CN116099034A - Biological adhesive for ophthalmic surgery and application thereof - Google Patents
Biological adhesive for ophthalmic surgery and application thereof Download PDFInfo
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- CN116099034A CN116099034A CN202310271420.2A CN202310271420A CN116099034A CN 116099034 A CN116099034 A CN 116099034A CN 202310271420 A CN202310271420 A CN 202310271420A CN 116099034 A CN116099034 A CN 116099034A
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- bioadhesive
- gelatin
- gelma
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Images
Classifications
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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
- A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
- A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
- A61L24/0094—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing macromolecular fillers
-
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Materials Engineering (AREA)
- Engineering & Computer Science (AREA)
- Surgery (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Composite Materials (AREA)
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a biological adhesive for ophthalmic surgery, which consists of a main component and an auxiliary component, wherein the main component is a composite preparation of gelatin grafted with double bonds and aldehyde F127, the auxiliary component is riboflavin and L-arginine, and the transparent and tough biological adhesive based on modified gelatin and modified pluronic F127 can be applied to the technical field of ophthalmic surgery, such as conjunctival implantation adhesion, cornea lamellar implant adhesion, amniotic membrane implantation adhesion, cataract ocular surface adhesion and cornea defect repair adhesion. The adhesive has the characteristics of strong toughness, high cornea adhesiveness, good transparency, short operation time, low technical requirements on doctors and no foreign matter reaction, and the biological adhesive is used for replacing suture.
Description
Technical Field
The invention relates to the technical field of ophthalmic surgery, in particular to a biological adhesive for ophthalmic surgery and application thereof.
Background
Membrane grafting is a gold standard for treating vision impairment caused by corneal damage. Currently, both through-the-cornea and lamellar cornea transplants are used clinically to fix the transplanted cornea by suture surgery. However, the cornea suturing operation requires a high degree of skill, and there are complications such as erosion of suture, infiltration of suture site, infectious keratitis, loosening of suture and wound dehiscence, and wound dehiscence after removal, etc. there is a need to solve the above problems using bioadhesive.
Numerous studies and patents currently deal with bioadhesives, but most are not applicable to corneal surgery because of lack of adequate transparency. Chinese patent CN115554461a, publication No. 2023.01.03 discloses a preparation method and application of a highly transparent ophthalmic adhesive based on gelatin and dopamine, which relate to the technical field of ophthalmic surgery, and can be applied to adhesion after ocular surface surgery, in particular to adhesion of conjunctiva transplantation, adhesion of cornea lamellar implants, adhesion of amniotic membrane transplantation, ocular surface adhesion after cataract surgery or cornea defect repair adhesion. According to the method, the dopamine and the gelatin with high safety are selected, so that the potential virus infection risk of the existing blood-borne adhesive is avoided, the dopamine is dispersed on a gelatin chain in a double-bond free radical aggregation mode, the self-aggregation of the dopamine is avoided, the original transparent state of the gel is maintained while the viscosity is realized, the ultrahigh transparency is realized, and the vision of a patient is not influenced in the eye surgery process and the postoperative recovery process. Another chinese patent CN105597145a, publication No. 2016.05.25, discloses a retinal cell scaffold biological surgical adhesive and a method for preparing the same. It comprises laminin, type IV collagen, nidogen, human heparan sulfate glycoprotein, fibroblast growth factor, matrix metalloproteinase and phosphate buffer salt solution. The invention prepares the biological operation adhesive for the retina cell scaffold, and can be used for bonding the degradable human iPSCs source retina nerve scaffold (iRMP) with a host retina nerve layer, thereby providing guarantee for effective integration of the cell biological scaffold and the host retina.
Gelatin is an ideal macromolecule that stimulates cell attachment and growth as a polydisperse protein produced by irreversible hydrolysis of collagen fibers. Based on modified gelatin as a corneal adhesive or a corneal substitute, methacryloylated gelatin (GelMA) has received the most widespread use as a corneal substitute because of its controlled crosslinking under light, facilitating the preparation of in situ cured hydrogels, reported in literature (E.S.Sani, A.Kheirkhah, D.Rana, Z.Sun, W.Foulsham, A.Sheikhi, A.Khademhosseini, R.Dana, N.Annabi, sutureless repair of corneal injuries usingnaturally derived bioadhesive hydrogels, sci.adv.5 (2019), eaav 1281) and (I.A.Khalil, B.Saleh, D.M.Ibrahim, C.Jumelle, A.Yung, R.Dana, N.Annabi, cipro floxacin-loaded bioadhesive hydrogels for ocular applications, biomatter.sci.8 (2020) 5196), which exhibit a certain anchoring capacity on corneal tissue. However, considering the humidity of the surface of the eyeball and frequent external stimulation of the hydrogel caused by eye movement and blinking, the adhesion between GelMA and the corneal tissue is insufficient, and the mechanical strength of GelMA is poor, and it is fragile, so the corneal tissue adhesion of the GelMA-based bioadhesive needs to be further improved.
The biological adhesive for ophthalmic surgery and the application thereof have not been reported.
Disclosure of Invention
A first object of the present invention is to provide a bioadhesive for ophthalmic surgery, which addresses the deficiencies in the prior art.
A second object of the present invention is to provide the use of a bioadhesive.
In order to achieve the first object, the invention adopts the following technical scheme: a bioadhesive for ophthalmic surgery, said bioadhesive consisting of a set of a main component and an auxiliary component; the main component is a composite preparation of gelatin grafted with double bonds and aldehyde F127; the auxiliary components are riboflavin and L-arginine.
As a preferred example, the preparation of the bioadhesive comprises the steps of:
s1: synthesis of gelatin grafted with double bonds (GelMA): gelatin was completely dissolved in PBS buffer, methacrylic anhydride was then added, and the reaction was stopped after stirring for 2 to 3 hours. The reaction solution was dialyzed 10 times with a dialysis bag in which deionized water was replaced at a frequency of 2 hours/time. Filtering with a filter membrane after dialysis, and freeze-drying to obtain gelatin (GelMA) with grafted double bonds for later use;
s2: synthetic hydroformylation F127 (AF 127): f127 was dissolved in methylene chloride, and then pyridine and p-benzenesulfonyl chloride were added thereto to react at room temperature for 24 to 48 hours. The mixture was extracted with hydrochloric acid, the organic phase was washed with NaHCO3, recrystallized from tetrahydrofuran/diethyl ether mixed solvent and dried in vacuo to give the intermediate product. Dissolving the intermediate product in N, N-dimethylformamide, adding 4-hydroxybenzaldehyde and potassium carbonate, stirring at 80 ℃ for reaction for 48-72 hours, and cooling to room temperature. After adding water, the reaction solution was extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated, and precipitated in cold diethyl ether, filtered and dried in vacuo to give hydroformylation F127 (AF 127) for use;
s3: dissolving gelatin (GelMA) synthesized by S1 and aldehyde F127 (AF 127) synthesized by S2 in normal saline to form a composite preparation, namely obtaining a main component of the biological adhesive;
s4: and (3) adding the water-soluble riboflavin and the L-arginine serving as auxiliary components into the main component in the step (S3), and uniformly mixing to obtain the biological adhesive. .
More preferably, the mass-volume concentration of the gelatin (GelMA) grafted with double bonds in the step S1 is in the range of 5w/v% to 10w/v%; the mass volume concentration range of the hydroformylation F127 (AF 127) in the step S2 is 5-10 w/v%.
More preferably, the mass volume concentration of the gelatin (GelMA) grafted with double bonds in the step S1 is in the range of 10w/v%; in the step S2, the mass volume concentration range of the hydroformylation F127 (AF 127) is 5w/v%, and the light transmittance of GelMA (10 w/v%) +AF127 (5 w/v%) is the highest.
More preferably, the amino substitution degree of the gelatin (GelMA) grafted with double bond in the above step S1 ranges from 50% to 90% to ensure adhesive adhesiveness and self strength; the gelatin is heated to 37 ℃ during synthesis and then dissolved in physiological saline.
More preferably, the degree of hydroformylation of the hydroformylation F127 in the above step S2 is 100% to ensure adhesive adhesiveness and self-strength; the AF127 was dissolved in physiological saline at room temperature at the time of synthesis.
More preferably, the auxiliary component in step S4 needs to be preheated to 37 ℃ before being added, and the auxiliary component is turned upside down for several times to be uniformly dissolved, so as to form the final applied bioadhesive, and the upside down process should avoid air bubbles as much as possible.
More preferably, the mass volume fraction of the water-soluble riboflavin in the auxiliary component in step S4 in the binder system is 0.1w/v%; the amount in the L-arginine binder system is 0.4 times the mass of GelMA; the auxiliary components are fixed in composition.
In order to achieve the second purpose, the invention adopts the following technical scheme: the use of any of the above-described biological adhesives in ophthalmic surgical bonding, including, but not limited to, conjunctival graft bonding, corneal lamellar implant bonding, amniotic membrane graft bonding, cataract ocular surface bonding, and corneal defect repair bonding.
As a preferred example, the bioadhesive agent is preheated to 37 ℃ before application, is added dropwise to the implantation site, and after the implant is in place, is irradiated with ultraviolet light (365 nm,250 w) for 5-10 minutes at 10cm of the implantation area, preferably by irradiating for 5 minutes, intermittently for 1 minute, and then for 5 minutes.
The invention has the advantages that:
1. can be used to adhere corneal tissue and implants, the adhesion resulting from penetration between the adhesive and the corneal tissue in the liquid state and forming an interlocking network with the tissue after photocuring; while the aldehyde group of the aldehyde F127 is capable of forming a schiff base bond with the corneal tissue.
2. The adhesive of the present invention has high toughness and can resist great deformation, so that the biological adhesive is difficult to be destroyed by external force, and the adhesive force is further strengthened.
3. With optimized composition, the light transmission of the adhesive is higher than 90% without negatively affecting vision during treatment.
4. The photosensitizer in the auxiliary component is based on riboflavin, which is a drug used in cornea crosslinking technology commonly used in ophthalmic clinic, and is proved to be safe and reliable.
Drawings
FIG. 1 major components of the bioadhesive formulation.
FIG. 2 shows in vitro corneal tissue adhesion and self-toughness of bioadhesives.
FIG. 3 demonstrates the in vivo stability of a sticking and transplanted corneal implant (shaking the implant back and forth with a cotton swab).
Detailed Description
The invention is further described below in conjunction with the detailed description. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Further, it is understood that various changes and modifications of the present invention may be made by those skilled in the art after reading the description of the present invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
Example 1 preparation of an adhesive
A method for preparing an adhesive for use in seamless and corneal transplants, comprising the steps of:
s1, preparation of gelatin (GelMA) grafted with double bonds in a main component:
2g of gelatin was completely dissolved in 20mL of PBS buffer at 60℃and then 1.6mL of methacrylic anhydride was added thereto, followed by stirring for 2.5 hours, 80mL of PBS buffer was added thereto, and the reaction was stopped after continuing the reaction for 30 minutes. The reaction solution was dialyzed 10 times against deionized water at a frequency of 2 h/time with a dialysis bag having a molecular weight cutoff of 7000. Filtering with 0.22 μm filter membrane after dialysis, and freeze drying to obtain gelatin (GelMA) with grafted double bond;
s2, preparation of aldehyde F127 (AF 127) in a main component:
2g of F127 was dissolved in 15mL of methylene chloride, and then 5mg of pyridine and 0.1g of p-benzenesulfonyl chloride were added thereto, and the reaction was carried out at room temperature under anaerobic conditions for 24 hours. The mixture was extracted with hydrochloric acid and the organic phase was extracted with NaHCO 3 Washing, recrystallization from tetrahydrofuran/diethyl ether mixed solvent, and drying in vacuum to obtain intermediate product. The intermediate product was dissolved in N, N-dimethylformamide, excess 4-hydroxybenzaldehyde and potassium carbonate were added, reacted at 80 ℃ with stirring for 72 hours, and cooled to room temperature. After adding water, the reaction solution was extracted with dichloromethane. MgSO for organic layer 4 Dried, concentrated, and precipitated in cold diethyl ether, filtered, and dried in vacuo to give hydroformylation F127 (AF 127) ready for use. The degree of hydroformylation is 100%;
s3, preparing a composite preparation:
GelMA was dissolved in physiological saline at a mass volume concentration of 10w/v% at 37℃and AF127 was then dissolved in the above solution at a mass volume concentration of 5w/v%, to obtain the main component of the bioadhesive, as shown in FIG. 1. After photo-curing, the bioadhesive has extremely high corneal adhesiveness and self-toughness, and can withstand large deformations, as shown in fig. 2.
EXAMPLE 2 application of adhesive
S1: preparation of bioadhesive:
the main component was preheated to 37℃and the auxiliary component (water-soluble riboflavin (0.1 w/v%) and L-arginine (0.4 times the mass of GelMA in the main component)) was added to the main component, and the mixture was inverted several times and dissolved uniformly for use.
S2: cornea transplantation application (New Zealand white rabbit cornea transplantation):
cornea implant models and implants were made using a femtosecond laser system (Carl Zeiss Meditec) with a repetition rate of 500kHz, pulse energy of 230nJ, and a depth of approximately 2/3-3/4 cornea thickness. The diameter of the implant was set to 6.5 mm. The lamina is removed and ready for implantation, the recipient stromal bed is rinsed, and excess fluid on the corneal surface is wiped dry with a sponge. Then the biological adhesive is dripped on a matrix bed to be paved into a film. A donor graft of the appropriate thickness previously prepared with a femtosecond laser was mounted in place and excess pre-hydrogel was extruded from the interface and rubbed off with a sponge. The grafting area was irradiated with ultraviolet light (365 nm,250 w) for 5 minutes, followed by intermittent 1 minute and additional 5 minutes of irradiation. The eye drops of 0.5% levofloxacin and 1.0% prednisone acetate longan liquid were applied three times a day for one week as shown in figure 3.
S3: observation results:
the transplanted cornea can be stably attached to the stroma, and no obvious falling off occurs within 1 month; the degradation period of the adhesive is more than 4 weeks; the epithelialization degree is high.
The above description of the examples is provided to facilitate the understanding and application of the inventive method. Various modifications may be made on the basis of the present invention, and therefore, the present invention is not limited to the above-described embodiment, and those skilled in the art should, based on the present disclosure, make improvements and modifications within the scope of the present invention.
Claims (10)
1. A bioadhesive for ophthalmic surgery, said bioadhesive comprising a primary component and a secondary component; the main component is a composite preparation of gelatin grafted with double bonds and aldehyde F127; the auxiliary components are riboflavin and L-arginine.
2. The bioadhesive of claim 1, wherein the preparation of the bioadhesive comprises the steps of:
s1: synthesis of gelatin grafted with double bonds (GelMA): gelatin was completely dissolved in PBS buffer, methacrylic anhydride was then added, and the reaction was stopped after stirring for 2 to 3 hours. The reaction solution was dialyzed 10 times with a dialysis bag in which deionized water was replaced at a frequency of 2 hours/time. Filtering with a filter membrane after dialysis, and freeze-drying to obtain gelatin (GelMA) with grafted double bonds for later use;
s2: synthetic hydroformylation F127 (AF 127): f127 was dissolved in methylene chloride, and then pyridine and p-benzenesulfonyl chloride were added thereto to react at room temperature for 24 to 48 hours. The mixture was extracted with hydrochloric acid, the organic phase was washed with NaHCO3, recrystallized from tetrahydrofuran/diethyl ether mixed solvent and dried in vacuo to give the intermediate product. Dissolving the intermediate product in N, N-dimethylformamide, adding 4-hydroxybenzaldehyde and potassium carbonate, stirring at 80 ℃ for reaction for 48-72 hours, and cooling to room temperature. After adding water, the reaction solution was extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated, and precipitated in cold diethyl ether, filtered and dried in vacuo to give hydroformylation F127 (AF 127) for use;
s3: dissolving gelatin (GelMA) synthesized by S1 and aldehyde F127 (AF 127) synthesized by S2 in normal saline to form a composite preparation, namely obtaining a main component of the biological adhesive;
s4: and (3) adding the water-soluble riboflavin and the L-arginine serving as auxiliary components into the main component in the step (S3), and uniformly mixing to obtain the biological adhesive.
3. The bioadhesive according to claim 2, wherein the mass-volume concentration of the gelatin grafted with double bonds (GelMA) in step S1 is in the range of 5w/v% to 10w/v%; the mass volume concentration range of the hydroformylation F127 (AF 127) in the step S2 is 5-10 w/v%.
4. A bioadhesive according to claim 3, wherein the mass-volume concentration of the gelatin grafted with double bonds (GelMA) in step S1 is in the range of 10w/v%; the mass volume concentration range of the hydroformylation F127 (AF 127) in the step S2 is 5w/v percent.
5. The bioadhesive according to claim 2, wherein the amino substitution degree of the gelatin grafted with double bonds (GelMA) in step S1 ranges from 50% to 90%; the gelatin is heated to 37 ℃ during synthesis and then dissolved in physiological saline.
6. The bioadhesive of claim 2, wherein the degree of hydroformylation of F127 in step S2 is 100%; the AF127 was dissolved in physiological saline at room temperature at the time of synthesis.
7. The bioadhesive according to claim 2, wherein the auxiliary component in step S4 is preheated to 37 ℃ before being added, and the auxiliary component is uniformly dissolved by reversing the main component several times to form the final bioadhesive.
8. The bioadhesive according to claim 7, wherein the mass volume fraction of the water-soluble riboflavin in the auxiliary component in step S4 in the adhesive system is 0.1w/v%; the amount in the L-arginine binder system is 0.4 times the mass of GelMA; the auxiliary components are fixed in composition.
9. Use of the bioadhesive of any one of claims 1-8 in ocular surgical bonding.
10. The use according to claim 9, wherein the bioadhesive is preheated to 37 ℃ before application, is dropped into the implantation site and after the implant has been put in place, the implantation area is irradiated with ultraviolet light for 5 to 10 minutes at 10 cm.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN117085183A (en) * | 2023-08-28 | 2023-11-21 | 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) | In-situ curing and seamless transplanting material and preparation method and application thereof |
CN117085183B (en) * | 2023-08-28 | 2024-05-10 | 山东第一医科大学附属眼科研究所(山东省眼科研究所、山东第一医科大学附属青岛眼科医院) | In-situ curing and seamless transplanting material and preparation method and application thereof |
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