CN115414521A - Bi-component biological glue and application thereof - Google Patents
Bi-component biological glue and application thereof Download PDFInfo
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- CN115414521A CN115414521A CN202210925408.4A CN202210925408A CN115414521A CN 115414521 A CN115414521 A CN 115414521A CN 202210925408 A CN202210925408 A CN 202210925408A CN 115414521 A CN115414521 A CN 115414521A
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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
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
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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
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0042—Materials resorbable by the body
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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
- A61L24/08—Polysaccharides
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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
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08H—DERIVATIVES OF NATURAL MACROMOLECULAR COMPOUNDS
- C08H1/00—Macromolecular products derived from proteins
Abstract
The invention discloses bi-component biological glue and application thereof. The bi-component biological glue comprises methacrylamide gelatin, oxidized hyaluronic acid, a photoinitiator and a solvent. Oxidizing and modifying hyaluronic acid to obtain oxidized hyaluronic acid containing active aldehyde groups. Double bonds of the methacrylic groups are broken and re-linked under the irradiation of ultraviolet light to form a first-stage crosslinking network; the aldehyde group can react with amino group in biological tissue to generate stable Schiff base structure to form a second-level cross-linked network. The invention obviously improves the adhesion performance of the bi-component biological glue through the double-crosslinked network, has good light transmittance, water-containing property and biocompatibility, is gradually biodegraded in the using process, and can be used for conjunctival injury repair in the medical field.
Description
Technical Field
The invention belongs to the field of biological glue, and particularly relates to bi-component biological glue and application thereof.
Background
Suturing after surgery is time and energy consuming, and suturing after conjunctival surgery often causes various complications including but not limited to suture erosion, infiltration, infection, wound separation and even dehiscence, which places a great burden on patients and society. The biological glue has been rapidly developed as a non-invasive technology, not only solves the defects of suture, but also has the characteristics of strong wound shape adaptability, low infection rate, quick postoperative recovery and the like, shortens the operation and hospitalization time, and reduces the occurrence of complications.
In recent years, the biological glue hydrogel has attracted much attention because of its advantages of convenient operation, strong plasticity, capability of providing a microenvironment suitable for cell proliferation and differentiation, gradual degradation in the process of wound repair, and the like. The existing clinical biological glue has few varieties, generally adopts a single chemical crosslinking mode to adhere tissues, and has the disadvantages of poor mechanical property, low adhesion strength, short retention time and poor biological safety. Sharifi et al prepared gelatin-based bioadhesives using epoxy ring opening reaction and visible light crosslinking, but the preparation process was complicated and the adhesion was low (Sharifi S, islam M, sharifi H, et al., tuning gel-based hydrogel adhesives [ J ] Bioactive materials,2021,6 (11): 3947-3961.). Chinese patent No. CN113087819A provides a double-modified compound and a preparation method thereof, specifically, hyaluronic acid molecules or chondroitin sulfate molecules are used as basic skeletons to carry out hydroformylation and methacrylation double modification, but the hydrogel has single component, complex preparation and unknown adhesion capability.
Therefore, the existing biological glue has the main problem of weak bonding, and how to provide the biological glue with good adhesion stability and biocompatibility is a technical problem to be solved by those skilled in the art.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a two-component biological glue and application thereof, wherein the two-component biological glue is applied to treating conjunctival injury and aims to solve the problems of weak adhesion and biological safety of the existing biological glue.
The purpose of the invention is realized by the following technical scheme.
A bi-component biological glue comprises methacrylamide gelatin, oxidized hyaluronic acid, a photoinitiator and a solvent.
Preferably, the mass concentration of the oxidized hyaluronic acid in the two-component biological glue is 10-40mg/mL, and more preferably 20mg/mL.
Preferably, the mass concentration of the methacrylamide gelatin in the two-component biological glue is 50-150mg/mL, and more preferably 100mg/mL.
Preferably, the mass concentration of the photoinitiator in the two-component biological glue is 1-5mg/mL, and more preferably 1mg/mL.
Preferably, the grafting ratio of the methacrylamide gelatin is 85% -95%.
Preferably, the aldehyde group oxidation rate of the oxidized hyaluronic acid is 5% -15%.
Preferably, the methacrylamido gelatin has the following structural formula:
preferably, the oxidized hyaluronic acid has the following structural formula:
preferably, the photoinitiator is 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone; the solvent is an inorganic salt solvent; the inorganic salt solvent is PBS or water.
The application of the bi-component biological glue in preparing the preparation for treating conjunctival injury is disclosed.
The preparation method of the bi-component biological glue comprises the following steps:
(1) Adding gelatin powder and water into a reaction container, and heating for dissolving to obtain gelatin solution;
(2) Under the alkaline condition, adding methacrylic anhydride into the gelatin solution, heating and reacting in a dark place, dialyzing until the solution is colorless and transparent, and freeze-drying to obtain methacrylamido gelatin;
(3) Adding hyaluronic acid powder and water into a reaction container, and heating and dissolving to obtain a hyaluronic acid solution;
(4) Adding sodium periodate into the hyaluronic acid solution, reacting for 1-4h at room temperature in a dark condition, adding ethylene glycol to stop the reaction, dialyzing until the solution is odorless, colorless and transparent, and freeze-drying to obtain oxidized hyaluronic acid;
(5) And adding the methacrylamide gelatin, the oxidized hyaluronic acid, the photoinitiator and water into a reaction vessel for dissolving to obtain the bi-component biological glue.
Preferably, the step (1) is specifically: adding 5-10g of gelatin powder and 100-500g of water into a reaction vessel, and magnetically stirring and dissolving under heating to clarify to obtain a gelatin solution.
Further preferably, the gelatin is type a, 240 grams jelly strength (BLOOM value).
Preferably, the step (2) is specifically: adjusting the pH value of the gelatin solution to 7.5-8.5, adding 4-10mL of methacrylic anhydride, maintaining the pH value of the solution to 7.5-8.5, continuously stirring under dark magnetic force at the temperature of 20-40 ℃ for reaction for 2-5 hours, putting the reactant into a dialysis bag, dialyzing in water until the reactant is colorless and transparent, and freeze-drying to obtain the gelatin solution.
Further preferably, the dialysis bag has a molecular weight cut-off of 8 to 14 kilodaltons.
Preferably, the step (3) is specifically: adding 1-5g of hyaluronic acid powder and 100-500g of water into a reaction container, and magnetically stirring and dissolving under heating until the solution is clear and transparent to obtain a hyaluronic acid solution.
Further preferably, the hyaluronic acid powder has a molecular weight cut-off of 1-2 million daltons.
Preferably, the step (4) is specifically: adding 0.01-0.1mol of sodium periodate into the hyaluronic acid solution, reacting for 1-4h under magnetic stirring at room temperature in the dark, adding 10-30mL of ethylene glycol to stop the reaction, putting the reactant into a dialysis bag, dialyzing in water at 30-60 ℃ until the reactant is odorless, colorless and transparent, and freeze-drying to obtain the oxidized hyaluronic acid.
The bi-component biological glue takes gelatin molecules as basic components, and methacrylic acid molecules are grafted on the gelatin molecules to obtain methacrylamido gelatin; takes hyaluronic acid as another basic component, and modifies aldehyde groups on the hyaluronic acid molecules to obtain oxidized hyaluronic acid. On one hand, the two basic components adopted by the invention are gelatin and hyaluronic acid, which have good biocompatibility, biodegradability, high biological safety and wide application; on the other hand, the bi-component biological glue disclosed by the invention contains a methacrylic group and an aldehyde group, wherein the methacrylic group is photosensitive, the gel is formed by a chemical reaction under the irradiation of ultraviolet light to form a first-stage cross-linked network, then the aldehyde group can generate a chemical reaction with amino groups in biological tissues to generate a stable Schiff base structure, the second-stage cross-linked network is adopted, the adhesion performance of the bi-component biological glue is remarkably improved through the bi-cross-linked network, and the bi-component biological glue has good optical permeability, water-containing property and biocompatibility, is gradually biodegraded in the using process, and can be used for conjunctival injury repair in the medical field.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The basic components of the biological glue are methacrylamide-based glue and oxidized hyaluronic acid, so that the biological glue has good biocompatibility, is safe and nontoxic, and can be biodegraded.
(2) The biological glue has high bonding strength. After the methacrylamide gelatin-oxidized hyaluronic acid aqueous solution is added with a photoinitiator, aldehyde groups can react with amino groups in biological tissues to generate chemical bonds so as to be adhered to the tissues; the methacrylic group is subjected to a crosslinking reaction under the irradiation of ultraviolet light to form a hydrogel structure; the two-stage cross-linked network can increase the overall mechanical strength of the biological glue to ensure better adhesion; the purposes of adhering tissues and protecting wounds are achieved.
(3) The biological glue disclosed by the invention is simple in component, convenient and easy to use. The methacrylamido gelatin-oxidized hyaluronic acid aqueous solution is in a liquid form before being irradiated by ultraviolet light, and is easy to coat and spread on irregular tissue surfaces. The double-network crosslinking can be realized only by adding a small amount (less than 0.5%) of photoinitiator into the aqueous solution, and the use is convenient and efficient.
Drawings
FIG. 1 is a schematic diagram of the synthesis of methacrylamido gelatin according to example 1 of the present invention.
FIG. 2 is a schematic diagram of the synthesis of aldehyde-modified hyaluronic acid according to example 2 of the present invention.
FIG. 3 is a nuclear magnetic resonance spectrum of the gelatin and methacrylamido gelatin of example 1 of the present invention, and 5.4 to 5.6ppm are characteristic absorption peaks of Methacrylate (MA).
FIG. 4 is a nuclear magnetic resonance spectrum of hyaluronic acid and oxidized hyaluronic acid of example 2 of the present invention, and 4.1ppm is an aldehyde group characteristic absorption peak.
Fig. 5 is a graph showing the results of the light transmittance test of the bio-glue of example 3 of the present invention.
FIG. 6 is a graph showing the water content test result of the bio-glue of example 3 of the present invention.
FIG. 7 is a graph showing the results of the shear test of the biogel of example 3 of the present invention.
FIG. 8 is a graph showing the results of the adhesion test of the biogel of example 3 of the present invention.
Fig. 9 is a graph showing the good repairing effect of the biological glue of the embodiment 3 of the invention in the animal body.
Fig. 10 is a graph of the results of shear testing of the three-component biogenic glue of comparative example 1 of the present invention and the G10OHA2 biogenic glue of example 3.
Fig. 11 is a graph of the results of the eye piercing burst pressure test of the three-component bio-glue of comparative example 1 and the G10OHA2 bio-glue of example 3 according to the present invention.
Detailed Description
The following provides a more detailed description of the present invention, with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1: synthesis of methacrylamido gelatin
Adding 100 g distilled water into 10g gelatin (type A, 240 g jelly strength (BLOOM value)) powder, and magnetically stirring and heating to 60 deg.C for dissolving to obtain clear solution; subsequently adjusting the pH value to 8 by using 1mol per liter (mol/L) of sodium hydroxide solution; then adding 4 ml of methacrylic anhydride, and maintaining the pH value of the solution at 8.5; continuously reacting for 5 hours at 35 ℃ by magnetic stirring in a dark place; then putting into dialysis bag (with molecular weight cut-off of 8-14 kilodalton), dialyzing in distilled water at 50 deg.C for 7 days in dark place, and replacing distilled water every 12 hr; and finally, collecting the solution in the dialysis bag, and freeze-drying to obtain the methacrylamido gelatin. The synthetic route of the methacrylamide gelatin is shown in figure 1.
FIG. 3 shows the NMR spectra of the methacrylamido gelatin and gelatin obtained in this example, and 5.4-5.6ppm are characteristic absorption peaks of Methacrylate (MA), indicating that methacrylamido gelatin has been successfully synthesized.
Example 2: synthesis of oxidized hyaluronic acid
Adding 100 g of distilled water into 1 g of hyaluronic acid (molecular weight of 1-2 million daltons), and magnetically stirring to dissolve until the mixture is clear and transparent; adding 0.02mol of sodium periodate, and magnetically stirring in a dark place to react for 1 hour at room temperature; adding 20 ml of glycol to stop the reaction; then dialyzing in distilled water for 3 days in a dialysis bag (3.5 kilodalton molecular weight cut-off), and replacing distilled water every 12 hours; and finally, collecting the solution in the dialysis bag, and freeze-drying to obtain the oxidized hyaluronic acid. The synthetic route of the oxidized hyaluronic acid is shown in figure 2.
FIG. 4 is a nuclear magnetic resonance spectrum of the oxidized hyaluronic acid and hyaluronic acid obtained in this example, and 4.1ppm is an aldehyde group-specific absorption peak, showing that the oxidized hyaluronic acid was successfully synthesized.
Example 3: preparation of photo-curable methacrylamido gelatin-oxidized hyaluronic acid aqueous solution
I2959 solution: 100mg of 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone were dissolved in 100ml of purified water.
10G of the methacrylamido-based gelatin synthesized in example 1 and 0, 1, 2, 3, 4G of the oxidized hyaluronic acid synthesized in example 2 were dissolved in 100ml of I2959 solution to obtain a series of biological glues, which were designated as G10, G10OHA1, G10OHA2, G10OHA3, G10OHA4, respectively.
Fig. 5 is a graph showing the results of the light transmittance test of the bio-glue of example 3 of the present invention. In the visible light range, the light transmittance of the biological glue is over 95 percent. FIG. 6 is a graph showing the water content test result of the bio-glue of example 3 of the present invention. The equilibrium water content is below 30%, and the proper water content ensures the good adhesion of the biological glue. FIG. 7 is a graph showing the results of the shear force test of the bio-glue obtained in the present example. FIG. 8 is a graph showing the results of the adhesion test of the biogel obtained in the present example. It can be seen that the shear force and adhesion performance of the bio-glue obtained in this example are significantly higher than those of the commercial Fibrin glue (Fibrin glue). By screening, G10OHA2 had the best shear and adhesion properties. Fig. 9 is a graph showing the good repairing effect of the G10OHA2 biological glue obtained in the present example in the animal body. Within one month of conjunctival defect repair, the G10OHA2 biological glue firmly fixes the conjunctival stent at the wound without obvious irritation and inflammation, and the appearance and the structure of the regenerated conjunctiva are similar to those of normal tissues.
Comparative example 1: preparation of light-curable methacrylamide gelatin-oxidized hyaluronic acid-acrylic anhydride grafted sodium alginate aqueous solution
Acrylic anhydride grafted sodium alginate: dissolving 1mmol of sodium alginate in 100ml of deionized water, then adding a mixture of 15mmol of adipic dihydrazide, 3mmol of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) and 3mmol of N-hydroxysuccinimide (NHS), adjusting the pH to 5 and maintaining for 6h, then stirring at room temperature for reaction for 36h, dialyzing for 4 days (with the permeation molecular weight of 8000-14000 Da), and freeze-drying to obtain the acrylic anhydride grafted sodium alginate.
10g of methacrylamido gelatin synthesized in example 1 was dissolved in deionized water to give a 15% solution, the oxidized hyaluronic acid synthesized in example 2 was dissolved in deionized water to give a 10% solution, and acrylic anhydride-grafted sodium alginate was dissolved in deionized water to give a 15% solution. According to the mass ratio of the methacrylamido gelatin solution: oxidized hyaluronic acid solution: the acrylic anhydride grafted sodium alginate solution is mixed according to the volume ratio of 2 to 1 to prepare the three-component biological glue (G2 OHA1A 1). Adding a photoinitiator phenyl-2, 4, 6-trimethylbenzoyl lithium phosphinate (LAP) accounting for 3 percent of the mass of the acrylic anhydride grafted natural polymer (acrylic anhydride grafted sodium alginate) in the three-component biological glue.
Fig. 10 is a graph of the results of the shear test of the three-component bio-glue and the G10OHA2 bio-glue obtained in example 3. Fig. 11 is a graph of the results of the eye piercing burst pressure test of the three-component bio-glue and the G10OHA2 bio-glue obtained in example 3. The experimental result shows that the adhesive strength of the G10OHA2 biological glue obtained in the example 3 is obviously higher than that of the three-component biological glue in the comparative example, and the G10OHA2 is a biological glue formula which has good adhesive capacity and is easy to prepare.
The invention firstly adopts methacrylic anhydride to perform condensation reaction with amino on gelatin to graft on the amino to form the methacrylamide gelatin. Sodium periodate is then used for oxidizing two hydroxyl groups (-OH) at the ortho positions on the hyaluronic acid into aldehyde groups (= O) to obtain oxidized hyaluronic acid. Finally forming the two-component biological glue. The photo-curable methacrylamido gelatin-oxidized hyaluronic acid aqueous solution prepared in embodiment 3 of the invention can be used for photo-curing reaction, and can trigger the photo-curing reaction within the wavelength range of 350-370nm for 10 seconds.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. The bi-component biological glue is characterized by comprising methacrylamide gelatin, oxidized hyaluronic acid, a photoinitiator and a solvent.
2. The two-component biological glue according to claim 1, wherein the mass concentration of the oxidized hyaluronic acid in the two-component biological glue is 10-40mg/mL.
3. The two-component biological glue according to claim 2, wherein the mass concentration of the oxidized hyaluronic acid in the two-component biological glue is 20mg/mL.
4. The two-component biogum according to any of claims 1 to 3, wherein the mass concentration of the methacrylamide-based gelatin in the two-component biogum is from 50 to 150mg/mL.
5. The two-component biological glue according to claim 4, wherein the mass concentration of the methacrylamide-based gelatin in the two-component biological glue is 100mg/mL.
6. The two-component biogum according to any of claims 1 to 3, wherein the mass concentration of the photoinitiator in the two-component biogum is from 1 to 5mg/mL.
7. The two-component biogenic glue according to any one of claims 1 to 3, wherein the grafting ratio of the methacrylamido gelatin is from 85% to 95%.
8. The two-component biogenic glue according to any one of claims 1 to 3, wherein the aldehyde group oxidation rate of said oxidized hyaluronic acid is 5-15%.
9. The two-component biogenic glue according to any one of claims 1 to 3, wherein said photoinitiator is 2-hydroxy-2-methyl-1- [4- (2-hydroxyethoxy) phenyl ] -1-propanone; the solvent is PBS solution or water.
10. Use of a two-component biogenic glue according to any one of claims 1 to 9 for the preparation of a formulation for the treatment of conjunctival damage.
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