CN105999373A - Polyurethane/small intestinal submucosa (PU/SIS) dual-component injectable hydrogel - Google Patents
Polyurethane/small intestinal submucosa (PU/SIS) dual-component injectable hydrogel Download PDFInfo
- Publication number
- CN105999373A CN105999373A CN201610380033.2A CN201610380033A CN105999373A CN 105999373 A CN105999373 A CN 105999373A CN 201610380033 A CN201610380033 A CN 201610380033A CN 105999373 A CN105999373 A CN 105999373A
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- CN
- China
- Prior art keywords
- acetic acid
- component
- small intestine
- nertralizer
- injection aquagel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
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- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/40—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing ingredients of undetermined constitution or reaction products thereof, e.g. plant or animal extracts
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- A—HUMAN NECESSITIES
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- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
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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
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
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- A—HUMAN NECESSITIES
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Materials Engineering (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
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- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Botany (AREA)
- Zoology (AREA)
- Medicinal Preparation (AREA)
- Dispersion Chemistry (AREA)
Abstract
The invention discloses a dual-component injectable hydrogel product box, which includes two components which are separately stored: a component A: a polyurethane emulsion, and a component B is a sol containing small intestinal submucosa powder and acetic acid. The invention also provides a preparation method and an application of the product box. The two components in the hydrogel product box of the invention can be mediated by virtue of an endoscopic technique, so that injection implantation is achieved; in addition, the two components can rapidly achieve in-situ gelatinization; the two components are immobilized on an injured part; the hydrogel has a good effect on repairing wound surfaces, and operative wounds are minimal; therefore, a new choice is provided for minimally invasive restorative treatment of muscular lumen tissue injuries and for prevention of complications; and the injectable hydrogel has a good clinical application prospect.
Description
Technical field
The present invention relates to a kind of polyurethane/submucous layer of small intestine (PU/SIS) double-component injection aquagel.
Background technology
Since 20th century, along with medical science applied overall development, increasing achievement in research is employed for
In the Clinics and Practices of disease, therefore the cause of disease of some major diseases, pathogenesis, diagnoses and treatment or even
Prevention, made remarkable progress in past 100 years.Digestive endoscopy new technique is at full speed the most in recent years
Development, diagnosis and treatment to digestive system disease serve revolutionary impetus especially.Except routine
Outside gastroscope, intestinal mirror, the most peritoneoscope, thoracoscope, ventricularendoscope, arthroscope, cone intercalated disc chamber mirror etc.
Miniature endoscope.At Digestive System Department, Genneral Surgery, division of chest disease, department of obstetrics and gynecology, Urology Surgery, orthopaedics etc.
Extensively application.
Excision of the lesion can be obtained ratio more thoroughly by traditional surgical operation, but this is to excise big portion
Premised on dividing internal organs.Its problem is, Post operation easily makes the defunctionalization that internal organs are original, the wound caused
Wound is big, the strong influence quality of life of patient.Endoscopic technic is different from traditional surgery, and it is
Make scope front end arrive at the lesions position in patient body, carry out treatment operation at direct view under endoscope, complete complete
Portion's operation process.Therapeutic endoscopy actively can efficiently solve the insoluble problem of internal medicine conservative treatment,
Such as acute esophageal gastric fundus vein Rupture haemorrhag；Complexity can be simplified and the Therapeutic Method of danger or substitute some
Operation, such as acute pyogenic cholangitis, calculus of intrahepatic duct etc..It can be carried out while clarifying a diagnosis
Treatment, have simplicity, fast, efficient, safe, need not anesthesia, complication little to patient trauma
Less, the feature such as the low and total consuming of mortality rate is low, critical for numerous patients, particularly emergency treatment, how sick advanced age is
Person is accepted.Endoscopic technic has curative effect for benign disease；Permissible for malignant tumor patient
Effectively release or reduce misery, improve the quality of life of patient's life span.
China is Incidence of esophageal cancer and the highest country of mortality rate, and endoscopic inferior mucosa excision
(endoscopic mucosal resection, EMR) and demu osation (endoscopic mucosal
Dissection, ESD) it is increasingly becoming the preferred version of in early days esophageal carcinoma therapy.Wherein EMR mainly uses
In the diameter pathological changes less than 2 centimetres, diameter wide for extent of disease is more than 2 centimetres, and intramural invasion exists
More than SM1 layer, there is no the early stage esophageal carcinoma of metastasis, generally use ESD under scope to peel off pathological changes.
For guaranteeing complete resection pathological changes, ESD excision extension is normal within diseased region and periphery 0.5cm thereof
Mucosa, but the postoperative following complication of easy appearance: bore a hole, wound surface is hemorrhage, postoperative pain, ulcer healing
Time length (3～4 weeks) and later stage cicatricial contracture are narrow etc..Therefore for avoiding postoperative ulcer shape
The perforation, narrow become, carries out quick and complete reparation to this type of ulcer surface and seems most important.
Traditional ulcer treatment scheme typically use proton pump inhibitor (proton pump inhibitors,
PPIs) by gastric acid secretion inhibiting, reach to promote the effect of the postoperative ulcer healing of ESD.But this kind of medicine
Thing on a large scale and merges the still difficult final conclusion of preventive effect of the definite complication of ulcer burning infringement to ESD；
The external oral glucocorticoid that is also related to contributes to preventing the report of ESD postoperative esophageal stricture, but by
Side effect in hormone also makes its clinical practice face bigger problem.Domestic researcher uses metal clip
Clamp wound surface with in treatment gastrointestinal mucosa infantile tumour ESD art, the complication such as postoperative hemorrhage and perforation,
Achieve good effect, but in esophageal carcinoma therapy, have the risk causing esophagostenosis at a specified future date.
The natural acellular matrixes such as submucous layer of small intestine (smallintestinal submucosa, SIS), tool
Have good cell compatibility, rich in multiple somatomedin, non-immunogenicity, have antimicrobial acivity,
The advantages such as tissue specificity regeneration induction, may be used for the reparation of esophagus wound surface.But, under mucous membrane of small intestine
There are some obvious defects in layer as esophageal renovation material, as mechanical strength deficiency, degradation time are too fast,
Plastotype difficulty, needs to use traditional open surgery to treat, and there is big etc. the problem of wound.
Along with progressively going deep into of research, at present by the complex method by submucous layer of small intestine Yu other materials,
Solving the problem that submucous layer of small intestine mechanical strength is not enough, degradation time is the fastest, e.g., notification number is
The patent application of 104341608A discloses a kind of composite compound for polyurethane/SIS, solves small intestinal
The problem that tela submucosa mechanical strength is not enough.
But, it is still necessary to be treated by traditional open surgical, by being correlated with that it brings
Problem can not have been resolved.
Summary of the invention
It is an object of the invention to provide a kind of polyurethane/submucous layer of small intestine (PU/SIS) injectable water-setting
Glue material, its can by the way of scope wound repairing, wound is little, solves existing repair materials required
Open surgery is used to carry out repairing and there is the problem that wound is big.
The invention provides a kind of double-component injection aquagel product box, it includes two separately deposited
Component: component A is polyaminoester emulsion, component B is the colloidal sol containing submucous layer of small intestine powder and acetic acid.
Preferably, the mean diameter of described polyaminoester emulsion is 30～100nm, and solid content is 10%～25%,
Zeta potential is-60mV～-20mV.
It is further preferred that the preparation method of described polyaminoester emulsion is as follows:
(1) pre-polymerization: taking isocyanates and hydroxyl donor, pre-polymerization, the mol ratio of the two is (0.26～0.27):
(0.15～0.19)；
Described isocyanates is isophorone diisocyanate, lysinediisocyanate or diphenyl methane
Any one or more in diisocyanate；
Described hydroxyl donor is any one or more in PTMG, poly-epsilon-caprolactone glycol；
(2) chain extension: addition chain extender, chain extension, wherein, chain extender and hydroxyl donor in step (1)
Mol ratio be (0.15～0.19): (0.05～0.09)；Chain extension process adds acetone；
Described chain extender be in 1,4-butanediol, 2,2-dihydromethyl propionic acid, ethylene glycol any one or many
Kind；
(3) emulsifying is neutralized: take nertralizer, by polyurethane polymer dispersible in nertralizer, emulsifying 2h；
Wherein, nertralizer is (0.15～0.19) with the mol ratio of chain extender in step (2): (0.02～0.08)；
(4) purification: rotation is evaporated off acetone and excess nertralizer, deionized water dialysis removes impurity, to obtain final product.
Preferably, in step (1), the temperature of pre-polymerization is 75 DEG C；The time of pre-polymerization is 2～4h；Pre-polymerization
The catalyst used is stannous octoate, triethanolamine or dibutyl tin laurate；
In step (2), the temperature of chain extension is 50 DEG C～55 DEG C；The time of chain extension is 3～4h；
In step (3), under the conditions of the THE ADIABATIC SHEAR IN that rotating speed is 1500r/m, polyether polyols with reduced unsaturation is divided
Dissipate in nertralizer；Described nertralizer is triethylamine or sodium hydroxide；
In step (4), the temperature that rotation is steamed is 55 DEG C.
Preferably, described containing submucous layer of small intestine powder with the colloidal sol of acetic acid, its mean diameter is
600～900nm, solid content is 0.5%～4%, and Zeta potential is 20～50mV.
Preferably, in described colloidal sol, acetic acid is 4:100 with the volume ratio of water, submucous layer of small intestine powder
It is 2:100 with the mass volume ratio of aqueous acetic acid.
Preferably, the described preparation method containing the colloidal sol containing submucous layer of small intestine powder and acetic acid is:
Taking acetic acid, prepare aqueous acetic acid, acetic acid is 4:100 with the volume of water, adds submucous layer of small intestine
Powder, mixing, the addition of submucous layer of small intestine powder and the mass volume ratio of aqueous acetic acid are 2:100.
Preferably, described submucous layer of small intestine prepares by the following method:
I () takes pig small intestine, washing, cuts open, the section of being cut into；
(ii) muscle layer and the placenta percreta of small intestinal are struck off；
(iii), after washing is filtered dry, it is dipped in the mixed solution of chloroform and methanol, soak time
Being 4 hours, in described mixed solution, chloroform is 1:1 with the volume ratio of methanol；
(iv) after washing, putting in trypsin solution, 4 DEG C process overnight；
After (v) washing, process at least 4h with SDS；
(vi) after cleaning, lyophilizing；
(vii) pulverize, add containing in 3% acetic acid, 0.1% pepsic PBS solution, adjust pH
To neutrality, lyophilizing, then pulverize, to obtain final product.
Preferably, in described product box, component A is 1:(1～3 with the volume ratio of component B).
Present invention also offers a kind of method preparing aforementioned injection aquagel product bag, step is as follows:
I, polyaminoester emulsion is prepared
(1) pre-polymerization: taking isocyanates and hydroxyl donor, pre-polymerization, the mol ratio of the two is (0.26～0.27):
(0.15～0.19)；
Described isocyanates is isophorone diisocyanate, lysinediisocyanate or diphenyl methane
Any one or more in diisocyanate；
Described hydroxyl donor is any one or more in PTMG, poly-epsilon-caprolactone glycol；
(2) chain extension: addition chain extender, chain extension, wherein, chain extender and hydroxyl donor in step (1)
Mol ratio be (0.15～0.19): (0.05～0.09)；Chain extension process adds acetone；
Described chain extender be in 1,4-butanediol, 2,2-dihydromethyl propionic acid, ethylene glycol any one or many
Kind；
(3) neutralizing emulsifying: add nertralizer, polyurethane is polymerized by THE ADIABATIC SHEAR IN condition (1500r/m)
In thing dispersion nertralizer, emulsifying 2h；Wherein, nertralizer with the mol ratio of chain extender in step (2) is
(0.15～0.19): (0.02～0.08)；
Described nertralizer is triethylamine or sodium hydroxide；
(4) purification: rotation is evaporated off acetone and excess nertralizer, deionized water dialysis removes impurity, to obtain final product
Polyaminoester emulsion, packaging,；
II, preparation is containing submucous layer of small intestine powder and the colloidal sol of acetic acid
Taking acetic acid, prepare aqueous acetic acid, acetic acid is 4:100 with the volume of water, adds mucous membrane of small intestine
Lower floor's powder, mixing, packaging, wherein, the addition of submucous layer of small intestine powder and acetic acid water
The mass volume ratio of solution is 2:100；
Described submucous layer of small intestine powder prepares by the following method:
I () takes pig small intestine, washing, cuts open, the section of being cut into；
(ii) muscle layer and the placenta percreta of small intestinal are struck off；
(iii), after washing is filtered dry, it is dipped in the mixed solution of chloroform and methanol, soak time
Being 4 hours, in described mixed solution, chloroform is 1:1 with the volume ratio of methanol；
(iv) after washing, putting in trypsin solution, 4 DEG C process overnight；
After (v) washing, process at least 4h with SDS；
(vi) after cleaning, lyophilizing；
(vii) pulverize, add containing in 3% acetic acid, 0.1% pepsic PBS solution, adjust pH
To neutrality, lyophilizing, then pulverize, to obtain final product.
Present invention also offers the using method of aforesaid injection aquagel product bag, step is as follows: take
Aforesaid injection aquagel product bag, by component A and component B according to 1:(1～3) volume ratio mix
Close,.
Present invention also offers a kind of polyurethane/submucous layer of small intestine (PU/SIS) hydrogel, according to as follows
Prepared by method: take aforesaid injection aquagel product bag, by component A with component B according to 1:(1～3)
Volume ratio mixing, obtain hydrogel.
Present invention also offers aforementioned injection aquagel product bag and polyurethane/submucous layer of small intestine
(PU/SIS) hydrogel purposes in preparation wound repair material.
Use injection aquagel product bag of the present invention, when using endoscopic surgery that wound surface is checked
Can repair, it is not necessary to again carry out open surgery, it is to avoid the risk that second operation causes and medical treatment
Cost, is easily accepted by patients.
In injection aquagel product bag of the present invention, component A and component B can form gelinite rapidly
System, during use, first passes through scope and component B is overlying on wound surface, then component A is overlying on wound surface, Ji Keyuan
Position forms gel, is fixed on damage location, it is achieved repair.The present invention is with endoscopic technic treatment esophagus and stomach
As a example by mucosa, Wicresoft's repairing and treating and complication prevention for the damage of Ji Xing lumen organization provide a kind of new
Selection.
To sum up, two components in subject hydrogel product bag can be mediated by endoscopic technic, implants wound
Position, traumatic part, and can gelation the most in position, be fixed on damage location, good to the repairing effect of wound surface,
And operation wound is minimum, patient compliance is good, and the Wicresoft's repairing and treating damaged for Ji Xing lumen organization is with pre-
Anti-complication provides a kind of new selection, and potential applicability in clinical practice is good.
Below by detailed description of the invention, the present invention is described in further details, but is not to this
Bright restriction, according to the foregoing of the present invention, according to ordinary technical knowledge and the customary means of this area,
Without departing under the present invention above-mentioned basic fundamental thought premise, it is also possible to make other various ways amendment,
Replace or change.
Accompanying drawing explanation
0 week figure (dog esophagus ESD art) of Fig. 1 matched group
0 week figure (dog esophagus ESD art) of Fig. 2 esomeprazole group
0 week figure (dog esophagus ESD art) of Fig. 3 injectable of the present invention PU/SIS sticking patch group
4 weeks figures (dog esophagus ESD art) of Fig. 4 matched group
4 weeks figures (dog esophagus ESD art) of Fig. 5 esomeprazole group
Figure (dog gastric antrum ESD art) Fig. 7 comparison in 4 weeks of Fig. 6 injectable of the present invention PU/SIS sticking patch group
Organize 2 weeks figures (dog gastric antrum ESD art)
2 weeks figures (dog gastric antrum ESD art) of Fig. 8 esomeprazole group
2 weeks figures (dog gastric antrum ESD art) of Fig. 9 injectable of the present invention PU/SIS sticking patch group
4 weeks figures (dog gastric antrum ESD art) of Figure 10 matched group
4 weeks figures (dog gastric antrum ESD art) of Figure 11 esomeprazole group
4 weeks figures (dog gastric antrum ESD art) of Figure 12 injectable of the present invention PU/SIS sticking patch group
Figure 13 matched group healing time figure (dog gastric antrum ESD art)
Figure 14 esomeprazole group healing time week schemes (dog gastric antrum ESD art)
Figure 15 injectable of the present invention PU/SIS sticking patch group healing time week schemes (dog esophagus ESD art)
Figure 16 healing effect comparison figure
Detailed description of the invention
Initialism:
SIS: submucous layer of small intestine, PU: polyurethane, DMPA:2,2-dihydromethyl propionic acid.SDS: ten
Sodium dialkyl sulfate
1. the mensuration of polyaminoester emulsion solid content
Solid content is emulsion or coating dry under prescribed conditions after remainder account for the percent of total amount.Ginseng
According to GB1725-79, take dry surface plate and claim quality, and weigh the anion of 1.5～2.0g with weight reduction
Polyaminoester emulsion is laid in surface plate, puts into and is dried 24h in 40 DEG C of baking ovens, takes out, is cooled to room temperature
Rear weighing.Weigh Ag, example weight Bg with the weighing botle of clean dry before analytical balance accurate weighing, dry
Weigh after Gan (containing sample and weighing botle) Cg, calculates (C-A)/B*100% and draws solid content.
2. diameter characterization characterizes with Zeta potential
2.1 mean diameter detection methods
Use particle diameter tester that Average Particle Diameters and the distribution of fluid sample are tested.Take appropriate system
Standby aqueous polyurethane emulsion or SIS colloidal sol, take 1ml sample with liquid-transfering gun and be transferred in sample cell.Will
Sample cell equipped with fluid sample is put in instrument light path, and the particle diameter that is at room temperature averaged is tested.
2.2Zeta potentiometric detection method:
Use Zeta potential analyser that the Zeta potential of fluid sample is tested.Take appropriate preparation
Aqueous polyurethane emulsion or SIS colloidal sol, take about 1mL sample with liquid-transfering gun and be transferred in sample cell.Will
Sample cell equipped with fluid sample is put in instrument light path, at room temperature carries out Zeta potential test.
The preparation of embodiment 1 injectable gel of the present invention product box
(1) preparation method
The preparation of component A:
0.26mol lysinediisocyanate and 0.19mol poly-epsilon-caprolactone glycol 1000 are added four mouthfuls
In three-necked bottle, logical condensed water in course of reaction, the rotating speed of regulation puddler is 800～1000r/m..At nitrogen
Protection, dimethylethanolamine (3) are polymerization 4h under conditions of catalyst temperature is 75 DEG C, add afterwards
Enter 0.02mol small molecule chain extender ethylene glycol and 0.03mol hydrophilic chain extender DMPA, be cooled to 50 DEG C,
Continuing reflection 3～4h, course of reaction uses acetone regulation viscosity (after adding chain extender, to add third every 1h
The viscosity of ketone regulation system, each 8ml).Configuration 0.04mol/L triethylamine solution 1000mL, quickly cuts
Under tangent condition (1500r/m) by polyurethane polymer dispersible in triethylamine solution, emulsion reaction 2h,
The emulsion obtained is steamed in 55 DEG C of temperature backspins, removes the little molecule things such as the acetone in emulsion and triethylamine
Matter, deionized water is dialysed three days and is removed impurity.
After testing, mean diameter 89.7nm of the polyaminoester emulsion prepared, solid content 20.1%, Zeta
Numerical value-the 43.2ev of current potential.
The polyaminoester emulsion that subpackage prepares,.
The preparation of component B:
The preparation method of SIS powder:
In the present invention, SIS powder uses the conventional method of prior art to prepare, for example with following
Method prepares SIS powder:
1) taking fresh pig small intestinal, wash away content with water, salt rinses 3 times repeatedly with water after rubbing.Use hands
Small intestinal cut open by art cutter, and is cut into the intestinal segment of 10～20cm length；
2) strike off muscle layer and the placenta percreta of small intestinal with spatula, be stored in normal saline at 4 DEG C；
3) deionized water rinsed clean be dipped in (trichlorine in the mixed liquor of chloroform-methanol after being filtered dry
Methane: methanol=1:1) 4 hours, average 2h changes a not good liquor, and 0.5h stirs once；
4) putting in the trypsin solution that concentration is 0.25% after deionized water cleans repeatedly, 4 DEG C processed
Night；
5) at least 4h is processed with the SDS of 0.5% after rinsing 10 times with deionized water；
6) cleaning is placed on lyophilizing 24h at 70 DEG C.
7) SIS of low-temperature grinding is added containing 3% acetic acid, in 0.1% pepsic PBS solution,
Stirring 48h, after tune pH to neutrality, lyophilizing, then pulverize, i.e. obtain submucous layer of small intestine powder.Aluminum
Mould bag heat-sealing；Oxirane disinfection.
Taking acetic acid, prepare aqueous acetic acid, glacial acetic acid is 4mL:100mL with the volume of water, adds
Submucous layer of small intestine powder, mixing, form homogeneous sol system, the addition of submucous layer of small intestine powder
Amount is 2g:100mL with the mass volume ratio of aqueous acetic acid.
After testing, mean diameter 815nm of SIS colloidal sol for preparing, solid content 2%, Zeta electricity
The numerical value 28.65mV of position.
Subpackage prepare containing acetic acid and the colloidal sol of submucous layer of small intestine,.
(2) using method
First component B is coated on wound surface, then component A of 1～3 times of volume is coated on wound surface,.
The preparation of embodiment 2 injectable gel of the present invention product box
(1) preparation method
The preparation of component A:
0.27mol isoflurane chalcone diisocyanate and 0.15mol PTMG 1000 are added four mouthfuls
In three-necked bottle, logical condensed water in course of reaction, regulation speed of agitator is 800～1000r/m, adds 2
Stannous octoate catalyst, under 75 DEG C and nitrogen are protected, prepolymerization 2 hours, is then cooled to 55 DEG C, adds
Enter 0.04mol small molecule chain extender 1,4-butanediol and 0.05mol hydrophilic chain extender 2,2-hydroxymethyl propionic acid
(DMPA), chain extending reaction 3～4 hours are continued.Course of reaction can add acetone regulation reaction system
Viscosity (adding after chain extender, add the viscosity of acetone regulation system every 1h, the amount every time added is
8mL), make reaction maintain under plateau to carry out.Configuration 0.02mol/L triethylamine solution 1000mL,
THE ADIABATIC SHEAR IN condition (1500r/m) by polyurethane polymer dispersible in triethylamine solution, emulsion reaction
2h, steams the emulsion obtained in 55 DEG C of temperature backspins, and removes the little molecules such as the acetone in emulsion and triethylamine
Material, deionized water is dialysed three days and is removed impurity.
After testing, mean diameter 70.2nm of the polyaminoester emulsion prepared, solid content 18%, Zeta
Numerical value-the 28.43mV of current potential.
The polyaminoester emulsion that subpackage prepares,.
The preparation of component B:
The preparation method of SIS powder: with embodiment 1.
Taking acetic acid, prepare aqueous acetic acid, glacial acetic acid is 4mL:100mL with the volume of water, adds
Submucous layer of small intestine powder, mixing, form homogeneous sol system, the addition of submucous layer of small intestine powder
Amount is 0.5g:100mL with the mass volume ratio of aqueous acetic acid.
After testing, mean diameter 600nm of SIS colloidal sol for preparing, solid content 0.5%, Zeta
The numerical value 20mV of current potential.
Subpackage prepare containing acetic acid and the colloidal sol of submucous layer of small intestine,.
(2) using method
First component B is coated on wound surface, then component A of 1～3 times of volume is coated on wound surface,.
The preparation of embodiment 3 injectable gel of the present invention product box
(1) preparation method
The preparation of component A:
Poly-with 0.15mol for 0.27mol isoflurane chalcone diisocyanate ε-polycaprolactone glycol 2000 is added
In four mouthfuls of three-necked bottles, logical condensed water in course of reaction, the rotating speed of regulation puddler is 800～1000r/m..?
Nitrogen protection, dibutyltin diacetate (2) are polymerization 4h under conditions of catalyst temperature is 75 DEG C,
Add 0.07mol hydrophilic chain extender dihydromethyl propionic acid (being 2,2-dihydromethyl propionic acid) afterwards, by body
It is adjusted to 50 DEG C at a temperature of system, continues reaction 3～4h.Course of reaction uses appropriate acetone regulation viscosity (to add
After entering chain extender, add the viscosity of acetone regulation system, each 8mL every 1h).Configuration 0.08mol/L
Triethylamine solution 1200mL, by polyurethane polymer dispersible in three second under THE ADIABATIC SHEAR IN condition (1500r/m)
In amine aqueous solution, emulsion reaction 2h, steams the emulsion obtained in 55 DEG C of temperature backspins, removes third in emulsion
The small-molecule substance such as ketone and triethylamine, deionized water is dialysed three days and is removed impurity.
After testing, the mean diameter (110.2nm) of the polyaminoester emulsion prepared, solid content 23.5,
Numerical value-the 41.01eV of Zeta potential.
The polyaminoester emulsion that subpackage prepares,.
The preparation of component B:
The preparation method of SIS powder: with embodiment 1.
Taking acetic acid, prepare aqueous acetic acid, glacial acetic acid is 4mL:100mL with the volume of water, adds
Submucous layer of small intestine powder, mixing, form homogeneous sol system, the addition of submucous layer of small intestine powder
Amount is 4g:100mL with the mass volume ratio of aqueous acetic acid.
After testing, mean diameter 900nm of SIS colloidal sol for preparing, solid content 4%, Zeta electricity
The numerical value 50mV of position.
Subpackage prepare containing acetic acid and the colloidal sol of submucous layer of small intestine,.
(2) using method
First component B is coated on wound surface, then component A of 1～3 times of volume is coated on wound surface,.
Beneficial effects of the present invention is proved below by the mode of experimental example:
The curative effect of experimental example 1 subject hydrogel product box esophageal ulcer postoperative to ESD and prevention esophagus
Narrow effect
1, experimental technique
Set up the dog postoperative Ulcer Models of esophagus ESD through gastroscope, observe different treatment means to dog ESD art
The curative effect of rear esophageal ulcer and the effect of prevention esophagostenosis:
The dog postoperative Ulcer Models of esophagus ESD is set up: experimental dog anaesthetizes (pentobarbital sodium through gastroscope
1.2ml/kg, intraperitoneal injection) and tracheal intubation after, use gastroscope (Olympus GIF-Q260J),
Electric knife (Olympus ESG-100) and related accessories, select away from beagle dog (10kg, male) door
Between 40-45 centimetre of tooth, ring week peels off 5cm dolichoesophagus mucous layer, uses the all-round stripping method of tunnel type
(ESTD) esophageal ulcer model, is set up.
Set up the dog postoperative Ulcer Models of esophagus ESD through gastroscope, be randomly divided into matched group (placebo), basis
The invention bi-component injectable PU/SIS hydrogel sticking patch (injection aquagel of the embodiment of the present invention 1 preparation
Product box) and esomeprazole (PPIs mono-kind) medication therapy groups.
It is administered: (1) esomeprazole group: within postoperative 3rd day, start from addition Esso U.S.A in daystart dog diet and draw
Azoles 20mg, once a day.(2) bi-component injectable PU/SIS gel for treating group of the present invention: postoperative
Within 3 days, directly insert spray line through gastroscope movable detecting hole, first inject B component 5ml and be covered on wound surface, then
Inject component A 5ml and be covered on component A,；(3) matched group: disregard after modeling.
2, experimental result
Experimental result is as shown in table 1:
Table 1: the different treatment means Comparison of therapeutic to the dog postoperative ulcer healing of esophagus ESD
Matched group: forming ulcer at mucous membrane of esophagus stripping in postoperative 2nd day, table covers HUANGBAI(sic) tongue；After 2 weeks
Esophageal ulcer starts healing, and ulcer lower edge starts to occur narrow；After 3 weeks, ulcer heals further, surface
White fur is thinning, and regenerative cell is grown into, and ulcer lower edge starts narrow, and scope cannot pass through, and experimental dog is taken food
Reduce, be only capable of a small amount of liquid diet of taking food；After 4 weeks, ulcer heals completely, surface no fur, ulcer surface scar
Trace contracture, upper lower edge is the narrowest substantially, and scope cannot pass through, diameter about 0.5cm, experimental dog gradually without
Method is taken food, dead after 6 weeks.
Esomeprazole therapy on treatment group: forming ulcer at mucous membrane of esophagus stripping in postoperative 2nd day, table covers HUANGBAI(sic)
Tongue；After 2 weeks, esophageal ulcer starts healing, and ulcer lower edge starts to occur narrow；When 3 weeks, ulcer heals substantially,
Narrow substantially scope can pass through reluctantly, and experimental dog feed reduces, but can consuming solid foods；4 weeks
Time ulcer heal completely, ulcer surface cicatricial contracture, scope can pass through the most reluctantly, but easily wipe and touch cicatrix limit
Edge causes hemorrhage, diameter about 0.8-1.0cm, and experimental dog feed reduces further, still can consuming solid foods.
Bi-component injectable PU/SIS hydrogel sticking patch group of the present invention: after postoperative 1 week, esophageal ulcer starts more
Closing, ulcer lower edge starts to occur narrow；Ulcer major part healing when 2 weeks, upper lower edge occurs the narrowest
Narrow, scope passes through non-resistance, and experimental dog feed slightly reduces；Within 3 weeks, wound surface ulcer heals the most completely, ulcer
Upper lower edge is shown in contracture ring, and tube chamber is without obvious stenosis, and experimental dog feed is the same；Within postoperative 4 weeks, experimental dog is complete
Normal feed.
Result shows: three groups of ESD postoperative esophageal ulcer healing time differences, bi-component of the present invention can
Injection PU/SIS hydrogel group repairing effect is more excellent, and this material has promotion esophageal ulcer healing, and prevention is burst
The effect that infections cicatricial contracture is narrow, internal reparation, without obvious calcification phenomenon, uses safety, glues for digestive tract
Film healing provides a kind of new selection.
The effect of experimental example 2 subject hydrogel ulcer postoperative to gastric antrum ESD
1, experimental technique
Set up the dog postoperative Ulcer Models of gastric antrum ESD through gastroscope, observe different treatment means to dog ESD art
The curative effect of rear gastric ulcer:
The dog postoperative Ulcer Models of gastric antrum ESD is set up: experimental dog anaesthetizes (pentobarbital sodium through gastroscope
1.2ml/kg, intraperitoneal injection) and tracheal intubation after, use gastroscope (Olympus GIF-Q260J),
Select beagle dog (10kg, male) gastric antrum antetheca to use ESD technology to peel off antrum, formed straight
The footpath postoperative ulcer of 3cm circle ESD, is successfully established dog gastric ulcer model.
Set up dog ESD postoperative gastric Ulcer Models 12 through gastroscope, and be randomly divided into: matched group, Esso
Azoles (PPIs mono-kind) medication therapy groups and bi-component injectable PU/SIS gel draw in U.S.A, and (present invention implements
The injection aquagel product box of example 1 preparation) treatment group, often group 4.
It is administered: (1) esomeprazole group: within postoperative 3rd day, start from addition Esso U.S.A in daystart dog diet and draw
Azoles 20mg, once a day.(2) bi-component injectable PU/SIS gel for treating group of the present invention: postoperative
Within 3 days, directly insert spray line through gastroscope movable detecting hole, first inject B component 1.5ml and be covered on wound surface,
Reinject component A 4.5ml and be covered on component A,；(3) matched group: not locate after modeling
Reason.
2, experimental result
Experimental result is as shown in table 2 and Figure 16:
Table 2: the different treatment means Comparison of therapeutic to the dog postoperative ulcer healing of gastric antrum ESD
(1) matched group: when 1 week, ulcer equal size about 2.5*2.5cm, around ulcer, mucosa is smooth, the end
Recessed；Seeing that ulcer heals earlier above when 2 weeks, locally mucosa shrinkage, the end, is rubescent, and equal size is about
2.0*1.5cm；When 4 weeks, visible ulcer relatively takes a step forward and reduces, equal size about 1.0*0.5cm, around mucosa
Slightly swelling, surface is rubescent, piebald shape；When 6 weeks, it is seen that ulcer major part heals, equal size about 0.5*0.5
Cm, around mucosa is red and white, clear in structure；When 7 weeks, it is seen that skin surface is piebald shape, but group
Knitting structure close to normal mucosa, around mucosa turns white slightly shrinkage.The average healing is 50 days.
(2) esomeprazole group: when 1 week, ulcer equal size about 2.5*2.0cm, around ulcer, mucosa is put down
Whole, the end, is recessed；Seeing that ulcer heals earlier above when 2 weeks, locally mucosa is the most smooth, the end be in depression shape companion
Rubescent, equal size about 1.5*1.5cm；When 4 weeks, visible ulcer relatively takes a step forward and reduces, and equal size is about
0.5*0.5cm, around mucosa slightly swells, radially；When 6 weeks, it is seen that ulcer heals the most substantially, table
Face is piebald shape, but organizational structure is close to normal mucosa, and around mucosa turns white slightly shrinkage.When averagely healing
Between be 42 days.
(3) PU/SIS gel group of the present invention: after injection 1 week, ulcer equal size about 2.0*2.0cm,
Around ulcer, mucosa is the most smooth, and the end is recessed and surface particles sample is coarse；See that ulcer heals earlier above when 2 weeks
Closing, locally mucosa slightly shrinkage companion protuberance, the end shape that is in depression occurs together red, surface still in granular, equal size
About 1.5*1.0cm；When 4 weeks, visible ulcer heals the most substantially, and surface is slightly swelled in piebald shape, organizational structure
Close to normal mucosa, around mucosa turns white slightly shrinkage.The average healing is 30 days.
Result shows: three groups of ESD postoperative esophageal ulcer healing time length are followed successively by matched group ＞ Esso U.S.
Draw azoles group ＞ PU/SIS gel group.Histologic analysis shows that postoperative surrounding PU/SIS group ulcer surface is the most complete
Re-epithelialization, it is believed that healed, as shown in Figure 10, this is consistent with the result of gross examination of skeletal muscle.Real
Testing result explanation, PU/SIS gel of the present invention has the effect promoting the postoperative ulcer healing of ESD, has
Potential applicability in clinical practice, and be to repair under the Wicresoft of clinical Ji Xing lumen organization damage, chamber mirror to provide one
New thinking.
To sum up, two components in subject hydrogel product bag can be mediated by endoscopic technic, it is achieved note
Penetrate implantation, and can gelation the most in position, be fixed on damage location, good to the repairing effect of wound surface,
And be to repair under the Wicresoft of clinical Ji Xing lumen organization damage, chamber mirror to provide a kind of new selection, clinical
Application prospect is good.
Claims (12)
1. a double-component injection aquagel product box, it is characterised in that: it includes two separately deposited
Individual component: component A is polyaminoester emulsion, component B is molten containing submucous layer of small intestine powder and acetic acid
Glue.
Injection aquagel product box the most according to claim 1, it is characterised in that: described component
The mean diameter of A polyaminoester emulsion is 30～100nm, and solid content is 10%～25%, and Zeta potential is-60
MV～-20mV.
Injection aquagel product box the most according to claim 2, it is characterised in that: described poly-ammonia
The preparation method of ester emulsion is as follows:
(1) pre-polymerization: taking isocyanates and hydroxyl donor, pre-polymerization, the mol ratio of the two is (0.26～0.27):
(0.15～0.19)；
Described isocyanates is isophorone diisocyanate, lysinediisocyanate or diphenyl methane
Any one or more in diisocyanate；
Described hydroxyl donor is any one or more in PTMG, poly-epsilon-caprolactone glycol；
(2) chain extension: addition chain extender, chain extension, wherein, chain extender and hydroxyl donor in step (1)
Mol ratio be (0.15～0.19): (0.05～0.09)；Chain extension process adds acetone；
Described chain extender be in 1,4-butanediol, 2,2-dihydromethyl propionic acid, ethylene glycol any one or many
Kind；
(3) emulsifying is neutralized: take nertralizer, by polyurethane polymer dispersible in nertralizer, emulsifying 2h；
Wherein, nertralizer is (0.15～0.19) with the mol ratio of chain extender in step (2): (0.02～0.08)；
(4) purification: rotation is evaporated off acetone and excess nertralizer, deionized water dialysis removes impurity, to obtain final product.
Injection aquagel product bag the most according to claim 3, it is characterised in that: step (1)
In, the temperature of pre-polymerization is 75 DEG C；The time of pre-polymerization is 2～4h；The catalyst that pre-polymerization uses is that octanoic acid is sub-
Stannum, triethanolamine or dibutyl tin laurate；
In step (2), the temperature of chain extension is 50 DEG C～55 DEG C；The time of chain extension is 3～4h；
In step (3), under the conditions of the THE ADIABATIC SHEAR IN that rotating speed is 1500r/m, polyether polyols with reduced unsaturation is divided
Dissipate in nertralizer；Described nertralizer is triethylamine or sodium hydroxide；
In step (4), the temperature that rotation is steamed is 55 DEG C.
Injection aquagel product box the most according to claim 1, it is characterised in that: described component
B contains in the colloidal sol of submucous layer of small intestine powder and acetic acid, and acetic acid is 4:100 with the volume ratio of water, small intestinal
Tela submucosa powder is (0.5～4) with the mass volume ratio of acetic acid and the total amount of water: 100, preferably 2:
100。
Injection aquagel product box the most according to claim 1 or 5, it is characterised in that: described
The mean diameter of colloidal sol is 600～900nm, and solid content is 0.5%～4%, and Zeta potential is 20～50mV.
7. according to the injection aquagel product box described in claim 1,5 or 6, it is characterised in that:
The described preparation method containing submucous layer of small intestine powder and the colloidal sol of acetic acid is: takes acetic acid, prepares acetic acid
Aqueous solution, acetic acid is 4:100 with the volume of water, adds submucous layer of small intestine powder, mixing, small intestinal
The addition of tela submucosa powder and the mass volume ratio of aqueous acetic acid are 2:100.
8. according to the injection aquagel product box described in claim 1,5～7 any one, its feature
It is: described submucous layer of small intestine prepares by the following method:
I () takes pig small intestine, washing, cuts open, the section of being cut into；
(ii) muscle layer and the placenta percreta of small intestinal are struck off；
(iii), after washing is filtered dry, it is dipped in the mixed solution of chloroform and methanol, soak time
Being 4 hours, in described mixed solution, chloroform is 1:1 with the volume ratio of methanol；
(iv) after washing, putting in trypsin solution, 4 DEG C process overnight；
After (v) washing, process at least 4h with sodium lauryl sulphate；
(vi) after cleaning, lyophilizing；
(vii) pulverize, add containing in 3% acetic acid, 0.1% pepsic PBS solution, adjust pH
To neutrality, lyophilizing, then pulverize, to obtain final product.
9., according to the injection aquagel product box described in claim 1～8 any one, its feature exists
In: component A is 1:(1～3 with the volume ratio of component B).
10. the method preparing injection aquagel product bag described in claim 1～9 any one,
It is characterized in that: step is as follows:
I, polyaminoester emulsion is prepared
(1) pre-polymerization: taking isocyanates and hydroxyl donor, pre-polymerization, the mol ratio of the two is (0.26～0.27):
(0.15～0.19)；
Described isocyanates is isophorone diisocyanate, lysinediisocyanate or diphenyl methane
Any one or more in diisocyanate；
Described hydroxyl donor is any one or more in PTMG, poly-epsilon-caprolactone glycol；
(2) chain extension: addition chain extender, chain extension, wherein, chain extender and hydroxyl donor in step (1)
Mol ratio be (0.15～0.19): (0.05～0.09)；Chain extension process adds acetone；
Described chain extender be in 1,4-butanediol, 2,2-dihydromethyl propionic acid, ethylene glycol any one or many
Kind；
(3) neutralizing emulsifying: add nertralizer, polyurethane is polymerized by THE ADIABATIC SHEAR IN condition (1500r/m)
In thing dispersion nertralizer, emulsifying 2h；Wherein, nertralizer with the mol ratio of chain extender in step (2) is
(0.15～0.19): (0.02～0.08)；
Described nertralizer is triethylamine or sodium hydroxide；
(4) purification: rotation is evaporated off acetone and excess nertralizer, deionized water dialysis removes impurity, to obtain final product
Polyaminoester emulsion, packaging,；
II, preparation is containing submucous layer of small intestine powder and the colloidal sol of acetic acid
Taking acetic acid, prepare aqueous acetic acid, acetic acid is 4:100 with the volume ratio of water, adds small intestinal and glues
Film lower floor powder, mixing, packaging, wherein, the addition of submucous layer of small intestine powder and acetic acid
The mass volume ratio of aqueous solution is 2:100；
Described submucous layer of small intestine powder prepares by the following method:
I () takes pig small intestine, washing, cuts open, the section of being cut into；
(ii) muscle layer and the placenta percreta of small intestinal are struck off；
(iii), after washing is filtered dry, it is dipped in the mixed solution of chloroform and methanol, soak time
Being 4 hours, in described mixed solution, chloroform is 1:1 with the volume ratio of methanol；
(iv) after washing, putting in trypsin solution, 4 DEG C process overnight；
After (v) washing, process at least 4h with SDS；
(vi) after cleaning, lyophilizing；
(vii) pulverize, add containing in 3% acetic acid, 0.1% pepsic PBS solution, adjust pH
To neutrality, lyophilizing, then pulverize, to obtain final product.
11. 1 kinds of polyurethane/submucous layer of small intestine (PU/SIS) hydrogels, it is characterised in that: according to such as
Prepared by lower section method: take the injection aquagel product bag described in claim 1～8 any one, by component
A with component B according to 1:(1～3) volume ratio mix, obtain hydrogel.
Injection aquagel product bag described in 12. claim 1～8 any one and claim 11
Described hydrogel purposes in preparation wound repair material.
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| CN201610380033.2A CN105999373B (en) | 2016-05-30 | 2016-05-30 | A kind of polyurethane/submucous layer of small intestine (PU/SIS) two-component injection aquagel |
| PCT/CN2017/083577 WO2017206673A1 (en) | 2016-05-30 | 2017-05-09 | Polyurethane/small intestinal submucosa (pu/sis) two-component injectable hydrogel |
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| WO2017206673A1 (en) * | 2016-05-30 | 2017-12-07 | 拓睿美（北京）医疗科技有限公司 | Polyurethane/small intestinal submucosa (pu/sis) two-component injectable hydrogel |
| CN110724245A (en) * | 2018-07-17 | 2020-01-24 | 四川大学 | Injectable polyurethane and process for its preparation |
| CN114848893A (en) * | 2022-04-08 | 2022-08-05 | 大连医科大学 | Silk fibroin-combined decellularized small intestine submucosa extracellular matrix hydrogel for pigs, and preparation method and application thereof |
| CN115737924A (en) * | 2021-09-03 | 2023-03-07 | 四川大学华西医院 | Injectable polyurethane-small intestinal submucosa cell microcarrier and preparation method and application thereof |
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| CN114377210B (en) * | 2020-10-19 | 2024-02-20 | 四川大学华西医院 | Polyurethane/small intestine submucosa/polypyrrole composite material and preparation method and application thereof |
| CN115282262A (en) * | 2022-08-16 | 2022-11-04 | 四川大学华西医院 | A composition for treating skin defect |
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| WO2017206673A1 (en) | 2017-12-07 |
| CN105999373B (en) | 2019-08-16 |
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