CN104689380A - Submucous injection material composed of physical cross-linked hydrogel and application thereof - Google Patents
Submucous injection material composed of physical cross-linked hydrogel and application thereof Download PDFInfo
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Abstract
The invention belongs to the fields of high polymer materials and medical equipment and relates to a submucous injection material composed of physical cross-linked hydrogel and an application thereof to preparing injection materials for endoscopic submucosal dissection. The submucous injection material consists of an amphiphilic block copolymer, a solvent which takes water as a main body, and a coloring indicator, wherein the amphiphilic block copolymer is formed by taking polyethylene glycol (PEG) as a hydrophilic block and taking degradable polyester as a hydrophobic block. The material has thermal induced gel-forming properties; when the temperature is lower than a sol-gel transition temperature, a water system presents low-viscosity solution, has good injectable property, and can be subjected to endoscopic injection to the submucosal position so as to spontaneously form in-situ physical hydrogel under the body temperature, good gel morphology is maintained during an ESD operation, the uplift height and duration of the submucous injection material are superior to those of an existing pure liquid material, and the ESD operation is smoothly performed.
Description
Technical field
The invention belongs to macromolecular material and medical instruments field, relate to a kind of submucosal injection material of being made up of physical cross-linking hydrogel and application thereof, the described submucosal injection material be made up of physical cross-linking hydrogel can be used for preparing alimentary canal mucous membrane hemostasis material, especially for the preparation of the application in the injection material in Endoscopic submucosal dissection.
Background technology
Endoscopic submucosal dissection (ESD) is therapeutic endoscopy technology fast-developing in recent years, be mainly used in the excision of early gastrointestinal carcinoma, precancerous lesion and resection of submucosal tumor, its indication comprises esophageal lesion, gastropathy, Large bowel disease etc., the advantage of the complete Pathologic specimen that has minimally-invasive treatment, avoids pathological changes to remain, can obtain.The implementation process of ESD comprises labelling, submucosal injection, edge slit, stripping, Wound treatment double teacher.But due to its cutting and stripping process difficulty higher, easily cause the postoperative complications such as tissue burn, hemorrhage and even perforation.For the ease of the smooth enforcement of ESD, a kind of very important method is (Submucosa) and surrounding injection submucosal injection liquid thereof below focus.Its effect is swelled by mucosa lesions position, realizes and being separated of muscularis propria, be beneficial to the removal of lesions that ESD is complete, and do not damage muscularis propria, and reduce the generation of perforation and the complication such as hemorrhage.
Desirable submucosal injection liquid should have following feature: 1. provide fluid cushion under a thick mucosa; 2. the sufficiently long mucosa protuberance time is maintained; 3. guarantee that ESD excises the tissue specimen obtained complete, an accurate pathological staging can be provided; 4. reasonable price, easily obtains.
At present, the submucosal injection material used clinically comprises following several:
Normal saline: be isotonic liquid, more difficult maintenance ideal height, is substantially absorbed into the surrounding tissues very soon, holds time and probably only has a few minutes, need repeatedly to inject, and injected dose is larger.
Hypertonic saline or hypertonic glucose: low price, be easy to get and more easily preserve.Because osmotic pressure is high, can maintain ideal height, hold time also longer, frequency injection and quantity are also less than normal saline, but studies have reported that, hyperosmotic solution can cause damage to normal mucosa and tissue.
Hyaluronate sodium: isotonic liquid, to organizing not damaged, have high viscosity and water-retaining property, the protuberance time is obviously better than hyperosmotic solution, can better ensure pathological changes complete resection.But it is expensive, need special preservation condition, and clinical practice shows that hyaluronate sodium likely promotes the growth of tumor cell, therefore its application is subject to a definite limitation.
Above-mentioned submucosal injection liquid has common deficiency in ESD operation is implemented: be all always the good liquid of mobility, and after being injected into Submucosa, diffusion rapidly, its bump height and equal relative deficiency of holding time.
Present inventor intends providing a kind of novel submucosal injection material, using injectable thermic hydrogel as injection material or slow releasing carrier of medication, be injected to the physical hydrogel of spontaneous formation original position under body temperature below mucous layer by the entry needle of scope, be beneficial to carrying out smoothly of ESD operation.
Summary of the invention
The object of this invention is to provide a kind of medical macromolecular materials with heat-induced gel voltinism energy, relate to a kind of submucosal injection material of being made up of physical cross-linking hydrogel and application thereof, the described submucosal injection material be made up of physical cross-linking hydrogel can be used for preparing alimentary canal mucous membrane hemostasis material, especially for the preparation of the application in the injection material in Endoscopic submucosal dissection.
In the present invention using injectable thermic hydrogel as injection material, this material is low viscous solution at low temperatures, there is good syringeability, the entry needle carried by scope is injected to below mucous layer, the physical hydrogel of spontaneous formation original position under body temperature subsequently, and good gel form is kept between whole ESD operation implementation period, be all better than existing pure liquid material in bump height with on the persistent period, be conducive to carrying out smoothly of ESD operation.
ESD Post operation is implemented based on esophagus, because in wound site agglutination, mucous layer thickens, easily cause the generation of esophageal stricture phenomenon, this injection material also can be used as a kind of slow releasing carrier of medication, for reaching Submucosa by the injection of endoscopic injection pin after carrying medicament, be used for the treatment of the complication such as the postoperative esophageal stricture caused of ESD.This injection material also can load cells, for the reparation of ESD postoperative digestive tract defect mucosa.
Concrete, the submucosal injection material be made up of physical cross-linking hydrogel of the present invention, is made up of jointly amphipathic nature block polymer, solvent based on water and painted indicator three; This submucosal injection material possesses thermic plastic characteristic, and namely it is in low viscous solution state when low temperature, can become gel state by Spontaneous conversion when human body temperature; Wherein, the hydrophilic block of described amphipathic nature block polymer is Polyethylene Glycol (PEG), and hydrophobic block is degradable polyester.
The sol-gel transition temperature of submucosal injection material of the present invention between 4-37 DEG C, preferred 20-37 DEG C, more preferably 30-37 DEG C.
In block copolymer of the present invention:
1) mean molecule quantity of hydrophilic Polyethylene Glycol block is 400-50000, and content is 10-90wt%, is designated as A block;
2) hydrophobic polyester block content is 90-10wt%, is designated as B block;
3) described polyester B block is selected from poly DL-lactide, poly-D-lactide, PLLA, PGA, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-valerolactone, poly-1,4, any one in 8-trioxa spiral shell [4.6]-9-hendecanone, poly-para-dioxanone, polyesteramide, Merlon, polyacrylate, polyether ester, or any type of copolymer of above-mentioned polyester;
4) described block copolymer can be the triblock copolymer of ABA or BAB type, the di-block copolymer of AB type, the graft copolymer of A-g-B or B-g-A type, (Α-Β)
nor (Β-Α)
nstar block copolymer and Α (Β Α)
nor B (AB)
nthe segmented copolymer of configuration, wherein n is the integer of 2 to 10;
5) the part or all of end of described block polymer is connected to function end group, and end group is any one in hydrophilic amino, carboxyl, imidazole radicals, aldehyde radical, cyano group, nitro; Or hydrophobic alkyl, sterin, alkoxyl, aromatic radical, aromatic heterocyclic, amide ester group, halogen atom, trichloromethyl, ester group, any one in sulfydryl;
In the present invention, the content of block copolymer in solvent is 3-50wt%, is wherein that preferably 10-25wt% is most preferably with 5-30wt%.
In the present invention, solvent is pure water, water for injection, normal saline, buffer solution, animals and plants or human body fluid, tissue culture medium, cell culture fluid, or is that other is with aqueous solution and the medium not based on organic solvent.
In the present invention, painted indicator is selected from one in methylene blue (also known as methylene blue, methylene blue) and indigo carmine (also known as isatin, indigo carminum, sodium indigotindisulfonate) or its combination, and its weight percent content in aqueous systems is 0.001%-0.1%, preferred 0.001-0.01%, more preferably 0.001-0.005%, determines because specifically needing.
In the system of block copolymer of the present invention, solvent and painted indicator, except block copolymer, solvent and painted indicator, the polymer of other type can be comprised or/and non-polymeric ingredients.
The alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel of the present invention can the antibiotics of load simultaneously, hormones or somatomedin class medicine.
The medicine of the alimentary canal mucous membrane hemostasis material polymers aqueous systems load be made up of physical cross-linking hydrogel of the present invention can be selected from one or more in epinephrine, dexamethasone, ametycin, prednisolone, 5-fluorouracil, triamcinolone acetonide.
The alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel of the present invention can simultaneously load cells.
The preparation method of the alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel of the present invention is as follows: first at dissolution in low temperature polymer in solvent, then store for future use at-20 DEG C or following, redissolve and add painted indicator before using, after mixing, becoming injection of solution agent.
Add the painted indicator of 0.001%-0.1% in said method, preferred 0.001-0.01%, more preferably 0.001-0.005%, determine because specifically needing.
In said method, low temperature refers to that 0 DEG C to room temperature.
In said method, polymer for be hydrophilic block by Polyethylene Glycol (PEG), the amphipathic nature block polymer that forms for hydrophobic block of degradable polyester.
In said method, block copolymer is obtained by the thermal condensation of PEG macromole and degradable polyester monomer or ring-opening polymerisation.
In said method, the catalyst that ring-opening polymerisation adopts is stannous octoate.
In said method, the solvent of the alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel can be pure water, water for injection, normal saline, buffer solution, animals and plants or human body fluid, tissue culture medium, cell culture fluid, or is that other is with aqueous solution and the medium not based on organic solvent.
In said method, the solution-gel transition temperature of the alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel between 4-37 DEG C, preferred 20-37 DEG C, more preferably 30-37 DEG C.
In said method, block copolymer comprises:
1) mean molecule quantity of hydrophilic Polyethylene Glycol block is 400-50000, and content is 10-90wt%, is designated as A block.
2) hydrophobic polyester block content is 90-10wt%, is designated as B block.
3) described polyester B block is selected from poly DL-lactide, poly-D-lactide, PLLA, PGA, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-valerolactone, poly-1,4, any one in 8-trioxa spiral shell [4.6]-9-hendecanone, poly-para-dioxanone, polyesteramide, Merlon, polyacrylate, polyether ester, or any type of copolymer of above-mentioned polyester.
4) described block copolymer can be the triblock copolymer of ABA or BAB type, the di-block copolymer of AB type, the graft copolymer of A-g-B or B-g-A type, (Α-Β)
nor (Β-Α)
nstar block copolymer and Α (Β Α)
nor B (AB)
nthe segmented copolymer of configuration, wherein n is the integer of 2 to 10;
5) the part or all of end of described block polymer is connected to function end group, and end group is any one in hydrophilic amino, carboxyl, imidazole radicals, aldehyde radical, cyano group, nitro; Or hydrophobic alkyl, sterin, alkoxyl, aromatic radical, aromatic heterocyclic, amide ester group, halogen atom, trichloromethyl, ester group, any one in sulfydryl.
In said method, the content of block copolymer in solvent is 3-50wt%, is wherein that preferably 10-25wt% is most preferably with 5-30wt%.
In said method, in the system of block copolymer, solvent and painted indicator, except block copolymer, solvent and painted indicator, the polymer of other type can be comprised or/and non-polymeric ingredients.
In said method, the alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel can the antibiotics of load simultaneously, hormones or somatomedin class medicine.
In said method, the medicine of the alimentary canal mucous membrane hemostasis material load be made up of physical cross-linking hydrogel can be selected from one or more in epinephrine, dexamethasone, ametycin, prednisolone, 5-fluorouracil, triamcinolone acetonide.
In said method, the alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel can simultaneously load cells.
Invention further provides the submucosal injection material be made up of physical cross-linking hydrogel and prepare the application in alimentary canal mucous membrane hemostasis material.
The alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel of the present invention can be injected at the Submucosa of esophagus, stomach, rectum and colon through digestive endoscope entry needle.
The alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel of the present invention can be applied but be not limited to the Endoscopic submucosal dissections such as stomach, esophagus, rectum and colon.
The alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel of the present invention arrives Submucosa by the injection of endoscopic injection pin, alimentary canal mucous membrane diseased region is effectively swelled, add the thickness of Submucosa, and realize being separated of pathological changes mucous layer to be stripped and muscularis propria, thus reduce the middle punch of ESD art, the generation of the complication such as hemorrhage, improve the safety of operation technique, reduce operation technique difficulty, shorten and performed the operation the required time, for colon cancer, rectal cancer, early gastric cancer, advanced gastric carcinoma, the ESD Diagnosis and Treat of the cancers such as the esophageal carcinoma provides convenient.
The alimentary canal mucous membrane hemostasis material that is made up of physical cross-linking hydrogel of load of the present invention medicine reaches Submucosa by the injection of endoscopic injection pin, is used for the treatment of the complication such as the postoperative esophageal stricture caused of ESD.
The alimentary canal mucous membrane hemostasis material be made up of physical cross-linking hydrogel of load of the present invention cell reaches Submucosa, for repairing the postoperative alimentary canal mucous membrane defect caused of ESD by the injection of endoscopic injection pin.
The invention has the advantages that:
The alimentary canal mucous membrane hemostasis liquid material be made up of physical cross-linking hydrogel that the present invention proposes has spontaneous heat-induced gel characteristic, namely its aqueous systems can present good mobility below gel transition temperature, the entry needle easily carried by scope is injected into below mucous layer easily, forms protuberance; Rise with ambient temperature after being injected in vivo, solution-gel occurs rapidly solution changes, the physical hydrogel of original position is formed below mucous layer, and can desirable bump height and persistent period be maintained, the submucosal injection liquid material of more traditional use has obviously advantage, be conducive to Endoscopic submucosal dissection intactly removal of lesions, and do not damage muscularis propria, effectively can reduce the incidence rate of the complication such as hemorrhage, perforation.
The alimentary canal mucous membrane hemostasis liquid material be made up of physical cross-linking hydrogel that the present invention proposes has good biocompatibility and degradability; the pipeline that carries by endoscope of residue gel after diseased region excision directly siphons away, though leave remaining also can degradable be within a certain period of time nontoxic polymer monomer.This material is semisolid gel state in vivo, compared with the hyperosmotic solution used, can not damage the generation of normal mucosa and surrounding tissue thereof with tradition.
Painted indicator in the alimentary canal mucous membrane hemostasis liquid material be made up of physical cross-linking hydrogel that the present invention proposes is its indispensable ingredient.Due to polymer water system usually human body temperature formed be clear gel, extremely not easily distinguish in ESD operation, easily cause complication such as boring a hole, hemorrhage, and painted indicator has made on whole gelinite frenulum bright color, improve the safety of operation technique, avoid the maloperation that may occur in operation, and shortening is performed the operation the required time.
Accompanying drawing explanation
Fig. 1. for the normal saline solution of block copolymer C opolymer-1 variable concentrations is along with phasor during variations in temperature, wherein adopt voltage regulator tube method to measure.
Fig. 2. for adopting block copolymer thermic hydrogel of the present invention to make the stomach mucosa protuberance situation of vivo porcine as submucosal injection material, wherein with hyaluronic acid and Glycerin Fructose for reference.
Detailed description of the invention
Further describe the present invention below by example, but be not limited to these embodiments.
Embodiment 1
30g PEG(1500 is added in 250mL there-necked flask), oil bath is heated to 130 DEG C, under agitation evacuation 3h, to remove moisture residual in PEG.Then, add 56g DL-lactide (LA), 8.9g Acetic acid, hydroxy-, bimol. cyclic ester (GA) and 0.1wt% stannous octoate (containing a small amount of toluene), below 100 DEG C, evacuation 30min will be will wherein remove by toluene.Be warming up to 150 DEG C, after the whole melting of monomer, react 12h under an argon atmosphere.After reaction terminates, product, to remove unreacted monomer and low-boiling products, is poured out by vacuum filtration 3h while hot, and washed several times with water postlyophilization, obtains triblock copolymer, and productive rate is about 80%.The number measuring described BAB block copolymer (PLGA-PEG-PLGA, Copolymer-1) by chromatograph of gel permeation (GPC) (adopt polystyrene as standard specimen) all with weight average molecular weight (M
n, M
w) be respectively 6690 and 8300, molecular weight distribution index (M
w/ M
n) be 1.24.Its aqueous systems has the characteristic of heat-induced gel.
Embodiment 2
In 250mL there-necked flask, add the Polyethylene Glycol (MPEG750) of 22.5g mono methoxy end-blocking, oil bath is heated to 130 DEG C, under agitation evacuation 3h, to remove moisture residual in MPEG.Add 45g DL-LA, 6g GA and 0.1wt% stannous octoate (containing a small amount of toluene), below 100 DEG C, evacuation 30min will be will wherein remove by toluene.Be warming up to 150 DEG C, after the whole melting of monomer, react 12h under an argon atmosphere.After reaction terminates, product, to remove unreacted monomer and low-boiling products, is poured out by vacuum filtration 3h while hot, washed several times with water postlyophilization, and obtain di-block copolymer material, productive rate is about 75%.The number measuring described BA di-block copolymer (MPEG-PLGA, Copolymer-4) by GPC all with weight average molecular weight (M
n, M
w) be respectively 3570 and 4640, molecular weight distribution index (M
w/ M
n) be 1.30.Its aqueous systems has the characteristic of heat-induced gel.
Embodiment 3
Getting PEG(1500) 15.0g is in 250mL there-necked flask, and 130 DEG C of lower evacuation 3h of stirring are wherein moisture with removing.Add caprolactone (CL) 29.0g and 0.3wt% stannous octoate, 120 DEG C, react 24h under argon gas atmosphere.After reaction terminates, vacuum filtration 3h is to remove unreacted monomer and low-boiling products, and then head product is dissolved in dichloromethane solution, ether sedimentation, productive rate is about 85%.The number measuring described BAB block copolymer (PCL-PEG-PCL, Copolymer-8) by GPC all with weight average molecular weight (M
n, M
w) be respectively 7100 and 9230, molecular weight distribution index (M
w/ M
n) be 1.30.This copolymer originally has the performance of heat-convertible gel in water.
Embodiment 4
Get 11.0g MPEG(550) be dissolved in 80mL toluene, be distilled to 30mL and remove remaining moisture content in polymer.Add 21.0g CL and 0.3wt% stannous octoate, reflux 24h at 120 DEG C.Add HDMI1.62mL subsequently, at 60 DEG C, react 7h.Then in above-mentioned solution, add ether, precipitation obtains head product.Gained head product is dissolved in 30mL dichloromethane, and slowly add ether and precipitate to make it, in product, residual solvent is removed by evacuation, and obtain PECE material, productive rate is about 65%.The number measuring described ABA block copolymer (PEG-PCL-PEG, Copolymer-9) by GPC all with weight average molecular weight (M
n, M
w) be respectively 5350 and 6150, molecular weight distribution index (M
w/ M
n) be 1.15.This copolymer originally has the performance of heat-convertible gel in water.
Embodiment 5
Getting PEG(1000) 20.0g is in 250mL there-necked flask, and 130 DEG C of lower evacuation 3h of stirring are wherein moisture with removing.Add CL20.0g, trimethylene carbonate 9g and 0.1wt% stannous octoate, 120 DEG C, react 24h under argon gas atmosphere.After reaction terminates, vacuum filtration 3h is to remove unreacted monomer and low-boiling products.Head product is dissolved in dichloromethane solution, ether sedimentation, productive rate is about 85%.The number measuring described BAB block copolymer (PCTC-PEG-PCTC, Copolymer-10) by GPC all with weight average molecular weight (M
n, M
w) be respectively 4930 and 6510, molecular weight distribution index (M
w/ M
n) be 1.32.This copolymer originally has the performance of heat-convertible gel in water.
Embodiment 6
Getting PEG(1500) 22.5g is in 250mL there-necked flask, and 130 DEG C of lower evacuation 3h of stirring are wherein moisture with removing.Add CL43.0g, GA5.4g and 0.1wt% stannous octoate, 150 DEG C, react 12h under argon gas atmosphere.After reaction terminates, vacuum filtration 3h is to remove unreacted monomer and low-boiling products.Head product is dissolved in dichloromethane solution, ether sedimentation, productive rate is about 85%.The number measuring described BAB block copolymer (PCGA-PEG-PCGA, Copolymer-11) by GPC all with weight average molecular weight (M
n, M
w) be respectively 7010 and 9030, molecular weight distribution index (M
w/ M
n) be 1.29.This copolymer originally has the performance of heat-convertible gel in water.
Embodiment 7
Get 11.0g MPEG(550) be dissolved in 80mL toluene, be distilled to 30mL and remove remaining moisture content in polymer.Add 31.0g trimethylene carbonate and 0.1wt% stannous octoate, reflux 24h at 120 DEG C.Then in above-mentioned solution, add ether, precipitation obtains head product.Gained head product is dissolved in 30mL dichloromethane, and slowly add ether and precipitate to make it, in product, residual solvent is removed by evacuation, and obtain MPEG-PTMC di-block copolymer material, productive rate is about 65%.The number measuring described BA di-block copolymer (PMPEG-PTMC, Copolymer-12) by GPC all with weight average molecular weight (M
n, M
w) be respectively 5600 and 7840, molecular weight distribution index (M
w/ M
n) be 1.40.This copolymer originally has the performance of heat-convertible gel in water.
Embodiment 8
According to the basic step that embodiment 1 provides, synthesize other various block copolymers by the PEG of different molecular weight and different monomers, its characterization result is as following table 1:
Table 1
In above-mentioned table, block copolymer all has the performance of heat-induced gel.Copolymer is made into certain density aqueous solution, and it lower than being solution state during gel transition temperature in temperature, rises and form gel gradually, and this process being reversible process with temperature.
Embodiment 9
Take appropriate block copolymer C opolymer-1, add a certain amount of normal saline solution, prepare to obtain the solution of 25wt%.This solution has heat-induced gel characteristic, when temperature is higher than sol-gel phase transition temperature, and can spontaneous formation gel.Measure its sol-gel phase transition temperature by test tube anastrophe, the test tube being about to be loaded with sample balances 180 ° of inversions after 10min in a water bath, obviously flows, be then judged as gel state if do not observe sample in 30s.It is 33 DEG C that result shows its gel transition temperature.
Embodiment 10
Take appropriate block copolymer C opolymer-2, obtain the solution of 23wt% with phosphate buffer solution preparation.This solution has heat-induced gel characteristic, and it is 10 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 11
Take appropriate block copolymer C opolymer-4, obtain the aqueous solution of 9wt% with deionized water preparation.This solution has heat-induced gel characteristic, and it is 35 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 12
Take appropriate block copolymer C opolymer-9, with the solution of phosphate buffer solution preparation 30wt%, this solution has heat-induced gel characteristic, and it is 27 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 13
Take appropriate block copolymer C opolymer-10, obtain the aqueous solution of 18wt% with normal saline.This solution has heat-induced gel characteristic, and it is 28 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 14
Take appropriate block copolymer C opolymer-11, obtain the aqueous solution of 15wt% with deionized water preparation.This solution has heat-induced gel characteristic, and it is 37 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 15
Take appropriate block copolymer C opolymer-12, obtain the aqueous solution of 40wt% with normal saline.This solution has heat-induced gel characteristic, and it is 22 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 16
Take appropriate block copolymer C opolymer-13, obtain the aqueous solution of 20wt% with normal saline.This solution has heat-induced gel characteristic, and it is 25 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 17
Take appropriate block copolymer C opolymer-14, obtain the aqueous solution of 35wt% with deionized water preparation.This solution has heat-induced gel characteristic, and it is 27 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 18
Take appropriate block copolymer C opolymer-15, obtain the aqueous solution of 25wt% with normal saline.This solution has heat-induced gel characteristic, and it is 28 DEG C that test tube anastrophe records its sol-gel phase transition temperature.
Embodiment 19
With the block copolymer C opolymer-1 solution of the Different Weight percent concentration of normal saline from 5% to 25%, Fig. 1 is the temperature variant phasor of normal saline solution of block copolymer C opolymer-1 variable concentrations.
Embodiment 20
Add in above-mentioned block copolymer solution weight percent content be painted indicator methylene blue between 0.001%-0.1% or indigo carmine time, find all not affect its sol-gel phase transition temperature and syringeability.
Embodiment 21
The 25wt% normal saline solution of Copolymer-1 is carried out sterilization treatment by 0.22 μm of microporous filter membrane.Get above-mentioned solution 2.5mL, with 2.5mL injector to inject to inside postanesthetic miniature pig back leg, visible subcutaneous obvious protuberance.Observe body inner gel degraded situation in time, when being found to the 20th day, its form is still obviously visible, also can be observed the existence of subcutaneous a little gel when the 30th day.
Embodiment 22
In in vitro Gaster Sus domestica, submucosal injection experiment is carried out with the 25wt% normal saline solution (methylene blue containing 0.001wt%) of Copolymer-3.Get solution 0.8mL with No. 23 syringe needles, be expelled to the Submucosa of in vitro Gaster Sus domestica, ambient temperature is maintained more than the gel transition temperature of solution, under mucosa, form gel to make solution.Observe protuberance form and the persistent period of mucosa, find to reach satisfied bump height, and the protuberance time can maintain more than 1h, can ensure the smooth enforcement that ESD performs the operation.
Embodiment 23
In isolated pig colon, submucosal injection experiment is carried out with the 20wt% normal saline solution (indigo carmine containing 0.1wt%) of Copolymer-10.Get solution 1.5mL with No. 23 syringe needles, be expelled to the Submucosa of isolated pig colon, ambient temperature is maintained more than the gel transition temperature of solution, under mucosa, form gel to make solution.Observe protuberance form and the persistent period of mucosa, find to reach satisfied bump height, and the protuberance time can maintain more than 1h, can ensure the smooth enforcement that ESD performs the operation.
Embodiment 24
Use the 25wt% normal saline solution (indigo carmine containing 0.005wt%) of Copolymer-1, carry out sterilization treatment according to method in embodiment 21.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement submucosal injection in Gaster Sus domestica portion.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By scope pipeline, this injection material No. 23 entry needles are expelled to stomach Submucosa, injection material consumption is 3mL.Adopt hyaluronic acid and Glycerin Fructose in contrast.Observe injection rear 0 respectively, 15, the protuberance form of mucous layer and change thereof after 30 minutes and one week, although result shows three's original raised, height is basically identical, but the mucous layer protuberance that hyaluronic acid and Glycerin Fructose obtain as injection obviously reduces after 15min, substantially disappears after 30min, and hydrogel can to maintain form as mucous layer protuberance during submucosal injection material substantially constant, as shown in Figure 2, even one week afterwale is still visible.
Embodiment 25
Use the 18wt% normal saline solution (methylene blue containing 0.05wt%) of Copolymer-10, carry out sterilization treatment according to method in embodiment 21.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement submucosal injection at position, pig feed road.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By scope pipeline, this injection material is expelled to the Submucosa of esophagus with No. 23 entry needles, injection material consumption is 5mL.Observe protuberance form and the persistent period of esophageal mucosa, find to reach satisfied bump height, and the protuberance time can maintain more than 1h, can ensure the smooth enforcement that ESD performs the operation.
Embodiment 26
Use the 15wt% deionized water solution (methylene blue containing 0.01wt%) of Copolymer-11, carry out sterilization treatment according to method in embodiment 21.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement submucosal injection at pig rectum position.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By scope pipeline, this injection material is expelled to the Submucosa of rectum with No. 23 entry needles, injection material consumption is 5mL.Observe protuberance form and the persistent period of esophageal mucosa, find to reach satisfied bump height, and the protuberance time can maintain more than 1h, can ensure the smooth enforcement that ESD performs the operation.
Embodiment 27
Use the 20wt% phosphate buffer solution (methylene blue containing 0.008wt%) of Copolymer-11, carry out sterilization treatment according to method in embodiment 21.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement submucosal injection at hog middle position.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By scope pipeline, this injection material is expelled to the Submucosa of colon with No. 23 entry needles, injection material consumption is 5mL.Observe protuberance form and the persistent period of esophageal mucosa, find to reach satisfied bump height, and the protuberance time can maintain more than 1h, can ensure the smooth enforcement that ESD performs the operation.
Embodiment 28
Use the 15wt% normal saline solution (indigo carmine containing 0.01wt%) of Copolymer-1, carry out sterilization treatment according to method in embodiment 21, obtain the injection material for submucosal injection.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement ESD operation in Gaster Sus domestica portion.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By endoscope channel, this material No. 23 entry needles are expelled to its Submucosa, material usage is 10mL, and visible mucous layer forms obvious protuberance, and size and highly suitable, implement mucosa afterwards and peel off.First cut protuberance mucous layer around with electric knife, and complete ring cutting, the hydrogel material sucking-off that the pipeline then carried by scope will be injected, finally entirety is carried out to protuberance mucosa and peel off, and with endoscope, pathological analysis is done in complete for cut-out taking-up.In whole operation process, this hydrogel material can maintain gratifying bump height all the time, the processing ease of incision mucous layer is carried out, and a shot can complete whole operation, greatly facilitates the implementation process of operation.Not there is perforated phenomenon in intra-operative, but there is a small amount of hemorrhage generation, but get final product spontaneous stopping without the need to process, show that this hydrogel material improves the safety of ESD operation to a great extent as submucosal injection material, and substantially reduce the time of operation technique.
Embodiment 29
Use the 30wt% phosphate buffer solution (methylene blue containing 0.05wt%) of Copolymer-12, carry out sterilization treatment according to method in embodiment 21, obtain the injection material for submucosal injection.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement ESD operation in pig feed road.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By endoscope channel, this material No. 23 entry needles are expelled to its Submucosa, material usage is 10mL, and visible mucous layer forms obvious protuberance, and size and highly suitable, implement mucosa afterwards and peel off.First cut protuberance mucous layer around with electric knife, and complete ring cutting, the hydrogel material sucking-off that the pipeline then carried by scope will be injected, finally entirety is carried out to protuberance mucosa and peel off, and with endoscope, pathological analysis is done in complete for cut-out taking-up.In whole operation process, this hydrogel material can maintain gratifying bump height all the time, the processing ease of incision mucous layer is carried out, and a shot can complete whole operation, greatly facilitates the implementation process of operation.There is not phenomenons such as boring a hole, hemorrhage in intra-operative, shows that this hydrogel material improves the safety of ESD operation to a great extent as submucosal injection material, and substantially reduce the time of operation technique.
Embodiment 30
Use the 20wt% phosphate buffer solution (methylene blue containing 0.001wt%) of Copolymer-11, carry out sterilization treatment according to method in embodiment 21, obtain the injection material for submucosal injection.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement ESD operation at hog middle.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By endoscope channel, this material No. 23 entry needles are expelled to its Submucosa, material usage is 15mL, and visible mucous layer forms obvious protuberance, and size and highly suitable, implement mucosa afterwards and peel off.First cut protuberance mucous layer around with electric knife, and complete ring cutting, the hydrogel material sucking-off that the pipeline then carried by scope will be injected, finally entirety is carried out to protuberance mucosa and peel off, and with endoscope, pathological analysis is done in complete for cut-out taking-up.In whole operation process, this hydrogel material can maintain gratifying bump height all the time, the processing ease of incision mucous layer is carried out, and a shot can complete whole operation, greatly facilitates the implementation process of operation.There is not phenomenons such as boring a hole, hemorrhage in intra-operative, shows that this hydrogel material improves the safety of ESD operation to a great extent as submucosal injection material, and substantially reduce the time of operation technique.
Embodiment 31
Use the 20wt% phosphate buffer solution (indigo carmine containing 0.005wt%) of Copolymer-10, carry out sterilization treatment according to method in embodiment 21, obtain the injection material for submucosal injection.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement ESD operation at pig rectum.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By endoscope channel, this material No. 23 entry needles are expelled to its Submucosa, material usage is 20mL, and visible mucous layer forms obvious protuberance, and size and highly suitable, implement mucosa afterwards and peel off.First cut protuberance mucous layer around with electric knife, and complete ring cutting, the hydrogel material sucking-off that the pipeline then carried by scope will be injected, finally protuberance mucosa is peeled off, and with endoscope, pathological analysis is done in complete for cut-out taking-up.In whole operation process, this hydrogel material can maintain gratifying bump height all the time, the processing ease of incision mucous layer is carried out, and a shot can complete whole operation, greatly facilitates the implementation process of operation.There is not phenomenons such as boring a hole, hemorrhage in intra-operative, shows that this hydrogel material improves the safety of ESD operation to a great extent as submucosal injection material, and substantially reduce the time of operation technique.
Embodiment 32
Use the 35wt% normal saline solution (methylene blue containing 0.01wt%) of Copolymer-14, carry out sterilization treatment according to method in embodiment 21, obtain the injection material for submucosal injection.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement ESD operation at Gaster Sus domestica.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By endoscope channel, this material No. 23 entry needles are expelled to its Submucosa, material usage is 30mL, and visible mucous layer forms obvious protuberance, and size and highly suitable, implement mucosa afterwards and peel off.First cut protuberance mucous layer around with electric knife, and complete ring cutting, the hydrogel material sucking-off that the pipeline then carried by scope will be injected, finally protuberance mucosa is peeled off, and with endoscope, pathological analysis is done in complete for cut-out taking-up.In whole operation process, this hydrogel material can maintain gratifying bump height all the time, the processing ease of incision mucous layer is carried out, and a shot can complete whole operation, greatly facilitates the implementation process of operation.There is not phenomenons such as boring a hole, hemorrhage in intra-operative, shows that this hydrogel material improves the safety of ESD operation to a great extent as submucosal injection material, and substantially reduce the time of operation technique.
Embodiment 33
Use the 25wt% normal saline solution (methylene blue containing 0.05wt%) of Copolymer-15, carry out sterilization treatment according to method in embodiment 21, obtain the injection material for submucosal injection.Take miniature pig as animal experimental model, use standard endoscopic equipment to implement ESD operation in pig feed road.Operation consent, to animal fasting two days, is anaesthetized it before implementing.By endoscope channel, this material No. 23 entry needles are expelled to its Submucosa, material usage is 25mL, and visible mucous layer forms obvious protuberance, and size and highly suitable, implement mucosa afterwards and peel off.First cut protuberance mucous layer around with electric knife, and complete ring cutting, the hydrogel material sucking-off that the pipeline then carried by scope will be injected, finally protuberance mucosa is peeled off, and with endoscope, pathological analysis is done in complete for cut-out taking-up.In whole operation process, this hydrogel material can maintain gratifying bump height all the time, the processing ease of incision mucous layer is carried out, and a shot can complete whole operation, greatly facilitates the implementation process of operation.There is not phenomenons such as boring a hole, hemorrhage in intra-operative, shows that this hydrogel material improves the safety of ESD operation to a great extent as submucosal injection material, and substantially reduce the time of operation technique.
Embodiment 34
After the operation technique completing embodiment 24, put to death animal, carry out histological stain observation to the tissue of its thermic hydrogel injection site, result shows that its normal mucosa has no obvious damage at once.
Embodiment 35
After the operation technique completing embodiment 25, put to death animal, carry out histological stain observation to the tissue of its thermic hydrogel injection site, result shows that its normal mucosa has no obvious damage at once.
Embodiment 36
After the operation technique completing embodiment 26, put to death animal, carry out histological stain observation to the tissue of its thermic hydrogel injection site, result shows that its normal mucosa has no obvious damage at once.
Embodiment 37
After the operation technique completing embodiment 27, put to death animal, carry out histological stain observation to the tissue of its thermic hydrogel injection site, result shows that its normal mucosa has no obvious damage at once.
Embodiment 38
After completing the ESD operation technique of embodiment 28, continue letting animals feed 1 week, put to death animal afterwards, histological stain observation is carried out to its operative site tissues, as seen its inflammatory reaction not obvious, and have new epithelial tissue generation.
Embodiment 39
After completing the ESD operation technique of embodiment 29, continue letting animals feed 1 week, put to death animal afterwards, histological stain observation is carried out to its operative site tissues, as seen its inflammatory reaction not obvious, and have new epithelial tissue generation.
Embodiment 40
After completing the ESD operation technique of embodiment 30, continue letting animals feed 1 week, put to death animal afterwards, histological stain observation is carried out to its operative site tissues, as seen its inflammatory reaction not obvious, and have new epithelial tissue generation.
Embodiment 41
After completing the ESD operation technique of embodiment 31, continue letting animals feed 1 week, put to death animal afterwards, histological stain observation is carried out to its operative site tissues, as seen its inflammatory reaction not obvious, and have new epithelial tissue generation.
Embodiment 42
After completing the ESD operation technique of embodiment 32, continue letting animals feed 4 weeks, put to death animal afterwards, histological stain observation is carried out to its operative site tissues, as seen its inflammatory reaction not obvious, and have new epithelial tissue generation.
Embodiment 43
With the 20wt% solution of normal saline Copolymer-3, and bag carries anti-inflammatory drug dexamethasone, and make its mix homogeneously by stirring, obtaining drug loading is 2mg/mL dexamethasone medicine carrying colloidal sol.This material has the feature that sol-gel phase in version occurs with temperature rising, and gel transition temperature is 32 DEG C.The gel sustained-release preparation that this bag has carried dexamethasone can reach 2 weeks by slow releasing pharmaceutical in vitro.
Embodiment 44
Animal is divided into three groups, uses the 15wt% normal saline solution of Copolymer-1, carry out ESD operation according to method in embodiment 28 at position, pig feed road.According to method in embodiment 43, be the dexamethasone medicine carrying gel of 2mg/mL with the 20wt% normal saline solution preparation drug loading of Copolymer-3.At enforcement ESD Post operation, by endoscope tube road direction operative site, this medicine carrying solution 2mL is injected to the first treated animal (experimental group), make it form gel at this point, and the second treated animal injection 2mL contains the hyaluronic acid solution of same concentrations medicine, the 3rd treated animal does not do any process.After 1 month, put to death animal and dissect its esophagus, find that the operative site generation mucous layer of the 3rd treated animal esophagus thickens, the obvious stenosis of esophagus is narrow; The animal esophagus of injection dexamethasone hyaluronic acid solution also has the phenomenon of esophageal stricture to occur, but alleviates to some extent than the 3rd group; And the test group of animals injecting dexamethasone hydrogel has no obvious mucous layer thickens.
Embodiment 45
Animal is divided into two groups, uses the 20wt% normal saline solution of Copolymer-1, carry out ESD operation according to method in embodiment 28 in Gaster Sus domestica portion.At enforcement ESD Post operation, first treated animal (experimental group) is loaded with to the 25wt% normal saline solution 2mL of the Copolymer-10 of mucosa cells by the injection of endoscope tube road direction operative site, make it form gel at this point, and the second treated animal does not do any process.After 1 month, put to death animal and its stomach is dissected, finding that the operative site mucous layer of control animals stomach is repaired not yet completely; And be loaded with mucosa cells the gastric mucosa of test group of animals repair substantially completely.
Claims (12)
1. the submucosal injection material be made up of physical cross-linking hydrogel, is characterized in that, jointly forms submucosal injection material by amphipathic nature block polymer, solvent based on water and painted indicator three; This submucosal injection material has thermic plastic characteristic, and namely it is in low viscous solution state when low temperature, can become gel state by Spontaneous conversion when human body temperature;
The hydrophilic block of described amphipathic nature block polymer is Polyethylene Glycol (PEG), and hydrophobic block is degradable polyester.
2. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 1, is characterized in that, the sol-gel transition temperature of described polymer water system is between 10-40 DEG C.
3. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 1, is characterized in that, in described block copolymer:
1) mean molecule quantity of hydrophilic Polyethylene Glycol block is 400-50000, and content is 10-90wt%, is designated as A block;
2) hydrophobic polyester block content is 90-10wt%, is designated as B block;
3) described polyester B block is selected from poly DL-lactide, poly-D-lactide, PLLA, PGA, poe, poly-epsilon-caprolactone, poly-ε-alkyl replacement caprolactone, poly-δ-valerolactone, poly-1,4, any one in 8-trioxa spiral shell [4.6]-9-hendecanone, poly-para-dioxanone, polyesteramide, Merlon, polyacrylate, polyether ester, or any type of copolymer of above-mentioned polyester;
4) described block copolymer is the triblock copolymer of ABA or BAB type, the di-block copolymer of AB type, the graft copolymer of A-g-B or B-g-A type, (Α-Β)
nor (Β-Α)
nstar block copolymer and Α (Β Α)
nor B (AB)
nthe segmented copolymer of configuration, wherein n is the integer of 2 to 10;
5) the part or all of end of described block polymer is connected to function end group, and end group is any one in hydrophilic amino, carboxyl, imidazole radicals, aldehyde radical, cyano group, nitro; Or hydrophobic alkyl, sterin, alkoxyl, aromatic radical, aromatic heterocyclic, amide ester group, halogen atom, trichloromethyl, ester group, any one in sulfydryl.
4. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 1, is characterized in that, the content of described polymer in solvent is 3-50wt%.
5. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 1, it is characterized in that, the solvent in described polymer solution be selected from pure water, normal saline, buffer solution, tissue culture medium, cell culture fluid, animals and plants or human body body fluid or be other aqueous solution and the medium not based on organic solvent.
6. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 1, it is characterized in that, described painted indicator is selected from one in methylene blue and indigo carmine or its combination, and its weight percent content in aqueous systems is 0.001%-0.1%.
7. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 1, is characterized in that, described polymer water system load simultaneously antibiotics, hormones or somatomedin class medicine.
8. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 7, it is characterized in that, the medicine of institute's load is selected from one or more in epinephrine, dexamethasone, ametycin, prednisolone, 5-fluorouracil, triamcinolone acetonide.
9. the submucosal injection material be made up of physical cross-linking hydrogel according to claim 1, is characterized in that, described polymer water system is load cells simultaneously.
10. the preparation method of the submucosal injection material be made up of physical cross-linking hydrogel as described in one of claim 1-9, it is characterized in that: first at dissolution in low temperature polymer in solvent, then store for future use at-20 DEG C or following, redissolve and add painted indicator before using, after mixing, becoming injection of solution agent;
Described low temperature is the sol-gel transition temperature lower than polymer;
Prepared submucosal injection material can form hydrogel by thermal reversion in temperature higher than during sol-gel transition temperature;
The painted indicator of 0.001%-0.1% is added in said method.
The 11. submucosal injection materials be made up of physical cross-linking hydrogel according to claim 1 are for the preparation of the application in the injection material in Endoscopic submucosal dissection.
12. by the application of claim 11, and it is characterized in that, described submucosal injection material is injected through the Submucosa of digestive endoscope entry needle at esophagus, stomach, rectum and colon.
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105055302A (en) * | 2015-07-17 | 2015-11-18 | 许月芳 | Methylene blue temperature-sensitive hydrogel, preparation thereof, and application thereof in anatomical hepatectomies |
| CN107335127A (en) * | 2016-04-28 | 2017-11-10 | 美敦力心血管股份有限公司 | The method of medical treatment device and the balloon-expandable for covering medical treatment device |
| CN107998462A (en) * | 2017-11-10 | 2018-05-08 | 西安交通大学医学院第附属医院 | A kind of magnetic gel, its preparation and its application system for being used for mucous membrane under endoscope and peeling off operation |
| CN108498879A (en) * | 2017-02-28 | 2018-09-07 | 苏州安德佳生物科技有限公司 | Submucosal injection composition and reagent combination and its application |
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| CN113024783A (en) * | 2021-03-12 | 2021-06-25 | 山东谷雨春生物科技有限公司 | Method for synthesizing degradable block copolymer hydrogel |
| CN113133996A (en) * | 2020-01-20 | 2021-07-20 | 山东威高药业股份有限公司 | Use of acetylcysteine or its chemically acceptable salt/ester in preparation of isolated preparation of connective tissue |
| CN114404650A (en) * | 2022-02-09 | 2022-04-29 | 山东畜牧兽医职业学院 | Preparation method and product of temperature-sensitive hydrogel dressing |
| CN114949377A (en) * | 2022-06-22 | 2022-08-30 | 四川大学华西医院 | Submucosal injection and application thereof in preparation of auxiliary agent for endoscopic submucosal dissection |
| CN116159191A (en) * | 2023-02-16 | 2023-05-26 | 中国医科大学附属盛京医院 | Preparation method of temperature-sensitive submucosa injection for endoscopic submucosa dissection |
| US11998653B2 (en) | 2018-01-12 | 2024-06-04 | Beijing Universal Likang Technology Co., Ltd. | Method for treating active bleeding by sequentially applying a biocompatible hemostatic composition and a sealant composition |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1282345A (en) * | 1997-10-03 | 2001-01-31 | 麦克罗梅德公司 | Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
| US6413539B1 (en) * | 1996-10-31 | 2002-07-02 | Poly-Med, Inc. | Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof |
| CN1823726A (en) * | 2005-12-30 | 2006-08-30 | 复旦大学 | Degradable temperature sensitive physical aquagel and its preparation method |
| CN102058909A (en) * | 2011-01-18 | 2011-05-18 | 复旦大学 | Polyethylene glycol-copolyester segmented copolymer material capable of preventing adhesion, a preparation method and application thereof |
| CN102146200A (en) * | 2011-04-19 | 2011-08-10 | 复旦大学 | Temperature-sensitive hydrogel based on chemical cross-linking gel granules and preparation method of temperature-sensitive hydrogel |
| CN102639097A (en) * | 2011-03-21 | 2012-08-15 | 博任达生化科技（上海）有限公司 | Reverse thermo-sensitivity reversible aquogel composite |
-
2013
- 2013-12-10 CN CN201310669635.6A patent/CN104689380A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6413539B1 (en) * | 1996-10-31 | 2002-07-02 | Poly-Med, Inc. | Hydrogel-forming, self-solvating absorbable polyester copolymers, and methods for use thereof |
| CN1282345A (en) * | 1997-10-03 | 2001-01-31 | 麦克罗梅德公司 | Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
| CN1823726A (en) * | 2005-12-30 | 2006-08-30 | 复旦大学 | Degradable temperature sensitive physical aquagel and its preparation method |
| CN102058909A (en) * | 2011-01-18 | 2011-05-18 | 复旦大学 | Polyethylene glycol-copolyester segmented copolymer material capable of preventing adhesion, a preparation method and application thereof |
| CN102639097A (en) * | 2011-03-21 | 2012-08-15 | 博任达生化科技（上海）有限公司 | Reverse thermo-sensitivity reversible aquogel composite |
| CN102146200A (en) * | 2011-04-19 | 2011-08-10 | 复旦大学 | Temperature-sensitive hydrogel based on chemical cross-linking gel granules and preparation method of temperature-sensitive hydrogel |
Non-Patent Citations (1)
| Title |
|---|
| 俞麟等: "可注射性热致水凝胶在内镜黏膜下剥离术中的应用", 《2013 年全国高分子学术论文报告会》 * |
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| EP3810213A4 (en) * | 2018-06-21 | 2022-03-23 | University of Pittsburgh - of the Commonwealth System of Higher Education | Use of a urinary bladder ecm hydrogel as an esophageal submucosal fluid cushion |
| EP3810214A4 (en) * | 2018-06-21 | 2022-03-23 | University of Pittsburgh - of the Commonwealth System of Higher Education | Extracellular matrix (ecm) hydrogel as a submucosal fluid cushion |
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| CN113024783A (en) * | 2021-03-12 | 2021-06-25 | 山东谷雨春生物科技有限公司 | Method for synthesizing degradable block copolymer hydrogel |
| CN114404650A (en) * | 2022-02-09 | 2022-04-29 | 山东畜牧兽医职业学院 | Preparation method and product of temperature-sensitive hydrogel dressing |
| CN114949377A (en) * | 2022-06-22 | 2022-08-30 | 四川大学华西医院 | Submucosal injection and application thereof in preparation of auxiliary agent for endoscopic submucosal dissection |
| CN116159191A (en) * | 2023-02-16 | 2023-05-26 | 中国医科大学附属盛京医院 | Preparation method of temperature-sensitive submucosa injection for endoscopic submucosa dissection |
| CN116159191B (en) * | 2023-02-16 | 2024-02-23 | 中国医科大学附属盛京医院 | Preparation method of temperature-sensitive submucosa injection for endoscopic submucosa dissection |
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