Method and device for secondary filtration and re-removal of cholesteryl ester after continuous blood purification and blood fat filtration

Abstract

The invention provides a method and a device for secondary filtration and re-removal of cholesterol ester after continuous blood purification and blood fat filtration, and belongs to the technical field of medical blood purification. According to the method and the device, the technology of combining enzymolysis, adsorption and membrane separation is adopted for residual CE in a CBP filtering product. The method comprises the following steps: firstly, decomposing CE into small molecules by using specific enzyme, and weakening the combination of CE and other components; residual impurities are further adsorbed through a high-performance adsorption material; and finally, efficient removal of CE is realized by virtue of a high-precision membrane separation technology, so that the residual quantity is reduced to be below a safety threshold value. Compared with a traditional technology, the problems that the CE-containing filtrate is high in recycling risk and low in resource utilization rate are effectively solved, the purity of a filtered product is remarkably improved, technical support is provided for industrial scenes such as plasma exchange, filtrate feedback, biopharmacy and extracorporeal circulation in the medical field, and the application prospect is wide. The safety and the resource utilization efficiency of the blood purification technology are promoted.

Description

Technical Field

[0001] The present invention belongs to the field of medical blood purification technology, and specifically relates to a method and device for secondary removal of residual cholesterol esters in the filtered product after continuous blood purification (CBP) blood lipid filtration, aiming to improve the purity of the filtered product to support its safe reuse. Background Art

[0002] Continuous blood purification (CBP) technology is widely used in the interventional treatment of dyslipidemia in critically ill patients. Existing technologies can initially remove harmful lipids such as low-density lipoprotein (LDL) and triglycerides (TG) from the blood through adsorption or membrane separation, but a large amount of cholesterol esters (CE) remains in the filtered product. The presence of these CEs may lead to the following problems:

[0003] 1. Reuse risk: If the filtrate containing CE is reinfused or used for other treatments (such as plasma exchange), it may trigger an inflammatory reaction or the risk of secondary embolism;

[0004] 2. Waste of resources: High-purity filtrate has reuse value in biopharmaceuticals, extracorporeal circulation and other scenarios, but CE residues limit its application.

[0005] The existing technology lacks an efficient solution for removing CE in the filtrate after CBP, and a secondary treatment method is urgently needed. Summary of the Invention

[0006] 1. Method Overview

[0007] This method is based on multi-stage targeted adsorption and enzymatic hydrolysis coupled membrane separation technology, and the CBP filtrate is subjected to secondary treatment. The steps are as follows:

[0008] (1) Pretreatment: The CBP primary filtrate is introduced into the buffer adjustment module, the pH is adjusted to 6.8-7.4, and a stabilizer (such as albumin) is added to prevent protein denaturation;

[0009] (2) Enzymatic hydrolysis: CE was hydrolyzed into free cholesterol (FC) and fatty acids (FA) using an immobilized cholesterol esterase (CEase) reaction column at 37°C and a flow rate of 50–100 mL / min.

[0010] (3) Targeted adsorption: A porous resin adsorption column with surface modified β-cyclodextrin is used to specifically bind free cholesterol;

[0011] (4) Membrane separation: The macromolecular residues are intercepted and the high-purity filtrate is collected through a nanoscale hollow fiber membrane with a pore size of ≤5nm.

[0012] 2. Device Design

[0013] The device consists of the following modules (attachedFigure 1 ):

[0014] (1) Buffer adjustment unit: integrated pH sensor and automatic liquid filling pump;

[0015] (2) Enzymatic reaction column: filled with silica microspheres covalently bound to CEase, with temperature control function;

[0016] (3) Adsorption column: β-cyclodextrin modified polystyrene resin (specific surface area ≥ 800m 2 / g);

[0017] (4) Nano-membrane module: Hollow fiber membrane group parallel design, supporting backwash regeneration;

[0018] (5) Intelligent control system: Dynamically adjust the flow rate and reaction time based on the CE concentration detection results (using fluorescent-labeled antibody sensors).

[0019] Detailed technical route:

[0020] 1. Pretreatment step: filtrate buffer adjustment and stabilization

[0021] Design Principles

[0022] (1) Objective: To optimize the physical and chemical environment of the filtrate to avoid the decrease in efficiency caused by pH fluctuation or protein denaturation during the subsequent enzymatic hydrolysis and adsorption process.

[0023] (2) Scientific basis;

[0024] (3) The optimal pH for cholesterol esterase (CEase) is neutral (6.8-7.4). Exceeding this range will result in a significant decrease in enzyme activity;

[0025] (4) Residual plasma proteins (such as albumin) in the filtrate may aggregate due to pH changes or shear forces, clogging subsequent membrane components.

[0026] Technical route

[0027] 1. Buffer adjustment module:

[0028] (1) Using a dual-channel dynamic feedback system;

[0029] (2) An integrated pH sensor (accuracy ±0.1) at the inlet monitors the pH of the filtrate in real time;

[0030] (3) Phosphate buffer (PBS, 0.1 M) or bicarbonate solution was injected via a peristaltic pump to stabilize the pH at 7.0 ± 0.2;

[0031] (4) Human serum albumin (HSA, final concentration 0.5-1.0 g / dL) was added as a stabilizer to protect the lipoprotein structure through its hydrophobic binding domain.

[0032] 2. Temperature control:

[0033] 1. Preheat the filtrate to 37°C (error ±0.5°C) to avoid thermal shock in the subsequent enzymatic hydrolysis reaction.

[0034] Parameter settings

[0035]

[0036] 2. Enzymatic reaction steps: Cholesterol esterase catalyzed hydrolysis

[0037] Design Principles

[0038] Core idea: Convert CE into free cholesterol (FC) and fatty acids (FA), reduce the molecular hydrophobicity, and facilitate subsequent adsorption and removal.

[0039] Innovation:

[0040] (1) Use immobilized CEase instead of free enzyme to avoid enzyme contamination of the filtrate and improve reuse rate;

[0041] (2) After enzymatic hydrolysis, the polarity of FC increases, making it easier to be captured by β-cyclodextrin adsorbent.

[0042] Technical route

[0043] 1. Design of immobilized enzyme reaction column:

[0044] (1) Carrier selection: porous silica microspheres (particle size 100-200 μm, pore size 10-30 nm), providing high specific surface area (300-500 m 2 / g);

[0045] (2) Immobilization method: CEase was covalently bound to the silica gel surface by glutaraldehyde cross-linking, with an enzyme loading of ≥20 U / g carrier;

[0046] (3) Temperature control system: The reaction column is placed in a circulating water bath (37°C) to maintain the optimal temperature for enzyme activity.

[0047] 2. Reaction kinetics optimization:

[0048] (1) Ensure CE hydrolysis rate > 95% by residence time control (flow rate 50-100 mL / min);

[0049] (2) Monitor the outlet FA concentration (conductivity sensor) and dynamically adjust the flow rate to prevent product inhibition effect.

[0050] Parameter settings

[0051]

[0052] 3. Targeted adsorption step: β-cyclodextrin modified resin specific adsorption

[0053] Design Principles

[0054] (1) Molecular mechanism: The hydrophobic cavity of β-cyclodextrin (β-CD) can selectively embed the steroid ring structure of FC, with a binding constant of 10 3 -104M- 1 ;

[0055] (2) Material optimization: Through the high specific surface area of ​​polystyrene resin (≥800m 2 / g) to increase the adsorption capacity.

[0056] Technical route

[0057] 1. Adsorbent preparation:

[0058] (1) Resin substrate: macroporous polystyrene resin (pore size 50-100 nm, cross-linking degree 8%);

[0059] (2) Surface modification: β-CD is grafted onto the resin surface via epoxy groups with a grafting density ≥ 5 μmol / g;

[0060] (3) Activation treatment: high temperature curing (120°C, 2h) under nitrogen protection to enhance chemical stability.

[0061] 2. Adsorption column operating parameters:

[0062] (1) Column volume (BV): 2 L, packing height 50 cm, diameter-to-height ratio 1:5;

[0063] (2) Dynamic adsorption flow rate: 80-120 mL / min (empty tower contact time 3-5 min);

[0064] (3) Regeneration method: After backwashing (flow rate 200 mL / min), FC was eluted with ethanol-water (1:1).

[0065] 3. Parameter settings

[0066]

[0067] 4. Membrane separation step: nanoscale hollow fiber membrane fine filtration

[0068] Design Principles

[0069] (1) Sieving effect: macromolecular residues (such as unhydrolyzed CE and enzyme carrier fragments) are retained by membranes with a pore size of ≤5 nm;

[0070] (2) Fluid mechanics optimization: Parallel hollow fiber membrane groups (single fiber inner diameter 200 μm) were used to reduce the transmembrane pressure (TMP) and avoid membrane fouling.

[0071] Technical route

[0072] 1. Membrane module design:

[0073] (1) Material: polysulfone (PSU) hollow fiber membrane, pore size 4-5 nm, molecular weight cut-off 10 kDa;

[0074] (2) Configuration: 30 fibers in parallel, effective membrane area 0.5m 2 ;

[0075] (3) Flow direction: tangential flow mode (tangential flow velocity 1-2 m / s) to reduce concentration polarization.

[0076] 2. Operation and regeneration:

[0077] (1) Operating pressure: inlet pressure 0.1-0.3MPa, outlet pressure 0.05-0.1MPa;

[0078] (2) Online cleaning: Reverse pulse (0.5% NaOH, pressure 0.5 MPa) was applied every 24 hours to restore the flux.

[0079] Parameter settings

[0080]

[0081] Synergy and validation data

[0082] Overall removal efficiency:

[0083] (1) Initial CE concentration: 2.8 mmol / L → 0.14 mmol / L after enzymatic hydrolysis (hydrolysis rate: 95%) → 0.02 mmol / L after adsorption (clearance rate: 98.5%) → final concentration after membrane separation: 0.005 mmol / L (total clearance rate: 99.8%);

[0084] (2)Comparison with traditional technology:

[0085] (3) The removal rate of the single-stage adsorption method is only 70-80%, and it cannot treat unhydrolyzed CE;

[0086] (4) The biocompatibility of the filtrate from the combined technology is significantly improved (hemolysis rate <0.1%, in compliance with ISO 10993-4 standards). The above technical details fully cover the core innovations and engineering implementation paths of the method, supporting the practicality and significance of the patent.

[0087] originality

[0088] The originality of the present invention is mainly reflected in the following aspects:

[0089] 1. Multi-level collaborative clearing mechanism:

[0090] (1) For the first time, enzymatic hydrolysis, targeted adsorption and nano-membrane separation technology were organically combined to form a multi-stage synergistic removal mechanism, which solved the technical bottleneck of the traditional single method that could not efficiently remove cholesterol ester (CE).

[0091] (2) CE was converted into free cholesterol (FC) and fatty acids (FA) by enzymatic hydrolysis, which significantly improved the efficiency of subsequent adsorption and membrane separation.

[0092] 2. Design of immobilized enzyme reaction column:

[0093] (1) Cholesterol esterase (CEase) was immobilized on the surface of porous silica microspheres by covalent bonding, which not only improved the stability and reusability of the enzyme but also avoided the contamination of the filtrate by free enzyme.

[0094] (2) The enzyme reaction column is integrated with a temperature control system to ensure that the enzymatic hydrolysis reaction is carried out at the optimal temperature (37°C), further improving the reaction efficiency.

[0095] 2.β-cyclodextrin modified resin adsorbent:

[0096] (1) β-cyclodextrin (β-CD) was innovatively modified on the surface of macroporous polystyrene resin, and the hydrophobic cavity of β-CD was used to specifically bind to FC, achieving highly selective adsorption.

[0097] (2) The adsorbent has a high specific surface area (≥800m 2 / g) and high grafting density (≥5μmol / g), which significantly improved the adsorption capacity and removal efficiency.

[0098] 4. Nanoscale hollow fiber membrane components:

[0099] (1) The use of polysulfone hollow fiber membranes with a pore size of ≤5 nm, combined with a tangential flow mode, effectively intercepts macromolecular residues (such as unhydrolyzed CE and enzyme carrier fragments) while reducing the risk of membrane fouling.

[0100] (2) The membrane components support online backwashing and chemical cleaning, which extends the service life and reduces operating costs.

[0101] 5. Intelligent control system:

[0102] (1) The integration of pH sensor, conductivity sensor, pressure sensor and flow meter enables dynamic monitoring and feedback control of the entire process.

[0103] (2) Dynamically adjust flow rate, temperature and pressure based on real-time data to ensure that the system operates within the optimal parameter range.

[0104] 6. Enzyme-membrane coupling technology: Reduce the polarity of CE molecules through enzymatic hydrolysis and improve the removal efficiency by combining targeted adsorption (experiments show that the CE removal rate is ≥98%);

[0105] 7. Closed-loop resource design: adsorption columns and nano-membranes can be regenerated online, reducing consumables costs;

[0106] 8. Compatibility: The device can seamlessly connect to existing CBP equipment (such as ), supports fully automated operation.

[0107] Beneficial effects

[0108] The beneficial effects of the present invention are embodied in the following aspects:

[0109] 1. Efficient removal of cholesterol esters:

[0110] (1) Through a multi-level collaborative clearance mechanism, the CE clearance rate can reach over 99.8%, which is significantly better than the traditional single method (clearance rate is usually 70-80%).

[0111] (2) The CE concentration in the final filtrate dropped to below 0.005 mmol / L, meeting the safety standards for medical and industrial reuse.

[0112] 2. Improve the biocompatibility of filtrate:

[0113] (1) The hemolysis rate of the filtrate after CE removal is less than 0.1%, which meets the ISO 10993-4 standard and can be directly used for clinical treatments such as autologous blood transfusion and plasma exchange.

[0114] (2) The residual protein and lipid components in the filtrate remain stable, avoiding the risk of inflammatory response or secondary embolism caused by CE residue.

[0115] 3. Resource recycling:

[0116] (1) High-purity filtrate can be used to purify plasma-derived products in biopharmaceuticals (such as human serum albumin and immunoglobulin), reducing the cost of raw materials.

[0117] (2) In the extracorporeal circulation support system, the filtrate can be used as a supplementary component of the perfusion fluid to reduce dependence on exogenous plasma products.

[0118] 4. Low operating costs:

[0119] (1) The immobilized enzyme reaction column and adsorbent support online regeneration, which significantly reduces the frequency of consumable replacement and operating costs.

[0120] (2) The service life of the nano-membrane module is extended to more than 6 months through back flushing and chemical cleaning, further reducing maintenance costs.

[0121] 5. Compatibility and scalability:

[0122] (1) The device can be seamlessly connected to existing continuous blood purification (CBP) equipment (such as ), no additional modification is required.

[0123] (2) The technical route can be extended to the treatment of other lipid metabolism disorders (such as familial hypercholesterolemia) and has broad application prospects.

[0124] 6. Environmentally friendly:

[0125] (1) The generation of medical waste is reduced through resource reuse, which is in line with the development trend of green medicine.

[0126] (2) The regeneration design of the adsorbent and membrane components reduces the use of chemical cleaning agents and reduces pollution to the environment.

[0127] The ingenuity of this invention lies in its efficient and safe removal of cholesterol esters through a multi-stage coordinated removal mechanism and intelligent control system, while simultaneously enhancing the biocompatibility and resource recycling value of the filtrate. Its beneficial effects are reflected not only in its high efficiency and safety in clinical treatment but also in its economical and environmentally friendly nature in industrial applications, offering significant technical advantages and social benefits.

[0128] Application Prospects

[0129] This technology can be extended to:

[0130] Individualized blood purification therapy for critically ill patients;

[0131] Purification of plasma-derived products in biopharmaceuticals;

[0132] Filtrate regeneration of extracorporeal circulatory support systems. BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Figure 1 : Schematic diagram of the device structure, marking the connection relationship and flow direction of each module;

[0134] Figure 2 : CE clearance comparison experimental data (traditional adsorption vs. the present invention).

[0135] 1. Sample 1: CBP filtrate from a patient with acute hyperlipidemia. The clearance rate of the traditional adsorption method was 75%, while the clearance rate of the method of the present invention was 99.8%.

[0136] 2. Sample 2: Biopharmaceutical plasma filtrate, the clearance rate of the traditional adsorption method is 70%, and the clearance rate of the method of the present invention is 99.9%;

[0137] 3. Sample 3: filtrate of extracorporeal circulation support system. The clearance rate of the traditional adsorption method was 65%, while the clearance rate of the method of the present invention was 99.7%.

[0138] Comparative Analysis

[0139] 1. Improved cleaning efficiency:

[0140] Under the three experimental conditions, the CE removal rate of the method of the present invention was significantly higher than that of the traditional adsorption method (increased by 24.8%-34.7%);

[0141] The clearance rate of the method of the present invention is stable at above 99.7%, which is close to complete clearance.

[0142] 2. Wide range of applications:

[0143] The method of the present invention exhibits efficient clearance capabilities in different sample types and is suitable for various scenarios such as clinical treatment, biopharmaceuticals, and extracorporeal circulation support systems.

[0144] 3.Technical advantages:

[0145] Traditional adsorption methods rely on a single adsorption mechanism, and the removal efficiency is limited by the capacity and selectivity of the adsorbent;

[0146] The present invention significantly improves the removal efficiency and filtrate purity through the multi-stage synergistic mechanism of enzymatic hydrolysis-adsorption-membrane separation. DETAILED DESCRIPTION

[0147] The following is a detailed technical description of the specific implementation method, covering the operation method, execution process and key parameters of each step to ensure the completeness and operability of the technical solution:

[0148] Example 1: Filtrate treatment of patients with acute hyperlipidemia after CBP treatment

[0149] 1.1 Preprocessing steps

[0150] How to do it:

[0151] (1) The CBP primary filtrate passes through the buffer adjustment module, and the pH sensor at the inlet monitors the pH of the filtrate in real time;

[0152] (2) If the pH exceeds the range of 6.8-7.4, start the peristaltic pump to inject phosphate buffered saline (PBS, 0.1 M) to adjust to the target pH;

[0153] (3) Add human serum albumin (HSA, final concentration 0.5-1.0 g / dL) via a syringe pump and mix well;

[0154] (4) The filtrate is preheated to 37°C (error ±0.5°C) and enters the enzymatic reaction column.

[0155] Execution process:

[0156] Input: CBP primary filtrate (CE concentration 2.8 mmol / L, pH 7.2-7.8);

[0157] Output: adjusted filtrate (pH 7.0 ± 0.2, temperature 37°C, HSA concentration 0.8 g / dL).

[0158] Key parameters:

[0159]

[0160] 1.2 Enzymatic reaction step operation method:

[0161] (1) Pump the pretreated filtrate into the immobilized CEase reaction column at a flow rate of 50-100 mL / min;

[0162] (2) The reaction column is placed in an external circulating water bath system to maintain the temperature at 37°C (error ±0.5°C);

[0163] (3) FA concentration was monitored by a conductivity sensor at the outlet, and the flow rate was dynamically adjusted to ensure CE hydrolysis rate >95%;

[0164] (4) After enzymatic hydrolysis, the filtrate enters the targeted adsorption column.

[0165] Execution process:

[0166] Input: adjusted filtrate (CE concentration 2.8 mmol / L);

[0167] Output: filtrate after enzymatic hydrolysis (CE concentration 0.14 mmol / L, hydrolysis rate 95%).

[0168] Key parameters:

[0169]

[0170] 1.3 Targeted adsorption step

[0171] How to do it:

[0172] 1. Pump the filtrate after enzymatic hydrolysis into the β-cyclodextrin modified resin adsorption column at a flow rate of 80-120 mL / min;

[0173] 2. Monitor the cross-column pressure (<0.2MPa) through the in-column pressure sensor to ensure the stability of the adsorbent bed;

[0174] 3. After processing 10 BV of filtrate, start backwash (flow rate 200 mL / min) and elute FC with ethanol-water (1:1);

[0175] 4. After adsorption, the filtrate enters the membrane separation module.

[0176] Execution process:

[0177] Input: filtrate after enzymatic hydrolysis (CE concentration 0.14 mmol / L);

[0178] Output: filtrate after adsorption (CE concentration 0.02 mmol / L, clearance rate 98.5%).

[0179] Key parameters:

[0180]

[0181] 1.4. Membrane separation step

[0182] How to do it:

[0183] 1. Pump the adsorbed filtrate into the nano-scale hollow fiber membrane module, and control the tangential flow velocity at 1-2m / s;

[0184] 2. Operating pressure: inlet pressure 0.1-0.3MPa, outlet pressure 0.05-0.1MPa;

[0185] 3. Monitor the membrane flux through the flow meter. If the flux decay is greater than 30%, start reverse pulse cleaning (0.5% NaOH, pressure 0.5 MPa);

[0186] 4. Collect high-purity filtrate for subsequent treatment or reuse.

[0187] Execution process:

[0188] Input: filtrate after adsorption (CE concentration 0.02 mmol / L);

[0189] Output: Final filtrate (CE concentration 0.005 mmol / L, total clearance 99.8%).

[0190] Key parameters:

[0191]

[0192] Example 2: Purification of plasma components in biopharmaceuticals

[0193] 1.1 Preprocessing steps

[0194] How to do it:

[0195] (1) The plasma filtrate was introduced into the buffer adjustment module and the pH was adjusted to 7.0 ± 0.2;

[0196] (2) adding HSA (final concentration 0.5 g / dL) as a stabilizer;

[0197] (3) Preheat to 37°C and enter the enzymatic reaction column.

[0198] Execution process:

[0199] Input: plasma filtrate (CE concentration 1.5 mmol / L, pH 7.5);

[0200] Output: adjusted filtrate (pH 7.0 ± 0.2, temperature 37°C, HSA concentration 0.5 g / dL).

[0201] 1.2 Enzymatic reaction steps

[0202] How to do it:

[0203] (1) The filtrate was passed through the immobilized CEase reaction column at a flow rate of 80 mL / min;

[0204] (2) Maintaining the temperature at 37°C, hydrolyze CE to a concentration of 0.075 mmol / L (hydrolysis rate 95%).

[0205] Execution process:

[0206] Input: adjusted filtrate (CE concentration 1.5 mmol / L);

[0207] Output: filtrate after enzymatic hydrolysis (CE concentration 0.075mmol / L).

[0208] 1.3 Targeted adsorption step

[0209] How to do it:

[0210] (1) The filtrate was passed through a β-cyclodextrin modified resin adsorption column at a flow rate of 100 mL / min;

[0211] (2) After adsorption, the CE concentration dropped to 0.01 mmol / L (clearance rate 98.7%).

[0212] Execution process:

[0213] Input: filtrate after enzymatic hydrolysis (CE concentration 0.075 mmol / L);

[0214] Output: filtrate after adsorption (CE concentration 0.01mmol / L).

[0215] 1.4 Membrane separation steps

[0216] How to do it:

[0217] (1) The filtrate passes through the nanomembrane module at a tangential flow rate of 1.5 m / s;

[0218] (2) The final CE concentration dropped to 0.002 mmol / L (total clearance rate 99.9%).

[0219] Execution process:

[0220] Input: filtrate after adsorption (CE concentration 0.01 mmol / L);

[0221] Output: Final filtrate (CE concentration 0.002 mmol / L).

[0222] Through the above detailed technical description and parameter settings, this method demonstrated efficient and stable CE removal capabilities in both clinical and industrial scenarios, providing reliable technical support for the reuse of the filtrate.

Claims

1. A method for secondary filtration and removal of cholesterol esters after continuous blood purification and blood lipid filtration, characterized in that The following steps are involved: The CBP primary filtrate is pretreated by adjusting the pH to 6.8-7.4 and adding a stabilizer (such as human albumin) to prevent protein denaturation; The pretreated filtrate was passed through an immobilized cholesterol esterase (CEase) reaction column and enzymatically hydrolyzed at 37°C to hydrolyze cholesterol ester (CE) into free cholesterol (FC) and fatty acids (FA); The filtrate after enzymatic hydrolysis is passed through a β-cyclodextrin-modified adsorption column to specifically bind and remove free cholesterol; The adsorbed filtrate is finely filtered through a nano-scale hollow fiber membrane assembly to intercept macromolecular residues and obtain a high-purity filtrate.

2. The method according to claim 1, wherein: In the pretreatment step, phosphate buffered saline (PBS, 0.1 M) was used for pH adjustment, and human serum albumin (HSA, final concentration 0.5-1.0 g / dL) was used as the stabilizer; In the enzymatic hydrolysis step, the enzyme loading capacity of the immobilized CEase reaction column is ≥20 U / g carrier, the reaction flow rate is 50-100 mL / min, and the hydrolysis rate is ≥95%; In the adsorption step, the specific surface area of ​​the β-cyclodextrin modified resin is ≥800m 2 / g, grafting density ≥5μmol / g, adsorption flow rate 80-120mL / min; In the membrane separation step, the pore size of the nanoscale hollow fiber membrane is ≤5 nm, the tangential flow velocity is 1-2 m / s, and the operating pressure is 0.1-0.3 MPa.

3. A device for implementing the method according to claim 1-2, characterized in that Includes the following modules: Buffer adjustment unit: integrated pH sensor and automatic liquid adding pump, used to adjust the pH of the filtrate and add stabilizer; Immobilized CEase reaction column: filled with silica microspheres covalently bound to CEase, and equipped with an external circulating water bath system to maintain the reaction temperature at 37°C; β-cyclodextrin modified adsorption column: uses macroporous polystyrene resin as a carrier, modified with β-cyclodextrin on the surface, and integrated with a pressure sensor to monitor the cross-column pressure; Nano-scale hollow fiber membrane components: Made of polysulfone, pore size ≤ 5nm, supports tangential flow mode and backwash regeneration; Intelligent control system: Dynamically adjusts flow rate, temperature and pressure based on real-time data from pH sensors, conductivity sensors, pressure sensors and flow meters.

4. The device according to claim 3, wherein: The silica microspheres of the immobilized CEase reaction column have a particle size of 100-200 μm, a pore size of 10-30 nm, and a specific surface area of ​​300-500 m 2 / g; The resin pore size of the β-cyclodextrin modified adsorption column is 50-100 nm, the cross-linking degree is 8%, and the adsorption capacity is ≥5 μmol / g; The effective membrane area of ​​the nanoscale hollow fiber membrane assembly is 0.5m 2 The inner diameter of the single filament is 200 μm, and the parallel design is used to reduce the transmembrane pressure.

5. The device according to claim 3-4, characterized in that: The intelligent control system comprises: pH sensor: real-time monitoring of filtrate pH, accuracy ±0.1; Conductivity sensor: monitors the FA concentration in the filtrate after enzymatic hydrolysis and dynamically adjusts the reaction flow rate; Pressure sensor: monitors the operating pressure of the adsorption column and membrane assembly to ensure system stability; Flow meter: monitors membrane flux and triggers back flushing signal.

6. An immobilized CEase reaction column for use in the device according to claims 3-5, characterized in that: The carrier of the reaction column is porous silica microspheres, and CEase is covalently bound to the surface by glutaraldehyde cross-linking; The reaction column is externally provided with a circulating water bath system to maintain a reaction temperature of 37° C. and support online regeneration.

7. A β-cyclodextrin modified adsorption column for use in the device according to claims 3-5, characterized in that: The resin of the adsorption column is a macroporous polystyrene resin, and β-cyclodextrin is grafted onto the surface via epoxy groups; The adsorption column supports backwashing and ethanol-water (1:1) elution regeneration, and the regeneration cycle is per 10 BV processing volume.

8. A nanoscale hollow fiber membrane assembly for the device according to claims 3-5, characterized in that: The membrane component is made of polysulfone, with a pore size of ≤5nm and a molecular weight cut-off of 10kDa; The membrane assembly supports tangential flow mode and reverse pulse cleaning (0.5% NaOH, pressure 0.5 MPa), which prolongs the service life.

9. Application of the method according to claims 1-2 in the medical field, characterized in that: Used for the treatment of filtrate after CBP treatment in patients with acute hyperlipidemia, with a final CE concentration of ≤0.005mmol / L, meeting the clinical re-infusion standard; Used for the purification of plasma components in biopharmaceuticals, the final CE concentration is ≤0.002mmol / L, which meets the plasma product standards of the European Pharmacopoeia.

10. An industrial application of the method according to claims 1-2, characterized in that: Used for regeneration of filtrate in extracorporeal circulation support system to reduce dependence on exogenous plasma products; Used to prepare high-purity plasma derivative products (such as human serum albumin, immunoglobulin) and reduce raw material costs. The point to be protected is that the achievable effect environment of this patent cannot be simulated by separating and disassembling the various functions of this patent in a separate manner. The implementation methods of the present invention are not limited to the above-mentioned embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the scope of protection of the present invention. The specific implementation methods of the compound formula of the present invention are not exhaustive. Any transformation by those skilled in the art without creative work falls within the scope of protection of the present invention.

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