CN115252875B - Medical tissue adhesive and preparation method thereof - Google Patents
Medical tissue adhesive and preparation method thereof Download PDFInfo
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- CN115252875B CN115252875B CN202110471951.7A CN202110471951A CN115252875B CN 115252875 B CN115252875 B CN 115252875B CN 202110471951 A CN202110471951 A CN 202110471951A CN 115252875 B CN115252875 B CN 115252875B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
Abstract
The invention relates to medical tissue adhesive and a preparation method thereof, belonging to the field of adhesive. The medical tissue adhesive provided by the invention comprises an active ingredient, an auxiliary crosslinking agent and a dispersing agent, wherein the active ingredient is a polymer chain modified by a tissue adhesion group or micro-nano particles modified by the tissue adhesion group, the auxiliary crosslinking agent is a compound which is crosslinked with the adhesion group or a compound which excites the tissue adhesion group to crosslink, the dispersing agent is melted into liquid which uniformly disperses the active ingredient and the auxiliary crosslinking agent under the heating condition and does not react with the active ingredient and the auxiliary crosslinking agent, and the dispersing agent is any one or more of polyethylene glycol and derivatives thereof or saccharide compounds. Because the medical tissue adhesive provided by the invention is in a solid form, the medical tissue adhesive is convenient to store, and in the use process, the medical tissue adhesive provided by the invention can be integrally and rapidly cured, so that the medical tissue adhesive has good blood discharge performance, hemostatic performance and tissue adhesion performance.
Description
Technical Field
The invention relates to the field of adhesive, in particular to medical tissue adhesive and a preparation method thereof.
Background
The medical adhesive mainly comprises a tissue adhesive, a hemostatic agent and a tissue sealant, and is widely applied to clinical operations. Tissue adhesives can be broadly defined as any substance having in situ polymeric properties that can adhere tissue to tissue or tissue to non-tissue surfaces, control bleeding (hemostatic agents), and act as a barrier to gas and liquid leakage (sealants).
The ideal biomedical adhesive needs to meet the requirements of biocompatibility, biodegradability, mechanical compliance with underlying tissues, acceptable swelling index, storage stability, and the like. In particular, the following features should be present: safe and nontoxic, and easy to sterilize, prepare and store; the powder is in a solid or semi-solid form before use, is convenient to store and can be cut into a proper size or ground into powder according to requirements; controllable gel formation can be realized in a physiological environment, and bleeding and operation time are reduced; has excellent tissue adhesion performance and is stable in a specific time; the original mechanical property is maintained in the healing process; the degradation time is proper, and the degradation products are nontoxic.
The medical adhesive commonly used in the market at present is generally prepared by subpackaging an active ingredient and a crosslinking agent, respectively dissolving the active ingredient and the crosslinking agent to prepare solutions when the medical adhesive is used, and then injecting the mixed active ingredient and the crosslinking agent to a bleeding part after the mixed active ingredient and the crosslinking agent are mixed by a blending injection head. However, the method is inconvenient in clinical use and uncontrollable in gel forming speed (too fast or too slow in gel forming), and is easy to wash away by a large amount of blood on the surface of the tissue, so that the hemostasis effect is not ideal, and the method is only suitable for hemostasis under the condition of small amount of bleeding. In addition, it is difficult for the liquid adhesive to precisely cover the bleeding point when the wound is too deep or the hematocrit is excessive.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide a medical tissue adhesive and a method for preparing the same.
The invention provides a medical tissue adhesive, which has the characteristics that: the active component is a polymer chain modified by a tissue-adhesive group or micro-nano particles modified by the tissue-adhesive group, the auxiliary crosslinking agent is a compound which is crosslinked with the tissue-adhesive group or a compound which excites the tissue-adhesive group to crosslink itself, the dispersing agent is melted into a liquid which uniformly disperses the active component and the auxiliary crosslinking agent under the heating condition and does not react with the active component and the auxiliary crosslinking agent, and the dispersing agent is any one or more of polyethylene glycol and derivatives thereof or saccharide compounds.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the tissue-adhesive group comprises: the structure of the o-nitrobenzyl photo-trigger group, the active ester group, the isocyanate group, the isothiocyanate group, the epoxy group, the cyclic carbonate group, the thiocyclic carbonate group, the active carbonyl group or the active double bond group is shown as the formula I or the formula II:
In formula I and formula II, LG is a halogen atom, O-R ', S-R ', or NH-R '; r' is any one of hydrogen, alkyl, ether, thioether, ketone, ester, thioester, amide, sulfate, sulfonate, phosphonate or phosphonate,
R 1 is any one of hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, aldehyde, ketone, ester, amide, thioester, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl; r is R 2 、R 3 ，R 4 ，R 5 Any one or more of them is/are bonded to a polymer chain or micro-nano particles, R 2 、R 3 ，R 4 ，R 5 Any one or more of the hydroxyl, sulfhydryl, halogen atom, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxy, carbonate, cyclic carbonate, thiocyclic carbonate, active carbonyl or active double bond modified aryl, alkyl or modified alkyl before bonding with the polymer chain or the micro-nano particles, R 2 、R 3 ，R 4 ，R 5 In which substitution is not linked to macromolecular chains or to micro-nano particlesThe groups are each independently selected from any one of hydrogen, halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, aldehyde group, ketone group, carboxyl group, ester group, thioester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfate group, sulfonic group, sulfonate group, phosphonic group, phosphonate group, sulfone group, sulfoxide group, aryl group, alkyl group, or modified alkyl group;
the active ester group is a succinimide active ester group shown in a formula III or a triazole active ester group shown in a formula IV:
active ester group of succinimide through R 6 Bonded to a polymer chain or micro-nano particles represented by P, R in formula III 6 Directly bonding with polymer chain or micro-nano particles, or bonding with polymer chain or micro-nano particles through any one of terminal modified ether bond, thioether bond, ketone bond, ester bond, thioester bond, amide bond, sulfuric acid bond, sulfonic acid bond, phosphonic acid bond, phosphoric acid bond, sulfone bond, sulfoxide bond, aryl bond, alkyl bond or modified alkyl bond,
R 7 、R 8 Each independently selected from hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, aldehyde, ketone, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, cyclic carbonate, thiocyclic carbonate, amide, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl or R 7 And R is R 8 The two are bonded to form a ring,
the triazole active ester group passes through R 9 Bonding with polymer chain or micro-nano particles represented by P,
in formula IV, R 9 Directly bonded to macromolecular chains or micro-nano particles, or by terminally modified ethersAny one of bond, thioether bond, ketone bond, ester bond, thioester bond, amide bond, sulfuric acid bond, sulfonic acid bond, phosphonic acid bond, phosphoric acid bond, sulfone bond, sulfoxide bond, aryl group, alkyl group or modified alkyl group is bonded with a polymer chain or micro-nano particles,
R 10 、R 11 each independently selected from any one of hydrogen, halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, aldehyde group, ketone group, ester group, thioester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfate group, sulfonate group, phosphonic acid group, phosphonate group, sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group, or R 10 And R is R 11 Bonding the two groups to form a ring;
the structural formula of the isocyanate group is shown as formula V:
O＝C＝N-R 12
v (V)
In formula V, R 12 Bonded with macromolecular chains or micro-nano particles, R 12 Any one of aryl, heteroaryl, alkyl or modified alkyl modified by terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxy, carbonate, cyclic carbonate, thiocyclic carbonate, active carbonyl or active double bond groups is used before bonding with the polymer chain or micro-nano particles;
the isothiocyanate group is of the formula VI:
S＝C＝N-R 13
VI (VI)
In formula VI, R 13 Bonded with macromolecular chains or micro-nano particles, R 13 Before bonding with polymer chain or micro-nano particles, the polymer chain or micro-nano particles are terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxyAny one of a group, a carbonate group, a cyclic carbonate group, a thiocyclic carbonate group, a reactive carbonyl group or a reactive double bond group-modified aryl, heteroaryl, alkyl or modified alkyl;
The epoxy group is shown as a formula VII:
in formula VII, R 14 Bonded with macromolecular chains or micro-nano particles, R 14 Any one of aryl, heteroaryl, alkyl or modified alkyl modified by terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxy, carbonate, cyclic carbonate, thiocyclic carbonate, active carbonyl or active double bond groups is used before bonding with the polymer chain or micro-nano particles,
R 15 is any one of hydrogen, halogen atom, hydroxyl, sulfhydryl, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, cyclic carbonate, thiocyclic carbonate, amide, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl, modified alkyl, or a derivative thereof, or R 14 Bonding to form a ring;
the cyclic carbonate group is represented by formula VIII:
in formula VIII, R 16 Bonded with macromolecular chains or micro-nano particles, R 16 Before bonding with polymer chain or micro-nano particle, is terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active esterAny one of a group, an isocyanate group, an isothiocyanate group, an epoxy group, a carbonate group, a cyclic carbonate group, a thiocyclic carbonate group, an aryl group modified with a reactive carbonyl group or a reactive double bond group, a heteroaryl group, an alkyl group, or a modified alkyl group,
R 17 is any one of hydrogen, halogen atom, hydroxyl, sulfhydryl, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, cyclic carbonate, thiocyclic carbonate, amide, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl or is combined with R 16 Bonding to form a ring;
the thio cyclic carbonate group is any one of seven compounds shown in a formula IX:
the reactive carbonyl group is shown as a formula X:
In formula X, R 18 Bonded with macromolecular chains or micro-nano particles, R 18 Before bonding with polymer chain or micro-nano particles, is any one of aryl, heteroaryl, alkyl or modified alkyl modified by terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, thio cyclic carbonate group, active carbonyl group or active double bond group,
R 19 is hydrogen, halogen atom, hydroxy, mercapto, amino, nitro, cyano, aldehyde, ketone, or carboxylAny one of a group, an ester group, a thioester group, an isocyanate group, an isothiocyanate group, an epoxy group, a carbonate group, a thiocarbonate group, a cyclic carbonate group, a thiocyclic carbonate group, an amide group, a sulfate group, a sulfonate group, a phosphonate group, a sulfone group, a sulfoxide group, an aryl group, an alkyl group or a modified alkyl group, or a combination thereof 18 Bonding to form a ring;
the active double bond group is shown as a formula XI:
in formula XI, R 20 Bonded with macromolecular chains or micro-nano particles, R 20 Before bonding with polymer chain or micro-nano particles, is any one of aryl, heteroaryl, alkyl or modified alkyl modified by terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, thio cyclic carbonate group, active carbonyl group or active double bond group,
R 21 Is any one of hydrogen, halogen atom, hydroxyl, sulfhydryl, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, cyclic carbonate, thiocyclic carbonate, amide, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl or is combined with R 20 Bonding into a ring.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the polyethylene glycol and the derivative thereof are any one or more of linear polyethylene glycol, branched polyethylene glycol, multi-arm polyethylene glycol homopolymer, copolymer and end group modified or salified products thereof.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the saccharide compound is one or more of glucose, fructose, maltose, xylitol or sorbitol.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the mass ratio of the active ingredients to the auxiliary crosslinking agent to the dispersing agent is 1: (0.01-10): (0.1-30).
The medical tissue adhesive provided by the invention has the following characteristics: wherein the auxiliary crosslinking agent is a compound which generates crosslinking reaction with the tissue adhesion group, and the auxiliary crosslinking agent is any one or more of compounds containing amino, carboxyl, sulfhydryl or hydroxyl.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the amino-containing compound is one or more of polyethylenimine, polylysine, polyarginine, polyhistidine, gelatin, collagen, elastin, silk fibroin, chitosan and derivatives or copolymers thereof,
the compound containing carboxyl is one or more of hyaluronic acid, carboxymethyl chitosan, carboxymethyl cellulose, carboxymethyl starch, alginic acid, chondroitin sulfate, heparin, polyuronic acid, polyglutamic acid, polyaspartic acid, gelatin, collagen, silk fibroin, polylactic acid and derivatives or copolymers thereof,
the sulfhydryl-containing compound is one or more of polycysteine, gelatin, collagen and its derivatives,
the compound containing hydroxyl is one or more of hyaluronic acid, chitosan, agarose, cellulose, starch, alginic acid, chondroitin sulfate, heparin, polyuronic acid, cyclodextrin, polyserine, gelatin, collagen, silk fibroin, polyvinyl alcohol and derivatives or copolymers thereof.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the auxiliary crosslinking agent is a compound capable of exciting tissue adhesion groups, and the auxiliary crosslinking agent is a peroxide or a reducing agent.
Medical tissue provided by the inventionThe adhesive glue also has the following characteristics: wherein the peroxide is selected from alkyl peroxide (ROOH), dialkyl peroxide (ROOR '), diacyl peroxide (RCOOOOCR'), peroxyester (RCOOOR '), peroxycarbonate (ROCOOOOCOR') and ketone peroxide [ R ] 2 C(OOH) 2 ]Preferably any one or more of benzoyl peroxide, t-butyl peroxide, cyclohexanone peroxide, methyl ethyl ketone peroxide, hydrogen peroxide, persulfates, potassium persulfate, ammonium persulfate.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the reducing agent is one or more of sulfite, bisulfite, ferrous salt, naphthenate, tertiary amine compound and mercaptan, preferably sodium sulfite, sodium bisulfite, ferrous chloride, ferrous sulfate, cobalt naphthenate, N-dimethylaniline and tetraethyl ethylenediamine.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the high molecular chain is natural saccharide compound or hydrophilic or water-soluble synthetic polymer.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the natural saccharide compound is any one of hyaluronic acid, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, alginic acid, dextran, agarose, heparin, chondroitin sulfate, ethylene glycol chitosan, propylene glycol chitosan, chitosan lactate, carboxymethyl chitosan or chitosan quaternary ammonium salt.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the hydrophilic or water-soluble synthetic polymer is any one or more of two-arm polyethylene glycol, multi-arm polyethylene glycol, polyethylenimine, dendron, synthetic polypeptide, polyurethane, polylysine, polyglutamic acid, polyacrylic acid, polymethacrylic acid, polyacrylate, polymethacrylate, polyacrylamide, polymethacrylamide, polyvinyl alcohol and polyvinylpyrrolidone.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the auxiliary crosslinking agent is any one or more of an amino group-containing compound capable of undergoing a crosslinking reaction with an adhesive group, a nanoparticle formed from the amino group-containing compound, or a microparticle formed from the amino group-containing compound.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the amino group-containing compound is any one or more of hydrophilic or water-soluble animal and plant proteins, collagen, serum proteins, silk fibroin, elastin, protein degradation products, polyethylenimine, dendrimers, synthetic polypeptides, polylysine, polyarginine, polyhistidine, amino-terminated two-arm polyethylene glycol, amino-terminated multi-arm polyethylene glycol or amino-terminated polyurethane.
The medical tissue adhesive provided by the invention has the following characteristics: wherein the micro-nano particles are nano particles or micro particles formed by polymer chains.
The invention provides a preparation method of medical tissue adhesive, which is used for preparing any one of the medical tissue adhesive, and has the characteristics that the preparation method comprises the following steps: grinding the active ingredients and the auxiliary crosslinking agent into powder, adding the melted solid dispersing agent, and uniformly dispersing to obtain the composite material.
The medical tissue adhesive provided by the invention has the following action mechanism:
when the medical tissue adhesive contacts the wet tissue surface containing tissue fluid or blood, the solid dispersing agent in the medical tissue adhesive absorbs water and dissolves, and the dissolved dispersing agent squeezes away the tissue fluid or blood on the tissue surface, so that the active ingredient and the auxiliary crosslinking agent can fully contact the tissue surface. The molecular fragments with adhesion in the active ingredient then quickly form chemical bonds with amino, carboxyl or hydroxyl groups on the tissue surface to form a strong tissue adhesion. At the same time, the medical tissue adhesive further absorbs tissue fluid and water in blood, the absorbed water is gradually mixed with the dispersing agent, and the active ingredient and the auxiliary crosslinking agent are gradually infiltrated, so that the active ingredient and the auxiliary crosslinking agent are fully dissolved, and the molecular fragments with adhesiveness in the active ingredient and amino groups on the auxiliary crosslinking agent are triggered to react or the molecules with adhesiveness are triggered to crosslink themselves, so that the medical tissue adhesive is integrally formed into an adhesive and solidified, and the effects of wound surface sealing and tissue blood seepage are finally achieved.
Effects and effects of the invention
According to the medical tissue adhesive according to the present invention, the medical tissue adhesive provided by the present invention is in a solid form because of the active ingredient of the molecular fragment having adhesion, the auxiliary crosslinking agent, and the water-soluble solid dispersing agent, and is convenient to store. In the use process, the approximate position of the wound is only needed to be known, the solid glue is utilized to carry out positioning pressing, and the dissolved dispersing agent not only can be used for expelling tissue fluid or blood on the surface of the tissue, so that a molecular fragment with adhesiveness in the active ingredient can quickly generate chemical bonds with amino groups on the surface of the tissue to form stronger tissue adhesion force, but also can trigger the molecular fragment with adhesiveness in the active ingredient to react with the amino groups on the auxiliary crosslinking agent, so that the medical tissue adhesive is integrally and quickly glued and solidified, and has good blood expelling performance, hemostatic performance and tissue adhesion performance.
Drawings
FIG. 1 is a diagram of a medical tissue adhesive gel in accordance with a first embodiment of the present invention;
FIG. 2 is a diagram of medical tissue adhesive cement in a second embodiment of the present invention;
FIG. 3 is a diagram of medical tissue adhesive cement in a third embodiment of the present invention;
FIG. 4 is a graph showing the effect of medical tissue adhesive in the performance test of water absorption and gelling according to the first embodiment of the present invention;
FIG. 5 is a graph showing another application effect of the medical tissue adhesive according to the first embodiment of the present invention in the water-absorbing and gelling performance test;
FIG. 6 is a graph showing the effect of the water absorption and gelling performance test of the medical tissue adhesive in test example one of the present invention;
FIG. 7 is a graph showing the effect of the water-absorbing gelling and swelling properties test of the medical tissue adhesive in test example one of the present invention;
FIG. 8 is a graph showing the water-absorbing and gelling effects of a tissue adhesive in accordance with the second embodiment of the present invention;
FIG. 9 is a graph showing the initial effect of the tissue adhesive for use in test example three of the present invention;
FIG. 10 is a graph showing the effect of the tissue adhesive for use in the third test example of the present invention after bonding;
FIG. 11 is a graph of a model of abdominal aortic hemorrhage in a rabbit in test case four according to the present invention;
FIG. 12 is a graph showing the effect of hemostasis of the abdominal aorta of a rabbit in test example four of the invention;
FIG. 13 is a graph of a model of rabbit femoral artery hemorrhage in test case four according to the present invention;
FIG. 14 is a graph showing the effect of a conventional medical gauze in a fourth test example of the present invention;
FIG. 15 is a graph showing the effect of the conventional gauze of the fourth test example of the present invention after use;
FIG. 16 is a graph showing the effect of the tissue adhesive in the fourth example of the present invention;
FIG. 17 is a graph showing the effect of the tissue adhesive for use in the fourth test example of the present invention; and
FIG. 18 is a graph showing the effect of the test example five of the present invention on the adhesive strength of the tissue adhesive.
Detailed Description
In order to make the technical means, creation characteristics, achievement purposes and effects of the medical tissue adhesive realized by the present invention easy to understand, the present invention and the preparation method thereof are specifically described below with reference to the examples and the accompanying drawings.
In the examples which follow, the N-hydroxysuccinimide is replaced by its abbreviation "NHS" and the 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride by its abbreviation "EDC" for the sake of simplicity of description.
The molecular weight distribution of some of the raw materials used in the following examples was as follows:
polyglutamic acid: the molecular weight is 70-100 ten thousand;
polyethyleneimine: the molecular weight is 7 ten thousand;
hyaluronic acid: the molecular weight is 100 ten thousand;
polylysine: the molecular weight is 1500;
carboxyl-terminated four-arm polyethylene glycol: the molecular weight is 2000;
amino-terminated four-arm polyethylene glycol: the molecular weight is 2000.
Example 1
The medical tissue adhesive provided in this example is prepared from 1 part by weight of active ester modified four-arm polyethylene glycol (4 a-PEG-NHS) with 100% grafting rate, 0.12 part by weight of Polyethylenimine (PEI) and 3 parts by weight of polyethylene glycol 1000 (PEG-1000).
The preparation method of the active ester modified four-arm polyethylene glycol (4 a-PEG-NHS) comprises the following steps: dissolving carboxyl end capped four-arm polyethylene glycol (4 a-PEG-COOH) EDC and NHS in water according to the mass ratio of 1:0.1:0.1, adjusting the pH value to 5.5, heating to 35 ℃, stirring and reacting for 0.5 hours, and then dialyzing and freeze-drying to obtain the active ester modified four-arm polyethylene glycol with the grafting rate of 100%.
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: the grafting rate of the active ester modified four-arm polyethylene glycol with 100 percent, the amino-terminated four-arm polyethylene glycol and the polyethylene glycol 1000 are mixed according to the mass ratio of 1:0.12: and 3, after melting polyethylene glycol 1000 under the condition of drying and heating at 50 ℃, adding active ester modified four-arm polyethylene glycol and amino-terminated four-arm polyethylene glycol, uniformly mixing, and then performing reverse molding and cooling to obtain the final product shown in figure 1.
< example two >
The medical tissue adhesive provided in this example was prepared from 1 part by weight of tissue-adhesive group-modified microparticles (mHA-NHS, microsphere diameter 5 microns) having a grafting rate of 100%, 0.5 part by weight of chitosan, and 2 parts by weight of glycerol.
The preparation method of the tissue-adhesive group modified microparticles comprises the following steps: hyaluronic acid, EDC and NHS are dissolved in water according to the mass ratio of 1:0.1:0.1, the pH value is adjusted to 5.5, the mixture is heated to 35 ℃, the mixture is stirred and reacted for 0.5 hour, and then the mixture is centrifugally washed for 3 times, so that the tissue adhesion group modified microparticles (mHA-NHS) with the grafting rate of 100% are obtained.
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: melting polyethylene glycol 1000 at 50 ℃, and then modifying the polyethylene glycol 1000 with the tissue adhesion group modified micron particles with the grafting rate of 100% and chitosan according to the mass ratio of 2:1: and 0.5, and the final product is shown in figure 2.
Example III
The medical tissue adhesive provided in this example consists of 1 part of acrylate-terminated four-arm polyethylene glycol (4 a-PEG-AA), 1 part of sodium periodate, 1 part of vitamin C and 2 parts of polyethylene glycol 1000 (PEG-1000) in molar parts.
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: acrylate-terminated four-arm polyethylene glycol, sodium periodate, vitamin C and polyethylene glycol 1000 are mixed according to the molar ratio of 1:1:1:2, uniformly mixing under the condition of drying and heating at 50 ℃, and then carrying out reverse die cooling to obtain the final product shown in figure 3.
Example IV
The medical tissue adhesive provided in this example is prepared from 1 part by weight of methacrylic anhydride modified polyglutamic acid (PGAMA) with a grafting rate of 10%, 0.1 part by weight of sodium periodate, 0.1 part by weight of vitamin C and 3 parts by weight of polyethylene glycol 1500 (PEG-1500).
The preparation method of the methacrylic anhydride modified polyglutamic acid (PGAMA) comprises the steps of completely dissolving 1 part by weight of polyglutamic acid into deionized water, and carrying out the following steps: methacrylic anhydride molar ratio 10:1, regulating the pH value to 8-9, stirring and reacting for 4 hours, dialyzing and freeze-drying to obtain the methacrylic anhydride modified polyglutamic acid with the grafting rate of 10%.
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: the method comprises the following steps of (1) mixing 10% of methacrylic anhydride modified polyglutamic acid, sodium periodate, vitamin C and polyethylene glycol 1500 according to a mass ratio: 0.1:0.1:3 mixing uniformly under the condition of drying and heating at 50 ℃, cooling, grinding the sample into powder, and finally obtaining the product shown in figure 4.
< example five >
The present embodiment providesThe medical tissue adhesive is prepared from 1 part by weight of active ester modified four-arm polyethylene glycol (4 a-PEG-NHS) with 100 percent of grafting rate, and 0.2 part by weight of amino-terminated four-arm polyethylene glycol (4 a-PEG-NH) 2 ) And 1.5 parts of polyethylene glycol 1000 (PEG-1000).
The preparation method of the active ester capped four-arm polyethylene glycol (4 a-PEG-NHS) comprises the following steps: dissolving carboxyl end capped four-arm polyethylene glycol (4 a-PEG-COOH) EDC and NHS in water according to the mass ratio of 1:0.1:0.1, adjusting the pH value to 5.5, heating to 35 ℃, stirring and reacting for 0.5 hours, and then dialyzing and freeze-drying to obtain the active ester modified four-arm polyethylene glycol with the grafting rate of 100%.
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: the grafting rate of the active ester modified four-arm polyethylene glycol with 100 percent, the amino-terminated four-arm polyethylene glycol and the polyethylene glycol 1000 are mixed according to the mass ratio of 1:0.2:1.5, uniformly mixing under the condition of drying and heating at 50 ℃, and then, carrying out reverse mould cooling to obtain the product.
< example six >
The medical tissue adhesive provided in this example is prepared from 1 part by mole of sodium periodate, 1 part by mole of vitamin C and 2 parts by mole of acrylate-terminated four-arm polyethylene glycol 1000 (4 a-PEG-AA-1000).
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: sodium periodate, vitamin C and acrylate end capped four-arm polyethylene glycol 1000 are mixed according to the mass ratio of 1:1:2, uniformly mixing under the condition of drying and heating at 50 ℃, and then, reversing the mould and cooling to obtain the product.
< example seven >
The medical tissue adhesive provided in this example is prepared from 1 part by weight of active ester modified four-arm polyethylene glycol (4 a-PEG-NHS) with 100% grafting rate, 0.12 part by weight of Polyethylenimine (PEI) and 2 parts by weight of maltose.
The preparation method of the active ester modified four-arm polyethylene glycol comprises the following steps: dissolving carboxyl end capped four-arm polyethylene glycol (4 a-PEG-COOH) EDC and NHS in water according to the mass ratio of 1:0.1:0.1, adjusting the pH value to 5.5, heating to 35 ℃, stirring and reacting for 0.5 hours, and then dialyzing and freeze-drying to obtain the active ester modified four-arm polyethylene glycol with the grafting rate of 100%.
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: melting maltose under the condition of drying and heating at 150 ℃, and mixing with 100% of active ester modified four-arm polyethylene glycol (4 a-PEG-NHS) and Polyethyleneimine (PEI) according to the weight ratio of 2:1: and (3) uniformly mixing the materials, and then, carrying out reverse mold cooling to obtain the product.
< example eight >
The medical tissue adhesive provided in this example was prepared from 1 part by mole of sodium periodate and 1 part by mole of acrylate-terminated four-arm polyethylene glycol 1000 (4 a-PEG-AA-1000) as a comparative example.
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: uniformly mixing sodium periodate and acrylate-terminated four-arm polyethylene glycol 1000 according to the mass ratio of 1:1 under the condition of drying and heating at 50 ℃, and then performing reverse molding and cooling to obtain the modified polyethylene glycol.
< example nine >
The medical tissue adhesive provided in this example is prepared from 1 part by mole of sodium periodate, 0.5 part by mole of vitamin C and 1 part by mole of acrylate-terminated four-arm polyethylene glycol 1000 (4 a-PEG-AA-1000).
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: sodium periodate, vitamin C and acrylate end capped four-arm polyethylene glycol 1000 are mixed according to the mass ratio of 1:0.5:1 are evenly mixed under the condition of drying and heating at 50 ℃, and then are subjected to reverse mold cooling to obtain the product.
< example ten >
The medical tissue adhesive provided in this example is prepared from 1 part by mole of vitamin C and 1 part by mole of acrylate-terminated four-arm polyethylene glycol 1000 (4 a-PEG-AA-1000).
The preparation method of the medical tissue adhesive provided by the embodiment comprises the following steps: vitamin C and acrylate end capped four-arm polyethylene glycol 1000 are mixed according to the mass ratio of 1:1 are evenly mixed under the condition of drying and heating at 50 ℃, and then are subjected to reverse mold cooling to obtain the product.
Test example 1
Water-absorbing gel formation property test
The water absorption and gelling performance testing method comprises the following steps: 2ml deionized water was added to the petri dish, followed by placing 10mm 1mm cylindrical medical tissue adhesive as provided in example one in water.
The results of the water-absorbing gelling properties are shown in FIGS. 5-6.
As shown in FIG. 5, the medical tissue adhesive provided in the first embodiment uses the solid dispersing agent polyethylene glycol, so that liquid such as water can be drained through the action of gravity and contacted with the bottom of a culture dish, and then the water is absorbed and solidified into the adhesive, thereby proving that the tissue adhesive has good drainage performance and water absorption and adhesive forming performance.
As shown in FIG. 6, the hydrophilic dispersant polyethylene glycol used in the medical tissue adhesive provided in the first embodiment can be dissolved in water, the active ingredient and the auxiliary crosslinking agent are quickly dissolved after the water dissolves the dispersant to form the adhesive, the color is gradually changed from milky white to colorless and transparent from outside to inside, and the adhesive is completely changed to colorless and transparent after 5 minutes to form a complete adhesive.
The second water-absorbing and gelling performance test method comprises the following steps: 2ml of deionized water was added to the petri dish, and then the medical tissue adhesive provided in example two, which was a disk with a diameter of 10mm, was placed in water.
The test results of the water-absorbing gelling properties are shown in FIG. 7.
As shown in fig. 7, the medical adhesive provided in the second embodiment uses a hydrophilic solid dispersant polyethylene glycol, and in the process of dissolving in water, the microparticles dispersed therein can react with an auxiliary crosslinking agent to form an adhesive, and the adhesive is changed from white to colorless and transparent, so that the adhesive is formed into a finished adhesive in the form of interconnecting microparticles, and hardly swells.
< test example two >
Water-absorbing gel formation property test
The water absorption performance test method comprises the following steps: 1mL of deionized water was added to the centrifuge tube, followed by 100mg of the medical tissue adhesive provided in example six, example eight, example nine, example ten, based on 1000 weight of the four-arm polyethylene glycol, to the water.
The results of the water absorption gel formation test are shown in FIG. 8.
As shown in fig. 8, the medical tissue adhesive according to the sixth embodiment can form a hydrogel in a complete form due to the auxiliary crosslinking agent having redox properties and the four-arm polyethylene glycol as an active ingredient of the solid dispersing agent. Example nine only a portion of the hydrogel was formed because the level of secondary cross-linking agent was not optimal. While examples eight and ten failed to form a gel by dispersion in water because they contained only a single oxidizing or reducing agent component and failed to form an auxiliary crosslinking. The necessity of an auxiliary crosslinking agent to act on the active ingredient is demonstrated.
Test case III
Adhesion Performance test in blood
The testing method comprises the following steps: first, fresh tissue was immersed in blood, 200mg of the medical tissue adhesive according to example seven was pressed against the blood-bearing tissue surface for 15s as shown in FIG. 9, and left to stand in blood for 3 minutes.
The test results are shown in fig. 10.
As shown in fig. 10, the medical tissue adhesive provided in the seventh embodiment can firmly adhere to the surface of blood-bearing tissue and form gel, so that the gel on the tissue can be clearly seen, and the adhesion performance of the tissue adhesive in blood is proved.
Test case IV
Test of tissue adhesion Property, wound surface sealing Property and hemostatic Property
The first test method comprises the following steps: first, as shown in FIG. 11, a large number of ejection of blood column was observed on a large hemorrhage model of abdominal aortic injury by needle-made with a diameter of 2mm on the abdominal aorta of a rabbit; the medical tissue adhesive provided in example one was then immediately glued to the lesion for 15 seconds, followed by release of the press.
The test results are shown in fig. 12.
As shown in FIG. 12, the medical tissue adhesive provided in the first embodiment can firmly adhere to the surface of the abdominal aorta and absorb the aqueous gel in blood, meanwhile, no blood flows out, and the abdominal aorta and the gel adhered on the defect can be clearly seen, so that the tissue adhesive has good tissue adhesion performance, wound surface sealing performance and hemostatic performance.
The second test method is as follows: first, as shown in fig. 13, the femoral artery of the rabbit was cut directly with a scalpel, and a large amount of blood gushing was observed; immediately after this, the wound was pressed with a normal medical gauze, and the gauze was seen to be rapidly stained red with blood, and after pressing for 3 minutes, it was seen that a large amount of blood was still oozed out through the gauze, as shown in fig. 14. After removal of the gauze, a significant amount of blood jet was seen to still be present, with no reduction in bleeding, as shown in fig. 15.
The test results are shown in FIGS. 16-17.
As shown in fig. 16, in the case of massive hemorrhage with equal femoral artery cut, the medical tissue adhesive provided in example three was spread on gauze and pressed to the lesion for 10 seconds, and then the pressing was released, so that the gauze was not stained red with blood, i.e., bleeding had stopped. And the medical tissue adhesive provided in the third embodiment has good tissue adhesion performance, wound surface sealing performance and hemostatic performance.
As shown in figure 17, after the gauze is removed, the wound is covered and sealed by a layer of adhesive, and no blood flows out, so that the medical tissue adhesive has strong sealing and hemostatic capabilities.
< test example five >
Adhesive Strength test
The testing method comprises the following steps: the medical tissue adhesive of the fifth example was sandwiched between two pigskins at 0.1cm x 0.01cm, then the pigskins coated with the tissue adhesive were soaked in water, and after 5min, the two pigskins were pulled with a universal mechanical tester.
The test results are shown in fig. 18.
As shown in fig. 18, the medical tissue adhesive of the fifth embodiment can bond two pigskin together, and after the two pigskin are pulled, the colloid remains between the two pigskin, which proves that the medical tissue adhesive of the fifth embodiment has strong bonding strength.
Effects and effects of the examples
According to the medical tissue adhesive and the preparation method thereof, as the used dispersing agent is the solid hydrophilic dispersing agent, and the solid dispersing agent firstly contacts the tissue surface due to the action of gravity and the action of density at the moment of contacting blood, the adhesive groups on the active ingredients can fully contact and react with the amino groups on the tissue surface along with the dissolution of water absorption, the adhesion is not affected by the reaction of the amino groups on the proteins in blood and tissue fluid, then the solid hydrophilic dispersing agent can absorb the water in the blood and the tissue fluid, the active ingredients are further dissolved, and the molecular fragments with the adhesion in the active ingredients are triggered to react with the amino groups on the auxiliary crosslinking agent, so that the medical tissue adhesive in the first to fourth embodiments can be quickly crosslinked into adhesive while having good blood drainage performance, and the quick adhesion of tissues and wound surface closure can be realized.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. A medical tissue adhesive comprising:
an active ingredient, an auxiliary crosslinking agent and a dispersing agent,
wherein the active ingredient is a polymer chain modified by a tissue adhesion group or micro-nano particles modified by the tissue adhesion group,
the auxiliary crosslinking agent is a compound which generates crosslinking reaction with the tissue adhesion group or a compound which excites the tissue adhesion group to generate crosslinking by itself,
the dispersing agent is a solid dispersing agent which melts into a liquid which uniformly disperses the active ingredient and the auxiliary crosslinking agent under the heating condition and does not react with the active ingredient and the auxiliary crosslinking agent,
the dispersing agent is any one or more of polyethylene glycol and derivatives thereof or saccharide compounds,
the medical tissue adhesive is prepared by the following steps:
grinding the active ingredients and the auxiliary crosslinking agent into powder, adding the melted dispersing agent, and uniformly dispersing to obtain the modified starch.
2. The medical tissue adhesive according to claim 1, wherein:
Wherein the tissue-adhesive group comprises: an o-nitrobenzyl photo-trigger group, an active ester group, an isocyanate group, an isothiocyanate group, an epoxy group, a cyclic carbonate group, a thiocyclic carbonate group, an active carbonyl group or an active double bond group,
the structure of the o-nitrobenzyl optical trigger group is shown as a formula I or a formula II:
in formula I and formula II, LG is a halogen atom, O-R ', S-R ', or NH-R '; r' is any one of hydrogen, alkyl, ether, thioether, ketone, ester, thioester, amide, sulfate, sulfonate, phosphonate or phosphonate;
R 1 is any one of hydrogen, halogen atom, hydroxyl, mercapto, amino, nitro, cyano, aldehyde, ketone, ester, amide, thioester, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl;
R 2 、R 3 ，R 4 ，R 5 any one or more of the above are bonded to the polymer chain or the micro-nano particles,
R 2 、R 3 ，R 4 ，R 5 any one or more of the polymer chains or the micro-nano particles are before being bonded with terminal amino, hydroxyl, sulfhydryl, halogen atom, acyl halide, anhydride, carboxyl, carboxylate, active ester group and isocyanate group Any one of an aryl group, an alkyl group or a modified alkyl group modified by an isothiocyanate group, an epoxy group, a carbonate group, a cyclic carbonate group, a thiocyclic carbonate group, a reactive carbonyl group or a reactive double bond group,
R 2 、R 3 ，R 4 ，R 5 wherein the substituents which are not bonded to the polymer chain or the micro-nano particles are each independently selected from any one of hydrogen, halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, aldehyde group, ketone group, carboxyl group, ester group, thioester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfuric acid ester group, sulfonic acid ester group, phosphonic acid ester group, sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group;
the active ester group is a succinimide active ester group shown in a formula III or a triazole active ester group shown in a formula IV:
the succinimide active ester group passes through R 6 Is bonded with the polymer chain or the micro-nano particle represented by P,
in formula III, R 6 Directly bonding with the polymer chain or the micro-nano particles, or bonding with the polymer chain or the micro-nano particles through any one of terminal modified ether bond, thioether bond, ketone bond, ester bond, thioester bond, amide bond, sulfuric acid bond, sulfonic acid bond, sulfonate bond, phosphonic acid bond, phosphoric acid bond, sulfone bond, sulfoxide bond, aryl bond, alkyl bond or modified alkyl bond,
R 7 、R 8 Are each independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, amino, nitro, cyano, aldehyde, ketone, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, and cyclic carbonateA group, thiocyclic carbonate group, amide group, sulfate group, sulfonate group, phosphonate group, sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group, or R 7 And R is R 8 The two are bonded to form a ring,
the triazole active ester group passes through R 9 Is bonded with the polymer chain or the micro-nano particle represented by P,
in formula IV, R 9 Directly bonding with the polymer chain or the micro-nano particles, or bonding with the polymer chain or the micro-nano particles through any one of terminal modified ether bond, thioether bond, ketone bond, ester bond, thioester bond, amide bond, sulfuric acid bond, sulfonic acid bond, sulfonate bond, phosphonic acid bond, phosphate bond, sulfone bond, sulfoxide bond, aryl group, alkyl group or modified alkyl group,
R 10 、R 11 each independently selected from any one of hydrogen, halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, aldehyde group, ketone group, ester group, thioester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfate group, sulfonate group, phosphonic acid group, phosphonate group, sulfone group, sulfoxide group, aryl group, alkyl group or modified alkyl group, or R 10 And R is R 11 Bonding the two groups to form a ring;
the structural formula of the isocyanate group is shown as formula V:
O＝C＝N-R 12
v (V)
In formula V, R 12 Is bonded with the polymer chain or micro-nano particles, R 12 In an aryl, heteroaryl, alkyl or modified alkyl group modified by a terminal amino, hydroxyl, mercapto, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxy, carbonate, cyclic carbonate, thiocyclic carbonate, active carbonyl or active double bond group prior to bonding to the polymeric chain or the micro-nano particleAny one of (3);
the isothiocyanate group is shown in a formula VI:
S＝C＝N-R 13
VI (VI)
In formula VI, R 13 Is bonded with the polymer chain or micro-nano particles, R 13 Any one of aryl, heteroaryl, alkyl or modified alkyl modified by terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxy, carbonate, cyclic carbonate, thiocyclic carbonate, active carbonyl or active double bond groups before bonding with the polymer chain or the micro-nano particles;
The epoxy group is shown as a formula VII:
in formula VII, R 14 Is bonded with the polymer chain or micro-nano particles, R 14 Any one of aryl, heteroaryl, alkyl or modified alkyl modified by terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxy, carbonate, cyclic carbonate, thio cyclic carbonate, active carbonyl or active double bond groups is used before bonding with the polymer chain or the micro-nano particles,
R 15 is hydrogen, halogen atom, hydroxyl group, mercapto group, amino group, nitro group, cyano group, aldehyde group, ketone group, carboxyl group, ester group, thioester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, thiocarbonate group, cyclic carbonate group, thiocyclic carbonate group, amide group, sulfate group, sulfonate group, phosphonic acid group, phosphonate group, sulfone group, sulfoxide group, aryl group, alkyl group, modified alkaneAny one of the radicals, or with R 14 Bonding to form a ring;
the cyclic carbonate group is shown as a formula VIII:
In formula VIII, R 16 Is bonded with the polymer chain or the micro-nano particles, R 16 Before bonding with the polymer chain or the micro-nano particles, the polymer chain or the micro-nano particles is any one of aryl, heteroaryl, alkyl or modified alkyl modified by a terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester, isocyanate, isothiocyanate, epoxy, carbonate, cyclic carbonate, thio cyclic carbonate, active carbonyl or active double bond,
R 17 is any one of hydrogen, halogen atom, hydroxyl, sulfhydryl, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, cyclic carbonate, thiocyclic carbonate, amide, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl or is combined with R 16 Bonding to form a ring;
the thio cyclic carbonate group is any one of seven compounds shown in a formula IX:
The reactive carbonyl group is shown as a formula X:
in formula X, R 18 Is bonded with the polymer chain or the micro-nano particles, R 18 Before bonding with the polymer chain or micro-nano particles, the polymer chain or micro-nano particles are any one of aryl, heteroaryl, alkyl or modified alkyl modified by terminal amino, hydroxyl, sulfhydryl, halogen, acyl halide, anhydride, carboxyl, carboxylate, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, thio cyclic carbonate group, active carbonyl group or active double bond group,
R 19 is any one of hydrogen, halogen atom, hydroxyl, sulfhydryl, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, cyclic carbonate, thiocyclic carbonate, amide, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl or is combined with R 18 The bonding is carried out to form a ring,
the active double bond group is shown as a formula XI:
In formula XI, R 20 Is bonded with the polymer chain or the micro-nano particles, R 20 An aromatic group modified with a terminal amino group, hydroxyl group, mercapto group, halogen, acyl halide, acid anhydride group, carboxyl group, carboxylate group, active ester group, isocyanate group, isothiocyanate group, epoxy group, carbonate group, cyclic carbonate group, thiocyclic carbonate group, active carbonyl group or active double bond group before bonding with the polymer chain or micro-nano particlesAny of a group, heteroaryl, alkyl or modified alkyl,
R 21 is any one of hydrogen, halogen atom, hydroxyl, sulfhydryl, amino, nitro, cyano, aldehyde, ketone, carboxyl, ester, thioester, isocyanate, isothiocyanate, epoxy, carbonate, thiocarbonate, cyclic carbonate, thiocyclic carbonate, amide, sulfate, sulfonate, phosphonate, sulfone, sulfoxide, aryl, alkyl or modified alkyl or is combined with R 20 Bonding into a ring.
3. The medical tissue adhesive according to claim 1, wherein:
wherein the polyethylene glycol and the derivatives thereof are any one or more of linear polyethylene glycol, branched polyethylene glycol, multi-arm polyethylene glycol homopolymer, copolymer and end group modified or salified products thereof.
4. The medical tissue adhesive according to claim 1, wherein:
wherein the saccharide compound is any one or more of glucose, fructose, maltose, xylitol or sorbitol.
5. The medical tissue adhesive according to claim 1, wherein:
wherein the mass ratio of the active ingredient to the auxiliary crosslinking agent to the dispersing agent is 1: (0.01-10): (0.1-30).
6. The medical tissue adhesive according to claim 1, wherein:
wherein the auxiliary crosslinking agent is a compound which generates crosslinking reaction with the tissue adhesion group, and the auxiliary crosslinking agent is any one or more of compounds containing amino, carboxyl, sulfhydryl or hydroxyl.
7. The medical tissue adhesive of claim 6, wherein:
wherein the amino-containing compound is any one or more of polyethylenimine, polylysine, polyarginine, polyhistidine, gelatin, collagen, elastin, silk fibroin, chitosan and derivatives or copolymers thereof,
the compound containing carboxyl is any one or more of hyaluronic acid, carboxymethyl chitosan, carboxymethyl cellulose, carboxymethyl starch, alginic acid, chondroitin sulfate, heparin, polyuronic acid, polyglutamic acid, polyaspartic acid, gelatin, collagen, silk fibroin, polylactic acid and derivatives or copolymers thereof,
The sulfhydryl-containing compound is any one or more of polycysteine, gelatin, collagen and derivatives thereof,
the compound containing hydroxyl is any one or more of hyaluronic acid, chitosan, agarose, cellulose, starch, alginic acid, chondroitin sulfate, heparin, polysaccharide aldehyde acid, cyclodextrin, polyserine, gelatin, collagen, silk fibroin, polyvinyl alcohol and derivatives or copolymers thereof.
8. The medical tissue adhesive according to claim 1, wherein:
wherein the auxiliary crosslinking agent is a compound capable of exciting the tissue adhesion group to crosslink itself,
the auxiliary crosslinking agent is peroxide or reducing agent.
9. The medical tissue adhesive of claim 8, wherein:
wherein the peroxide is any one or more of alkyl peroxide, dialkyl peroxide, diacyl peroxide, peroxyester, peroxycarbonate or ketone peroxide.
10. The medical tissue adhesive of claim 8, wherein:
wherein the reducing agent is any one or more of sulfite, bisulfite, ferrous salt, naphthenate, tertiary amine compound or mercaptan.
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