CN108567993A - A method of hypoglycemic artificial intelligence pancreas is used for based on 3D printing structure - Google Patents

A method of hypoglycemic artificial intelligence pancreas is used for based on 3D printing structure Download PDF

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CN108567993A
CN108567993A CN201810236193.9A CN201810236193A CN108567993A CN 108567993 A CN108567993 A CN 108567993A CN 201810236193 A CN201810236193 A CN 201810236193A CN 108567993 A CN108567993 A CN 108567993A
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pancreas
printing
hypoglycemic
artificial intelligence
gelatin
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CN108567993B (en
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薛巍
阮淼亮
戴箭
宋镕光
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Jinan University
University of Jinan
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Jinan University
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    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/222—Gelatin
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • 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
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
    • 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
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow

Abstract

The present invention discloses a kind of method based on 3D printing structure for hypoglycemic artificial intelligence pancreas, is related to 3D biometric prints and artificial pancreas field.This method include acetalized dextran load the preparation of nm-class insulin particles, the preparation of printing hydrogel, hydrogel support bath preparation, 3D printing prepare and etc..Artificial intelligence pancreas prepared by 3D printing of the present invention has good biocompatibility, the advantages of biodegradable, the release of insulin can be controlled according to real time blood sugar concentration, it avoids in normal range (NR) to achieve the purpose that intelligence is hypoglycemic and reaches control blood sugar concentration for a long time and repeatedly carries out blood sugar test and hypodermic injection.The present invention need not carry portable device, not have to replace battery, and conduit etc. can greatly mitigate the burden of patient, the prospect of marketing of value and great potential with more prominent applied basic research.

Description

A method of hypoglycemic artificial intelligence pancreas is used for based on 3D printing structure
Technical field
The present invention relates to 3D biometric prints and artificial pancreas fields, specifically a kind of to be built based on 3D printing for dropping The method of the artificial intelligence pancreas of blood glucose.
Background technology
Insulin is mainly by constantly detecting blood glucose and carrying out multiple subcutaneous injections according to the result of measurement at present, to disease People brings many pains and inconvenience.In addition for insulin injection there is smooth absorption is unable to, there is peak concentrations, can not Simulation insulin secretion, the amount of injection are difficult to be accurately calculated according to patient's absorption level well, and counting loss may be led The shortcomings of causing hypoglycemia.The administration of insulin needs to accomplish to provide the insulin of exact dose in due course, to make blood Sugared concentration is restored to normal level.Due to this characteristic, researcher devises the artificial pancreas of a variety of different principles to attempt Solve the problems, such as this.(Renard E, Costalat G, Chevassus H, the Bringer J.Closed such as Renard, Eric loop insulin delivery using implanted insulin pumps and sensors in Type 1diabetic patients.Diabetes Res.Clin.Pract.74, S173-S177 (2006)) using based on a coupling The implantable insulin pump of molding type controls the injection of insulin by the glucolase sensor in peritonaeum approach and vein.By In sensor performance deficiency, it is stopped for 24 hours after implantation, during operation, glucose is effectively maintained at 80-240mg/ Within dl up to 84.1% time.(Ikeda H, Kobayashi N, Tanaka Y, the et al.Anewly such as Ikeda H developed bioartificial pancreas successfully controls blood glucose in totally pancreatectomized diabetic pigs.Tissue Eng.2006Jul；12(7):1799-809.) open A kind of bone specificity of the novel transparent glucose and insulin being made of polythene-ethenol (EVAL) doughnut is sent out Nonwoven polytetrafluoroethylene (PTFE) (PTFE) cell adherence of alkaline phosphatase (BAP) and poly- amidourethane coating.Pig pancreas islet is attached to The surface of PTFE fabric, rather than the surface of EVAL doughnuts allow between the blood that fiber and outside flow Nutrition and oxygen exchange.It is inoculated with this BAP with pig pancreas islet and is connected to the cycle of the glycosuria sick pig of complete pancreatectomy In.Blood glucose level is reduced to normal range (NR), substantially improves health status, extends life span.
The closed loop artificial pancreas system of patent CN104958077A intelligent controls is monitored by real-time reception continuous blood sugar The blood sugar for human body monitoring data of equipment, and according to real-time body's glucose monitor data, it is micro- using built-in fuzzy self-adaption ratio Integral control algorithm, calculates the dosage of real-time insulin infusion devices, but needs portable external equipment, and periodically Conduit is replaced, it is greatly inconvenient to be brought to patient's daily life, and charges for the battery of implanted device, in the storage cavern of implantation The problems such as chronic insulin stability, is also difficult to solve.And bio-artificial pancreas includes that then there is immune for glucose sensitive micro-capsule etc. The shortcomings that shape size etc. is difficult to mutually agree with defect pancreas when rejection and implantation.
Invention content
In order to overcome the disadvantages and deficiencies of the prior art, the purpose of the present invention is to provide one kind is used based on 3D printing structure In the method for hypoglycemic artificial intelligence pancreas.
This invention address that hypoglycemic artificial intelligence pancreas is used for using 3D printing structure, to solve existing hypoglycemic hand Section needs that repeated detection blood glucose be subcutaneously injected and current people's public affairs pancreas needs to carry external equipment and replaces accessory etc. Disadvantage.
The present invention will build " modified gelatin-sodium alginate-acetalized dextran microballoon " Trinity hydrogel, by grape Carbohydrate oxidase is dispensed into hydrogel, and insulin is contained into acetalized dextran microballoon, is discharged as intelligent response type System.When blood sugar concentration increases, glucose is oxidized to gluconic acid by glucose oxidase, reduces the pH value at this, acid-sensitive The acetalized dextran microballoon fast degradation of sense further decreases blood glucose to release insulin, avoids repeatedly into promoting circulation of blood Sugar detection and hypodermic injection.
It is to be printed with fine according to pancreas defect or the actual conditions of excision by biological 3D printing advantage The artificial pancreas of structure and respective shapes size, to preferably be agreed with impaired pancreas.Used composite hydrogel With enough intensity, and sodium alginate, the materials such as gelatin all have good biocompatibility and biodegradability, degradation Speed can be adjusted according to the needs its proportioning and control, and needing replacing battery, conduit etc. to solving existing artificial pancreas lacks Point.The correspondence of concentration of glucose and insulin releasing can contain amount and the control Portugal of glucose oxidase by changing The conversion ratio of hydroxyl is adjusted in glycan acetalation, to reach for a long time control blood sugar concentration in normal range (NR) Purpose.
The purpose of the invention is achieved by the following technical solution：
A method of hypoglycemic artificial intelligence pancreas is used for based on 3D printing structure, is included the following steps：
(1) preparation of acetalized dextran load nm-class insulin particles
Insulin is dissolved in dilute hydrochloric acid first, stirring after a certain period of time, adjusts its pH=3.0 or so, dissolves, obtains insulin Solution；Acetalized dextran is dissolved in dichloromethane again, is added in insulin solutions, lotion is made in ultrasound；It should Lotion adds in 3%w/w PVA (polyvinyl alcohol) solution (in PBS, MW=13000-23 000g/mol, 87-89% Hydrolyzed), double lotions are made in ice-bath ultrasonic；Then by double lotions of gained pour into immediately the second PVA solution (10mL, The PBS of 0.3%w/w), stirring makes organic solvent evaporation, centrifuges, and is washed (twice) with PBS (primary) and distilled water, vortex Centrifugation removal supernatant, is finally resuspended with distilled water after ultrasound, is lyophilized, and acetalized dextran is made and loads insulin nanoparticles Son；
(2) preparation of printing hydrogel
Configure photocuring gelatin 2%~6% (preferably 4.5%) and sodium alginate 1%~5% (preferably 3%) magnetic force It stirs evenly, ultraviolet sterilization processing is added 2959 photoinitiators of 0.1%Irgacure, is sufficiently mixed, gelatin alginic acid is made Sodium mixture solution；Glucose oxidase is dissolved in physiological saline before printing, then loads pancreas islet with acetalized dextran Plain nano-particle is added together into gelatin sodium alginate mixture solution, is stirred, obtained printing hydrogel；
(3) preparation of hydrogel support bath
The material of hydrogel support bath is Thermo-sensitive gelatin, and preparation method is：First, CaCl is used2Solution allocation 4.5% (w/v) gelatin solution, place it in jar 4~8 DEG C, 12~for 24 hours (preferably 4 DEG C, 12h), then under the conditions of 4 DEG C, add Enter CaCl2Solution fully smashes gelatin particle；It is centrifuged off supernatant, and CaCl is used under the conditions of 4 DEG C2Solution, which is resuspended, to be continued Centrifugation, until bubble is not observed at the top of supernatant, this shows that most of Soluble Gelatin is removed, and hydrogel branch is made Support bath, 4 DEG C of storages；It is imported in container when use, surplus liquid is sucked with cleansing tissue；
(4) prepared by 3D printing
Pancreas 3D models are extracted from MRI image, are imported in 3D printing software, slicing treatment；Support bath gelatin is loaded Into transparent vessel used, surplus liquid is sucked；Printing is centrifuged off bubble with hydrogel, is then loaded into print head, Carry out the printing of pancreas；Since support bath gelatin contains calcium ion, sodium alginate completes solidification in print procedure, after the completion of printing 30~60 seconds (preferably 30 seconds) are crosslinked at 5~10cm (preferably 7cm) complete printing with 365nm ultraviolet lamp power 800mW The dual cross moulding of pancreas；Subsequent 37 ± 1 DEG C of heating water baths make support bath gelatin melt, and obtain printed artificial intelligence pancreas Gland.Printer uses extrusion type biology 3D printer, print temperature to be set as 37 ± 1 DEG C；Print speed is 15mm/s~25mm/ s；Print 0.1~0.25mm of syringe needle internal diameter；House print pressure is 0.2~0.5KPa.
In step (1),
Preferably, the dilute hydrochloric acid is 1mmol/L HCl (pH=3.0).
Preferably, described its pH=3.0 of tune or so is is adjusted with 10mmol/L HCl (pH 2.0).
Preferably, in the insulin solutions insulin a concentration of 200~400mg/mL；More preferably 200mg/ mL。
Preferably, the mass ratio of the acetalized dextran and insulin is 10:1~20:1；More preferably 20:1.
Preferably, the condition of the ultrasound is 5~10s of 30W ultrasounds；More preferably 30W ultrasounds 5s.
Preferably, the condition of the ice-bath ultrasonic is 30~60s of 30W ice-bath ultrasonics；More preferably 30W ice-bath ultrasonics 30s。
Preferably, the time of the stirring is 3~4h；More preferably 3h.
Preferably, the condition of the centrifugation be 14800g, 4 DEG C centrifugation 15~20min；More preferably 14800g, 4 DEG C from Heart 15min.
Preferably, second PVA solution is 0.3%w/w PVA solutions.
In step (2),
Preferably, the photocuring gelatin is GelMA (methacrylate gelatin).
Preferably, a concentration of 100mg/mL of the glucose oxidase in physiological saline.
Preferably, the mass ratio of the glucose oxidase and acetalized dextran load nm-class insulin particles is 4: 1~1:1；More preferably 1:1.
In step (3),
Preferably, the CaCl2Solution is 11mM CaCl2Solution.
Preferably, the time of the stirring is 120s~240s；More preferably 165s.
Preferably, the condition of the centrifugation is that 4200rpm centrifuges 2~4min；More preferably 4200rpm centrifuges 2min.
In step (4),
Preferably, the condition of the centrifugation is that 800~1000rpm centrifuges 1min；More preferably 800rpm centrifuges 1min.
Preferably, the print speed is 15mm/s；Print syringe needle internal diameter 0.25mm；House print pressure is 0.5KPa。
The present invention mechanism be：
The present invention is based on 3D printing structures to be used for hypoglycemic artificial intelligence pancreas, can be controlled according to real time blood sugar concentration The release of insulin, to achieve the purpose that intelligence is hypoglycemic.3D printing technique then can be according to pancreas defect or the reality of excision Border situation prints the artificial pancreas with fine structure and respective shapes size, to preferably be carried out with impaired pancreas Agree with.Compared with existing artificial pancreas, the present invention need not carry portable device, not have to replace battery, conduit etc., Neng Gouji The earth mitigates the burden of patient, the prospect of marketing of value and great potential with more prominent applied basic research.
The present invention has the following advantages and effects with respect to the prior art：
Artificial intelligence pancreas prepared by 3D printing of the present invention has the advantages of good biocompatibility, biodegradable, does not have to It carries external equipment and replaces battery conduit.And common repeatedly measurement blood sugar concentration and subcutaneous insulin injection, to disease People brings greatly pain and inconvenience, and for insulin injection there is smooth absorption is unable to, there is peak concentrations, can not in addition Simulation insulin secretion, the amount of injection are difficult to be accurately calculated according to patient's absorption level well, and counting loss may be led The shortcomings of causing hypoglycemia.Modified gelatin-sodium alginate-acetalized dextran microballoon " Trinity hydrogel-glucose oxidase Intelligent blood sugar concentration-response type delivery systme can be good at avoiding these problems.Concentration of glucose is corresponding with insulin releasing Relationship can by change contain glucose oxidase amount and control glucan acetalation in hydroxyl conversion ratio come It is adjusted, to achieve the purpose that control blood sugar concentration for a long time in normal range (NR).
Patent 201610830529.5 is thin by hyaluronic acid, sodium alginate, gelatin, glutamine transaminage and brain tumor Born of the same parents, which directly mix, carries out 3 D-printing and in vitro culture brain tumor external model, but with the raising of the printing number of plies, support is strong Degree is insufficient, cannot restore tumor tissues structure well, common 3D biometric print methods, in steric configuration and internal structure It handles unsatisfactory.And the suspension printing technique that the present invention uses, it is directly printed relative to hydrogel, it can be to avoid due to water-setting Problem is collapsed when the deficiency of glue mechanical strength causes the printing number of plies higher, while more complicated suspension structure can be printed. Compared to the pancreas model of conventional method manufacture, biological 3D suspensions printing advantage is can be according to pancreas defect or the reality of excision Border situation prints the artificial pancreas with fine structure and respective shapes size, to preferably be carried out with impaired pancreas Agree with.Used composite hydrogel has enough intensity, and sodium alginate, the materials such as gelatin all have good bio-compatible Property and biodegradability, degradation speed can be adjusted according to the needs its proportioning and controlled.
Description of the drawings
Fig. 1 is the flow diagram for hypoglycemic artificial intelligence pancreas the present invention is based on 3D printing structure.
Fig. 2 is the schematic diagram for hypoglycemic artificial intelligence pancreas the present invention is based on 3D printing structure；Wherein, A：Biology 3D printer；B：Pancreas 3D models；C, D：Gel 3D printing pancreas.
Specific implementation mode
Present invention will now be described in further detail with reference to the embodiments and the accompanying drawings, but embodiments of the present invention are unlimited In this.
Flow diagram the present invention is based on 3D printing structure for hypoglycemic artificial intelligence pancreas, as shown in Figure 1.
It is prepared by the 1 hypoglycemic artificial pancreas of intelligence of embodiment
(1) preparation of acetalized dextran load nm-class insulin particles
10mg insulin is dissolved in 1mmol/L HCl (50 μ L of pH=3.0) first, stirring after a certain period of time, is used 10mmol/L HCl (pH 2.0) adjust its pH=3.0 or so, and dissolving obtains insulin solutions.Again by 200mg acetalized dextrans It is dissolved in 1mL dichloromethane, is added in insulin solutions, with ultrasonic probe 30W ultrasound 5s, lotion is made.By the breast Liquid adds in 3%w/w PVA solutions (in PBS, MW=13,000-23,000g/mol, 87-89%hydrolyzed), 30W ice Ultrasound 30s is bathed, double lotions are made.Then by double lotions of gained pour into immediately the second PVA solution (10mL, 0.3%w/w's PBS), stir 3 hours, make organic solvent evaporation, 14800g, 4 DEG C of centrifugation 15min, with 50mL PBS (primary) and distilled water (twice) it washs, centrifugation removal supernatant, finally uses distilled water (2mL, pH=8.0) to be resuspended after the ultrasound that is vortexed, and contracting is made in freeze-drying Hydroformylation glucan loads nm-class insulin particles.
(2) preparation of printing hydrogel
It is uniform with 3% magnetic agitation of sodium alginate to configure GelMA (photocuring gelatin) 4.5%, ultraviolet sterilization processing is added 2959 photoinitiators of 0.1%Irgacure, are sufficiently mixed, and gelatin sodium alginate mixture solution is made；By the Portugals 10mg before printing Grape carbohydrate oxidase is dissolved in 100 μ L physiological saline, then together with 10mg acetalized dextrans load nm-class insulin particles It is added into gelatin sodium alginate mixture solution, stirs, obtained printing hydrogel.
(3) preparation of the support bath of hydrogel
The material of hydrogel support bath is Thermo-sensitive gelatin, and preparation method is：With 11mM CaCl2Solution allocation 150mL 4.5% (w/v) gelatin solution places it in 4 DEG C, 12h in the jar of 500mL, 35 0mL 11mM CaCl of subsequent 4 DEG C of additions2 Solution is fully smashed gelatin particle with household grade juice extractor stirring 165s.It is then charged into 50mL centrifuge tubes, 4200rpm centrifugations 2min.Supernatant is removed, and uses 11mM CaCl at 4 DEG C2Solution replaces, and resuspension continues to centrifuge, until not having at the top of supernatant Observe bubble, this shows that most of Soluble Gelatin is removed.4 DEG C of storages.It imports in container when use, is inhaled with cleansing tissue Remove surplus liquid.
(4) prepared by 3D printing
Pancreas 3D models are extracted from MRI image, are imported in 3D printing software, slicing treatment.Support bath gelatin is loaded Into transparent vessel used, surplus liquid is drawn.Printing hydrogel is removed into bubble in 800rpm centrifugations 1min, is then loaded Into print head, the printing of pancreas is carried out.Since support bath gelatin contains calcium ion, sodium alginate is completed admittedly in print procedure Change, the dual cross moulding that 30s completes printing pancreas is crosslinked at 7cm with 365nm ultraviolet lamp power 800mW after the completion of printing. Subsequent 37 DEG C of heating water baths make support bath gelatin melt, and obtain printed artificial intelligence pancreas.Printer machine uses extrusion type Biological 3D printer, print temperature are set as 37 DEG C；Print speed is 15mm/s；Print syringe needle internal diameter 0.25mm；House print Pressure is 0.5KPa.
Schematic diagram of the present embodiment based on 3D printing structure for hypoglycemic artificial intelligence pancreas, as shown in Fig. 2, its In, A：Biological 3D printer；B：Pancreas 3D models；C and D：Gel 3D printing pancreas.As can be seen from FIG. 2, using in the present invention Method can utilize biological 3D printer to provide the artificial intelligence pancreas of practical pancreas form according to 3D image printings, can Agreed with well with defect pancreas.
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment Limitation, it is other it is any without departing from the spirit and principles of the present invention made by changes, modifications, substitutions, combinations, simplifications, Equivalent substitute mode is should be, is included within the scope of the present invention.

Claims (10)

1. a kind of method based on 3D printing structure for hypoglycemic artificial intelligence pancreas, it is characterised in that including following step Suddenly：
(1) preparation of acetalized dextran load nm-class insulin particles
Insulin is dissolved in dilute hydrochloric acid first, stirring after a certain period of time, adjusts its pH=3.0, dissolves, obtains insulin solutions；Again Acetalized dextran is dissolved in dichloromethane, is added in insulin solutions, lotion is made in ultrasound；The lotion is added Into 3%w/w PVA solutions, double lotions are made in ice-bath ultrasonic；Then double lotions of gained are poured into the second PVA solution immediately, Stirring, makes organic solvent evaporation, centrifuges, washed once with PBS and distilled water washes twice, after the ultrasound that is vortexed in centrifugation removal Clear liquid is finally resuspended with distilled water, freeze-drying, and acetalized dextran is made and loads nm-class insulin particles；
(2) preparation of printing hydrogel
It is uniform with 1%~5% magnetic agitation of sodium alginate to configure photocuring gelatin 2%~6%, ultraviolet sterilization processing is added 2959 photoinitiators of 0.1%Irgacure, are sufficiently mixed, and gelatin sodium alginate mixture solution is made；By glucose before printing Oxidizing ferment is dissolved in physiological saline, is then added to gelatin seaweed with together with acetalized dextran load nm-class insulin particles It in sour sodium mixture solution, stirs, obtained printing hydrogel；
(3) preparation of hydrogel support bath
The material of hydrogel support bath is Thermo-sensitive gelatin, and preparation method is：First, CaCl is used24.5% gelatin of solution allocation is molten Liquid, place it in jar 4~8 DEG C, 12~for 24 hours, then under the conditions of 4 DEG C, be added CaCl2Solution, gelatin particle is abundant It smashes；It is centrifuged off supernatant, and CaCl is used under the conditions of 4 DEG C2Solution resuspension continues to centrifuge, until not having at the top of supernatant Observe bubble, this shows that most of Soluble Gelatin is removed, and hydrogel support bath, 4 DEG C of storages are made；It imports and holds when use In device, surplus liquid is sucked with cleansing tissue；
(4) prepared by 3D printing
Pancreas 3D models are extracted from MRI image, are imported in 3D printing software, slicing treatment；Support bath gelatin is loaded into institute With in transparent vessel, surplus liquid is sucked；Printing is centrifuged off bubble with hydrogel, is then loaded into print head, is carried out The printing of pancreas；Since support bath gelatin contains calcium ion, sodium alginate completes solidification in print procedure, is used after the completion of printing 365nm ultraviolet lamp power 800mW is crosslinked 30~60 seconds dual cross mouldings for completing printing pancreas at 5~10cm；Subsequent 37 ± 1 DEG C of heating water bath makes support bath gelatin melt, and obtains printed artificial intelligence pancreas；Printer uses extrusion type biology 3D Printer, print temperature are set as 37 ± 1 DEG C；Print speed is 15mm/s~25mm/s；Printing syringe needle internal diameter 0.1~ 0.25mm；House print pressure is 0.2~0.5KPa.
2. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
In step (1),
A concentration of 200~400mg/mL of insulin in the insulin solutions；
The mass ratio of the acetalized dextran and insulin is 10:1~20:1.
3. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
In step (1),
The condition of the ultrasound is 5~10s of 30W ultrasounds；
The condition of the ice-bath ultrasonic is 30~60s of 30W ice-bath ultrasonics.
4. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
In step (1),
The time of the stirring is 3~4h；
The condition of the centrifugation be 14800g, 4 DEG C centrifugation 15~20min.
5. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
Second PVA solution is 0.3%w/w PVA solutions.
6. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
In step (2),
The photocuring gelatin is GelMA；
A concentration of 100mg/mL of the glucose oxidase in physiological saline.
7. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
The mass ratio of the glucose oxidase and acetalized dextran load nm-class insulin particles is 4:1~1:1.
8. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
In step (3),
The time of the stirring is 120s~240s；
The condition of the centrifugation is that 4200rpm centrifuges 2~4min.
9. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
In step (4),
The condition of the centrifugation is that 800~1000rpm centrifuges 1min.
10. the method according to claim 1 based on 3D printing structure for hypoglycemic artificial intelligence pancreas, feature It is：
The print speed is 15mm/s；Print syringe needle internal diameter 0.25mm；House print pressure is 0.5KPa.
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CN109318476A (en) * 2018-10-12 2019-02-12 中南大学 It is a kind of without support color three dimension physical model manufacturing method and hepatic model
CN111812022A (en) * 2020-06-16 2020-10-23 重庆大学 Coal rock three-dimensional strain field visualization system and method under complex geological structure
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CN114479117A (en) * 2020-11-13 2022-05-13 中山大学附属第一医院 Hydrogel supporting suspension 3D printing and having biological activity and application method thereof

Cited By (6)

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Publication number Priority date Publication date Assignee Title
CN109318476A (en) * 2018-10-12 2019-02-12 中南大学 It is a kind of without support color three dimension physical model manufacturing method and hepatic model
WO2020244037A1 (en) * 2019-06-04 2020-12-10 浙江大学 Imaging principle-based integrated color light 3d bioprinting system
CN111812022A (en) * 2020-06-16 2020-10-23 重庆大学 Coal rock three-dimensional strain field visualization system and method under complex geological structure
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