WO2024021389A1 - 一种胰酶灭活支架引流管及其制备方法 - Google Patents

一种胰酶灭活支架引流管及其制备方法 Download PDF

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WO2024021389A1
WO2024021389A1 PCT/CN2022/133687 CN2022133687W WO2024021389A1 WO 2024021389 A1 WO2024021389 A1 WO 2024021389A1 CN 2022133687 W CN2022133687 W CN 2022133687W WO 2024021389 A1 WO2024021389 A1 WO 2024021389A1
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drainage tube
stent drainage
stent
pvc
inactivation layer
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PCT/CN2022/133687
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English (en)
French (fr)
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熊力
林良武
杨治平
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中南大学
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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
    • A61M27/00—Drainage appliance for wounds or the like, i.e. wound drains, implanted drains
    • A61M27/002—Implant devices for drainage of body fluids from one part of the body to another
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/1114—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis of the digestive tract, e.g. bowels or oesophagus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/041—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
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    • A61L29/106—Inorganic materials other than carbon
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    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
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    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C18/00—Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating
    • C23C18/16—Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by reduction or substitution, e.g. electroless plating
    • C23C18/31—Coating with metals
    • C23C18/38—Coating with copper
    • C23C18/40—Coating with copper using reducing agents
    • C23C18/405—Formaldehyde
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C18/00—Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating
    • C23C18/16—Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by reduction or substitution, e.g. electroless plating
    • C23C18/31—Coating with metals
    • C23C18/42—Coating with noble metals
    • C23C18/44—Coating with noble metals using reducing agents
    • C—CHEMISTRY; METALLURGY
    • C23—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; CHEMICAL SURFACE TREATMENT; DIFFUSION TREATMENT OF METALLIC MATERIAL; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL; INHIBITING CORROSION OF METALLIC MATERIAL OR INCRUSTATION IN GENERAL
    • C23C—COATING METALLIC MATERIAL; COATING MATERIAL WITH METALLIC MATERIAL; SURFACE TREATMENT OF METALLIC MATERIAL BY DIFFUSION INTO THE SURFACE, BY CHEMICAL CONVERSION OR SUBSTITUTION; COATING BY VACUUM EVAPORATION, BY SPUTTERING, BY ION IMPLANTATION OR BY CHEMICAL VAPOUR DEPOSITION, IN GENERAL
    • C23C18/00—Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating
    • C23C18/16—Chemical coating by decomposition of either liquid compounds or solutions of the coating forming compounds, without leaving reaction products of surface material in the coating; Contact plating by reduction or substitution, e.g. electroless plating
    • C23C18/48—Coating with alloys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A61L2300/104—Silver, e.g. silver sulfadiazine
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
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    • A61M2025/006—Catheters; Hollow probes characterised by structural features having a special surface topography or special surface properties, e.g. roughened or knurled surface

Definitions

  • the invention relates to the technical field of surgical medical instruments, and in particular to a pancreatic enzyme inactivated stent drainage tube and a preparation method thereof.
  • Pancreaticojejunostomy is known as "the first kiss in the world” and "the kiss of death”. Because once the pancreaticojejunostomy is not done well and pancreatic fistula occurs, a large amount of pancreatic enzymes (including amylase, protease, lipase, etc.) in the pancreatic juice will corrode the surrounding blood vessels and organs, causing bleeding and infection, and abdominal and Various systemic complications range from prolonged hospitalization to severe cases that can lead to rapid death. At present, various pancreaticojejunostomy techniques used in clinical applications may inevitably cause postoperative complications of pancreatic fistula.
  • pancreatic enzymes including amylase, protease, lipase, etc.
  • pancreatic fistula In order to reduce the possible adverse effects of pancreatic fistula, stent drainage tubes are often used for antihypertensive drainage. On the one hand, it reduces the risk of pancreatic fistula. The high pressure of pancreatic juice exerts a squeezing effect on the wound. On the other hand, it can prevent the pancreatic duct from being blocked, causing pancreatic juice to leak from the wound, causing adverse effects.
  • the purpose of the present invention is to provide a pancreatic enzyme-inactivated stent drainage tube with a simple structure, high efficiency, convenience, practicality, economy, and safety, so as to solve the defect of the existing stent drainage tube used for pancreaticojejunostomy that does not have inactivated pancreatic enzyme activity. Improve the safety of pancreaticojejunostomy and turn the "kiss of death" into the "kiss of life.”
  • this embodiment provides a trypsin-inactivated stent drainage tube.
  • the trypsin-inactivated stent drainage tube includes a stent drainage tube skeleton and a trypsin inactivation layer; the stent drainage tube skeleton is an outer surface It is a smooth tubular structure with a large number of wrinkles on the inner surface; the outer surface of the stent drainage tube skeleton is also designed with barbs for fixation and side holes for observation.
  • the skeleton of the stent drainage tube is made of 3D printing of transparent medical polymer materials.
  • the trypsin inactivation layer is prepared by an inactivation layer coated with nanometer Ag or/and Cu particles.
  • the present invention also provides a method for preparing the above-mentioned trypsin-inactivated stent drainage tube, which includes the following steps:
  • the trypsin-inactivated layer is coated on the inner and outer surfaces of the above-mentioned stent drainage tube skeleton to obtain a trypsin-inactivated stent drainage tube;
  • the coating method is any one or both of the ion exchange method and the chemical plating method.
  • the high molecular polymer material is polyvinyl chloride (PVC), and the specific steps in step (1) are as follows:
  • Step 1 Mix polyvinyl chloride and butylene adipate with a mass ratio of 1: (1 ⁇ 6) and dissolve it in tetrahydrofuran. The ratio of the mixture to tetrahydrofuran is 1: (1 ⁇ 4). Stir magnetically to form a uniform dispersion. The emulsion solution is left to stand for 1-3 hours to eliminate bubbles, form a sealed seal, and be used as skeleton printing ink;
  • Step 2 Use a UV 3D printer for molding and printing to prepare a PVC stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • polymer material is polyimide (PI), and the specific steps in step (1) are as follows:
  • Step 1 Weigh a certain amount of TFDB, 6FDA and DMAc in proportion. First put TFDB and DMAc into a flask and stir for 30-60 minutes to fully dissolve. Then add 6FDA into the flask in batches. Only the remaining part of 6FDA is added each time. One-half of the solution is stirred under argon protection for 12-24h to obtain a polyamic acid solution, then a certain amount of phthalic anhydride is added, and stirred for 10-20h to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink;
  • Step 2 Use a selective laser sintering 3D printer to perform thermal imidization molding printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • the preparation of the nano-Ag particle inactivation layer of the trypsin-inactivated stent drainage tube made of PI includes the following steps:
  • stent drainage tube frame made of PI Immerse the stent drainage tube frame made of PI into a certain molar concentration of hot alkali solution (NaOH, KOH, 2.5 ⁇ 5M, 40 ⁇ 70°C) for 10 ⁇ 30 minutes to make the polyimide on the inner and outer surface of the polyimide tube
  • the amine opens the ring and complexes with alkali metal ions to form polyamic acid salt; after treatment, it is washed with deionized water to remove the surface alkali solution, and then immersed in a certain molar concentration of silver ammonia solution (0.04 ⁇ 0.5M) at room temperature.
  • the preparation of the nano-Ag particle inactivation layer of the trypsin-inactivated stent drainage tube made of PVC includes the following steps:
  • the PVC stent drainage tube skeleton is subjected to stress relief, oil removal, roughening and sensitization pretreatment to obtain a PVC stent drainage tube skeleton with uniform and rough inner and outer surfaces, and then the stent drainage tube skeleton is immersed in a chemical silver plating solution (nitric acid Silver: 0.001 ⁇ 0.1M, sodium thiosulfate: 10 ⁇ 50mg/L, sodium hydroxide: 0.001 ⁇ 0.01M, ammonia content: 0.1 ⁇ 1.0%, glucose: 0.01 ⁇ 0.1M), at a temperature of 20-40 °C, perform electroless silver plating for 10-20 minutes, take it out, clean it with deionized water, and dry it at room temperature to obtain a PVC stent drainage tube with an inactivation layer of nano-Ag particles on the inner and outer surfaces.
  • a chemical silver plating solution nitric acid Silver: 0.001 ⁇ 0.1M, sodium thiosulfate: 10 ⁇ 50mg/L, sodium hydroxide
  • the preparation of the nano-Cu particle inactivation layer of the trypsin-inactivated stent drainage tube made of PI includes the following steps:
  • the stent drainage tube skeleton is immersed in the chemical copper plating solution (copper sulfate pentahydrate: 0.001 ⁇ 0.1M, ethylenediaminetetraacetic acid Disodium: 0.01 ⁇ 0.1M, Thiourea: 0.1 ⁇ 1mg/L, Potassium sodium tartrate: 0.005 ⁇ 0.02M, Sodium hydroxide: 0.01 ⁇ 0.05M, Sodium lauryl sulfate: 10 ⁇ 50mg/L, Formaldehyde: 8 ⁇ 20mL/L, pH value: 11 ⁇ 13.5), perform electroless copper plating at a temperature of 20-80°C for 10-20 minutes, take it out, wash it with deionized water, and dry it at room temperature to obtain nano-Cu plated surfaces on the inner and outer surfaces.
  • the PI material stent drainage tube of the particle inactivation layer perform electroless copper plating at a temperature of 20-80°C for 10-20 minutes, take it out, wash it with deionized water, and dry it at
  • the preparation of the nano-Cu particle inactivation layer of the trypsin-inactivated stent drainage tube made of PVC includes the following steps:
  • the stent drainage tube skeleton is immersed in the electroless copper plating solution (copper sulfate pentahydrate: 0.001 ⁇ 0.01M, potassium tartrate Sodium: 0.005 ⁇ 0.02M, sodium hydroxide: 0.01 ⁇ 0.05M, ethylenediaminetetraacetic acid: 0.01 ⁇ 0.05M, formaldehyde: 8 ⁇ 20mL/L, pH value: 11 ⁇ 13.5), at a temperature of 20-80 °C, conduct electroless copper plating for 5-20 minutes, take it out, clean it with deionized water, and dry it at room temperature to obtain a PVC stent drainage tube with an inactivation layer of nano-Cu particles on the inner and outer surfaces.
  • the electroless copper plating solution copper sulfate pentahydrate: 0.001 ⁇ 0.01M, potassium tartrate Sodium: 0.005 ⁇ 0.02M, sodium hydroxide: 0.01 ⁇ 0.05M, ethylenediaminetetraacetic acid: 0.01 ⁇ 0.05M, formaldehyde:
  • the preparation of the nano-Cu@Ag composite inactivation layer of the trypsin-inactivated stent drainage tube made of PI or PVC includes the following steps:
  • pancreatic inactivation layer of nano-Ag and Cu particles on the inner and outer surfaces of the drainage tube of the pancreatic inactivation stent changes the corrosive properties of pancreatic enzymes flowing through the pancreaticojejunostomy in situ, thereby reducing the complications of pancreatic fistula after pancreaticojejunostomy and reducing pancreatic fistula complications.
  • the possible adverse effects of fistula improve the safety of pancreaticojejunostomy, and turn the "kiss of death" into the "kiss of life”;
  • the outer surface of the stent drainage tube is also designed with an inactivation layer in order to effectively inactivate the pancreatic juice flowing through the wound, thereby once again reducing the corrosive effect of the pancreatic juice on the wound;
  • Figure 1 is a schematic side view of a pancreatic enzyme inactivated stent drainage tube for pancreaticojejunostomy provided by an embodiment of the present invention
  • Figure 2 is a schematic cross-sectional structural diagram of a pancreatic enzyme inactivated stent drainage tube for pancreaticojejunostomy provided by an embodiment of the present invention.
  • pancreaticojejunostomy techniques used in clinical applications may inevitably cause postoperative complications of pancreatic fistula.
  • stent drainage tubes are often used for antihypertensive drainage. On the one hand, it reduces the risk of pancreatic juice leakage.
  • the squeezing effect of high pressure on the wound can, on the other hand, prevent the pancreatic duct from being blocked, causing pancreatic juice to leak from the wound, causing adverse effects.
  • the use of stent drainage tubes has reduced the risk of pancreaticojejunostomy surgery to a certain extent, the corrosive effect of pancreatic enzymes on the wound and surrounding tissues and organs is still inevitable.
  • the present invention provides a trypsin-inactivated stent drainage tube and a preparation method thereof.
  • TFDB, 6FDA and DMAc Weigh a certain amount of TFDB, 6FDA and DMAc, first put TFDB and DMAc into a flask and stir for 30 minutes to fully dissolve, then add 6FDA into the flask in batches, adding only one-half of the remaining 6FDA each time. Under argon protection, stir for 24 hours to obtain a polyamic acid solution, add a certain amount of phthalic anhydride, and stir for 20 hours to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink.
  • a selective laser sintering 3D printer was used for molding and printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • TFDB, 6FDA and DMAc Weigh a certain amount of TFDB, 6FDA and DMAc. First put TFDB and DMAc into a flask and stir for 60 minutes to fully dissolve. Then add 6FDA into the flask in batches. Only add one-half of the remaining 6FDA each time. Under argon protection, stir for 12 hours to obtain a polyamic acid solution. Add a certain amount of phthalic anhydride and stir for 10 hours to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink. A selective laser sintering 3D printer was used for molding and printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • TFDB, 6FDA and DMAc Weigh a certain amount of TFDB, 6FDA and DMAc, first put TFDB and DMAc into a flask and stir for 40 minutes to fully dissolve, then add 6FDA into the flask in batches, adding only one-half of the remaining 6FDA each time. Under argon protection, stir for 18 hours to obtain a polyamic acid solution. Add a certain amount of phthalic anhydride and stir for 15 hours to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink. A selective laser sintering 3D printer was used for molding and printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • the PVC stent drainage tube skeleton is subjected to stress relief, oil removal, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in a chemical silver plating solution (silver nitrate: 0.001M, sodium thiosulfate: 10mg /L, sodium hydroxide: 0.001M, ammonia content: 0.1%, glucose: 0.01M), conduct chemical silver plating at a temperature of 20°C for 20 minutes, take it out, wash with deionized water, and dry at room temperature to obtain the inner and outer surfaces.
  • a chemical silver plating solution silver nitrate: 0.001M, sodium thiosulfate: 10mg /L, sodium hydroxide: 0.001M, ammonia content: 0.1%, glucose: 0.01M
  • conduct chemical silver plating at a temperature of 20°C for 20 minutes, take it out, wash with deionized water, and dry at room temperature to obtain the inner and outer surfaces.
  • the PVC stent drainage tube skeleton is subjected to stress relief, oil removal, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in a chemical silver plating solution (silver nitrate: 0.05M, sodium thiosulfate: 25mg /L, sodium hydroxide: 0.005M, ammonia content: 0.5%, glucose: 0.03M), conduct chemical silver plating at a temperature of 25°C for 15 minutes, take it out, rinse with ionized water, and dry at room temperature to obtain the inner and outer surface plating.
  • a chemical silver plating solution silver nitrate: 0.05M, sodium thiosulfate: 25mg /L, sodium hydroxide: 0.005M, ammonia content: 0.5%, glucose: 0.03M
  • the PVC stent drainage tube skeleton is subjected to stress relief, degreasing, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in a chemical silver plating solution (silver nitrate: 0.1M, sodium thiosulfate: 50mg /L, sodium hydroxide: 0.01M, ammonia content: 1.0%, glucose: 0.1M), conduct chemical silver plating at a temperature of 40°C for 10 minutes, take it out, clean it with deionized water, and dry it at room temperature to obtain the inner and outer surfaces.
  • a chemical silver plating solution silver nitrate: 0.1M, sodium thiosulfate: 50mg /L, sodium hydroxide: 0.01M, ammonia content: 1.0%, glucose: 0.1M
  • conduct chemical silver plating at a temperature of 40°C for 10 minutes take it out, clean it with deionized water, and dry it at room temperature to obtain the inner and outer surfaces.
  • TFDB, 6FDA and DMAc Weigh a certain amount of TFDB, 6FDA and DMAc, first put TFDB and DMAc into a flask and stir for 30 minutes to fully dissolve, then add 6FDA into the flask in batches, adding only one-half of the remaining 6FDA each time. Under argon protection, stir for 24 hours to obtain a polyamic acid solution, add a certain amount of phthalic anhydride, and stir for 20 hours to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink.
  • a selective laser sintering 3D printer was used for molding and printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • the stent drainage tube frame made of PI is subjected to stress relief, degreasing, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in the chemical copper plating solution (copper sulfate pentahydrate: 0.001M, ethylenediamine tetrahydrofuran) Disodium acetate: 0.01M, Thiourea: 0.1mg/L, Potassium sodium tartrate: 0.005M, Sodium hydroxide: 0.01M, Sodium lauryl sulfate: 10mg/L, Formaldehyde: 8mL/L, pH value: 11 ), conduct electroless copper plating for 20 minutes at a temperature of 20°C, take it out, clean it with deionized water, and dry it at room temperature to obtain a PI material stent drainage tube with an inactivation layer of nano-Cu particles on the inner and outer surfaces.
  • the chemical copper plating solution copper sulfate pentahydrate:
  • TFDB, 6FDA and DMAc Weigh a certain amount of TFDB, 6FDA and DMAc. First put TFDB and DMAc into a flask and stir for 60 minutes to fully dissolve. Then add 6FDA into the flask in batches. Only add one-half of the remaining 6FDA each time. Under argon protection, stir for 12 hours to obtain a polyamic acid solution. Add a certain amount of phthalic anhydride and stir for 10 hours to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink. A selective laser sintering 3D printer was used for molding and printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • the stent drainage tube skeleton made of PI is subjected to stress relief, degreasing, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in a chemical copper plating solution (copper sulfate pentahydrate: 0.1M, ethylenediamine tetrahydrofuran) Disodium acetate: 0.1M, thiourea: 1mg/L, potassium sodium tartrate: 0.02M; sodium hydroxide: 0.05M, sodium lauryl sulfate: 50mg/L, formaldehyde: 20mL/L, pH value: 13.5) , conduct electroless copper plating for 10 minutes at a temperature of 80°C, take it out, clean it with deionized water, and dry it at room temperature to obtain a PI material stent drainage tube coated with a nano-Cu particle inactivation layer on the inner and outer surfaces.
  • a chemical copper plating solution copper sulfate pentahydrate:
  • TFDB, 6FDA and DMAc Weigh a certain amount of TFDB, 6FDA and DMAc, first put TFDB and DMAc into a flask and stir for 40 minutes to fully dissolve, then add 6FDA into the flask in batches, adding only one-half of the remaining 6FDA each time. Under argon protection, stir for 18 hours to obtain a polyamic acid solution. Add a certain amount of phthalic anhydride and stir for 15 hours to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink. A selective laser sintering 3D printer was used for molding printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • the stent drainage tube frame made of PI is subjected to stress relief, degreasing, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in the chemical copper plating solution (copper sulfate pentahydrate: 0.005M, ethylenediamine tetrahydrofuran) Disodium acetate: 0.05M, Thiourea: 0.5mg/L, Potassium sodium tartrate: 0.01M, Sodium hydroxide: 0.03M, Sodium lauryl sulfate: 30mg/L, Formaldehyde: 15mL/L, pH value: 12.5 ) was injected into the skeleton of the stent drainage tube, and electroless copper plating was performed at a temperature of 30°C for 15 minutes, then taken out, washed with deionized water, and dried at room temperature to obtain a PI material stent drainage tube coated with a nano-Cu particle inactivation layer on the inner and outer surfaces.
  • the PVC stent drainage tube skeleton is subjected to stress relief, oil removal, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in the chemical copper plating solution (copper sulfate pentahydrate: 0.001M, potassium sodium tartrate: 0.005M, sodium hydroxide: 0.01M, ethylenediaminetetraacetic acid: 0.01M, formaldehyde: 8mL/L, pH value: 11), conduct electroless copper plating at 20°C for 20 minutes, take out and deionize water Wash and dry at room temperature to obtain a PVC stent drainage tube coated with a nano-Cu particle inactivation layer on the inner and outer surfaces.
  • the chemical copper plating solution copper sulfate pentahydrate: 0.001M, potassium sodium tartrate: 0.005M, sodium hydroxide: 0.01M, ethylenediaminetetraacetic acid: 0.01M, formaldehyde: 8mL/L, pH value:
  • a UV 3D printer is used for molding printing to prepare a PVC material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • the PVC stent drainage tube skeleton is subjected to stress relief, degreasing, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in an electroless copper plating solution (copper sulfate pentahydrate: 0.01M, potassium sodium tartrate: 0.02M, sodium hydroxide: 0.05M, ethylenediaminetetraacetic acid: 0.05M, formaldehyde: 20mL/L, pH value: 13.5), perform electroless copper plating at a temperature of 80°C for 5 minutes, take out and deionized water Wash and dry at room temperature to obtain a PVC stent drainage tube coated with a nano-Cu particle inactivation layer on the inner and outer surfaces.
  • an electroless copper plating solution copper sulfate pentahydrate: 0.01M, potassium sodium tartrate: 0.02M, sodium hydroxide: 0.05M, ethylenediaminetetraacetic acid: 0.05M, formaldehyde: 20mL
  • the PVC stent drainage tube skeleton is subjected to stress relief, oil removal, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in the chemical copper plating solution (copper sulfate pentahydrate: 0.005M, potassium sodium tartrate: 0.01M, sodium hydroxide: 0.03M, ethylenediaminetetraacetic acid: 0.03M, formaldehyde: 15mL/L, pH value: 12.5) was injected into the stent drainage tube skeleton, and electroless copper plating was performed at 35°C for 15 minutes. Take it out, clean it with deionized water, and dry it at room temperature to obtain a PVC stent drainage tube with an inactivation layer of nano-Cu particles on the inner and outer surfaces.
  • the chemical copper plating solution copper sulfate pentahydrate: 0.005M, potassium sodium tartrate: 0.01M, sodium hydroxide: 0.03M, ethylenediaminetetraacetic acid: 0.
  • TFDB, 6FDA and DMAc Weigh a certain amount of TFDB, 6FDA and DMAc. First put TFDB and DMAc into a flask and stir for 60 minutes to fully dissolve. Then add 6FDA into the flask in batches. Only add one-half of the remaining 6FDA each time. Under argon protection, stir for 12 hours to obtain a polyamic acid solution. Add a certain amount of phthalic anhydride and stir for 10 hours to obtain a phthalic anhydride-terminated polyamide solution, which can be used as a 3D printing ink. A selective laser sintering 3D printer was used for molding and printing to prepare a PI material stent drainage tube skeleton with a smooth outer surface and a large number of wrinkles on the inner surface.
  • the stent drainage tube frame made of PI is subjected to stress relief, degreasing, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in an electroless copper plating solution (copper sulfate pentahydrate: 0.1M, ethylenediamine tetrahydrofuran) Disodium acetate: 0.1M, thiourea: 1mg/L, potassium sodium tartrate: 0.02M; sodium hydroxide: 0.05M, sodium lauryl sulfate: 50mg/L, formaldehyde: 20mL/L, pH value: 13.5) , conduct electroless copper plating for 10 minutes at a temperature of 80°C, take it out, clean it with deionized water, and dry it at room temperature to obtain a PI material stent drainage tube with an inactivation layer of nano-Cu particles on the inner and outer surfaces, and then immerse it in electroless silver plating again.
  • an electroless copper plating solution copper
  • the PVC stent drainage tube skeleton is subjected to stress relief, oil removal, roughening and sensitization pretreatment to obtain uniform and rough internal and external surfaces, and then immersed in the chemical copper plating solution (copper sulfate pentahydrate: 0.005M, potassium sodium tartrate: 0.01M, sodium hydroxide: 0.03M, ethylenediaminetetraacetic acid: 0.03M, formaldehyde: 15mL/L, pH value: 12.5) was injected into the stent drainage tube skeleton, and electroless copper plating was performed at 35°C for 15 minutes.
  • the chemical copper plating solution copper sulfate pentahydrate: 0.005M, potassium sodium tartrate: 0.01M, sodium hydroxide: 0.03M, ethylenediaminetetraacetic acid: 0.03M, formaldehyde: 15mL/L, pH value: 12.5
  • electroless copper plating was performed at 35°C for 15 minutes.
  • PVC stent drainage tube with an inactivation layer of nano-Cu particles on the inner and outer surfaces Take it out, clean it with deionized water, and dry it at room temperature to obtain a PVC stent drainage tube with an inactivation layer of nano-Cu particles on the inner and outer surfaces, and then immerse it in the chemical silver plating solution (silver nitrate: 0.1M, sodium thiosulfate: 50mg/ L, sodium hydroxide: 0.01M, ammonia content: 1.0%, glucose: 0.1M), conduct chemical silver plating at a temperature of 40°C for 5 minutes, take it out, clean it with deionized water, and dry it at room temperature to obtain the inner and outer surface plating.
  • PVC stent drainage tube with nano-Cu@Ag particle composite inactivation layer Take it out, clean it with deionized water, and dry it at room temperature to obtain the inner and outer surface plating.
  • pancreatic inactivation layer of nano-Ag and Cu particles on the inner and outer surfaces of the drainage tube of the pancreatic inactivation stent changes the corrosive properties of pancreatic enzymes flowing through the pancreaticojejunostomy in situ, thereby reducing the complications of pancreatic fistula after pancreaticojejunostomy and reducing pancreatic fistula complications.
  • the possible adverse effects of fistula improve the safety of pancreaticojejunostomy, and turn the "kiss of death" into the "kiss of life”;
  • the outer surface of the stent drainage tube is also designed with an inactivation layer in order to effectively inactivate the pancreatic juice flowing through the wound, thereby once again reducing the corrosive effect of the pancreatic juice on the wound;

Abstract

一种胰酶灭活支架引流管（1）及其制备方法，支架引流管（1）由支架引流管骨架（4）和胰酶灭活层（2、3）组成，支架引流管骨架（4）采用透明医用聚氯乙烯（PVC）或聚酰亚胺（PI）材料通过3D打印技术制备而成，为外表面光滑、内表面呈褶皱的管状结构；灭活层（2、3）由褶皱结构的纳米Ag、Cu颗粒层的一种或两种组成；灭活层（2、3）包覆在管状结构骨架的内外表面；外表面设计有用于固定的倒刺（5）、用于观察的侧孔等；以解决现有胰肠吻合术用支架引流管不具有灭活胰酶活性的缺陷，提高胰肠吻合术的安全性。

Description

一种胰酶灭活支架引流管及其制备方法
相关申请的交叉引用
本申请要求2022年07月25日提交的中国专利申请202210877645.8的权益，该申请的内容通过引用被合并于本文。
技术领域
本发明涉及手术用医疗器械技术领域，特别涉及一种胰酶灭活支架引流管及其制备方法。
背景技术
胰肠吻合手术被誉为“天下第一吻”、“死亡之吻”。因为一旦胰肠吻合做得不好，发生胰瘘情况，胰液中大量的胰酶(包括淀粉酶、蛋白酶、脂肪酶等)就会腐蚀周围的血管和脏器，从而引发出血感染，出现腹部和全身的各种并发症，轻则延长住院时间，重的可导致快速死亡。目前，临床应用的多种胰肠吻合技术不可避免地都可能发生术后胰瘘并发症，为了减轻胰瘘可能带来的不利影响，常采用搭支架引流管进行降压引流，一方面减小胰液因高的压力对创口产生的挤压作用，另一方面可防止胰腺管的阻塞，导致胰液从创口泄露，带来不利影响。
目前，虽然采用搭支架引流管的方式，在一定程度上降低了胰肠吻合手术的风险，但仍然不可避免的会发生胰酶对创口及其周围组织和器官的腐蚀影响。这主要是因为现有的支架引流管仅仅是起到导流 的作用，并不具备改变流经吻合部位胰酶腐蚀性能的能力，从而不可彻底避免“死亡之吻”的发生。因此，为了彻底解决这一问题，需要研发一种可以改变流经吻合部位胰酶腐蚀性能的支架引流管，即研发一种能使胰酶灭活的支架引流管来解决上述问题。
发明内容
本发明的目的是提供一种结构简单、高效、方便、实用、经济、安全的胰酶灭活支架引流管，解决现有胰肠吻合术用支架引流管不具有灭活胰酶活性的缺陷，提高胰肠吻合术的安全性，将“死亡之吻”变为“生命之吻”。
为了实现上述目的，本实施例提供了一种胰酶灭活支架引流管，所述胰酶灭活支架引流管包括支架引流管骨架和胰酶灭活层；所述支架引流管骨架为外表面光滑、内表面具有大量褶皱层的管状结构；所述支架引流管骨架的外表面还设计有用于固定的倒刺、用于观察的侧孔。
进一步的，所述支架引流管骨架采用透明医用高分子聚合物材料3D打印制成。
进一步的，所述胰酶灭活层由镀有纳米Ag或/和Cu颗粒的灭活层制备。
基于一个发明总的构思，本发明还提供了一种上述胰酶灭活支架引流管的制备方法，包括如下步骤：
(1)、采用3D打印的方法制备高分子聚合物材料的支架引流管骨 架；
(2)、胰酶灭活层包覆在上述支架引流管骨架的内外表面，获得胰酶灭活支架引流管；所述包覆方式为离子交换法、化学镀法中的任意一种或两种方法：
进一步的，所述高分子聚合物材料为聚氯乙烯(PVC)，步骤(1)中具体步骤如下：
步骤一、将质量比为1：(1～6)的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：(1～4)，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水；
步骤二、采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质的支架引流管骨架。
进一步的，所述高分子聚合物材料为聚酰亚胺(PI)，步骤(1)中具体步骤如下：
以4,4'-六氟亚异丙基-邻苯二甲酸酐(6FDA)、2,2'-二三氟甲基-联苯二胺(TFDB)以及N,N'-二甲基乙酰胺(DMAc)为原材料；
步骤一、按比例称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌30-60min充分溶解后，再把6FDA分数次加入到烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，搅拌12-24h得到聚酰胺酸溶液，再加入一定量的苯酐，搅拌10-20h得到苯酐封端的聚酰胺溶液，用作3D打印墨水；
步骤二、采用选择性激光烧结3D打印机进行热亚胺化成型打印， 制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
进一步的，PI材质胰酶灭活支架引流管的纳米Ag颗粒灭活层制备，包括如下步骤：
将PI材质的支架引流管骨架浸入一定摩尔浓度的热碱液(NaOH、KOH，2.5～5M、40～70℃)中，浸泡10～30min，使聚酰亚胺管内外表面层的聚酰亚胺开环，并与碱金属离子络合生成聚酰胺酸盐；处理完后用去离子水清洗，除去表面碱溶液，再浸入一定摩尔浓度的银氨溶液(0.04～0.5M)中，室温下进行离子交换5～30min，取出、去离子水清洗、室温晾干，于200～320℃下进行热亚胺化还原处理1～2h，获得内外表面镀有纳米Ag颗粒灭活层的PI材质的支架引流管。
进一步的，PVC材质胰酶灭活支架引流管的纳米Ag颗粒灭活层制备，包括如下步骤：
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到内外表面均匀粗糙的PVC材质的支架引流管骨架，再将支架引流管骨架浸入化学镀银液(硝酸银:0.001～0.1M，硫代硫酸钠:10～50mg/L，氢氧化钠：0.001～0.01M，氨水含量：0.1～1.0％，葡萄糖：0.01～0.1M)中，在温度为20-40℃下，进行化学镀银10-20min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Ag颗粒灭活层的PVC材质的支架引流管。
进一步的，PI材质胰酶灭活支架引流管的纳米Cu颗粒灭活层制备，包括如下步骤：
将PI材质支架引流管骨架进行去应力、除油、粗化和敏化预处 理后，再将支架引流管骨架浸入化学镀铜液(五水合硫酸铜:0.001～0.1M，乙二胺四乙酸二钠:0.01～0.1M，硫脲:0.1～1mg/L，酒石酸钾钠：0.005～0.02M，氢氧化钠：0.01～0.05M，十二烷基硫酸钠:10～50mg/L，甲醛：8～20mL/L，pH值：11～13.5)中，在温度为20-80℃下，进行化学镀铜10-20min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PI材质的支架引流管。
进一步的，PVC材质胰酶灭活支架引流管的纳米Cu颗粒灭活层制备，包括如下步骤：
将PVC材质支架引流管骨架进行去应力、除油、粗化和敏化等内表面预处理后，再将支架引流管骨架浸入化学镀铜液(五水合硫酸铜:0.001～0.01M，酒石酸钾钠：0.005～0.02M，氢氧化钠：0.01～0.05M，乙二胺四乙酸:0.01～0.05M，甲醛：8～20mL/L，pH值：11～13.5)中，在温度为20-80℃下，进行化学镀铜5-20min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PVC材质支架引流管。
进一步的，PI或PVC材质胰酶灭活支架引流管的纳米Cu@Ag复合灭活层制备，包括如下步骤：
将镀有Cu灭活层的PI或PVC材质胰酶灭活支架引流管去离子水清洗、室温晾干后，再次浸入化学镀银液(硝酸银:0.001～0.1M，硫代硫酸钠:10～50mg/L，氢氧化钠：0.001～0.01M，氨水含量：0.1～1.0％，葡萄糖：0.01～0.1M)中，在温度为20-40℃下，进行化学镀银5-15min，取出、去离子水清洗、室温晾干，获得内外表面镀 有纳米Cu@Ag颗粒复合灭活层的PI或PVC材质的支架引流管骨架。
本发明的胰酶灭活支架引流管在结构和技术等方面带来如下几个方面的有益效果：
(1)通过胰酶灭活支架引流管内外表面的纳米Ag、Cu颗粒灭活层原位改变流经胰肠吻合口胰酶的腐蚀性能，降低胰肠吻合术后胰瘘并发症，减轻胰瘘可能带来的不利影响，提高胰肠吻合术的安全性，将“死亡之吻”变为“生命之吻”；
(2)采用3D打印技术实现支架引流管精确制备褶皱结构内表面，可大幅度增加内表面灭活层的有效面积。一方面确保伤口愈合周期内(约7天)灭活层的有效性，提高胰液灭活的效率，从而降低肠道中胰液反流时对创口的腐蚀作用，另一方面采用3D打印技术可以快速、精准、面积可控地制备褶皱结构，有利于其大规模工业化生产，降低褶皱结构制备的成本；
(3)支架引流管的外表面也设计成有灭活层的目的是能有效地对流经创口的胰液进行二次灭活，从而再次降低胰液对创口的腐蚀作用；
(4)采用无毒、生物相容性好的PI和PVC等常规有机医用材料制备支架引流管骨架，制作成本低，适用于大规模生产与推广。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描 述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明实施例提供的胰肠吻合术的胰酶灭活支架引流管侧面示意图；
图2为本发明实施例提供的胰肠吻合术的胰酶灭活支架引流管截面结构示意图。
附图标记说明
1、支架引流管；2、内表面褶皱结构灭活层；3、外表面光滑灭活层；4、骨架层；5倒刺。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚，下面将结合附图及具体实施例进行详细描述。
除非另有定义，下文中所使用的所有专业术语与本领域技术人员通常理解含义相同。本文中所使用的专业术语只是为了描述具体实施例的目的，并不是旨在限制本发明的保护范围。
除非另有特别说明，本发明中用到的各种原材料、试剂、仪器和设备等均可通过市场购买得到或者可通过现有方法制备得到。
临床应用的多种胰肠吻合技术不可避免地都可能发生术后胰瘘并发症，为了减轻胰瘘可能带来的不利影响，常采用搭支架引流管进行降压引流，一方面减小胰液因高的压力对创口产生的挤压作用，另 一方面可防止胰腺管的阻塞，导致胰液从创口泄露，带来不利影响。目前，虽然采用搭支架引流管的方式，在一定程度上降低了胰肠吻合手术的风险，但仍然不可避免的会发生胰酶对创口及其周围组织和器官的腐蚀影响。这主要是因为现有的支架引流管仅仅是起到导流的作用，并不具备改变流经吻合部位胰酶腐蚀性能的能力，从而不可彻底避免“死亡之吻”的发生。
本发明针对上述的技术问题，提供了一种胰酶灭活支架引流管及其制备方法。
实施例1
称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌30min充分溶解后，再把6FDA分数次加入到此烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，揽拌24h得到聚酰胺酸溶液，在加入一定量的苯酐，搅拌20h得到苯酐封端的聚酰胺溶液，用作3D打印墨水。采用选择性激光烧结3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
将PI材质的支架引流管骨架浸入一定摩尔浓度的热碱液(2.5M、40℃的NaOH溶液)中，浸泡30min，使聚酰亚胺管内表面层的聚酰亚胺开环，并与碱金属离子络合生成聚酰胺酸盐。处理完后用去离子水清洗，除去表面碱溶液，再浸入一定摩尔浓度的银氨溶液(0.04M)中，室温下进行离子交换30min，取出，用去离子水清洗、室温晾干，于300℃下进行热亚胺化还原处理1h，获得内外表面镀有纳 米Ag颗粒灭活层的PI材质的支架引流管。
实施例2
称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌60min充分溶解后，再把6FDA分数次加入到此烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，揽拌12h得到聚酰胺酸溶液，在加入一定量的苯酐，搅拌10h得到苯酐封端的聚酰胺溶液，用作3D打印墨水。采用选择性激光烧结3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
将PI材质的支架引流管骨架浸入一定摩尔浓度的热碱液(4.0M、70℃的NaOH溶液)中，浸泡10min，使聚酰亚胺管内表面层的聚酰亚胺开环，并与碱金属离子络合生成聚酰胺酸盐。处理完后用去离子水清洗，除去表面碱溶液，再浸入一定摩尔浓度的银氨溶液(0.3M)中，室温下进行离子交换5min，取出，用去离子水清洗、室温晾干，于260℃下进行热亚胺化还原处理2h，获得内外表面镀有纳米Ag颗粒灭活层的PI材质支架引流管。
实施例3
称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌40min充分溶解后，再把6FDA分数次加入到此烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，揽拌 18h得到聚酰胺酸溶液，在加入一定量的苯酐，搅拌15h得到苯酐封端的聚酰胺溶液，用作3D打印墨水。采用选择性激光烧结3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PI材质支架引流管骨架。
将PI材质的支架引流管骨架浸入一定摩尔浓度的热碱液(2.5M、40℃的KOH溶液)中，浸泡30min，使聚酰亚胺管内表面层的聚酰亚胺开环，并与碱金属离子络合生成聚酰胺酸盐。处理完后用去离子水清洗，除去表面碱溶液，再浸入一定摩尔浓度的银氨溶液(0.04M)中，室温下进行离子交换30min，取出，用去离子水清洗、室温晾干，于300℃下进行热亚胺化还原处理1h，获得内外表面镀有纳米Ag颗粒灭活层的PI材质支架引流管。
实施例4
将质量比为1：1的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：1，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水。采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质的支架引流管骨架。
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀银液(硝酸银：0.001M，硫代硫酸钠：10mg/L，氢氧化钠：0.001M，氨水含量：0.1％，葡萄糖：0.01M)中，在温度为20℃下，进行化学镀银20min， 取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Ag颗粒灭活层的PVC材质支架引流管。
实施例5
将质量比为1：3的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：2，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水。采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质的支架引流管骨架。
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀银液(硝酸银：0.05M，硫代硫酸钠：25mg/L，氢氧化钠：0.005M，氨水含量：0.5％，葡萄糖：0.03M)中，在温度为25℃下，进行化学镀银15min，取出、离子水清洗、室温晾干，获得内外表面镀有纳米Ag颗粒灭活层的PVC材质支架引流管。
实施例6
将质量比为1：6的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：4，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水。采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质支架引流管骨架。
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀银液(硝酸银：0.1M，硫代硫酸钠：50mg/L，氢氧化钠：0.01M，氨水含量：1.0％，葡萄糖：0.1M)中，在温度为40℃下，进行化学镀银10min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Ag颗粒灭活层的PVC材质支架引流管。
实施例7
称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌30min充分溶解后，再把6FDA分数次加入到此烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，揽拌24h得到聚酰胺酸溶液，在加入一定量的苯酐，搅拌20h得到苯酐封端的聚酰胺溶液，用作3D打印墨水。采用选择性激光烧结3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
将PI材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.001M，乙二胺四乙酸二钠：0.01M，硫脲:0.1mg/L，酒石酸钾钠：0.005M，氢氧化钠：0.01M，十二烷基硫酸钠：10mg/L，甲醛：8mL/L，pH值：11)中，在温度为20℃下，进行化学镀铜20min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PI材质支架引流管。
实施例8
称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌60min充分溶解后，再把6FDA分数次加入到此烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，揽拌12h得到聚酰胺酸溶液，在加入一定量的苯酐，搅拌10h得到苯酐封端的聚酰胺溶液，用作3D打印墨水。采用选择性激光烧结3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
将PI材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.1M，乙二胺四乙酸二钠：0.1M，硫脲：1mg/L，酒石酸钾钠：0.02M；氢氧化钠：0.05M，十二烷基硫酸钠：50mg/L，甲醛：20mL/L，pH值：13.5)中，在温度为80℃下，进行化学镀铜10min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PI材质支架引流管。
实施例9
称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌40min充分溶解后，再把6FDA分数次加入到此烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，揽拌18h得到聚酰胺酸溶液，在加入一定量的苯酐，搅拌15h得到苯酐封端的聚酰胺溶液，用作3D打印墨水。采用选择性激光烧结3D打印机 进行成型打印，制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
将PI材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.005M，乙二胺四乙酸二钠：0.05M，硫脲：0.5mg/L，酒石酸钾钠：0.01M，氢氧化钠：0.03M，十二烷基硫酸钠：30mg/L，甲醛：15mL/L，pH值：12.5)注入支架引流管骨架中，在温度为30℃下，进行化学镀铜15min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PI材质支架引流管。
实施例10
将质量比为1：1的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：1，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水。采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质的支架引流管骨架。
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.001M，酒石酸钾钠：0.005M，氢氧化钠：0.01M，乙二胺四乙酸：0.01M，甲醛：8mL/L，pH值：11)中，在温度为20℃下，进行化学镀铜20min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PVC材质支架引流管。
实施例11
将质量比为1：3的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：2，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水。采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质支架引流管骨架。
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.01M，酒石酸钾钠：0.02M，氢氧化钠：0.05M，乙二胺四乙酸：0.05M，甲醛：20mL/L，pH值：13.5)中，在温度为80℃下，进行化学镀铜5min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PVC材质支架引流管。
实施例12
将质量比为1：6的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：4，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水。采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质的支架引流管骨架。
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.005M，酒石酸钾钠：0.01M，氢氧化钠：0.03M，乙二胺 四乙酸：0.03M，甲醛：15mL/L，pH值：12.5)注入支架引流管骨架中，在温度为35℃下，进行化学镀铜15min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PVC材质支架引流管。
实施例13
称量一定量的TFDB、6FDA和DMAc，先将TFDB和DMAc放入烧瓶中搅拌60min充分溶解后，再把6FDA分数次加入到此烧瓶中，每次只加6FDA剩余部分的二分之一，在氩气保护下，揽拌12h得到聚酰胺酸溶液，在加入一定量的苯酐，搅拌10h得到苯酐封端的聚酰胺溶液，用作3D打印墨水。采用选择性激光烧结3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
将PI材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.1M，乙二胺四乙酸二钠：0.1M，硫脲：1mg/L，酒石酸钾钠：0.02M；氢氧化钠：0.05M，十二烷基硫酸钠：50mg/L，甲醛：20mL/L，pH值：13.5)中，在温度为80℃下，进行化学镀铜10min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PI材质的支架引流管，再次浸入化学镀银液(硝酸银：0.05M，硫代硫酸钠：25mg/L，氢氧化钠：0.00 5M，氨水含量：0.5％，葡萄糖：0.03M)中，在温度为25℃下，进行化学镀银5min，取出、离子 水清洗、室温晾干，获得内外表面镀有纳米Cu@Ag颗粒复合灭活层的PI材质的支架引流管。
实施例14
将质量比为1：6的聚氯乙烯和己二酸丁二脂混合后溶于四氢呋喃，混合物与四氢呋喃的比例为1：4，磁力搅拌，形成均匀分散的乳状溶液，静置1-3h，消除气泡，形成密封保存，用作骨架打印墨水。采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质支架引流管骨架。
将PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，得到其均匀粗糙的内外表面，再浸入化学镀铜液(五水合硫酸铜：0.005M，酒石酸钾钠：0.01M，氢氧化钠：0.03M，乙二胺四乙酸：0.03M，甲醛：15mL/L，pH值：12.5)注入支架引流管骨架中，在温度为35℃下，进行化学镀铜15min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PVC材质的支架引流管，再次浸入化学镀银液(硝酸银：0.1M，硫代硫酸钠：50mg/L，氢氧化钠：0.01M，氨水含量：1.0％，葡萄糖：0.1M)中，在温度为40℃下，进行化学镀银5min，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu@Ag颗粒复合灭活层的PVC材质的支架引流管。
上述方案具有如下优点：
(1)通过胰酶灭活支架引流管内外表面的纳米Ag、Cu颗粒灭 活层原位改变流经胰肠吻合口胰酶的腐蚀性能，降低胰肠吻合术后胰瘘并发症，减轻胰瘘可能带来的不利影响，提高胰肠吻合术的安全性，将“死亡之吻”变为“生命之吻”；
(2)采用3D打印技术实现支架引流管精确制备褶皱结构内表面，可大幅度增加内表面灭活层的有效面积。一方面确保伤口愈合周期内(约7天)灭活层的有效性，提高胰液灭活的效率，从而降低肠道中胰液反流时对创口的腐蚀作用，另一方面采用3D打印技术可以快速、精准、面积可控地制备褶皱结构，有利于其大规模工业化生产，降低褶皱结构制备的成本；
(3)支架引流管的外表面也设计成有灭活层的目的是能有效地对流经创口的胰液进行二次灭活，从而再次降低胰液对创口的腐蚀作用；
(4)采用无毒、生物相容性好的PI和PVC等常规有机医用材料制备支架引流管骨架，制作成本低，适用于大规模生产与推广。
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原理的前提下，还可以作出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种胰酶灭活支架引流管，其特征在于，所述胰酶灭活支架引流管包括支架引流管骨架和胰酶灭活层；
    所述支架引流管骨架为外表面光滑、内表面具有大量褶皱层的管状结构；所述支架引流管骨架的外表面还具有倒刺和侧孔。
  2. 根据权利要求1所述的胰酶灭活支架引流管，其特征在于，所述支架引流管骨架采用透明医用高分子聚合物材料3D打印制成；
    所述胰酶灭活层由镀有纳米Ag或/和Cu颗粒灭活层制备。
  3. 一种如权利要求1或2所述胰酶灭活支架引流管的制备方法，其特征在于，包括如下步骤：
    (1)、制备3D打印墨水备用，再采用医用高分子聚合物材料3D成型打印制备支架引流管骨架；
    (2)、胰酶灭活层包覆在所述支架引流管骨架的内外表面，获得胰酶灭活支架引流管；所述包覆方式包括离子交换法或化学镀法中的一种或两种。
  4. 根据权利要求3所述的制备方法，其特征在于，所述高分子聚合物材料为聚氯乙烯(PVC)，步骤(1)中具体步骤如下：
    步骤一、将PVC和己二酸丁二脂按质量比混合后溶于四氢呋喃，磁力搅拌，形成均匀分散的乳状溶液，静置、消除气泡、密封，制备 3D打印墨水备用；
    步骤二、采用UV 3D打印机进行成型打印，制备外表面光滑内表面具有大量褶皱的PVC材质的支架引流管骨架；
    所述PVC和己二酸丁二脂的质量比为1∶(1～6)；所述PVC和己二酸丁二脂混合后与四氢呋喃的质量比为1∶(1～4)。
  5. 根据权利要求3所述的制备方法，其特征在于，所述高分子聚合物材料为聚酰亚胺(PI)，步骤(1)中具体步骤如下：
    步骤一、按比例称量2，2′-二三氟甲基-联苯二胺(TFDB)、4，4′-六氟亚异丙基-邻苯二甲酸酐(6FDA)和N，N′-二甲基乙酰胺(DMAc)备用，将TFDB和DMAc放入烧瓶中搅拌充分溶解后，分数次加入6FDA，每次加入量为剩余6FDA部分的二分之一，在氩气保护下，搅拌得到聚酰胺酸溶液，再加入苯酐，搅拌得到苯酐封端的聚酰胺溶液备用，用作3D打印墨水；
    步骤二、采用选择性激光烧结3D打印机进行热亚胺化成型打印，制备外表面光滑内表面具有大量褶皱的PI材质的支架引流管骨架。
  6. 根据权利要求4所述的制备方法，其特征在于，所述胰酶灭活层为纳米Ag颗粒灭活层，步骤(2)的具体制备步骤为：将所述PVC材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理，再浸入化学镀银液中进行化学镀银，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Ag颗粒灭活层的PVC材质的支架引流管；
    所述化学镀银液为：硝酸银：0.001～0.1M，硫代硫酸钠：10～50mg/L，氢氧化钠：0.001～0.01M，氨水含量：0.1～1.0％，葡萄糖：0.01～0.1M；
    所述化学镀银的温度为20-40℃，所述化学镀银的时间为10-20min。
  7. 根据权利要求5所述的制备方法，其特征在于，所述胰酶灭活层为纳米Ag颗粒灭活层，步骤(2)的具体制备步骤为：将所述PI材质的支架引流管骨架浸入热碱液中浸泡，用去离子水清洗除去表面碱溶液，浸入银氨溶液中，室温下进行离子交换反应，取出、去离子水清洗、室温晾干，进行热亚胺化还原处理，获得内外表面镀有纳米Ag颗粒灭活层的PI材质的支架引流管；
    所述热碱液：温度为40～70℃，2.5～5M的NaOH、KOH；所述银氨溶液浓度为0.04～0.5M；
    所述离子交换反应时间为5～30min；
    所述热亚胺化还原的温度为200～320℃，时间为1～2h。
  8. 根据权利要求4所述的制备方法，其特征在于，所述胰酶灭活层为纳米Cu颗粒灭活层，步骤(2)的具体制备步骤为：将步骤(1)中所述PVC材质支架引流管骨架进行去应力、除油、粗化和敏化等内表面预处理后，浸入化学镀铜液中，进行化学镀铜，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PVC 材质支架引流管；
    所述化学镀铜液：五水合硫酸铜：0.001～0.1M，乙二胺四乙酸二钠：0.01～0.1M，硫脲：0.1～1mg/L，酒石酸钾钠：0.005～0.02M，氢氧化钠：0.01～0.05M，十二烷基硫酸钠：10～50mg/L，甲醛：8～20mL/L，pH值：11～13.5；
    所述化学镀铜的温度为20-80℃，所述化学镀铜的时间为5-20min。
  9. 根据权利要求5所述的制备方法，其特征在于，所述胰酶灭活层为纳米Cu颗粒灭活层，步骤(2)的具体制备步骤为：将步骤(1)中所述PI材质的支架引流管骨架进行去应力、除油、粗化和敏化预处理后，再浸入化学镀铜液中进行化学镀铜，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu颗粒灭活层的PI材质的支架引流管；
    所述化学镀铜液：五水合硫酸铜：0.001～0.01M，酒石酸钾钠：0.005～0.02M，氢氧化钠：0.01～0.05M，乙二胺四乙酸：0.01～0.05M，甲醛：8～20mL/L，pH值：11～13.5；
    所述化学镀铜的温度为20-80℃，所述化学镀铜的时间为10-20min。
  10. 根据权利要求4或5所述的制备方法，其特征在于，所述胰酶灭活层为纳米Cu@Ag颗粒复合灭活层，步骤(2)的具体制备步 骤为：将权利要求8或9所述的内外表面镀有纳米Cu颗粒灭活层的PVC或PI材质的支架引流管，再次浸入化学镀银液中进行化学镀铜，取出、去离子水清洗、室温晾干，获得内外表面镀有纳米Cu@Ag颗粒复合灭活层的PVC或PI材质的支架引流管；
    所述化学镀银液为：硝酸银：0.001～0.1M，硫代硫酸钠：10～50mg/L，氢氧化钠：0.001～0.01M，氨水含量：0.1～1.0％，葡萄糖：0.01～0.1M；
    所述化学镀银的温度为20-40℃，所述化学镀银的时间为5-15min。
PCT/CN2022/133687 2022-07-25 2022-11-23 一种胰酶灭活支架引流管及其制备方法 WO2024021389A1 (zh)

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