CN113512133A - Preparation method of biological tissue adhesive - Google Patents

Preparation method of biological tissue adhesive Download PDF

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CN113512133A
CN113512133A CN202110579963.1A CN202110579963A CN113512133A CN 113512133 A CN113512133 A CN 113512133A CN 202110579963 A CN202110579963 A CN 202110579963A CN 113512133 A CN113512133 A CN 113512133A
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polymer
dopamine
tissue adhesive
monomer
reaction
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CN113512133B (en
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龚祖光
周应山
周鼎
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Shanghai New Valve Medical Devices Co ltd
Jiangsu Newvalue Medical Products Co ltd
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Jiangsu Newvalue Medical Products Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • 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
    • A61L24/0031—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials resorbable by the body
    • 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
    • A61L24/08—Polysaccharides
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J105/00—Adhesives based on polysaccharides or on their derivatives, not provided for in groups C09J101/00 or C09J103/00
    • C09J105/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

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  • Adhesives Or Adhesive Processes (AREA)

Abstract

The invention provides a preparation method of a biological tissue adhesive, which comprises the following steps: s1: the method comprises the following steps of (1) obtaining an aldehyde-based polymer by taking a polymer as a raw material and performing specific oxidation by using an oxidant, wherein at least part of C-C bonds at 2-position and 3-position on a first polymeric monomer, namely a polysaccharide monomer (hexose) in the polymer are broken, and are subjected to ring opening to form aldehyde groups, so as to obtain a second polymeric monomer; s2: adding dopamine, and performing Schiff base reaction on at least part of the second polymeric monomer and the dopamine to generate a third polymeric monomer; s3: adding a reducing agent to reduce at least a portion of the imine linkages of the third polymeric monomer to C-N linkages to form a fourth polymeric monomer. The preparation method of the biological tissue adhesive provided by the invention has the advantages that the dopamine grafting rate is high, the obtained biological tissue adhesive has good adhesion performance, imine bonds are reduced, the stability of the tissue adhesive is improved, and the degradation time of the tissue adhesive can be controlled by regulating and controlling the preparation process.

Description

Preparation method of biological tissue adhesive
Technical Field
The invention belongs to the technical field of medical material preparation, and particularly relates to a preparation method of a biological tissue adhesive, wherein the tissue adhesive is used for adhering and repairing a moist environment tissue.
Background
The biological tissue adhesive is a biological medical material which can be directly applied to human bodies and can be used for biological tissue adhesion, local tissue bleeding closure and repair. The suture can be replaced or assisted in surgery, the tissue adhesive can close wounds more rapidly than conventional surgical sutures, is more applicable especially in the face of irregular wound surfaces, and can also accelerate wound healing in later treatments.
At present, the biological tissue adhesive is mainly made of chemical materials (polyurethane, cyanoacrylate and the like), degradable synthetic macromolecules (polyvinyl alcohol, polycaprolactone and the like), biological macromolecules (chitosan, alginic acid, hyaluronic acid and the like) and biological macromolecule polypeptides (polyglutamic acid, polylysine, fibrin and the like). But chemical and degradable synthetic macromolecules have poor biocompatibility, binding property with surrounding tissue interfaces and degradability. The biomacromolecule polysaccharide and the polypeptide have the advantages of better structure adjustability, biocompatibility, degradability and the like. However, the existing biological tissue adhesives prepared at present generally have the problems of poor wet adhesion performance, incomplete bonding with biological tissues, insufficient sealing performance, uncontrollable biodegradation performance and the like, and limit the further application of the biological tissue adhesives. For example, when the degradation degree of the existing biological tissue adhesive in a human body is uncontrollable, the adhesive capacity is disabled, and inflammatory reaction is generated.
In order to solve the problems, the prior art develops a mussel bionic tissue adhesive, and catechins are introduced into the tissue adhesive to improve the adhesive strength of the adhesive. Generally, the free carboxyl groups (-COOH) on the polysaccharide chain can undergo condensation reaction with carbodiimide to graft catechol under the catalysis of N-hydroxysuccinimide. However, the grafting reaction has a large number of by-products, a low yield of the product and a low grafting yield, which limits the adhesion properties.
Disclosure of Invention
In order to solve the problems of poor wet adhesion performance and uncontrollable biodegradation performance of the existing biological tissue adhesive, the invention provides a preparation method of the biological tissue adhesive.
The invention discloses a preparation method of a biological tissue adhesive, which comprises the following steps:
s1: taking a polymer as a raw material, and carrying out oxidation reaction in the presence of an oxidant to obtain an aldehyde-based polymer, wherein C-C bonds on at least part of first polymeric monomers in the polymer are broken to generate second polymeric monomers with dialdehyde structures; wherein the first polymerized monomer has the following structural formula:
Figure BDA0003085784350000021
wherein R is2Is OH or NH2；
The second polymeric monomer has the following structural formula:
Figure BDA0003085784350000022
s2: performing a grafting reaction on the hydroformylation polymer and dopamine to obtain a dopamine grafted polymer, wherein at least part of second polymeric monomers and dopamine undergo Schiff base reaction to generate third polymeric monomers, and the structure of the third polymeric monomers is that at least one of two aldehyde groups of the second polymeric monomers is replaced by an imine bond to be connected with the dopamine;
s3: adding a reducing agent into the solution of the dopamine graft polymer, and obtaining a reduced graft polymer under the catalysis of the reducing agent, wherein at least part of imine bonds of the third polymerization monomer are reduced into C-N bonds to generate a fourth polymerization monomer.
By adopting the technical scheme, the tissue adhesive is prepared by taking polysaccharide as a base material through reaction, and has good biocompatibility; in the preparation process, the oxidative hydroformylation process enables polysaccharide monomers to open rings, reduces the influence of the steric hindrance of a ring structure on the grafted dopamine, generates sufficient aldehyde groups, and ensures that a large amount of dopamine is grafted by utilizing the Schiff base rapid condensation reaction between the aldehyde groups and amino groups, so that the adhesive strength of the polymer can be improved. After Schiff base reaction is carried out on the polysaccharide subjected to hydroformylation and dopamine, the polysaccharide is grafted with the dopamine; dopamine is grafted in polysaccharide to form a mussel bionic tissue adhesive, so that the adhesive strength of the adhesive in a wet environment is improved; however, the structural monomer and dopamine are connected by virtue of an imine bond, and the imine bond stability is poor. According to the invention, after Schiff base reaction, reduction reaction is further carried out, the imine bond is specifically reduced into a C-N bond which is not easy to hydrolyze, so that the whole structural system is more stable, and when the Schiff base adhesive is used as a tissue adhesive in the later period, the reduction degree of the imine bond can be regulated and controlled by a preparation process to control the degradation time, so that the action time of the adhesive is prolonged, and the degradation time of the adhesive is controllable.
According to another embodiment of the present invention, there is provided a method for preparing a biological tissue adhesive, R in the polymer1Is COOH, CH2OH、CH2OCH2One kind of COOH.
By adopting the scheme, the raw material of the polymer can be at least one of hyaluronic acid, chitosan, alginic acid and carboxymethyl cellulose.
According to another embodiment of the present invention, there is provided a method for preparing a biological tissue adhesive, R in the polymer1Is COOH, R2Is OH; and the polymer further comprises a fifth polymerized monomer, the fifth polymerized monomer having the formula:
Figure BDA0003085784350000031
and the fifth polymerization monomer is respectively connected with the first polymerization monomer, the second polymerization monomer, the third polymerization monomer and the fourth polymerization monomer to form a repeating unit of the reduction graft polymer.
By adopting the scheme, the raw material of the polymer is hyaluronic acid, and the polymer has excellent biocompatibility.
According to another embodiment of the present invention, there is provided a method for preparing a biological tissue adhesive, wherein the reducing agent is sodium cyanoborohydride, and step S3 includes: dissolving the dopamine grafted hyaluronic acid in a phosphate buffer solution with the pH value of 5.0, adding sodium cyanoborohydride, reacting for 4-6 hours at 25 ℃, purifying and drying; wherein the mass ratio of the dopamine grafted hyaluronic acid to the sodium borohydride is 1: 0.5-1.
By adopting the scheme, sodium cyanoborohydride is selected as a reducing agent, and the activity of cyano groups for weakening boron hydrogen bonds is provided by the sodium cyanoborohydride, so that the sodium cyanoborohydride selectively reduces Schiff base; suitable for the imine bond reduction step of the present invention.
According to another embodiment of the present invention, in the method for preparing a biological tissue adhesive according to the present invention, in step S3, the reduction rate of the imine bond is 40 to 65%.
By adopting the scheme, when the reduction rate reaches the proportion range, the tissue adhesive has better adsorption performance and degradation time.
According to another embodiment of the present invention, the method for preparing the biological tissue adhesive, step S3, comprises the steps of loading the reaction solution after the reaction into a dialysis membrane with a molecular weight cutoff of 8000-14000Da, dialyzing with ultrapure water for 1-3 days, and drying to freeze-drying.
According to another embodiment of the present invention, there is provided a method for preparing a biological tissue adhesive, wherein the oxidizing agent is sodium periodate;
step S1 includes: dissolving the polymer in phosphate buffer solution with pH value of 5.0, adding sodium periodate, reacting at 25 ℃ in the dark for 4-6 hours, finally adding ethylene glycol to react to terminate the reaction, purifying, and freeze-drying to obtain aldehyde-based polymer;
step S2 includes: dissolving the aldehydized polymer in phosphate buffer solution with pH value of 5.0, adding dopamine hydrochloride, reacting at 25 ℃ for 10-14 hours, purifying, and freeze-drying to obtain dopamine grafted polymer;
wherein the mass ratio of the polymer to the sodium periodate is 1: 0.3-0.6; the mass ratio of the aldehyde polymer to the dopamine hydrochloride is 1: 0.5-1.
By adopting the scheme, sodium periodate is selected as an oxidant, and can selectively break the adjacent dihydroxy in the polysaccharide monomer to generate corresponding polysaccharide aldehyde, so that the reaction efficiency is high.
According to another embodiment of the present invention, in the method for preparing a biological tissue adhesive, in step S1, the hydroformylation rate of hyaluronic acid is 75 to 90%; in step S2, the molar substitution degree of dopamine is 0.35 to 0.65.
By adopting the scheme, the reduced graft polymer used as the tissue adhesive has good wet adhesion performance and longer degradation time.
According to another embodiment of the present invention, there is provided a method for preparing a biological tissue adhesive, the method further comprising: s4: reducing the graft polymer to prepare aqueous solution, adding a cross-linking agent for cross-linking reaction to obtain the tissue adhesive hydrogel.
In the preparation process of the gel adhesive, different polymer solubilities, cross-linking agent ratios and cross-linking time are selected to obtain tissue adhesive products with differences.
According to another embodiment of the invention, the preparation method of the biological tissue adhesive provided by the invention comprises the following steps of (1) preparing a polymer aqueous solution by mass percentage, wherein the polymer aqueous solution is 5-10%; the cross-linking agent comprises sodium periodate aqueous solution with the mass percentage concentration of 2.5-10%; the volume ratio of the aqueous solution of the polymer to the aqueous solution of the sodium periodate in the crosslinking reaction is 1:1, and the reaction time is 20 to 40 seconds.
By adopting the scheme, the gel formed by using the sodium periodate as the cross-linking agent has better performance.
Detailed Description
For the purposes of the following detailed description, it is to be understood that, except in any operating examples, or where otherwise indicated, all numbers expressing, for example, quantities of ingredients used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained by the present application. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
The terminology used in the present application is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The expression "at least one" of an expression, for example, modifies an entire list of elements when preceding or following the list of elements, without modifying individual elements of the list.
Further, the terms "comprises" or "comprising," when used in this specification, specify the presence of stated features, regions, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and/or groups thereof.
As used herein, "about" or "approximately" includes the recited value and means, for example, within an acceptable range of deviation for the particular value as determined by one of ordinary skill in the art in view of the measurement in question and the error associated with measurement of the particular quantity (i.e., limitations of the measurement system). All ratios of components refer to weight percent (wt.%), unless otherwise specified; unless otherwise indicated, all parameter ranges disclosed include the endpoints and all values therebetween.
In the description of the present invention, unless otherwise specified, terms have the same meaning as those generally understood by those skilled in the art, but if different, the definition of the present invention shall control; unless otherwise specified, the test methods are all conventional methods; unless otherwise specified, the raw materials and test materials used in the present invention are all available commercially.
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in further detail below.
The invention provides a preparation method of a tissue adhesive, which comprises the following steps:
s1: taking a polymer as a raw material, and carrying out oxidation reaction in the presence of an oxidant to obtain an aldehyde-based polymer, wherein C-C bonds on at least part of first polymeric monomers in the polymer are broken to generate second polymeric monomers with dialdehyde structures; wherein the first polymerized monomer has the following structural formula:
Figure BDA0003085784350000061
wherein R is2Is OH or NH2；
The second polymeric monomer has the following structural formula:
Figure BDA0003085784350000062
specifically, the first polymeric monomer is a polysaccharide monomer (hexose), wherein R is1The polymer may be COOH or CH, depending on the raw material of the polymer2OH、CH2OCH2COOH、CH2OCHO、CH2OCH3、CH2NH2、CH2OSO3Na、CH2COOH, wherein the carboxyl group (COOH) may also be present in the form of a sodium salt (COONa). The polymer of the present invention may be a polysaccharide useful as a tissue adhesive, for example, one containing R2Hyaluronic acid, carboxymethyl cellulose, alginic acid, beta-1, 3-glucan, carboxymethyl starch, etc. of a first polymerized monomer which is OH, and an acid containing R2Is NH2The first polymerizable monomer of (2) may be chitosan, etc., and may be hyaluronic acid, alginic acid, a modified derivative of chitosan, etc.
The polymer raw material is partially polymerized by oxidation reactionOpening the ring between the 2-and 3-carbon atoms in the monomer, and allowing hydroxyl (-OH) or amino (-NH) groups thereon2) Converting to an aldehyde group, thereby obtaining a second polymeric monomer; the oxidizing agent required for the oxidation reaction may be at least one of periodate, lead tetraacetate, and the like, and sodium periodate is preferred.
S2: and carrying out a grafting reaction on the hydroformylation polymer and dopamine to obtain a dopamine grafted polymer, wherein at least part of the second polymeric monomer and dopamine undergo Schiff base reaction to generate a third polymeric monomer, and the structure of the third polymeric monomer is that at least one of two aldehyde groups of the second polymeric monomer is replaced by an imine bond to be connected with the dopamine. The third polymerized monomer may have a structure of one of the following:
Figure BDA0003085784350000071
s3: adding a reducing agent into the solution of the dopamine graft polymer, and obtaining a reduction graft polymer under the catalysis of the reducing agent, wherein at least part of imine bonds (C ═ N) of a third polymerization monomer are reduced into C-N bonds, so as to generate a fourth polymerization monomer; the fourth polymerized monomer may have a structure of one of the following:
Figure BDA0003085784350000072
the reducing agent for the reduction reaction may be lithium aluminum hydride (LiAlH)4) Sodium borohydride (NaBH)4) Sodium cyanoborohydride (NaBH)3CN), sodium triacetoxyborohydride (NaBH (OAc)3) And catalytic hydrogenation, and the like.
In the invention, the oxidative hydroformylation process enables polysaccharide monomers to open rings, reduces the influence of the steric hindrance of a ring structure on the grafted dopamine, generates sufficient aldehyde groups, and ensures that a large amount of dopamine is grafted by utilizing the Schiff base rapid condensation reaction between the aldehyde groups and amino groups, thereby improving the adhesive strength of the polymer. After Schiff base reaction is carried out on the polysaccharide subjected to hydroformylation and dopamine, the polysaccharide is grafted with the dopamine; dopamine is grafted in polysaccharide to form a mussel bionic tissue adhesive, and a chemical bond can be generated between a catechol group on the mussel bionic tissue adhesive and a sulfhydryl group of a biological tissue, so that the biological tissue adhesive has good sealing performance and wet adhesion performance, the molar substitution degree of the dopamine in the preparation process can reach over 0.65, and compared with the preparation process in which carboxyl is grafted to ensure that the substitution degree is about 0.1, the adhesive strength of the adhesive in a wet environment is greatly improved. However, the structural monomer and dopamine are connected by virtue of imine bonds, the imine bonds are poor in stability and easy to hydrolyze to enable dopamine to be free, so that the tissue adhesive has the defects of ineffective adhesion performance and uncontrollable biodegradation, and meanwhile, the hydrolysis reaction product of the structural monomer can cause an organism to initiate an inflammatory reaction. According to the invention, after Schiff base reaction, reduction reaction is further carried out, and imine bond specificity is reduced into C-N bond which is not easy to hydrolyze, so that the whole structural system is more stable, and the degradation time can be controlled by adjusting the reduction degree of imine bond when the composite material is used as a tissue adhesive in the later period; particularly, the hydrolysis reaction of the tissue adhesive applied to human tissues can be reduced by increasing the reduction degree of imine bonds, the action time of the adhesive is prolonged, and the degradation time of the adhesive is controlled more accurately.
According to another embodiment of the present invention, R in the polymer1Is COOH, CH2OH、CH2OCH2One kind of COOH.
Specifically, when R is1Is COOH, R2When the first polymeric unit is OH, the first polymeric unit is hexuronic acid, and can be polysaccharide monomer of alginic acid and hyaluronic acid; when R is1Is CH2OH，R2Is NH2When the first polymerization unit is hexosamine, a polymerization monomer of chitosan can be used; when R is1Is CH2OCH2COOH，R2In the case of OH, it may be a monomer polymerized with carboxymethyl cellulose.
According to another embodiment of the present invention, R in the polymer1Is COOH, R2Is OH; and the polymer further comprises a fifth polymerized monomer, the fifth polymerized monomer having the formula:
Figure BDA0003085784350000081
and the fifth polymerization monomer is respectively connected with the first polymerization monomer, the second polymerization monomer, the third polymerization monomer and the fourth polymerization monomer to form a repeating unit of the reduction graft polymer.
Specifically, the first polymeric monomer is D-glucuronic acid, the fifth polymeric monomer is N-acetylglucosamine, the first polymeric monomer and the fifth polymeric monomer are connected through beta-1, 3-glycosidic bonds to form a first repeating unit which is a repeating unit of hyaluronic acid, and the repeating units are connected through beta-1, 4-glycosidic bonds; therefore, the polymer raw material is hyaluronic acid and has excellent biocompatibility; the specific structure of the repeating unit of hyaluronic acid is as follows:
Figure BDA0003085784350000082
the method comprises the following steps of (1) enabling hyaluronic acid to react through oxidation to enable part of first polymerization monomers to be subjected to ring-opening hydroformylation to form second polymerization monomers, wherein the formed hydroformylation polymer has the following structure:
Figure BDA0003085784350000091
and further carrying out Schiff base reaction with dopamine to graft part of the second polymeric monomer and the dopamine by imine bonds to form a third polymeric monomer, wherein the formed graft polymer has the following structure:
Figure BDA0003085784350000092
finally, reduction reaction is carried out to reduce the imine bond of part of the third polymerization monomer to form a fourth polymerization monomer, and the formed reduction graft polymer has the following structure:
Figure BDA0003085784350000093
it should be noted that, in the above structural formula, the third polymerized monomer and the fourth polymerized monomer are represented by a structure in which both the carbons at the 2-position and the 3-position are grafted with dopamine, but a structure in which one of the carbons at the 2-position and the 3-position is grafted with dopamine should also exist, and the number of repeating units d formed by the third polymerized monomer and the fifth polymerized monomer and the number of repeating units c formed by the fourth polymerized monomer and the fifth polymerized monomer should actually be the number converted into the structure according to the substitution of dopamine.
On the basis that the oxidant selectively breaks the adjacent dihydroxy in the hyaluronic acid polymerization monomer and all aldehyde groups are formed, the repetition number of the polymerization unit in the polymer is theoretically related as follows: n is x + y; x is a + b; a is c + d.
In the preparation process of the polymer, the proportion of the four repeating units can be changed by adjusting the chemical reaction conditions, and then the adhesive with different adhesive properties and degradation properties can be obtained subsequently. Specifically, the use amount and the use type of the medicines (such as dopamine hydrochloride, an oxidant and a reducing agent) used in the 3 chemical reaction processes of hydroformylation, dopamine grafting and imine bond reduction can be regulated and controlled, so that products with function difference can be obtained; the time of the reaction may also be varied.
According to another embodiment of the present invention, the reducing agent is sodium cyanoborohydride, and step S3 includes: dissolving the dopamine grafted hyaluronic acid in a phosphate buffer solution with the pH value of 5.0, adding sodium cyanoborohydride, reacting at 25 ℃ for 4-6 hours, purifying and drying; wherein the mass ratio of the dopamine grafted hyaluronic acid to the sodium borohydride is 1: 0.5-1.
Specifically, in the imine bond reduction step, when different reducing agents are used, because different reducing efficiencies will result in chemically modified products of different reduction degrees, wherein the sodium cyanoborohydride reducing agent is a very common and efficient reducing agent, and the sodium cyanoborohydride provides the activity of cyano groups for weakening boron hydrogen bonds, so that the sodium cyanoborohydride selectively reduces the schiff base; suitable for the imine bond reduction step of the present invention. And the reduction process parameters can be changed to adjust the reduction degree of the imine bond so as to control the degradation time. After the reaction is finished, the purification step can be membrane separation, precipitation, column chromatography and the like, and the drying step can be freeze drying, spray drying and the like.
According to another embodiment of the present invention, in step S3, the reduction rate of the imine bond is 40-65%.
When the reduction rate reaches the above ratio range, the tissue adhesive is superior in both the adsorption property and the degradation time.
According to another embodiment of the present invention, in step S3, the purification method comprises loading the reaction solution after the reaction into a dialysis membrane with molecular weight cutoff of 8000-14000Da, dialyzing with ultrapure water for 1-3 days, and drying to freeze-dry.
Specifically, the selected purification method is membrane separation, and the drying method is freeze drying, so that the separation and purification process is efficient and environment-friendly, and the reduction graft polymer is prevented from chemical change.
According to another embodiment of the invention, the oxidizing agent is sodium periodate; step S1 includes: dissolving the polymer in phosphate buffer solution with pH value of 5.0, adding sodium periodate, reacting at 25 deg.C in dark for 4-6 hr, adding glycol to react for terminating reaction (wherein the glycol can react with sodium periodate not participating in reaction), purifying, and freeze drying to obtain the aldehyde-base polymer. Step S2 includes: dissolving the aldehyde polymer in phosphate buffer solution with the pH value of 5.0, adding dopamine hydrochloride, reacting for 10-14 hours at 25 ℃, purifying, freezing and drying to obtain the dopamine graft polymer. Wherein the mass ratio of the polymer to the sodium periodate is 1: 0.3-0.6; the mass ratio of the aldehyde polymer to the dopamine hydrochloride is 1: 0.5-1.
The invention selects sodium periodate as an oxidant, the sodium periodate can selectively break the adjacent dihydroxy or the adjacent trihydroxy in the polysaccharide monomer to generate corresponding polysaccharide aldehyde, for example, the monomer D-glucuronic acid, alginic acid monomer and chitosan monomer of hyaluronic acid can be subjected to ring-opening hydroformylation between 2 and 3 carbon atoms under the oxidation of the sodium periodate. And the reduction process parameters can be changed to adjust the hydroformylation rate and the molar substitution degree of dopamine so as to control the adhesion performance.
According to another embodiment of the present invention, in step S1, the hydroformylation rate of hyaluronic acid is 75 to 90%; in step S2, the molar substitution degree of dopamine is 0.35 to 0.65.
When the molar substitution degree of dopamine in the reduction graft polymer reaches the proportion range, the wet adhesion performance of the dopamine serving as a tissue adhesive is good, and when the reduction rate reaches the proportion range, the degradation time is long; the test proves that the adhesion strength of the obtained tissue adhesive can be more than 25kPa, and the degradation time can reach 8 days or more. The hydroformylation rate and the molar substitution degree and reduction rate of dopamine can be detected by nuclear magnetic resonance spectroscopy (NMR), and can be detected by a German Bruker AMX400M nuclear magnetic instrument1H-NMR was scanned for detection.
According to another embodiment of the present invention, the preparation method further comprises: s4: reducing the graft polymer to prepare aqueous solution, adding a cross-linking agent for cross-linking reaction to obtain the tissue adhesive hydrogel.
Specifically, the tissue adhesive is in a hydrogel state, the reduced graft polymer is prepared into an aqueous solution, a cross-linking agent is added into the aqueous solution, and the hydrogel is generated through cross-linking, wherein the mass percentage concentration of the reduced graft polymer is 2-25%, and the reduced graft polymer contains a catechol structure, so that the reduced graft polymer can be cross-linked to form the hydrogel in the presence of the cross-linking agent sodium periodate, ferric ions and the like, and the cross-linking agent can also be a photoinitiator; but the adhesive properties of the gels formed by different oxidizing agents vary.
According to another embodiment of the present invention, the aqueous solution of the polymer has a concentration of 5 to 10% by mass; the cross-linking agent comprises sodium periodate aqueous solution with the mass percentage concentration of 2.5-10%; the volume ratio of the aqueous solution of the polymer to the aqueous solution of the sodium periodate in the crosslinking reaction is 1:1, and the reaction time is 20 to 40 seconds.
The polymer can be quickly crosslinked to form hydrogel under the oxidation of sodium periodate, and the mechanism of the hydrogel is probably that catechol of dopamine in the polymer is connected with each other to form the hydrogel. And the gel formed by using the sodium periodate as a cross-linking agent has better performance.
Hereinafter, a preferred process for preparing a tissue adhesive using hyaluronic acid as a raw material will be described with reference to specific examples, but the present invention is not limited thereto.
Example 1
1. Preparation of aldehyde hyaluronic acid
Dissolving 1.0g of hyaluronic acid in phosphate buffer solution (PBS buffer solution) with the pH value of 5.0, adding 0.4g of sodium periodate, reacting for 5 hours at 25 ℃ in a dark condition, and finally adding ethylene glycol, wherein the ethylene glycol reacts with the sodium periodate which does not participate in the reaction, thereby terminating the oxidation reaction. After the reaction is finished, the reaction solution is filled into a dialysis membrane (the molecular weight cutoff is 8000- ­ 14000Da) and dialyzed for two days by ultrapure water, and the aldehyde hyaluronic acid solid is obtained by freeze drying.
Taking a proper amount of aldehyde group hyaluronic acid solid sample, dissolving the aldehyde group hyaluronic acid solid sample in heavy water, and then performing reaction by using a nuclear magnetic instrument1H-NMR scanning is carried out to detect the substitution degree of aldehyde groups. The detection proves that the hydroformylation rate is 80%.
2. Preparation of dopamine grafted hyaluronic acid by Schiff base reaction
Dissolving 1.0g of the aldehyde hyaluronic acid solid obtained in the step 1 in a phosphate buffer solution with the pH value of 5.0, adding 0.5g of dopamine hydrochloride, and reacting at 25 ℃ for 12 hours. After the reaction is finished, the reaction solution is filled into a dialysis membrane (the molecular weight cutoff is 8000-.
Taking a proper amount of dopamine grafted hyaluronic acid solid sample, dissolving the dopamine grafted hyaluronic acid solid sample in heavy water, and then performing with a nuclear magnetic instrument1H-NMR scans to determine the degree of dopamine molar substitution. The molar substitution degree of dopamine is detected to be 0.35.
3. Reduction of dopamine grafted aldehydized hyaluronic acid
Dissolving 1.0g of the dopamine grafted hyaluronic acid obtained in the step 2 in phosphate buffer solution (PBS buffer solution) with the pH value of 5.0, then using 0.5g of sodium cyanoborohydride to selectively reduce Schiff base, reacting for 4h at 25 ℃, after the reaction is finished, filling the reaction solution into a dialysis membrane (the molecular weight cutoff is 8000-.
Taking a proper amount of partially reduced dopamine grafted hyaluronic acid solid sample, dissolving the partially reduced dopamine grafted hyaluronic acid solid sample in heavy water, and then performing reaction by using a nuclear magnetic instrument1H-NMR scans were performed to check the reduction rate. The Schiff base reduction rate is 40% by detection.
4. Preparation of the adhesive
And (3) taking 1.0g of the reduced dopamine grafted hyaluronic acid solid obtained in the step (3), preparing a solution with the solubility of 5% by mass by using deionized water, preparing a sodium periodate solution with the solubility of 2.5% by mass, mixing in equal volume, standing for 30s, and quickly crosslinking to obtain the tissue adhesive.
Example 2
The preparation method comprises the following steps of referring to example 1, except that in the preparation of the aldehyde hyaluronic acid in the step 1, 0.5g of sodium periodate is added, the reaction time is 4 hours, and the aldehyde rate is 80%; step 2, adding 0.6g of dopamine hydrochloride into the dopamine grafted hyaluronic acid prepared by Schiff base reaction for 10 hours to ensure that the molar substitution degree of dopamine is 0.35; step 3, during reduction of the dopamine grafted aldehyde hyaluronic acid, adding sodium cyanoborohydride for reaction for 5 hours, wherein the Schiff base reduction rate is 43%; in the step 4, in the preparation of the adhesive, the solid of the reduced dopamine grafted hyaluronic acid is prepared into a solution with the solubility of 8 percent by mass, the solubility of the prepared sodium periodate solution is 5 percent by mass, and the standing time is 40 s.
Example 3
The preparation method comprises the following steps of referring to example 1, except that in the preparation of the aldehyde hyaluronic acid in the step 1, 0.5g of sodium periodate is added, the reaction time is 6 hours, and the aldehyde rate is 85%; step 2, adding 0.7g of dopamine hydrochloride into the dopamine grafted hyaluronic acid prepared by Schiff base reaction for 13 hours to ensure that the molar substitution degree of dopamine is 0.5; step 3, during reduction of the dopamine grafted aldehyde hyaluronic acid, adding 0.75g of sodium cyanoborohydride, wherein the reaction time is 5h, and the Schiff base reduction rate is 50%; in the step 4, in the preparation of the adhesive, the dopamine grafted hyaluronic acid solid is prepared into a solution with the mass solubility of 5%, and the standing time is 20 s.
Example 4
The preparation method comprises the following steps of referring to example 1, except that in the preparation of the aldehyde hyaluronic acid in the step 1, 0.3g of sodium periodate is added, the reaction time is 5 hours, and the aldehyde rate is 75%; step 2, adding 0.8g of dopamine hydrochloride into the dopamine grafted hyaluronic acid prepared by Schiff base reaction for 12 hours to ensure that the molar substitution degree of dopamine is 0.5; step 3, during reduction of the dopamine grafted aldehyde hyaluronic acid, adding 0.6g of sodium cyanoborohydride, wherein the reaction time is 6 hours, and the Schiff base reduction rate is 50%; in the step 4, in the preparation of the adhesive, the dopamine grafted hyaluronic acid solid is prepared into a solution with 10% mass solubility, the mass percent solubility of the prepared sodium periodate solution is 5%, and the standing time is 30 s.
Example 5
The preparation method comprises the following steps of referring to example 1, except that in the preparation of the aldehyde hyaluronic acid in the step 1, 0.6g of sodium periodate is added, the reaction time is 5 hours, and the aldehyde rate is 90%; step 2, adding 0.9g of dopamine hydrochloride into the dopamine grafted hyaluronic acid prepared by Schiff base reaction for 14 hours to ensure that the molar substitution degree of dopamine is 0.65; and 3, in the reduction of the dopamine grafted aldehyde hyaluronic acid, adding 0.8g of sodium cyanoborohydride, reacting for 6 hours, wherein the Schiff base reduction rate is 62%.
Example 6
The preparation method comprises the following steps of referring to example 1, except that in the preparation of the aldehyde hyaluronic acid in the step 1, 0.5g of sodium periodate is added, the reaction time is 6 hours, and the aldehyde rate is 90%; step 2, adding 1.0g of dopamine hydrochloride into the dopamine grafted hyaluronic acid prepared by Schiff base reaction, wherein the reaction time is 12 hours, so that the molar substitution degree of dopamine is 0.65; step 3, during reduction of the dopamine grafted aldehyde hyaluronic acid, adding 1.0g of sodium cyanoborohydride, wherein the reaction time is 5h, and the Schiff base reduction rate is 65%; in the step 4, in the preparation of the adhesive, the dopamine grafted hyaluronic acid solid is prepared into a solution with 5% mass solubility, the mass percent solubility of the prepared sodium periodate solution is 10%, and the standing time is 40 s.
The tissue adhesives obtained in examples 1 to 6 were subjected to the following property measurements:
(1) adhesion strength test:
the on-board shear strength test was performed at room temperature using a universal materials tester (Instron 5848) by simulating the organism tissue with fresh pig skin, with reference to ASTM F2255-05 test standards. The specific operation is as follows: fresh pigskin was carefully scraped to remove the surface fat layer, cut into strips of 2cm in width and 6cm in length, and moistened with Phosphate Buffered Saline (PBS) at pH 7.4. For testing, one pig skin was coated with 0.2mL of the dopamine-grafted, formylated hyaluronic acid solution of the example solubility at the front end, while another pig skin was coated with 0.2mL of the sodium periodate/sodium hydroxide solution of the example solubility at the front end (pH 8.0-9.0), and the length of the coated area on the surface of the pig skin was 1 cm. Contacting two pigskins to form a 1X 2cm2While pressing with a 200g weight for 5 min. Tensile testing was performed using a universal material testing machine at a rate of 1 mm/min. Each set measures 5 replicates.
(2) And (3) testing the bursting pressure:
burst pressure testing was performed at room temperature with reference to ASTM F2392-04. The specific operation is as follows: fresh pigskin was taken and cut into 4X 4cm shape and the surface fat layer was carefully scraped off. A circular incision of 5mm diameter was made in the center of the pigskin with a scalpel and the pigskin was moistened with Phosphate Buffered Saline (PBS) pH 7.4. During testing, equal volumes of the dopamine-grafted hydroformylation hyaluronic acid solution and the alkaline sodium periodate solution with the solubility of the example are injected into the circular incision at the same time, and the blasting pressure test is carried out after the circular incision is kept still for 5 minutes. The pressure was continuously increased by injecting air at a rate of 5mL/min using an injector, the burst pressure was monitored in real time using a digital pressure gauge and data was read, and the maximum burst pressure was considered to be reached when the pressure value dropped. Each set measures 5 replicates.
(3) In vitro degradation performance testing:
the gel binders obtained in the examples were freeze-dried, weighed and recorded as m0. The dried gel was soaked in Phosphate Buffered Saline (PBS) at pH 7.4 containing hyaluronidase with a solubility of 0.125mg/mL at 37 ℃ for in vitro degradation testing. The gel was removed at the set time point, freeze dried and weighed to record the mass mx. At the same time, useFresh hyaluronidase buffer was replaced. The in vitro Degradation Rate (DR) is calculated as follows:
Figure BDA0003085784350000151
the test results are given in the following table:
examples Adhesive Strength (kPa) Burst pressure (kPa) Degradation time (Day)
1 25.1±2.9 20.2±2.1 8
2 35.6±4.8 24.7±3.1 9
3 42.1±4.4 38.8±2.4 11
4 55.8±3.9 49.3±3.9 10
5 67.7±5.3 55.2±4.9 12
6 76.5±4.7 63.8±2.9 13
As can be seen from the above table, the tissue adhesive prepared from hyaluronic acid has high adhesive strength and degradation performance. In addition, in the examples, from 1 to 6, the molar substitution degree of dopamine is gradually increased, and the adhesion strength of the obtained tissue adhesive is also gradually increased; and the reduction degree of the Schiff base is increased, the stability of the tissue adhesive is enhanced, and the degradation time is prolonged. The invention can realize controllable degradation time of the tissue adhesive by adjusting the content of the repeating unit.
The foregoing is a more detailed description of the present invention that is presented in conjunction with specific embodiments, and the practice of the invention is not to be considered limited to those descriptions. For those skilled in the art to which the invention pertains, several simple deductions or substitutions can be made without departing from the spirit of the invention, and all shall be considered as belonging to the protection scope of the invention.

Claims (10)

1. A method of preparing a biological tissue adhesive, the method comprising:
s1: taking a polymer as a raw material, and carrying out oxidation reaction in the presence of an oxidant to obtain an aldehyde-based polymer, wherein C-C bonds on at least part of first polymeric monomers in the polymer are broken to generate second polymeric monomers with dialdehyde structures; wherein the content of the first and second substances,
the first polymerized monomer has the following structural formula:
Figure FDA0003085784340000011
wherein R is2Is OH or NH2；
The structural formula of the second polymeric monomer is as follows:
Figure FDA0003085784340000012
s2: performing a grafting reaction on the hydroformylation polymer and dopamine to obtain a dopamine grafted polymer, wherein at least part of the second polymeric monomer and dopamine undergo Schiff base reaction to generate a third polymeric monomer, and the structure of the third polymeric monomer is that at least one of two aldehyde groups of the second polymeric monomer is replaced by an imine bond to be connected with the dopamine;
s3: adding a reducing agent into the solution of the dopamine graft polymer, and obtaining a reduction graft polymer under the catalysis of the reducing agent, wherein at least part of imine bonds of the third polymerization monomer are reduced into C-N bonds to generate a fourth polymerization monomer.
2. The method of claim 1, wherein R in the polymer is R1Is COOH, CH2OH、CH2OCH2One kind of COOH.
3. The method of preparing a biological tissue adhesive according to claim 2, wherein R in the polymer is1Is COOH, R2Is OH; and the polymer further comprises a fifth polymerized monomer having the formula:
Figure FDA0003085784340000021
and the fifth polymerization monomer is respectively connected with the first polymerization monomer, the second polymerization monomer, the third polymerization monomer and the fourth polymerization monomer to form the repeating unit of the reduction graft polymer.
4. The method of preparing a biological tissue adhesive according to claim 3, wherein the reducing agent is sodium cyanoborohydride, and the step S3 includes:
dissolving dopamine grafted hyaluronic acid in phosphate buffer solution with the pH value of 5.0, adding the sodium cyanoborohydride, reacting for 4-6 hours at 25 ℃, purifying and drying;
wherein the mass ratio of the dopamine grafted hyaluronic acid to the sodium borohydride is 1: 0.5-1.
5. The method of claim 4, wherein in the step S3, the reduction rate of the imine bond is 40-65%.
6. The method for preparing the biological tissue adhesive according to claim 4, wherein in the step S3, the purification method comprises loading the reaction solution after the reaction into a dialysis membrane with a molecular weight cutoff of 8000-14000Da, and dialyzing with ultrapure water for 1-3 days, and the drying is freeze-drying.
7. The method of preparing a biological tissue adhesive according to any one of claims 3 to 6, wherein the oxidizing agent is sodium periodate;
the step S1 includes: dissolving the polymer in a phosphate buffer solution with the pH value of 5.0, adding sodium periodate, reacting for 4-6 hours at 25 ℃ in a dark place, finally adding ethylene glycol to react to terminate the reaction, purifying, and freeze-drying to obtain an aldehyde-based polymer;
the step S2 includes: dissolving the aldehydized polymer in a phosphate buffer solution with the pH value of 5.0, adding dopamine hydrochloride, reacting for 10-14 hours at 25 ℃, purifying, and freeze-drying to obtain a dopamine grafted polymer;
wherein the mass ratio of the polymer to the sodium periodate is 1: 0.3-0.6; the mass ratio of the aldehyde polymer to the dopamine hydrochloride is 1: 0.5-1.
8. The method of preparing the biological tissue adhesive according to claim 7, wherein in the step S1, the aldehyde formation rate of the hyaluronic acid is 75 to 90%; in the step S2, the molar substitution degree of dopamine is 0.35 to 0.65.
9. The method of preparing a biological tissue adhesive according to any one of claims 1 to 6, further comprising:
s4: the reduction graft polymer is prepared into aqueous solution, and crosslinking agent is added for crosslinking reaction to obtain the tissue adhesive hydrogel.
10. The method of claim 9, wherein the aqueous solution of the reduced graft polymer has a concentration of 5 to 10% by mass; the cross-linking agent comprises sodium periodate aqueous solution with the mass percentage concentration of 2.5-10%; the volume ratio of the aqueous solution of the polymer to the aqueous solution of the sodium periodate in the crosslinking reaction is 1:1, and the reaction time is 20-40 seconds.
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