CN105169469A - Tissue sealant and preparation method and application thereof - Google Patents
Tissue sealant and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a tissue sealant and a preparation method and application thereof. The sealant mainly comprises hydrophilic raw material, nucleophilic raw material, a marker and physiological thinner, wherein the hydrophilic raw material mainly refers to the derivatives of polyethylene glycol and the nucleophilic raw material mainly refers to polyamino acid. The preparation method includes: physically mixing the hydrophilic raw material, the nucleophilic raw material, the marker and the physiological thinner through a mixing tool, and performing covalent cross-linking to form hydrogel. The tissue sealant has the advantages that the sealant mainly used for sealing small wounds after eye surgery is good in tissue cohesive force and film-forming property, good in biocompatibility, capable of promoting epithelization healing and preventing seepage leakage, simple in preparation method, capable of being quantified to form a stable production line, and good in clinical application value.
Description
Technical field
The invention belongs to biodegradable polymer field, particularly relate to a kind of medical tissue sealer or hydrogel and preparation method thereof and application of in-situ cross-linked molding.
Background technology
Cataract is the result of the disease that a kind of crystalline lens is day by day fuzzy, normally aging, but also may have other factors.The data display U.S. about has 3,300,000 people to accept cataract operation every year, and cataract operation is the crystalline lens removing self, then substitutes with intraocular lens the process recovering vision.During cataract operation, ophthalmologist can do a little otch on cornea, the crystalline lens of patient self is removed by this otch, due to implantable artificial crystalline lens in most cases, otch less (within usual 3mm), therefore self-heal is understood by incision tissue after artificial intraocular lenses puts into, but, many factors is unstable to causing the time of otch self-heal, if there is liquid (to have report display seepage to mostly occur 1 day after surgery from otch seepage, occasional continues more than 7 days), hypotony can cause cornea compensatory malfunction, the reverse growth of endothelialization, also may occur that intraocular lens misplaces (refractive problem) and intraocular inflammation.Surgeon may just need to seal otch.Substantially be all adopt the mode sewed up at present, need stronger sew application technical ability, but the wound that cornea is new can be caused, and have the postoperative risk removing and increase infection, also increase pain and the sense of discomfort of patient, therefore the doctor of external coat is expecting one can also be had easy to use except stitching is outer, to patient comfort, does not require again the postoperative otch involution scheme removed always.
Hydrogel, as a kind of biocompatible materials, is medically mainly used in tissue encapsulation, prevents tissue fluid seepage, Post operation anti, hemorrhage, fills up defective tissue, slow releasing carrier of medication etc.Gel variations is various, and model of action is different.
Current hydrogel is as the sealant extensive use of clinical operation wound tissue, and especially in ophthalmologic operation, existing conventional ophthalmology tissue seal majority is natural material, such as Absorbable rod
gelatin, fibrin sealant and mussel adh esive protein etc., but this type of material belongs to animal derived, there is the risk that animal virus is propagated; Next is complete synthesis bioabsorbable polymer material, and such as a-cyanoacrylate class is as isobutyl ester, n-octyl and derivant thereof etc., but due to this binding agent be that non-degradable, setting time are short, zest is large, the inferior positions such as hardness is high, in clinical practice, effect is unsatisfactory, is necessary to improve.
Sum up the experience using adhesive of medical gained both at home and abroad, good ophthalmology tissue seal needs to possess following characteristic: have the sufficient time before 1. solidifying for patient's operation; 2. can produce enough bonding forces after solidifying, make wound airtight; 3. colloid is transparent, reduces the impact on vision; 4. inflammatory reaction is lighter; 5. allow liquid and metabolite infiltration, avoid tissue necrosis; 6. final disappearance at bonding mouth is beneficial to healing.Based on the requirement of above 6 product developments, the present invention designs a kind of hydrogel of Biodegradable in-situ cross moulding, as medical tissue sealant.
Summary of the invention
The object of this invention is to provide a kind of complete synthesis, without potential animal derived instant in-situ cross-linked molding, biodegradable and physical property and the adjustable medical tissue sealant of degradation property.
For this reason, the invention provides a kind of medical tissue sealant, it is characterized in that, be prepared from by following four kinds of components,
The first component is hydrophilic material; Be selected from end and contain the side chain of succinoamino, straight chain, star or tree structure hydrophilic compounds,
The second component is nucleophilic raw material; Be selected from oligopeptide, the amino acid contained residue number of oligopeptide is 2-6, or the salt that oligopeptide and acid are formed,
The third component is label; Be selected from the non-azo-based colorant of water solublity,
4th kind of component is physiological diluent, is selected from water or buffer,
The proportioning of each component is as follows:
Hydrophilic material constituent content is 10 ~ 1000mg/mL;
Nucleophilic Feedstock Component content is 0.5 ~ 50mg/mL;
The content of label is 0.05 ~ 0.2mg/mL;
All the other are physiological diluent.
Preferably,
Wherein said first component is selected from Polyethylene Glycol (PEG), polyvinyl alcohol (PVA), polyoxyethylene (PEO), its molecular weight is 500-20000, or be selected from the polyethyleneglycol derivative of following compound: four arm N-hydroxysuccinimide propanoic acid ester group Polyethylene Glycol (4-arm-PEG-SPA, molecular weight 10000), four arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (4-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (2-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide ester (2-arm-PEG-NHS, molecular weight 5000),
Described second component is selected from oligopeptide, and its amino acid contained residue number is 3-4; Aminoacid is wherein selected from: lysine, cysteine, leucine, histidine, or the salt of oligopeptide and acid formation,
Described three components is selected from the edible light blue that molecular weight is 792.86;
Described Four composition buffer is selected from the buffer of phosphate, carbonate, borate, phosphoric acid, acetic acid, hydrochloric acid preparation, and the osmotic pressure of buffer should be identical with the colloidal osmotic pressure of organism.
It is preferred,
Wherein said first component is selected from Polyethylene Glycol (PEG), polyvinyl alcohol (PVA), polyoxyethylene (PEO), and its molecular weight is 2000-10000
Described second component is selected from the oligopeptide of lysine, cysteine, or the salt of oligopeptide and acid formation,
Described Four composition buffer is selected from phosphate, borate buffer solution.
It is particularly preferred,
Wherein said first component is selected from the Polyethylene Glycol of molecular weight 5000
Described second component is selected from two lysines, three lysines, four lysines, five lysines, or the salt that they and acid are formed,
Described Four composition buffer is selected from phosphate buffer.
It is particularly preferred,
Wherein said first component is selected from the polyethyleneglycol derivative of following compound: four arm N-hydroxysuccinimide propanoic acid ester group Polyethylene Glycol (4-arm-PEG-SPA, molecular weight 10000), four arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (4-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (2-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide esters (2-arm-PEG-NHS, molecular weight 5000);
Described second component is selected from three lysines, or the salt that they and acid are formed,
Described Four composition buffer be selected from PH be 9.58 sodium tetraborate aqueous solution or PH be 5.8 ?7.0 sodium phosphate buffer.
Have most preferred,
Wherein said first component is selected from two arm N-hydroxysuccinimide esters (2-arm-PEG-NHS, molecular weight 5000);
Described second component is selected from three lysines or three lysine acetates.
Described three components to be molecular weight be 792.86 edible light blue;
Described Four composition buffer solution ph be 5.8 ?7.0 sodium phosphate buffer.
Wherein the nonstoichiometric molar ratio of hydrophilic functional groups and nucleophilic functional group is 1:1.
The preparation method of sealant of the present invention, described method step is as follows: be dissolved in Four composition by second component and three components, obtains just solution, then by this solution and the first component and developer mixing, cross-linking reaction occurs and forms hydrogel.
The present invention further provides a kind of test kit, it is characterized in that, comprising four kinds of components of the present invention.
Preferably, test kit of the present invention, comprising:
First component is two arm N-hydroxysuccinimide esters of molecular weight 5000; 124 parts
Second component three lysine; 5 parts
Three components to be molecular weight be 792.86 edible light blue; 0.01 part
Four composition buffer is 1000 parts, the PBS buffer solution of pH=7.4.
Medical tissue sealant of the present invention, wherein, the ratio of the weight between each component is as follows:
Hydrophilic component PEG derivant: nucleophilic component oligopeptide: the weight ratio of label light blue is 100:10:1 ~ 1000000:10000:1
Preferably, the ratio of the weight between each component is as follows:
Hydrophilic component PEG derivant: nucleophilic component oligopeptide: the weight ratio of label light blue is 1000:100:1 ~ 100000:1000:1
Most preferred, each component
?ratio is as follows:
Hydrophilic component PEG derivant: nucleophilic component oligopeptide: the weight ratio of label light blue is 10000:500:1
The ratio that wherein total solid content of the first component, second component and three components accounts for hydrogel cumulative volume is less than 10%.
Wherein, the ratio of the first component and second component can also calculate with active function groups mole, and its mol ratio is 1:1.
Be exemplified as: PEG-NHS: three lysine acetates, the active function groups of PEG-NHS is :-NHS, and the active function groups of three lysine acetates is :-NH
2, both mol ratios are 1:1, and being converted into part by weight is 30:1.
The present invention also provides the preparation method of medical tissue sealant of the present invention, and described method step is as follows:
Second component and three components are dissolved in Four composition, obtain just solution, then by this solution and the mixing of the first component, cross-linking reaction occurs and forms hydrogel.
Present invention also offers the clinical practice of medical tissue sealant, described application after being mainly used in operated eye little wound surface close, stop sepage leak, avoid causing the problem such as intraocular inflammation or dioptric, as the alternative medicine of suture way.
Hydrogel prepared by the present invention, hydrophilic component selects the Polyethylene Glycol of N-hydroxy-succinamide end-blocking, containing ester bond in its structure, after reacting with nucleophilic component, ester bond is still present in final cross-linking products, can at people's vivo degradation, and hydrophilic compounds main body Polyethylene Glycol also can resolve into micromolecule in human body.Degradation time can be made to control at 3-7 days by regulating component ratio.
Described hydrogel can in-situ cross-linked molding, during use, can Extemporaneous, therefore, the present invention also provides a kind of test kit, comprising four kinds of components of the present invention, Four composition buffer solution second component is adopted during use, then be mixed in immediately in the first component and form hydrogel, by spreader, hydrogel coating is covered wound tissue surface, be conducive to adhering to, this material should have to be enough to tolerate the tension force mechanical property produced by the hydrostatic existed in patient moving, tissue displacement, tissue etc.
Test kit of the present invention can be packaged into the nonrecoverable dosage of 1 people, also can be packaged into 10 people using dosage once, changeable, suitable to be applicable to being formulated as.Can also comprise description in test kit, use apparatus, preparation container etc., with easy to use.
For the ease of the service condition of tissues observed sealant, in the present invention, three components is developer, developer can be added in the first component or second component powder, and developer includes but not limited to the blue #3 of FD & C blue #1, FD & C blue #2, FD & C.
Medical tissue sealant of the present invention is mainly used for the postoperative cornea wound of closed intraocular lens, sepage is stoped to leak and cause the complication such as infection, pain, also can be used for stoping in the operation processs such as heart, abdominal cavity, thoracic cavity blood oozing from the wound surface and venule hemorrhage, promote wound healing, prevent tissue adhesion, close defective tissue etc.The primary raw material of hydrogel of the present invention adopts complete synthesis, to have biocompatibility material, by chemical modification link active hydrophilic and nucleophilic group, forms hydrogel in position during use through physical mixed.By adjusting the ratio of hydrophilic first component and nucleophilicity second component, prepare series of physical performance different, the hydrogel that degradation time is different.Adopt hydrogel prepared by Biodegradable material, after keeping certain hour in vivo, natural degradation becomes micromolecule eliminating external, can avoid second operation, reduce patient painful, reduce medical expense, also can avoid the risk causing pathophoresis owing to using natural material simultaneously.
Accompanying drawing illustrates:
fig. 1the swelling ratio of the formula hydrogel of different hydrophilic component and nucleophilic component
fig. 2the gelation time of the hydrogel of different hydrophilic component and nucleophilic component formula
fig. 33 days animal experimental observation results after hydrogel implantation
fig. 47 days animal experimental observation results after hydrogel implantation
Detailed description of the invention
Further illustrate the present invention by the following examples.Embodiment provides detailed embodiment and concrete operations, for understanding the present invention.
, wherein mainly there is covalent cross-linking by the first component and second component through blend tool mixing and form hydrogel in the preparation of medical tissue sealant of the present invention.Reaction mechanism is: the NHS of hydrophilic component (the first component) and the NH of nucleophilic component (second component)
2covalent bond combines, polymerization reaction take place, generates hydrogel, and a small amount of by-product biocompatibility is better, nontoxic nonirritant, and the degraded with gel is got rid of external, reacts schematically as follows:
Wherein R1, R3 are any one in H, CH3, CH2CH3, CH2CH2CH3, and comprising R1, R3 is identical structure etc.; R2 is OCCH2CO, OCCH2CH2CO, OCCH2CH2CH2CO etc.; R4 is NH or S; R5 is OC (CH2)
ncO, Polyethylene Glycol etc.
Medical tissue sealant provided by the present invention, meets following characteristics index:
1) gel time is less than 20s;
2) swelling ratio is preferably 0-300%
3) rupture strength is not less than 50mmHg;
4) degradation time is 3-7 days.
Medical tissue sealant test kit
Test kit of the present invention, comprises the Four composition of aforesaid the first component containing hydrophilic functional groups, the second component of nucleophilic functional group, developer three components and physiological buffer, wherein:
Hydrophilic functional groups (the first component): preferably two arm N-hydroxysuccinimide macrogol esters (2-arm-PEG-NHS, molecular weight 5000), structural formula is shown in
below:
Nucleophilic functional group (second component): three lysines (be shown in by structural formula
below), purchased from Mike woods Reagent Company.
Developer (three components): the blue #1 of FD & C (be shown in by structural formula
below), purchased from Mike woods reagent.
Physiological buffer (Four composition), has the PBS buffer solution of pH=7.4, the carbonate buffer solution of 0.2MpH=6.5 and the carbonate buffer solution of 0.2MpH=9.78.
The preparation method of hydrogel: the nonstoichiometric molar ratio of hydrophilic functional groups and Qin electricity functional group is 1:1.
Embodiment one hydrophilic component is the derivant of PEG
Nucleophilic component is three lysines, and hydrophilic component is the derivant of PEG, and solvent is the PBS buffer of pH=7.4, carries out the test of gel according to process below.
First three lysines containing nucleophilic functional group are dissolved in the PBS buffer solution of pH=7.4 of 5 μ L, obtain solution A; PEG derivant containing hydrophilic functional groups and developer are dissolved in solution A, abundant mix and blend, about 15s, observe the situation forming gel respectively.
The formula of the PBS buffer of the pH=7.4 of 0.1M: the sodium chloride weighing 4.005g is reagent A; The potassium chloride weighing 0.1g is reagent B; Weighing disodium hydrogen phosphate dodecahydrate 1.7907g is reagent C; The potassium dihydrogen phosphate claiming 0.135g is reagent D; By reagent A, B, C and D tetra-kinds of materials, be successively placed in the volumetric flask of 500mL, then dissolve, what obtain is the PBS buffer of pH=7.4.
By the observation of above experimental phenomena, PEG derivant and the identical nucleophilic component of different hydrophilic component form the gelation time of hydrogel, swelling ratio and degradation cycle all to be had different, and detection method is as follows:
1) gelation time: the gelation time of hydrogel directly affects the operation process that clinical gel uses front and back, concrete detection method is that second component and three components are first dissolved in physiological diluent, then with the first component miscibility, stir about 5s starts timing, to formation gel, criterion adopts toothpick or analog to provoke gel solution, in wire drawing state, is recorded as gel time.
2) swelling ratio: detection method is that the hydrogel of certain mass is weighed, record original quality, then hydrogel being placed in the pH being preheated to 37 ± 1 DEG C is 7.4 phosphate buffers, take out sample filter paper every several hours and suck surface moisture, weigh, to weight no longer increases, terminate to weigh.Be calculated as follows gel swelling rate.
3) in the external degradation cycle: the gel of certain mass being placed in 37 ± 1 DEG C of pHs isotonic with blood is 7.4 phosphate buffers, observe every day till invisible, be designated as gel degradation time in vitro.
The result that the PEG derivant of different hydrophilic component and nucleophilic component form hydrogel as
following table instituteshow:
Can find out, with three lysines for nucleophilic component, the PEG derivant of different molecular weight is hydrophilic component, and along with the molecular weight of PEG derivant increases, the gelation time of its hydrogel is faster, and swelling ratio becomes large, degradation cycle
meeting portiondivide and extend, therefore can select flexibly according to practical situations.
Embodiment two nucleophilic component is three lysine derivatives
Nucleophilic component is three lysine derivatives, and hydrophilic component is 2-arm-PEG-NHS, and solvent is the PBS buffer of pH=7.4, carries out the preparation test of gel according to process below.
First three lysine derivatives containing nucleophilic functional group are dissolved in the PBS buffer solution of pH=7.4 of 70 μ L, obtain solution; Immediately the 2-arm-PEG-NHS containing hydrophilic functional groups is dissolved in the solution, abundant mix and blend, about 5s, observe the situation forming gel.
The situation that different three lysine derivatives and hydrophilic component PEG derivant 2-arm-PEG-NHS form hydrogel as
following table instituteshow:
Embodiment three adopts different physiological diluent buffer as solvent
Nucleophilic component is three lysines, and hydrophilic component is 2-arm-PEG-NHS, and solvent is different physiological diluent buffer, carries out the test of gel according to process below.
First three lysine derivatives containing nucleophilic functional group are dissolved in the different physiological diluent solvents of 70 μ L, obtain solution; 2-arm-PEG-NHS containing hydrophilic functional groups is dissolved in the solution, abundant mix and blend, about 5s, observe the situation forming gel.
The formula of the phosphate buffer of 0.2MpH=6.5: claim 4.9g sodium dihydrogen phosphate, fixed molten to 68.5mL, obtain solution A; Claim 2.4g disodium hydrogen phosphate dodecahydrate, standardize solution, to 31.5mL, obtains solution B; By A, B two kinds of solution mixing, obtain 100mL, the phosphate buffered solution of the pH=6.5 of 0.2M.
The formula of the carbonate buffer solution of 0.2MpH=9.78: claim sodium carbonate 1.1448g, be surely dissolved in 40mL water, stirring and dissolving obtains solution A; Claim sodium bicarbonate 0.504g, be surely dissolved in 60mL water, stirring and dissolving obtains solution B; A, B solution, abundant mix homogeneously, obtains 100mL, the carbonate buffer solution of the pH=9.78 of 0.2M.
The different physiological diluent buffer situation of preparing hydrogel as
following table instituteshow:
By above-described embodiment two and embodiment three, can find out, with 2-arm-PEG-NHS molecular weight 5000 for hydrophilic component, three lysines, three lysine acetates or hydrochlorate are nucleophilic component, with the physiological diluent solution of different PH for solvent, the hydrogel of preparation is at gelation time, swelling ratio and degradation cycle are without significant difference, just in two kinds of component reaction processes, the acid-base value of reaction dissolvent system is different, major effect plastic speed and the final environment for use requirement of hydrogel, such as, when hydrogel is applied to the sealing of gynaecologic vaginal wound, the finished product using slant acidity can be considered, if when being applied to ophthalmology site tissue, can considering to use neutral finished product, therefore according to clinical practice applicable cases, can select flexibly.
In comprehensive above-described embodiment, the different component formula of hydrogel can affect its preparation process, simultaneously also variant in the gelation time of hydrogel, swelling ratio and degradation cycle, with three lysines for nucleophilic component, the PEG derivant of different molecular weight is hydrophilic component, and along with the molecular weight of PEG derivant increases, the gelation time of its hydrogel is faster, swelling ratio becomes large, degradation cycle
meeting portiondivide and extend, concrete statistical result
as Fig. 1with
fig. 2shown in, therefore in practical application, the ratio of each material and the buffer solution system of reaction can be adjusted according to different instructions for use, prepare the medical aquogel sealant met clinical needs.
Medical sealant sample is implanted under embodiment four animal skins
Select healthy adult
new westblue white rabbit, in its subcutaneous implantation with the experiment sequence number 1 composition of raw materials composition in embodiment one, the hydrogel sample of preparation, the implantation cycle is 3 days and 7 days, sample method for implantation is with reference to GBT16886.6-1997 BiologicalEvaluationofMedicalDevice the 6th part: after implanting, in local response test, the operative process of regulation carries out, postoperative every day observes animal, without any abnormal phenomena, without local, whole body and dystropy.
At observation 3 days cycles and 7 days point, put to death animal respectively, get implant site and adopt HE dyeing to carry out Histopathology assessment,
as Fig. 3 (after hydrogel implantation 3 days) and
fig. 4 (after hydrogel implantation 7 days) shown in, within postoperative 3 days, show acute and chronic inflammatory cell, around residual sample, have fibroblast proliferation; Within postoperative 7 days, display acute inflammatory cells disappears, and have a small amount of chronic inflammatory cell, but hydrogel sample film is degraded, noresidue.Therefore medical sealant hydrogel involved in the present invention all has similar good biological safety.Embodiment five
A kind of test kit
Comprise
First component is two arm N-hydroxysuccinimide esters of molecular weight 5000; 124 parts
Second component three lysine; 5 parts
Three components to be molecular weight be 792.86 edible light blue; 0.01 part
Four composition buffer is 1000 parts, the PBS buffer solution of pH=7.4
Described part is weight portion.
Using method is as follows: in the PBS buffer solution of the pH=7.4 be first dissolved in by three lysines, obtain solution A; Two arm N-hydroxysuccinimide esters of molecular weight 5000 are dissolved in solution A, add the abundant mixing and stirring of edible light blue that molecular weight is 792.86, within about 15 seconds, spendable gel can be formed.
The above embodiment is the preferred embodiments of the present invention, but namely the embodiment of the present invention 5 is tested hydrogel sample prepared by sequence number 1 composition of raw materials and is compared with other formula and in use have stronger analgesic effect unexpectedly, pretends as the most preferred formula of the present invention.
For persons skilled in the art, or else to deviate under the prerequisite of the principle of the invention and spirit any apparent change done by it, all should be contemplated as falling with within claims of the present invention.
Claims (10)
1. a medical tissue sealant, is characterized in that, is prepared from by following four kinds of components,
The first component is hydrophilic material; Be selected from end and contain the side chain of succinoamino, straight chain, star or tree structure hydrophilic compounds,
The second component is nucleophilic raw material; Be selected from oligopeptide, the amino acid contained residue number of oligopeptide is 2-6, or the salt that oligopeptide and acid are formed,
The third component is label; Be selected from the non-azo-based colorant of water solublity,
4th kind of component is physiological diluent, is selected from water or buffer,
The proportioning of each component is as follows:
Hydrophilic material constituent content is 10 ~ 1000mg/mL;
Nucleophilic Feedstock Component content is 0.5 ~ 50mg/mL;
The content of label is 0.05 ~ 0.2mg/mL;
All the other are physiological diluent.
2. sealant according to claim 1, is characterized in that,
Wherein said first component is selected from Polyethylene Glycol (PEG), polyvinyl alcohol (PVA), polyoxyethylene (PEO), its molecular weight is 500-20000, or be selected from the polyethyleneglycol derivative of following compound: four arm N-hydroxysuccinimide propanoic acid ester group Polyethylene Glycol (4-arm-PEG-SPA, molecular weight 10000), four arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (4-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (2-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide ester (2-arm-PEG-NHS, molecular weight 5000),
Described second component is selected from oligopeptide, and its amino acid contained residue number is 3-4; Aminoacid is wherein selected from: lysine, cysteine, leucine, histidine, or the salt of oligopeptide and acid formation,
Described three components is selected from the edible light blue that molecular weight is 792.86;
Described Four composition buffer is selected from the buffer of phosphate, carbonate, borate, phosphoric acid, acetic acid, hydrochloric acid preparation, and the osmotic pressure of buffer should be identical with the colloidal osmotic pressure of organism.
3. sealant according to claim 1, is characterized in that,
Wherein said first component is selected from Polyethylene Glycol (PEG), polyvinyl alcohol (PVA), polyoxyethylene (PEO), and its molecular weight is 2000-10000
Described second component is selected from the oligopeptide of lysine, cysteine, or the salt of oligopeptide and acid formation,
Described Four composition buffer is selected from phosphate, borate buffer solution.
4. sealant according to claim 1, is characterized in that,
Wherein said first component is selected from the Polyethylene Glycol of molecular weight 5000
Described second component is selected from two lysines, three lysines, four lysines, five lysines, or the salt that they and acid are formed,
Described Four composition buffer is selected from phosphate buffer.
5. sealant according to claim 1, is characterized in that,
Wherein said first component is selected from the polyethyleneglycol derivative of following compound: four arm N-hydroxysuccinimide propanoic acid ester group Polyethylene Glycol (4-arm-PEG-SPA, molecular weight 10000), four arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (4-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide succinic acid ester group Polyethylene Glycol (2-arm-PEG-SS, molecular weight 10000), two arm N-hydroxysuccinimide esters (2-arm-PEG-NHS, molecular weight 5000);
Described second component is selected from three lysines, or the salt that they and acid are formed,
Described Four composition buffer be selected from PH be 9.58 sodium tetraborate aqueous solution or PH be 5.8 ?7.0 sodium phosphate buffer.
6. sealant according to claim 1, is characterized in that,
Wherein said first component is selected from two arm N-hydroxysuccinimide esters (2-arm-PEG-NHS, molecular weight 5000); Described second component is selected from three lysines or three lysine acetates.
Described Four composition buffer solution ph be 5.8 ?7.0 sodium phosphate buffer.
7. sealant according to claim 1, is characterized in that,
Wherein said first component is two arm N-hydroxysuccinimide esters of molecular weight 5000;
Described second component three lysine;
Described three components to be molecular weight be 792.86 edible light blue;
Described Four composition buffer is the PBS buffer solution of pH=7.4
Wherein the nonstoichiometric molar ratio of hydrophilic functional groups and nucleophilic functional group is 1:1.
8. the preparation method of sealant according to claim 1, it is characterized in that, described method step is as follows: be dissolved in Four composition by second component and three components, obtains just solution, then by this solution and the first component and developer mixing, there is cross-linking reaction and form hydrogel.
9. a test kit, is characterized in that, comprising four kinds of components according to claim 1.
10. test kit according to claim 9, is characterized in that,
First component is two arm N-hydroxysuccinimide esters of molecular weight 5000; 124 parts
Second component three lysine; 5 parts
Three components to be molecular weight be 792.86 edible light blue; 0.01 part
Four composition buffer is 1000 parts, the PBS buffer solution of pH=7.4.
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| CN116983466A (en) * | 2023-08-16 | 2023-11-03 | 南方科技大学 | Medical gel dressing and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5645583A (en) * | 1990-07-12 | 1997-07-08 | University Of Miami | Injectable polyethylene oxide gel implant and method for production |
| CN1496241A (en) * | 2001-02-14 | 2004-05-12 | �������ɭ | Radiation cross-linked hydrogels |
| CN102911493A (en) * | 2012-09-28 | 2013-02-06 | 山东赛克赛斯药业科技有限公司 | Biodegradable medical hydrogel and preparation method and application thereof |
-
2015
- 2015-08-29 CN CN201510544144.8A patent/CN105169469B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5645583A (en) * | 1990-07-12 | 1997-07-08 | University Of Miami | Injectable polyethylene oxide gel implant and method for production |
| CN1496241A (en) * | 2001-02-14 | 2004-05-12 | �������ɭ | Radiation cross-linked hydrogels |
| CN102911493A (en) * | 2012-09-28 | 2013-02-06 | 山东赛克赛斯药业科技有限公司 | Biodegradable medical hydrogel and preparation method and application thereof |
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| CN110801528A (en) * | 2019-10-30 | 2020-02-18 | 金路平 | Dura mater spinalis sealing hydrogel and preparation method and application thereof |
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| CN113209357A (en) * | 2021-05-14 | 2021-08-06 | 南方科技大学 | Composite styptic powder |
| CN113209357B (en) * | 2021-05-14 | 2023-02-17 | 南方科技大学 | Composite styptic powder |
| CN115702948A (en) * | 2021-08-09 | 2023-02-17 | 上海其胜生物制剂有限公司 | Preparation and application of performance customized ophthalmic gel bandage based on symmetrical/asymmetrical combined crosslinking |
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