100mL of the solution, 0.5mL of a glutaraldehyde solution (containing 0.25g of glutaraldehyde) 50% v was added, the mixture was placed in a 60 ℃ drying oven and crosslinked for 3 hours, and after the reaction was completed, the PBT nonwoven fabric was washed with distilled water to obtain a glutaraldehyde-crosslinked 4armPEG PBT nonwoven fabric film for future use.
Example 4 Filter for Selective leukocyte removal while retaining platelets
1.000g of 4armPEG (Kekeka technology, 4ARM-PEG-NH2HCl, number average molecular weight 20000 Da) was accurately weighed by an electronic balance, and dissolved in 50mL of an aqueous solution to obtain a 4armPEG solution at 2% by weight. 20g of PBT nonwoven fabric was immersed in 100mL of the above solution, 0.5mL of a glutaraldehyde solution (containing 0.25g of glutaraldehyde) 50% v was added, the mixture was placed in a 60 ℃ dry box and crosslinked for 3 hours, and after the reaction was completed, the PBT nonwoven fabric was washed with distilled water to obtain a glutaraldehyde-crosslinked 4arm PEG PBT nonwoven fabric film for use.
Example 5 Filter Material for selectively removing leukocytes while retaining platelets
1.000g of 4armPEG (Kekeka technology, 4ARM-PEG-NH2HCl, number average molecular weight 10000 Da) was accurately weighed using an electronic balance, and dissolved in 50mL of an aqueous solution to obtain a 2% by weight 4armPEG solution. 20g of PBT nonwoven fabric was immersed in 100mL of the solution, and 2mL of 50 v% glutaraldehyde solution (containing 1.000g of glutaraldehyde) was added thereto, and the mixture was placed in a 60 ℃ dry box and crosslinked for 3 hours, and after the reaction was completed, the PBT nonwoven fabric was washed with distilled water to obtain a glutaraldehyde-crosslinked 4arm PEG PBT nonwoven fabric film for use.
EXAMPLE 6 Filter Material for selectively removing leukocytes while retaining platelets
2.500g of 4armPEG (Kekeka technology, 4ARM-PEG-NH2HCl, number average molecular weight 10000 Da) was accurately weighed using an electronic balance, and dissolved in 50mL of an aqueous solution to obtain a 2% by weight 4armPEG solution. 20g of PBT nonwoven fabric was immersed in 100mL of the solution, and 2mL of 50 v% glutaraldehyde solution (containing 1.000g of glutaraldehyde) was added thereto, and the mixture was placed in a 60 ℃ dry box and crosslinked for 3 hours, and after the reaction was completed, the PBT nonwoven fabric was washed with distilled water to obtain a glutaraldehyde-crosslinked 4arm PEG PBT nonwoven fabric film for use.
The technical solution of the present invention will be further described by experiments.
Experimental example 1 characterization experiment of Filter Material Properties
1. Experimental methods
1) And (3) measuring the surface tension:
the surface tension of the original PBT non-woven fabric and the filter materials prepared in examples 1 to 4 was measured, and the hydrophilicity of the materials was characterized. Sodium chloride (1-4.5%) and calcium chloride (3-5%) solutions with different concentrations are prepared respectively, and the surface tension of the solutions is detected by using a liquid automatic surface tension meter. Different concentrations of liquid were dropped onto the sample surface using a syringe and measured as the number of drops that completely spread in 10 min. Standing for 10min, and observing within 10 min-11 min. If at least 9 drops of 10 drops are soaked in the porous medium within 10min, the liquid with the surface tension is considered to be soaked in the medium material; conversely, if 2 or more of the 10 drops are not wetted or absorbed within 10 minutes, the surface-tension liquid is considered to be unable to wet the medium. For example, pure water (having a surface tension of 72X 10) -5 N/cm) is dropped on the surface of the material, and 9 drops are soaked within 10 min; while using a surface tension of 75X 10 -5 N/cm of 10 drops on the surface of the material, within 10min there are 3 drops not wetted, the critical surface tension of the material is defined as 73.5X 10 -5 N/cm。
2) Scanning electron microscope for observing surface morphology of filter material
And (3) carrying out gold spraying on the original PBT non-woven fabric and the filter materials prepared in the embodiments 1 to 4, and observing the surface morphology of the filter materials by adopting a scanning electron microscope.
2. Results of the experiment
1. And (3) hydrophilic characterization results: the surface tension of pure water is usually 72X 10 at room temperature -5 N/cm, surface tension of the original PBT non-woven fabric is 48 multiplied by 10 -5 N/cm. The hydrogel coating formed after the glutaraldehyde crosslinking of 4armPEG covers the fiber surface of the PBT non-woven fabric, and the hydrophilicity of the material is improved. As shown in the results in Table 1, the surface tension of the PBT filter material modified by 4arm PEG is significantly higher than that of the original PBT, and the filter material surface is improved with the increase of the molecular weight of 4arm PEGThe surface tension is increased and the hydrophilicity of the material surface is increased. This helps to increase the blood filtration rate.
TABLE 1 surface tension results for virgin PBT and modified filters
2. Surface topography characterization results: as shown in FIG. 1, compared with the original PBT non-woven fabric, the diameter of the filter material fiber modified by 4arm PEG is increased, granular attachments are arranged on the surface of the fiber, and the pores between the fibers are narrowed. The hydrogel formed after 4arm PEG crosslinking successfully covers the fiber surface of the PBT non-woven fabric.
Experimental example 2 Whole blood filtration experiment
1. Experimental methods
The 4 kinds of filter materials prepared in examples 1 to 4 were respectively put into a case of a leukocyte filter having a diameter of 60mm, and then passed through an ultrasonic welding filter, and a PVC pipe and a blood bag were connected. Each blood bag was filled with 200mL of whole blood, the blood was passed through a leukocyte filter under a net pressure differential of one meter, and the effluent was collected by the blood bag. Whole blood for the assay was provided from the daoyang central blood station.
The detection method of each parameter is as follows:
1) Platelet recovery rate calculation method
Platelet recovery (%) = (platelet concentration after filtration × volume after filtration)/(platelet concentration before filtration × volume before filtration) × 100
The concentrations before and after platelet filtration were measured by a five-classification cytometer, and the volume was obtained by weighing.
2) Method for calculating leukocyte removal rate
Leukocyte recovery (%) = (leukocyte concentration before filtration × volume before filtration-leukocyte concentration remaining after filtration × volume after filtration)/(leukocyte concentration before filtration × volume before filtration) × 100
The leukocyte concentration before filtration is measured by a five-classification hemocytometer, the leukocyte concentration after filtration is obtained by a cell counting plate, and the volume is obtained by a weighing mode.
3) Erythrocyte recovery rate calculation method
Erythrocyte recovery (%) = (concentration of erythrocytes after filtration × volume after filtration)/(concentration of erythrocytes before filtration × volume before filtration) × 100
The concentration of red blood cells before and after filtration is measured by a five-classification blood cell counter, and the volume is obtained by a weighing mode.
4) Method for calculating hemolysis rate
The experiment is carried out according to the method for measuring the hemolysis rate in YY-0329-2020 Disposable leukocyte-removing filter of the national medical standard. The test solution of the leukocyte-removed filter device or the filter material prepared by using sodium chloride injection with the volume fraction of 0.9 percent as a leaching medium is directly contacted with blood, and the amount of hemoglobin released by red blood cells is measured to detect the degree of hemolysis of the leukocyte-removed filter or the filter material in vitro.
5) Time of filtration
The time required for 200mL of whole blood to be filtered out.
6) Blood loss rate calculation method
Blood loss rate (%) = (weight of blood before filtration-weight of blood after filtration)/(weight of blood before filtration) × 100
The blood weight was obtained by weighing.
2. Results of the experiment
Whole blood filtration results:
the blood-related indices before and after filtration were measured and the results are shown in Table 2.
TABLE 2
From the properties in the table, with the increase of the molecular weight of 4arm PEG, the recovery rate of platelets, the removal rate of leucocytes, the recovery rate of erythrocytes and the loss rate of blood are shown to be increased firstly and then decreased; the hemolysis rate and filtration time appeared to decrease first and then increase. That is, in the whole view, the filtering performance of the filter material shows a tendency of increasing and then decreasing with the increase of the molecular weight of 4arm PEG. Wherein when the molecular weight of 4arm PEG is 10000Da, the prepared filter material has the best filtering performance. The quality of the filtered whole blood meets the quality requirement of whole blood and blood component (GB 18469-2012).
It can be seen from the above examples and experimental examples that the invention provides a novel leukocyte filtration material, which can be used for directly filtering whole blood, the recovery rate of platelets can reach above 80%, and the quality of the prepared blood product meets the requirements of quality of whole blood and blood components (GB 18469-2012). The invention can simplify the processing flow of blood products, reduce the processing cost and has good application prospect.
Claims (9)
1. A filter for selectively removing leukocytes while retaining platelets, comprising: the adhesive is obtained by crosslinking the following raw materials in parts by weight on non-woven fabric:
4-10 parts of four-arm polyethylene glycol amine compound,
1-4 parts of a crosslinking agent;
wherein the four-arm polyethylene glycol amine compound is a compound represented by formula I or a salt thereof:
wherein n is 1 、n 2 、n 3 And n 4 Each independently from 25-75.
2. The filter of claim 1, wherein: the number average molecular weight of the four-arm polyethylene glycol amine compound is 5000-20000.
3. The filter of claim 2, wherein: the number average molecular weight of the four-arm polyethylene glycol amine compound is 9000-11000.
4. The filter of claim 1, wherein: the cross-linking agent is selected from dialdehyde compounds.
5. The filter medium of claim 4 wherein: the dialdehyde compound is one or the combination of two or more of glutaraldehyde, succinaldehyde and hexanedial.
6. The filter of claim 1, wherein: the non-woven fabric is a PBT non-woven fabric, a PET non-woven fabric or a PP non-woven fabric.
7. The method for preparing the filter material of any one of claims 1 to 6, which comprises the following steps:
step 1, preparing the four-arm polyethylene glycol amine compound into a solution A, and preparing a cross-linking agent into a solution B;
step 2, adding the non-woven fabric into the solution A;
and 3, adding the solution B into the solution A, and performing crosslinking to obtain the polymer.
8. The method of claim 7, wherein: in the step 3, the reaction condition of the crosslinking is that the crosslinking is carried out for 2 to 12 hours at a temperature of between 25 and 80 ℃.
9. Use of the filter of any of claims 1 to 6 for filtering leukocytes from whole blood.
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