WO2020042200A1 - Dispositif d'élimination de plomb du sang pour l'élimination de plomb du sang in vitro - Google Patents

Dispositif d'élimination de plomb du sang pour l'élimination de plomb du sang in vitro Download PDF

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WO2020042200A1
WO2020042200A1 PCT/CN2018/103733 CN2018103733W WO2020042200A1 WO 2020042200 A1 WO2020042200 A1 WO 2020042200A1 CN 2018103733 W CN2018103733 W CN 2018103733W WO 2020042200 A1 WO2020042200 A1 WO 2020042200A1
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blood
lead
adsorbent
blood lead
magnetic
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PCT/CN2018/103733
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English (en)
Chinese (zh)
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毛春
万密密
沈健
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南京师范大学
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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
    • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
    • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/02—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material
    • B01J20/10—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate
    • B01J20/103—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising inorganic material comprising silica or silicate comprising silica
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28009—Magnetic properties
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/305—Addition of material, later completely removed, e.g. as result of heat treatment, leaching or washing, e.g. for forming pores
    • B01J20/3057—Use of a templating or imprinting material ; filling pores of a substrate or matrix followed by the removal of the substrate or matrix

Definitions

  • the invention belongs to a biomedical instrument, and particularly relates to a blood lead-clearing instrument for removing blood lead in vitro.
  • the clinical treatment methods for blood lead poisoning can be divided into taking lead-driving drugs and blood perfusion;
  • the treatment methods for mild blood lead poisoning are taking small-molecule lead-driving drugs such as disodium calcium edetate, dimercaptopropanol, two Mercaptosuccinic acid, long treatment cycle (40-60 days), large side effects and poor treatment effect;
  • the treatment method for severe blood lead poisoning is hemoperfusion, which uses blood perfusion device containing resin or activated carbon with adsorption function to treat blood. Wash to absorb toxic substances in the serum. Because the size of the adsorbent in the blood perfusion device is large and fixed inside the perfusion device, it cannot enter the red blood cells to remove lead ions in the red blood cells.
  • the blood perfusion generally removes toxic substances in the serum, and it is almost impossible to remove lead ions in the red blood cells carry out. Therefore, there is an urgent need for a new type of blood lead-clearing instrument whose adsorbent can freely enter and exit red blood cells to capture lead ions in the red blood cells.
  • the blood lead-clearing instrument needs to provide sufficient space and time for the contact between the adsorbent and blood, and can quickly The adsorbent is separated from the blood to achieve safe and efficient removal of lead ions from the blood (especially lead ions bound to red blood cells).
  • the hemoperfusion adsorbent that is currently used to remove blood lead is immobilized, the size of the adsorbent is large (micron level), and it cannot enter red blood cells to take away lead ions in red blood cells. , And can not be in full contact with blood.
  • the design of the present invention highlights a contact device and a magnetic separation device, which provide sufficient space and time (more than 10 minutes) for the adsorbent to freely enter and exit the red blood cells.
  • the adsorbent can freely enter and exit the red blood cells, capture lead ions in the red blood cells, and then magnetically separate them. Achieve separation of blood and adsorbent.
  • the blood lead-clearing instrument of the present invention realizes safe and efficient removal of lead ions in blood, especially lead ions bound to red blood cells.
  • a blood lead-clearing instrument which can be used to remove blood lead in vitro according to the present invention includes an extracorporeal circulation machine, an adsorbent sampling device, a contact device, and a magnetic separation device connected in sequence;
  • the adsorbent injection device contains an adsorbent, and the injection amount of the adsorbent can be controlled by adjusting the injection rate;
  • the composition of the adsorbent is a magnetic trioxide with a regular mesoporous channel using amine-rich organic compounds as a template agent Iron / aminated mesoporous silica composite.
  • the extracorporeal circulation machine and the adsorbent sampling device are connected to the contact device through a Y-shaped tube.
  • the contact device is composed of a blood perfusion tube, and the aspect ratio of the blood perfusion tube is 300: 1-1000: 1.
  • the magnetic separation device is composed of an external magnetic field and a separation tube, and the aspect ratio of the separation tube is 50: 1-200: 1.
  • an external magnetic field is formed by a magnet surrounded by a separation tube.
  • the diameter of the separation tube is larger than the diameter of the blood perfusion tube to separate the adsorbent from the blood.
  • the size of the adsorbent is 50-500 nm, and the ratio of the adsorbent to blood volume is 1: 10-10: 1g / L.
  • the blood lead-clearing instrument for removing blood lead in vitro includes the following steps:
  • step (2) Mix the Fe 3 O 4 solution prepared in step (1) with hydrazine hydrate uniformly, sonicate it, add tetraethyl orthosilicate, collect the obtained product, and re-disperse it to contain hydrazine hydrate and cetyltrimethyl Ammonium bromide in deionized water, add tetraethyl orthosilicate after ultrasonication again;
  • step (3) The product obtained in the last reaction of step (2) is dried and calcined to remove cetyltrimethylammonium bromide, and the product obtained is collected and dispersed in deionized water containing hydrazine hydrate and amine-rich organic template, and ultrasonic After the treatment, tetraethyl orthosilicate was added to the reaction, and the reaction was continued to obtain a product magnetic iron trioxide / aminated mesoporous silica composite blood lead ion adsorbent.
  • the reaction temperature in step (1) is 150-220 ° C, and the reaction time is 10-24 h.
  • reaction temperature for each addition of tetraethyl orthosilicate described in step (2) and step (3) is 60-90 ° C, and the reaction time is 1 to 5 hours.
  • the molar ratio of the tetraethyl orthosilicate to the amine-rich organic template is 5: 1 to 50: 1.
  • the amine-rich organic substance used as a template for the synthesis of the adsorbent includes one of hyperbranched polyamide, polylysine, or chitosan.
  • the process of steps (2) and (3) is: dissolving sodium lauroyl sarcosinate in citric acid / sodium citrate (0.1M, pH 5.2) In the buffer solution, add ⁇ -polylysine to the solution to generate polylysine / sodium lauroyl sarcosinate complex micelles; add Fe 3 O 4 prepared in step (1) to citric acid / In a sodium citrate buffer solution, add a polylysine / sodium lauroyl sarcosinate complex micelle solution; then add tetraethyl orthosilicate and APTES (3-aminopropyltriethoxysilane) in sequence, and continue The product was stirred and transferred to a high-temperature reaction kettle at 80 ° C. for 8 hours to obtain a magnetic iron trioxide / polylysine mesoporous silica composite blood lead ion adsorbent.
  • a blood lead-clearing instrument that can be used to remove blood lead in vitro, wherein the mechanism of removing the lead ions in the blood by the adsorbent in the whole blood lead-clearing instrument is that the composite material enters and exits red blood cells freely and passes through mesoporous silica
  • the complexation of lead ions by the amino group in the structure captures lead-containing hemoglobin, and fixes the lead-containing hemoglobin through the mesoporous channels to achieve the removal of lead ions in red blood cells.
  • the present invention can be used for a blood lead removal instrument for removing blood lead in vitro, including an extracorporeal circulation machine, an adsorbent sampling device, a contact device (blood perfusion tube), and a magnetic separation device (plus a magnetic field and a separation tube).
  • a blood lead removal instrument for removing blood lead in vitro, including an extracorporeal circulation machine, an adsorbent sampling device, a contact device (blood perfusion tube), and a magnetic separation device (plus a magnetic field and a separation tube).
  • the blood lead clearer first connects the venous vessels of lead poisoning model pigs, and the blood enters the extracorporeal circulation machine 1 through the catheter to drive the blood circulation throughout the treatment process.
  • the extracorporeal circulation machine 1 and the adsorbent injection device 2 use Y
  • the catheter is connected to the blood perfusion tube 3 in the contact device, and then the blood is contacted and mixed with the adsorbent pushed out by the adsorbent injection device 2 through the Y-shaped catheter, and the adsorbent and blood are fully contacted in the blood perfusion tube (more than 10 minutes)
  • the diameter of the separation tube is larger than the diameter of the blood perfusion tube to achieve the separation of the adsorbent from the blood.
  • the blood flows back through the artery to the lead poisoning model pig and is completed once. Blood lead removal process, continue to repeat the cycle to clear.
  • the present invention has the following advantages:
  • the use of the blood lead-clearing instrument of the present invention can directly remove lead ions in the blood in a short time through extracorporeal blood circulation, quickly alleviate the condition of patients with blood lead poisoning, and reduce the patients' daily medication.
  • the side-by-side blood lead-clearing instrument of the present invention for removing blood lead in vitro has a simple composition, is convenient to use, and can flexibly change its working position, which solves the problem that the blood perfusion device cannot remove lead ions in red blood cells in the blood, and improves work efficiency. It is suitable for widespread promotion and use, and has broad application prospects in the medical field.
  • the design of the blood lead-clearing device of the present invention highlights a contact device and a magnetic separation device, which provide sufficient space and time (over 10 minutes) for the free passage of the adsorbent into and out of the red blood cells.
  • the adsorbent can freely enter and exit the red blood cells and capture the lead in the red blood cells.
  • the ions are then separated from the adsorbent by magnetic separation.
  • the blood lead-clearing instrument of the present invention can provide sufficient space and time for the free passage of the adsorbent into and out of the red blood cells.
  • the lead-containing hemoglobin is captured by the complexation of the lead with the amino group in the mesoporous silica structure, and passes through the mesoporous channels. Fixing leaded hemoglobin to achieve the purpose of removing lead ions in red blood cells. It overcomes the shortcomings of unclear principle and low efficiency of blood lead removal in current clinical and research.
  • the blood lead-clearing instrument of the present invention can be truly used to remove lead ions complexed with hemoglobin in the content of up to 95% of red blood cells, and can safely enter red blood cells and effectively capture blood lead and hemoglobin contaminated by blood lead, and then safely leave the red blood cells. And blood.
  • the sorbent in the sorbent sampling device of the blood lead meter for blood lead removal in vitro utilizes the self-assembly performance of the amine-rich organic compounds, and the self-assembly of the amine-rich organic compounds is used to form micelles.
  • the behavior is to realize the dehydration condensation of silicon source on the surface of magnetic iron trioxide nanoparticles, and to obtain a magnetic iron trioxide / rich aminated mesoporous silica composite material using amine-rich organic compounds as a template and having regular mesoporous channels. That is, in the process of material synthesis, amine-rich organic compounds are used as template agents to realize material synthesis and functional group modification through a "one-step method".
  • the formation process of the ferric oxide core mesoporous molecular sieve and the organic functional group modification process are combined to obtain rich Aminated magnetic triiron tetroxide / aminated mesoporous silica composite material has good biocompatibility, simple preparation process, short production cycle, and effectively overcomes the complicated steps of the current technology (post-modification method) Disadvantages of energy waste and uneven distribution of functional groups.
  • the invention proposes a new blood lead-expulsion mechanism.
  • the blood lead-clearing instrument and the attached adsorbent material are used to make full contact with blood red blood cells to capture most of the lead ions in the red blood cells, thereby achieving the purpose of efficiently removing blood lead. It overcomes the shortcomings of the current clinical lead-expulsion methods, such as long cycle, large side effects, and poor effect, and has broad application prospects in the medical field.
  • the adsorbent material supported by the blood lead-clearing instrument of the present invention is magnetic iron trioxide / rich amine
  • the mesoporous silica composite material has a regular mesoporous structure and highly dispersed organic functional groups, and can freely enter and exit red blood cells.
  • the lead-containing hemoglobin is captured by the complexation of lead ions by the amino group in the mesoporous silica structure, and Fixation of leaded hemoglobin through mesoporous channels to achieve the purpose of removing lead ions from red blood cells. It overcomes the shortcomings of unclear principle and low efficiency of blood lead removal in current clinical and research.
  • Example 1 is a transmission electron microscope image of (a) Fe 3 O 4 NPs and (b) MMS / P NPs prepared in Example 1;
  • Fig. 2 is a scanning electron microscope image of (a) MMS / PNPs, and (b) an elemental energy spectrum analysis chart of MMS / PNPs;
  • Figure 3 is the infrared spectrum of (a) Fe 3 O 4 NPs and (b) MMS / P NPs;
  • Figure 4 is the nitrogen adsorption and desorption isotherm and pore size distribution of MMS / P NPs before (a) and after (b) template removal (inside);
  • FIG. 5 is a schematic diagram of the in vitro coagulation time of MMS / P NPs before and after anticoagulation treatment
  • Figure 6 is a schematic diagram of the hemolysis rate of MMS / P NPs before and after heparin loading
  • Figure 7 is a schematic diagram of the relative content of common ions in blood before and after MMS / P NPs adsorption
  • Figure 9 is (a) nitrogen adsorption and desorption curve of MMS / H NPs; (b) schematic diagram of pore size distribution;
  • Figure 10 is a schematic diagram of the adsorption effect of MMS / H NPs on lead ions in real blood (rabbit and human blood);
  • Figure 11 shows the process of MMS / H NPs entering and exiting red blood cells: (a) pure red blood cells, (b) MMS / H NPs entering red blood cells, and (c) TEM images of red blood cells after MMS / H NPs are separated from red blood cells;
  • FIG. 12 is a schematic structural diagram of a device that can be used for a blood lead remover for removing blood lead in vitro, an extracorporeal circulation machine 1, an adsorbent sampling device 2, a contact device 3 (a blood perfusion tube), a magnetic separation device (an external magnetic field 4 and separation) Tube 5);
  • FIG. 13 is a schematic diagram of a blood lead-clearing apparatus that can be used to remove blood lead in vitro;
  • FIG. 14 is a process of removing lead from blood in vitro using a blood lead-clearing instrument for removing lead from lead poisoning model pigs in vitro (i) intravenous intubation and (ii, iii) extracorporeal circulation;
  • FIG. 15 is a routine blood test of lead poisoning model pigs before and after surgery (blood lead removal).
  • ferric trichloride (1.35 g, 5 mmol) and dissolve it in 30 mL of ethylene glycol solution.
  • sodium acetate (NaAc, 3.6 g) and polyethylene glycol-2000 (PEG-2000 1.0 g) with stirring. Stirring was continued for 30 min, and the solution was transferred to a high-temperature reaction kettle at 200 ° C for 72 hours. After leaving to cool, it was washed with deionized water and ethanol solution several times in sequence, and dried under vacuum at 60 ° C.
  • 100 mg of sodium lauroyl sarcosinate was dissolved into 10 mL of a citric acid / sodium citrate buffer solution (0.1 M, pH 5.2) at room temperature, and 150 ⁇ L of ⁇ -polylysine (20 wt%) was added to the solution. At this time, the solution immediately became an emulsion, and a polylysine / sodium lauroyl sarcosinate complex micelle was formed.
  • Fe 3 O 4 NPs are uniformly dispersed with a size of about 120 nm. Generally, the size of Fe 3 O 4 NPs is about 50-300 nm. The size of the obtained MMS / P NPs is about 170 nm, and the size of the obtained adsorbent is usually 50-500 nm. Scanning electron microscopy was used to characterize the size and morphology of the composite.
  • Nitrogen adsorption and desorption curves are often used to reflect the pore structure of mesoporous materials. As shown in Figure 4, the pore size of MMS / PNPs is approximately 5.1 nm.
  • the composite material is a biocompatible material with a hemolysis rate of 0.5 to 5%, an activated partial thromboplastin time of 12 to 30 s, a plasma prothrombin time of 8 to 20 s, and a thrombin time of 8 to 20 s.
  • Quantitative magnetic triiron tetroxide / aminated mesoporous silica composite was placed in a centrifuge tube, 3 mL of lead-containing blood (0.6 ppm) was added, and the centrifuge tube was placed on a constant temperature shaker at 37 ° C for a fixed time. Take 2mL of the supernatant and digest the solution by high temperature digestion. After cooling, make up to 5mL.
  • Fe 3 O 4 NPs were synthesized by hydrothermal method. The specific method is as follows: Weigh ferric trichloride (1.35 g, 5 mmol) and dissolve it fully in 40 mL of ethylene glycol solution. Add sodium acetate (NaAc, 1.8 g) and sodium citrate trihydrate (Na 3 Cit 0.2 g) with stirring. Stirring was continued for 1 h, and the solution was transferred to a high-temperature reactor for 200 h at 200 ° C. After leaving to cool, it was washed with deionized water and ethanol solution several times in sequence, and dried under vacuum at 60 ° C.
  • the Fe 3 O 4 NPs solution (3 mg / mL, 50 mL) was mixed with 9 mL of hydrazine hydrate, and sonicated for 30 min. The mixture was transferred to a three-necked flask, and 70 mL of deionized water was added. Subsequently, 90 mg of TEOS was added, and stirring was continued at 90 ° C for 2 h. The resulting product was magnetically collected and re-dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 450 mg of CTAB. After sonicating again for 30 min, 0.6 mL of TEOS was added and stirred at 90 ° C for 2 h.
  • the obtained product was naturally cooled, and then washed with deionized water and an ethanol solution for several times, and dried under vacuum at 60 ° C. The dried product was calcined in an air atmosphere at 550 ° C for 5 hours to remove the template agent CTAB.
  • the obtained product (100 mg) was collected and dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 450 mg (0.45 mmol) of PAMAM. Sonicate for 30 min, add 0.6 mL (2.88 mmol) of TEOS, and continue stirring at 90 ° C for 2 h.
  • the particle size of MMS / H NPs is about 300 nm.
  • a nitrogen adsorption desorption curve is used to characterize the pore structure of the material.
  • the BET surface area is approximately 248 m 2 ⁇ g -1 and the pore size is approximately 24 nm.
  • Quantitative magnetic triiron tetroxide / aminated mesoporous silica composite was placed in a centrifuge tube, 3 mL of lead-containing blood (0.6 ppm) was added, and the centrifuge tube was placed on a constant temperature shaker at 37 ° C for a fixed time. Take 2mL of the supernatant and digest the solution by high temperature digestion. After cooling, make up to 5mL.
  • MMS / H NPs can enter red blood cells and can be magnetically separated without affecting the red blood cell morphology.
  • Fe 3 O 4 NPs were synthesized by hydrothermal method. The specific method is as follows: Weigh ferric trichloride (1.35 g, 5 mmol) and dissolve it fully in 40 mL of ethylene glycol solution. Add sodium acetate (NaAc, 1.8 g) and sodium citrate trihydrate (Na 3 Cit 0.2 g) with stirring. Stirring was continued for 1 h, and the solution was transferred to a high-temperature reactor for 200 h at 200 ° C. After leaving to cool, it was washed with deionized water and ethanol solution several times in sequence, and dried under vacuum at 60 ° C.
  • the Fe 3 O 4 NPs solution (3 mg / mL, 50 mL) was mixed with 9 mL of hydrazine hydrate, and sonicated for 30 min. The mixture was transferred to a three-necked flask, and 70 mL of deionized water was added. Subsequently, 90 mg of TEOS was added, and stirring was continued at 90 ° C for 2 h. The resulting product was magnetically collected and re-dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 450 mg of CTAB. After sonicating again for 30 min, 0.6 mL of TEOS was added and stirred at 90 ° C for 2 h.
  • the product obtained was naturally cooled, it was washed with deionized water and ethanol solution several times in that order, and dried under vacuum at 60 ° C. The dried product was calcined in an air atmosphere at 550 ° C for 5 hours to remove the template agent CTAB.
  • the obtained product (100 mg) was collected and dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 3.4 g (0.0576 mmol) of chitosan. Sonicate for 30 min, add 0.6 mL (2.88 mmol) of TEOS, and continue stirring at 90 ° C for 2 h.
  • Fe 3 O 4 NPs were synthesized by hydrothermal method. The specific method is as follows: Weigh ferric trichloride (1.35 g, 5 mmol) and dissolve it fully in 40 mL of ethylene glycol solution. Add sodium acetate (NaAc, 1.8 g) and sodium citrate trihydrate (Na 3 Cit 0.2 g) with stirring. Stirring was continued for 1 h, and the solution was transferred to a high-temperature reaction kettle at 150 ° C. for 24 h. After leaving to cool, it was washed with deionized water and ethanol solution several times in sequence, and dried under vacuum at 60 ° C.
  • the Fe 3 O 4 NPs solution (3 mg / mL, 50 mL) was mixed with 9 mL of hydrazine hydrate, and sonicated for 30 min. The mixture was transferred to a three-necked flask, and 70 mL of deionized water was added. Subsequently, 90 mg of TEOS was added, and stirring was continued at 90 ° C for 2 h. The resulting product was magnetically collected and re-dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 450 mg of CTAB. After sonicating again for 30 min, 0.6 mL of TEOS was added and stirred at 60 ° C. for 5 h.
  • the obtained product was naturally cooled, and then washed with deionized water and an ethanol solution for several times, and dried under vacuum at 60 ° C.
  • the dried product was calcined in an air atmosphere at 550 ° C for 5 hours to remove the template agent CTAB.
  • the obtained product (100 mg) was collected and dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 576 mg (0.576 mmol) of PAMAM. Sonicate for 30 min, add 0.6 mL (2.88 mmol) of TEOS, and continue stirring at 90 ° C for 2 h.
  • Fe 3 O 4 NPs were synthesized by hydrothermal method. The specific method is as follows: Weigh ferric trichloride (1.35 g, 5 mmol) and dissolve it fully in 40 mL of ethylene glycol solution. Add sodium acetate (NaAc, 1.8 g) and sodium citrate trihydrate (Na 3 Cit 0.2 g) with stirring. Stirring was continued for 1 h, and the solution was transferred to a high-temperature reaction kettle at 220 ° C. for 10 h. After leaving to cool, it was washed with deionized water and ethanol solution several times in sequence, and dried under vacuum at 60 ° C.
  • the Fe 3 O 4 NPs solution (3 mg / mL, 50 mL) was mixed with 9 mL of hydrazine hydrate, and sonicated for 30 min. The mixture was transferred to a three-necked flask, and 70 mL of deionized water was added. Subsequently, 90 mg of TEOS was added, and stirring was continued at 90 ° C for 2 h. The resulting product was magnetically collected and re-dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 450 mg of CTAB. After sonicating again for 30 min, 0.6 mL of TEOS was added and stirred at 90 ° C for 1 h.
  • the obtained product was naturally cooled, and then washed with deionized water and an ethanol solution for several times, and dried under vacuum at 60 ° C.
  • the dried product was calcined in an air atmosphere at 550 ° C for 5 hours to remove the template agent CTAB.
  • the obtained product (100 mg) was collected and dispersed into 150 mL of deionized water, which contained 2.1 mL of hydrazine hydrate and 450 mg of PAMAM. Sonicate for 30 min, add 0.6 mL of TEOS, and continue stirring at 90 ° C for 2 h. After leaving to cool, it was washed with deionized water and ethanol solution several times in sequence, and dried under vacuum at 60 ° C.
  • the product was immersed in a 10 mL heparin solution (10 mg / mL) for 12 h, and dried under vacuum at 60 ° C. to obtain a magnetic lead iron ion scavenger of ferric iron tetraoxide / hyperbranched polyamide mesoporous silica composite material.
  • Fe 3 O 4 NPs were synthesized by hydrothermal method. The specific method is as follows: Weigh ferric trichloride (1.35 g, 5 mmol) and dissolve it fully in 40 mL of ethylene glycol solution. Add sodium acetate (NaAc, 1.8 g) and sodium citrate trihydrate (Na 3 Cit 0.2 g) with stirring. Stirring was continued for 1 h, and the solution was transferred to a high-temperature reactor for 200 h at 200 ° C. After leaving to cool, it was washed with deionized water and ethanol solution several times in sequence, and dried under vacuum at 60 ° C.
  • a blood lead-clearing instrument which can be used for extracorporeal blood lead removal includes an extracorporeal circulation machine 1, an adsorbent sampling device 2, a contact device 3, and a magnetic separation device connected in sequence; an extracorporeal circulation machine 1 and an adsorption device
  • the agent injection device 2 is connected to the contact device 3 through a Y-shaped tube.
  • the composition of the contact device 3 is a blood perfusion tube.
  • the aspect ratio of the blood perfusion tube is 600: 1, and the aspect ratio of the blood perfusion tube can be 300: 1- Adjusting between 1000: 1, the magnetic separation device consists of an external magnetic field 4 (magnets can be used) and the separation tube 5, that is, the separation tube 5 has a magnet, and the length-to-diameter ratio of the separation tube is 100: 1. The ratio can be adjusted between 50: 1-200: 1. The diameter of the separation tube is larger than the diameter of the blood perfusion tube to achieve the separation of the adsorbent from the blood.
  • the composition of the adsorbent in the adsorbent injection device 3 is a magnetic triiron tetroxide / aminated mesoporous silica composite material using amine-rich organics as a template and having regular mesoporous channels.
  • This embodiment specifically uses
  • the magnetic lead iron ion adsorbent prepared in Example 2 is a magnetic iron trioxide / hyperbranched polyamide mesoporous silica composite material.
  • the blood lead clearer When used, the blood lead clearer first connects the venous vessels of lead poisoning model pigs, and the blood enters the extracorporeal circulation machine 1 through the catheter to drive the blood circulation throughout the treatment process.
  • the extracorporeal circulation machine 1 and the adsorbent injection device 2 use Y
  • the catheter is connected to the blood perfusion tube in the contact device 3, and then the blood is contacted and mixed with the adsorbent introduced by the adsorbent injection device 2 through the Y-type catheter, and the adsorbent and blood are fully contacted in the blood perfusion tube (more than 10 minutes)
  • the diameter of the separation tube 5 is larger than the diameter of the blood perfusion tube to separate the adsorbent from the blood, and the blood flows back through the artery to lead poisoning
  • the model pig complete the blood lead removal process once and continue to repeat the steps to remove lead.
  • a model of lead poisoning of about 0.5 ppm was established for pigs by the food poisoning method.
  • an extracorporeal circulation machine 1 for removing blood lead in vitro from Example 7, first, an extracorporeal circulation machine 1, an adsorbent sampling device 2, a contact device 3, and a magnetic separation device were connected to construct a blood lead cleaning device. Then establish the extracorporeal circulation pathway of the pigs ( Figure 13-14) as follows: Anesthetize the pigs by injecting 3% sodium pentobarbital (1ml / kg) in the abdominal cavity, and keep anesthesia during the blood lead cleaning, and continuously inject 0.9% NaCl And 2.5% sodium pentobarbital.
  • the venous vessels are connected to a blood lead cleaning device and return to arterial blood after passing through a magnetic separation device.
  • the blood flow speed is 25ml / min
  • the circulation time is 50min
  • the amount of adsorbent is 1g
  • the blood volume of the lead poisoning model pig is about 3L
  • the ratio of adsorbent to blood volume can be between 1: 10-10: 1g / L
  • the wound was sutured after the operation, and the blood routine and blood lead removal efficiency of the model pigs with lead poisoning before and after the operation were examined.
  • the experimental results show that when the blood lead content in pigs is 500ppb, after one cleaning process, the blood lead removal efficiency can reach 75%.
  • the secondary treatment can continue to improve the blood lead removal rate (the calculation method of the removal rate is:
  • the blood before and after the operation was detected with an inductively coupled plasma spectrometer before and after the operation.
  • E is the blood lead removal efficiency (%)
  • C 0 is the blood lead concentration (ppb) before the operation
  • C 1 is the blood lead concentration (ppb) after the operation).
  • the adsorbent has a better separation effect, which shows the higher removal efficiency of the adsorbent and the blood lead remover.
  • the blood routine before and after cleaning shows that the blood inflammation is reduced after the removal of lead ions ( Figure 15), which reflects the blood The safety and efficiency of the adsorbent and blood lead remover in the process of removing blood lead.

Abstract

La présente invention concerne un dispositif d'élimination de plomb du sang pour l'élimination de plomb du sang in vitro. Le dispositif d'élimination de plomb du sang comprend : une unité de circulation extracorporelle (1), un dispositif d'alimentation en échantillon adsorbant (2), un dispositif de contact (3), et un dispositif de séparation magnétique qui sont reliés en séquence; un adsorbant est chargé dans le dispositif d'alimentation en échantillon adsorbant (2), et la composition de l'adsorbant est un matériau composite d'oxyde ferroferrique magnétique/silice mésoporeuse riche en amine qui prend une matière organique riche en amine comme agent de matrice et présente un canal mésoporeux ordinaire. Par rapport à un médicament oral, l'utilisation du dispositif d'élimination de plomb du sang permet d'éliminer directement les ions de plomb du sang en un court laps de temps au moyen d'une circulation sanguine extracorporelle, soulage rapidement l'état d'un patient souffrant d'un empoisonnement du sang par du plomb, et réduit les effets secondaires provoqués par la prise quotidienne de médicaments. Le dispositif d'élimination de plomb du sang a comme effets bénéfiques que la structure est simple, l'utilisation est pratique, et une position de travail peut être modifiée de manière souple, résolvant ainsi le problème selon lequel un dispositif de perfusion sanguine ne peut éliminer les ions de plomb dans les globules rouges du sang, améliorant l'efficacité de travail, étant approprié pour une large application, et présentant de larges perspectives d'application dans le domaine médical.
PCT/CN2018/103733 2018-08-27 2018-09-03 Dispositif d'élimination de plomb du sang pour l'élimination de plomb du sang in vitro WO2020042200A1 (fr)

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