CN116370698B - Hydrogel scleral plug and preparation method and application thereof - Google Patents
Hydrogel scleral plug and preparation method and application thereof Download PDFInfo
- Publication number
- CN116370698B CN116370698B CN202310658474.4A CN202310658474A CN116370698B CN 116370698 B CN116370698 B CN 116370698B CN 202310658474 A CN202310658474 A CN 202310658474A CN 116370698 B CN116370698 B CN 116370698B
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- China
- Prior art keywords
- hydrogel
- scleral plug
- genipin
- plug
- hydrogel scleral
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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
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
- A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0031—Hydrogels or hydrocolloids
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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
- A61L24/0036—Porous materials, e.g. foams or sponges
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- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
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- A—HUMAN NECESSITIES
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- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
- A61L2300/604—Biodegradation
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- 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)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Surgery (AREA)
- Epidemiology (AREA)
- Materials Engineering (AREA)
- Dispersion Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention provides a hydrogel scleral plug, a preparation method and application thereof, and relates to the technical field of medical polymer materials. The preparation raw materials of the hydrogel scleral plug provided by the invention comprise gelatin A, water and genipin; the hydrogel scleral plug has tunnels on the surface and inside. The hydrogel scleral plug has the advantages of high safety, biodegradability, slow release drug administration and strong closure, and can be applied to plugging of scleral wounds after vitrectomy, prevention of eye infection, plugging of ocular trauma wounds and drug carriers. The hydrogel scleral plug provided by the invention has potential to replace the traditional suture of surgical lines and the mode of bonding high polymer materials, and has important clinical application value.
Description
Technical Field
The invention relates to the technical field of medical high polymer materials, in particular to a hydrogel scleral plug, a preparation method and application thereof.
Background
Vitrectomy is the main surgical mode of the current vitreoretinal disease, and is widely applied to diseases such as macula disease of the posterior pole of retina, proliferative diabetic retinopathy, retinal detachment and the like. Among them, conventional 20G trans-ciliary pars plana vitrectomy, and 25G/23G minimally invasive vitrectomy, have been widely used in ophthalmic clinics. Depending on the size of the incision, the incision is typically treated with a seamless or suture after the procedure is completed. The method can shorten the operation time, shorten the vision recovery speed of cornea astigmatism, reduce anterior segment inflammation, reduce postoperative discomfort and early recovery of patients. The self-sealing of minimally invasive surgical wounds depends on the wound structure and physiological ocular pressure, and when post-operatively at low ocular pressure, tears are drawn into the eye due to the "suction" effect, which can lead to endophthalmitis and hypotonia. Suture suturing can reduce the incidence of infection and hypotonia to some extent, but can extend the surgical time and vision recovery time. The suture reaction of the sclera lasts for half a year, so that the eyes of the patient have foreign body sensation, the life quality of the patient is influenced, and even the recovery of the eyesight of the eyes is influenced.
In addition to the above-described common treatments, the scleral incision may be adhered using materials such as bone scleral plug, cyanoacrylate glue, tissue fibrin glue, and the like. Although the bone scleral plug is simple to manufacture and convenient to implant, the bone scleral plug is not degradable in material, is unfavorable for tissue healing, has weak adhesion with the tissue, and is easy to extrude and fall off under the pressure of the aqueous humor; cyanoacrylate glue generates heat when being solidified and rapidly settles into a material which is not easy to bend and fragile, and the formed rough and hydrophobic surface can cause discomfort to patients; while fibrin glues are limited in practical use because of the theoretical risk of allergic reactions and disease transmission.
In addition, prior art CN114939192a discloses a hydrogel for scleral nails, which comprises polyethylene glycol diacrylate and a photoinitiator in addition to chitosan, and after photocrosslinking curing, the hydrogel for scleral nails is difficult to degrade in vivo, affecting scleral wound healing.
Disclosure of Invention
In view of the above, the present invention aims to provide a preparation method and application of a hydrogel scleral plug, which is degradable and can promote healing of ocular wounds.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a hydrogel scleral plug, which is prepared from the following raw materials of gelatin A, water and genipin; the hydrogel scleral plug has tunnels on the surface and inside.
Preferably, the solid-to-liquid ratio of the type A gelatin to water is 0.125-0.33 g/mL.
Preferably, the solid-to-liquid ratio of the genipin to the water is 0.1-2 mg/mL.
Preferably, the hydrogel scleral plug has a conical shape, the height of the conical shape is 3-6 mm, and the diameter of the bottom surface is 0.5-1.5 mm.
The invention provides a preparation method of the hydrogel scleral plug, which comprises the following steps:
mixing the gelatin type A, water and genipin, performing a crosslinking reaction, and freeze-drying to obtain the hydrogel scleral plug.
Preferably, the temperature of the mixing is 20-40 ℃ and the time is 12-48 h.
Preferably, the temperature of the crosslinking reaction is 20-40 ℃ and the time is 12-48 h.
The invention provides application of the hydrogel scleral plug according to the technical scheme or the preparation method according to the technical scheme in drug carriers, eye wound plugging materials or preparation of eye anti-infection drugs.
Preferably, the ocular wound comprises a scleral wound or an ocular trauma wound following vitrectomy of the eye.
Preferably, the infection includes one or more of endophthalmitis, scleritis and conjunctivitis.
The invention provides a hydrogel scleral plug, which is prepared from the following raw materials of gelatin A, water and genipin; the hydrogel scleral plug has tunnels on the surface and inside. The type A gelatin is a protein obtained by partially hydrolyzing collagen in animal skin, bones, tendons and ligaments through acid treatment, has excellent hydrophilicity and biocompatibility, can promote cell adhesion and growth, removes immunogenicity of the collagen, and reduces pathogen infection possibly existing; genipin is a product of geniposide hydrolyzed by beta-glucosidase, is an excellent natural biological cross-linking agent, and has toxicity far lower than chemical cross-linking agents such as formaldehyde, glutaraldehyde, diisocyanate and the like, so that the hydrogel scleral plug provided by the invention has high safety. The A-type gelatin is a natural high polymer material which is easy to degrade in vivo, the hydrogel scleral plug provided by the invention can promote wound healing after a surgical wound is plugged, and the hydrogel scleral plug is continuously degraded along with gradual healing of the wound until the wound is completely healed, and the scleral plug is completely degraded and disappears and can be biodegraded; meanwhile, compared with the photoinitiator (such as I2959, omnirad TPO-L, omnirad, omnirad 184D, darocur MBF, omniradDETX, omnirad 369, omnirad ITX and IGM 907), the degradation product of the hydrogel sclera plug provided by the invention is nontoxic and has no influence on the functions of the retina at the bottom of the eye. The hydrogel scleral plug provided by the invention has a large number of pore channels on the surface and in the inside, is a high-efficiency drug carrier, and is slowly released along with continuous degradation of the hydrogel scleral plug, so that the half life in the vitreous body is prolonged, repeated operation of clinical ocular administration is avoided, and the patient compliance is improved. The hydrogel scleral plug provided by the invention has good water absorption expansion performance, can be tightly plugged according to the shape of a wound, resists waterproof pressure, avoids falling off from a scleral incision, and provides a good recovery environment for the postoperative operation of the inner eye. In conclusion, the hydrogel scleral plug provided by the invention has the advantages of high safety, biodegradability, slow release drug administration and strong closure, can be applied to plugging of scleral wounds after vitrectomy, prevention of eye infection, plugging of ocular trauma wounds and drug carriers, can replace the traditional operation line suturing and high polymer material bonding modes, and has important clinical application value.
The preparation method of the hydrogel scleral plug provided by the technical scheme is simple to operate, environment-friendly, low in production cost and suitable for industrial production.
Drawings
FIG. 1 is a schematic representation of a hydrogel scleral plug prepared in example 21;
FIG. 2 is a graph of degradation rate of a hydrogel scleral plug;
FIG. 3 is a graph of the swelling factor of a hydrogel scleral plug;
FIG. 4 is a graph showing the comparison of the swelling of hydrogel scleral plugs prepared in examples 19-24;
FIG. 5 is a scanning electron microscope image of a hydrogel scleral plug prepared in example 21;
FIG. 6 is a cytogram of a hydrogel scleral plug prepared in example 21;
FIG. 7 is an intraoperative implant view of a hydrogel scleral plug prepared in example 21;
FIG. 8 is an external view of a hydrogel scleral plug prepared in example 21 after implantation;
FIG. 9 is a B-ultrasound view of the hydrogel scleral plug prepared in example 21 after implantation;
FIG. 10 is an OCT image of the anterior segment anterior chamber region after implantation of a hydrogel scleral plug prepared in example 21;
FIG. 11 is an OCT image of the anterior scleral region following implantation of the hydrogel scleral plug prepared in example 21, arrows indicating scleral incisions;
FIG. 12 is a hematoxylin-eosin staining chart of fundus retinal tissue following implantation of a hydrogel scleral plug prepared in example 21.
Detailed Description
The invention provides a hydrogel scleral plug, which is prepared from the following raw materials of gelatin A, water and genipin; the hydrogel scleral plug has tunnels on the surface and inside.
The raw materials adopted by the invention are all commercial products unless specified.
In the present invention, the solid-to-liquid ratio of the type A gelatin to water is preferably 0.125 to 0.33g/mL, and particularly preferably 0.125g/mL, 0.14g/mL, 0.17g/mL, 0.2g/mL, 0.25g/mL or 0.33g/mL.
In the invention, the solid-to-liquid ratio of genipin to water is preferably 0.1-2 mg/mL, and particularly preferably 0.1mg/mL, 0.25mg/mL, 0.5mg/mL, 0.75mg/mL, 1mg/mL or 2mg/mL.
In the present invention, the shape of the hydrogel scleral plug preferably includes a conical shape, and the height of the conical shape is preferably 3 to 6mm, more preferably 4 to 5mm; the diameter of the conical bottom surface is preferably 0.5-1.5 mm, more preferably 0.8-1.2 mm.
In the present invention, the diameter of the pore canal is preferably 2 to 200 μm, more preferably 50 to 150 μm.
The invention provides a preparation method of the hydrogel scleral plug, which comprises the following steps: mixing the gelatin type A, water and genipin, performing a crosslinking reaction, and freeze-drying to obtain the hydrogel scleral plug.
In the invention, the mixing temperature is preferably 20-40 ℃, more preferably 30-35 ℃; the mixing time is preferably 12 to 48 hours, more preferably 20 to 25 hours. In the present invention, the mixing is preferably: firstly mixing the gelatin A with water to obtain gelatin solution; and (3) mixing the gelatin solution with genipin for the second time to obtain gelatin-genipin mixed solution. In the present invention, the time of the first mixing is preferably 12 to 48 hours, more preferably 20 to 24 hours. In the present invention, the concentration of the gelatin solution is preferably 0.125 to 0.33g/mL, particularly preferably 0.125g/mL, 0.14g/mL, 0.17g/mL, 0.2g/mL, 0.25g/mL or 0.33g/mL. In the present invention, the second mixing time is preferably 10 to 60min, more preferably 20 to 30min. In the invention, the genipin is preferably used in the form of an aqueous solution of genipin, and the mass fraction of the aqueous solution of genipin is preferably 0.5-2%, more preferably 1-1.5%. In the invention, the concentration of genipin in the gelatin-genipin mixed solution is preferably 0.1-2 mg/mL, and particularly preferably 0.1mg/mL, 0.25mg/mL, 0.5mg/mL, 0.75mg/mL, 1mg/mL or 2mg/mL.
In the invention, the temperature of the crosslinking reaction is preferably 20-40 ℃, more preferably 30-35 ℃; the time of the crosslinking reaction is preferably 12 to 48 hours, more preferably 20 to 24 hours. In the present invention, the crosslinking reaction is preferably carried out in a mold, and the present invention is not particularly limited to the mold, and a mold well known to those skilled in the art may be used.
In the invention, the temperature of freeze-drying is preferably-80 to-40 ℃, more preferably-70 to-50 ℃; the time for lyophilization is preferably 1 to 6 hours, more preferably 2 to 4 hours.
The invention provides application of the hydrogel scleral plug according to the technical scheme or the preparation method according to the technical scheme in drug carriers, eye wound plugging materials or preparation of eye anti-infection drugs.
In the present invention, the ocular wound comprises a scleral or ocular trauma wound following an ocular vitrectomy, preferably comprising a 20G trans-ciliary pars plana vitrectomy, a 25G minimally invasive vitrectomy, a 23G minimally invasive vitrectomy, or a 27G minimally invasive vitrectomy. In the present invention, the ocular trauma preferably includes a punch-through wound.
In the present invention, the infection preferably includes one or more of endophthalmitis, scleritis and conjunctivitis.
In the present invention, the drug carrier is preferably a carrier for sustained release of an intraocular drug.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
1) And (3) stirring the type 1g A gelatin with 3mL, 4mL, 5mL, 6mL, 7mL or 8mL of water at 37 ℃ under 500r/min for 24 hours to obtain a gelatin solution with the concentration of 0.33-0.125 g/mL.
2) And (3) stirring the genipin aqueous solution with the mass fraction of 1% and the gelatin solution with the concentration of 0.33g/mL for min at 35 ℃ under the condition of 500r/min to obtain a gelatin-genipin mixed solution, wherein the genipin concentration is 0.1mg/mL.
3) Adding the gelatin-genipin mixed solution into a mould, carrying out crosslinking reaction for 24 hours at 35 ℃, putting the obtained crosslinked gelatin into a freeze dryer, freeze-drying for 2 hours at-60 ℃, and taking out the gel sclera plug from the mould.
Examples 2 to 36
A hydrogel scleral plug was prepared in the same manner as in example 1, wherein the concentration of the gelatin solution and the concentration of genipin in the gelatin-genipin mixed solution in examples 2 to 36 are shown in table 1, and the other preparation conditions were the same as in example 1.
TABLE 1 concentration of gelatin solutions in examples 1-36 and concentration of genipin in gelatin-genipin mixed solution
FIG. 1 is a schematic outline view of a hydrogel scleral plug prepared in example 21, which is a cone with a height of 5mm and a diameter of 1mm on the bottom surface, as can be seen from FIG. 1.
Comparative examples 1 to 6
A hydrogel scleral plug was prepared according to the method of example 1, wherein genipin was not added in comparative examples 1 to 6, and the concentration of the gelatin solution was 0.1mg/mL, 0.25mg/mL, 0.5mg/mL, 0.75mg/mL, 1mg/mL and 2mg/mL in this order, and the other preparation conditions were the same as in example 1.
Test example 1
In vitro degradation experiments of hydrogel scleral plug
The initial weights of the hydrogel scleral plugs prepared in examples 1 to 36 and comparative examples 1 to 6 were measured and recorded as M day0 . Placing the hydrogel sclera plugs in 1.5mL of phosphate buffer solution, shaking in a gas bath shaker at 37deg.C and 55r/min, centrifuging at x-th day (x=1, 3, 5, 7, 11, 14 and 21 days) to remove phosphate buffer solution, washing the obtained precipitate with ultrapure water for 3 times, lyophilizing in a lyophilizer for 24 hr to obtain hydrogel sclera plugs (denoted by M respectively) dayx ) Degradation rate of hydrogel scleral plug= (M day0 -M dayx ）/M day0 X 100%, each hydrogel scleral plug was subjected to 10 independent replicates and degradation rate results were expressed as mean ± standard deviation as shown in fig. 2.
As is clear from FIG. 2, when the gelatin concentration was 0.33g/mL, the genipin concentration was not more than 0.00025g/mL, and the hydrogel scleral plug was completely degraded within 24 hours. As the genipin concentration increased, the degradation rate decreased, and at day 7, the degradation rate of the hydrogel scleral plug was about 70% with a genipin concentration of 0.0005, 0.00075 g/mL. But at day 21, all genipin concentrations had hydrogel scleral plug degradation rates exceeding 50%.
When the gelatin concentration is 0.25g/mL, the genipin concentration is below 0.0001g/mL, the hydrogel scleral plug is completely degraded within 24 hours, and when the genipin concentration is 0.00025g/mL, the hydrogel scleral plug is completely degraded on the 5 th day. As the genipin concentration increases, the degradation rate decreases. At day 7, the degradation rate of the hydrogel scleral plug was approximately 50% at a genipin concentration of 0.0005g/mL, and at day 21, the degradation rates of the hydrogel scleral plugs were less than 50% at genipin concentrations of 0.001 and 0.002g/mL, respectively, approximately 45% and 35%.
When the gelatin concentration is 0.2g/mL, the genipin concentration is less than 0.0001g/mL, the hydrogel scleral plug is completely degraded in 24 hours, and when the genipin concentration is 0.00025g/mL, the genipin is completely degraded on the 3 rd day. As the genipin concentration increases, the degradation rate decreases. The degradation rate of the hydrogel scleral plug at day 7 was about 55% with a genipin concentration of 0.0005g/mL, and at day 21, the degradation rates of the hydrogel scleral plugs at both 0.001 and 0.002g/mL were less than 50%, about 40% and 20%, respectively.
When the gelatin concentration is 0.17g/mL, the genipin concentration is less than 0.0001g/mL, the hydrogel scleral plug is completely degraded in 24 hours, and when the genipin concentration is 0.00025g/mL, the genipin is completely degraded on the 5 th day. As the genipin concentration increases, the degradation rate decreases. At day 7, the degradation rate of the hydrogel scleral plug at a genipin concentration of 0.0005g/mL is about 40%, and at day 21, the degradation rate of the hydrogel scleral plug at a genipin concentration of 0.002g/mL is less than 50%, about 25%;
when the gelatin concentration is 0.14g/mL and the genipin concentration is below 0.00025g/mL, the hydrogel scleral plug is completely degraded within 24 hours. As the genipin concentration increases, the degradation rate decreases. At day 7, the degradation rate of the hydrogel scleral plug with the genipin concentration of 0.0005g/mL is about 90%, and at day 21, the degradation rate of the hydrogel scleral plug with the genipin concentration of 0.002g/mL is less than 50%, about 40%;
when the gelatin concentration is 0.125g/mL and the genipin concentration is below 0.00025g/mL, the hydrogel scleral plug is completely degraded within 24h. As the genipin concentration increases, the degradation rate decreases. The degradation rate of the hydrogel scleral plug at the genipin concentration of 0.0005g/mL was about 40% at day 7, and the degradation rate of the hydrogel scleral plug at the genipin concentration of 0.0005-0.001 g/mL was about 70% at day 21.
In conclusion, all hydrogel scleral plugs with genipin concentration below 0.00025g/mL completely degraded within 5 days; with the increase of the genipin concentration, the degradation rate is reduced, and the hydrogel scleral plug (example 27) with the gelatin concentration of 0.14g/mL and the genipin concentration of 0.0005g/mL can degrade by about 90% on the 7 th day, thereby conforming to the wound healing period of clinical patients and being suitable for clinical application. In addition, except for the examples 1-6 with the gelatin concentration of 0.33g/mL, the degradation rate of the hydrogel scleral plug with the genipin concentration of 0.002g/mL at all the other gelatin concentrations is less than 50 percent on the 21 st day, and the hydrogel scleral plug has potential to be used as a carrier for the slow release of intraocular drugs.
Test example 2
In vitro swelling experiments with hydrogel scleral plug
The initial weights of the hydrogel scleral plugs prepared in examples 1 to 36 and comparative examples 1 to 6 were measured and recorded as M 0min . The hydrogel scleral plug was then placed in 1.5mL of physiological saline, incubated at 37℃for 1, 3, 5, 10, 30min, 24h, and the weight of the hydrogel sclera was weighed (denoted as M) at various times of swelling t T=1 min, 3min, 5min, 10min, 30min or 24 h), weighed at different time points, the swelling coefficient was calculated, swelling coefficient=m t /M 0min Each hydrogel scleral plug was subjected to 10 independent replicates and the swelling coefficients were expressed as mean ± standard deviation, the results are shown in fig. 3.
As can be seen from FIG. 3, when the gelatin concentration is 0.33g/mL, the genipin concentration is 0.00025g/mL and above, the swelling coefficient within 1min is more than 1; the swelling coefficient of the hydrogel scleral plug with the genipin concentration of 0.0005, 0.00075, 0.001 and 0.002g/mL exceeds 10 in 30min, wherein the swelling coefficient of the hydrogel scleral plug with the genipin concentration of 0.00075g/mL reaches 15.
A hydrogel scleral plug having a genipin concentration of 0.00025g/mL and above when the gelatin concentration is 0.25g/mL, a swelling factor exceeding 1 within 1 min; a hydrogel scleral plug having a genipin concentration of 0.0005, 0.00075g/mL, a swelling factor of 18 within 30min, a hydrogel scleral plug having genipin concentrations of 0.0001, 0.00025, 0.001, and 0.002g/mL, a swelling factor of over 10 within 30min, wherein a hydrogel scleral plug having genipin concentrations of 0.0005 and 0.00075g/mL has a swelling factor of 18.
A hydrogel scleral plug having a genipin concentration of 0.00025g/mL or more when the gelatin concentration is 0.2g/mL, a swelling factor exceeding 1 within 1 min; the concentration of genipin is 0.00025-0.002g/mL, and the swelling coefficient exceeds 10 within 30min. Wherein the swelling coefficient of the hydrogel scleral plug with the genipin concentration of 0.001g/mL reaches 20.
When the gelatin concentration is 0.17g/mL, the genipin concentration is 0.00025-0.001 g/mL, and the swelling coefficient within 1min exceeds 2; a hydrogel scleral plug having a genipin concentration of 0.00025, 0.001g/mL, a swelling factor of greater than 15 within 30 minutes, and a hydrogel scleral plug having a genipin concentration of 0.0005, 0.00075g/mL, a swelling factor of greater than 20 within 30 minutes. Wherein the swelling coefficient of the hydrogel scleral plug with the genipin concentration of 0.0005g/mL is 25.
When the gelatin concentration is 0.14g/mL, the genipin concentration is 0.0005-0.001 g/mL, and the swelling coefficient in 1min is more than 1.5; the concentration of genipin is 0.00025-0.001 g/mL, and the swelling coefficient of the hydrogel scleral plug reaches 10 within 30min.
When the gelatin concentration is 0.125g/mL, the genipin concentration is 0.00075 and the hydrogel scleral plug is 0.001g/mL, and the swelling coefficient within 1min reaches 2.5; the concentration of genipin is 0.0005, 0.00075 and 0.001g/mL, the swelling coefficient is 20 in 30min, and the swelling coefficient is 13 in 30min.
In summary, the swelling coefficients of the hydrogel scleral plug with the gelatin concentration of 0.125-0.17 g/mL and the genipin concentration of 0.0005-0.001 g/mL within 1min are all more than 1.5, wherein the swelling coefficients of the hydrogel scleral plug with the gelatin concentration of 0.17g/mL and the genipin concentration of 0.00025-0.00075 g/mL are all 2.5 within 1 min; examples 40, 41 with gelatin concentration of 0.125g/mL, genipin concentration of 0.00075 and 0.001g/mL achieved swelling coefficients of 2.5 in 1 min. Further, the swelling factor of the hydrogel scleral plug (example 21) with a gelatin concentration of 0.17g/mL and a genipin concentration of 0.0005g/mL was 25; the hydrogel scleral plug (examples 33-35) with gelatin concentration of 0.125g/mL and genipin concentration of 0.0005-0.001 g/mL has a swelling coefficient of 20 in 30min.
Within the same time, the hydrogel scleral plugs prepared in the above examples (20-22 and 33-35) have the best swelling performance, the swelling coefficient can reach 2.5 in a short time (1 min), and the swelling coefficient can reach more than 20 in a long time (30 min). Can realize the purpose of swelling and plugging wounds when meeting water, and is suitable for clinical application.
The hydrogel scleral plugs prepared in examples 19 to 24 were swelled in phosphate buffer for 30min and then taken out, and photographed in comparison with the hydrogel scleral plugs before swelling, and the length was marked with a ruler, and the result is shown in fig. 4. As can be seen from fig. 4, the hydrogel scleral plugs (examples 21 and 23) with genipin concentration of 0.001 and 0.0005g/mL showed the greatest change in gel size before and after swelling, the side length increased from 3mm to 5mm, and the swelling was remarkable, indicating that the wound could be rapidly and tightly sealed in vivo, and the preparation was suitable for clinical application.
Test example 3
Image of hydrogel scleral plug under scanning electron microscope
The hydrogel scleral plug prepared in example 21 was placed in liquid nitrogen for 5min, then brittle-cut, cross-sectioned, and then subjected to a gold spraying treatment, and the morphology was observed under a scanning electron microscope under a low vacuum environment, as shown in fig. 5.
As can be seen from fig. 5, the hydrogel scleral plug prepared in example 21 forms a porous structure in which the porous structures are mutually communicated after freeze drying, the pore channels are irregular, the size is 2-200 μm, and the special structure of the hydrogel scleral plug is beneficial to adhesion and migration of cells, can maintain a moist environment and can absorb wound exudates; meanwhile, the medicine can be stored and can be used as a medicine storage to realize slow release.
Test example 4
Determination of the degree of crosslinking of the hydrogel scleral plug
The hydrogel scleral plug prepared in example 21 was placed in 1mL of ultrapure water, immersed for 2 hours at room temperature, broken by ultrasonic method, and then the degree of crosslinking was detected by ninhydrin method, and the specific steps were as follows: the hydrogel scleral is broken by ultrasound at 40W for 3min, weighed, heated with ninhydrin solution for 20min, the test solution cooled to room temperature and diluted in 95% ethanol, and the absorbance of the solution is recorded at 570nm using various known concentrations of glycine as standard solution with an uv-vis spectrophotometer. Crosslinking degree= (a Before cross-linking -A After crosslinking ) Before crosslinking,/A. Times.100%, 10 independent replicates were run and the degree of crosslinking was expressed as mean.+ -. Standard deviation. The hydrogel scleral plug prepared in example 21 had a degree of crosslinking of 19.4±4.37%.
Test example 5
Cytotoxicity assay of hydrogel scleral plug
Mouse retinal ganglion cells (661W), monkey choroidal-retinal endothelial cells (RF/6A), and human retinal epithelial cells (ARPE-19) were selected at 1X 10 4 Density of wells/density of wells was seeded in 96-well plates and incubated for 24h. The hydrogel scleral plugs prepared in example 21 were weighed, placed in 1mL of cell culture medium, soaked for 2 hours, then disrupted by sonication (40 watts, 3 min), the resulting solution was filtered sterilized, and further diluted with medium to a concentration of 0.5mg/4.5mL (0.11 mg/mL), and incubated with the above cells at 37 ℃ for 1, 3, 7 days, respectively. 0.5mg/mL of diphenyl tetrazolium bromide (MTT) solution was added to each well and incubation was continued for 4 hours at 37℃followed by the use of a microplate readerAbsorbance was measured at 450nm and survival was plotted. 3 independent replicates were performed and the results are shown in figure 6 as mean ± standard deviation.
As can be seen from FIG. 6, the hydrogel scleral plug prepared in example 21 showed no significant cytotoxicity to all three cells of mouse, monkey and human origin at a concentration of 0.11mg/mL, indicating high safety of the hydrogel scleral plug in vitro.
Test example 6
Performance investigation of hydrogel scleral plug for sealing vitrectomy scleral wound
New Zealand white rabbits are selected as animal models, pentobarbital sodium is injected along the veins of the rabbit ear margin at a dose of 30mg/kg for anesthesia, and then the operation is completed under the vein anesthesia. The conjunctival sac is washed 2 times with a physiological saline diluent containing gentamicin (8 units/mL), the eye drops of oxybuprocaine hydrochloride in the conjunctival sac are used for mydriasis, and the fur within the range of 5cm around the rabbit eyes is disinfected by iodophor. The inferior bulbar conjunctiva was separated under a microscope, the traction suture was disposed at the limbus, the visual field was fully exposed, and the sclera was pierced with a 23G microscopic vitreoretinal knife at about 3mm behind the limbus, and a vitrectomy scleral wound was made and vitrectomy was performed.
Experimental group scleral wound embedding the hydrogel scleral plug prepared in example 21 (shown in fig. 7), the hydrogel scleral plug was implanted at the scleral wound. The model group relies on tissue elasticity to seal the sclera autonomously after making a scleral incision (as shown in fig. 8), and then pulls the bulbar conjunctiva for reposition, and the conjunctival sac is coated with tobramycin dexamethasone eye ointment. Starting on the 2 nd day after operation, the eye is partially dropped with lomefloxacin eye liquid for 3 times/day. The conjunctival and scleral responses of the operated eyes were closely observed and photographs of the experimental and control/model eyes were taken. Eye tissue was observed for conjunctiva and scleral congestion, edema, and their extent. Each group was subjected to 5 independent replicates. The results are shown in FIGS. 9 to 10. Fig. 9 is a B-mode ultrasound image of the hydrogel scleral plug prepared in example 21 after implantation, and fig. 10 is an OCT image of the anterior segment anterior chamber region of the hydrogel scleral plug prepared in example 21 after implantation. As can be seen from fig. 9 to 10, the hydrogel sclera plug can tightly seal the 23G sclera wound of the rabbit without leakage, and simultaneously without vitreous inflammation, retinal detachment, anterior chamber inflammation, conjunctival and scleral congestion, edema or other adverse reactions, and is suitable for sealing clinical scleral incisions.
Test example 7
In vivo degradation performance investigation of hydrogel scleral plug
The hydrogel scleral plug prepared in example 21 was weighed and then implanted into a scleral incision of a rabbit eye and was closed for 7 days. During this period, anterior segment OCT examinations were performed on postoperative day 1 and day 7, respectively, to examine wound healing and degradation of hydrogel scleral plugs, and 5 independent replicates were performed. The experimental results are shown in FIG. 11.
As can be seen from fig. 11, the hydrogel scleral plug was significantly healed after the scleral wound was sealed for 7 days, the volume of the hydrogel scleral plug was significantly reduced, which indicates that the hydrogel scleral plug was degraded continuously with the continued healing of the wound, and the biocompatibility was high.
Test example 8
Investigation of safety of the fundus retina by the hydrogel scleral plug
The treated New Zealand white rabbits of test example 6, model group and experimental group animals were euthanized with carbon dioxide after operation for 1 week, 2 weeks, 4 weeks, 3 months and 6 months, the retina tissues were peeled off immediately after the surgical eyes were fixed with formaldehyde, the fixation was continued, wax blocks were made, and after slicing, the pathological changes were observed under an optical microscope by dewaxing, water-coating, hematoxylin staining for 5min, eosin staining for 2min, dehydration, sealing. 5 independent replicates were performed. The results are shown in FIG. 12.
As can be seen from fig. 12, compared with the model group, the retinal tissue of the experimental group for plugging the hydrogel scleral plug has no obvious pathological change, which indicates that the hydrogel scleral plug prepared by the invention has high intraocular safety and no influence on visual function.
In conclusion, the hydrogel scleral plug prepared by the invention has the advantages of biodegradability, high safety, high swelling rate, strong sealing performance and the like, is suitable for plugging scleral wounds after vitrectomy, avoids adverse reactions such as inflammation and the like, and is beneficial to healing of the wounds after the operation.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (8)
1. A hydrogel scleral plug is characterized in that the preparation raw materials comprise gelatin A, water and genipin; the surface and the inside of the hydrogel scleral plug are provided with pore passages; the solid-to-liquid ratio of the gelatin A to the water is 0.125-0.33 g/mL; the solid-to-liquid ratio of genipin to water is 0.1-2 mg/mL; the diameter of the pore canal is 2-200 mu m;
the preparation method of the hydrogel scleral plug comprises the following steps: mixing the gelatin type A, water and genipin, performing a crosslinking reaction, and freeze-drying to obtain the hydrogel scleral plug.
2. The hydrogel scleral plug of claim 1, wherein the shape of the hydrogel scleral plug comprises a conical shape having a height of 3-6 mm and a base diameter of 0.5-1.5 mm.
3. The method for preparing the hydrogel scleral plug according to any one of claims 1 to 2, comprising the steps of:
mixing the gelatin type A, water and genipin, performing a crosslinking reaction, and freeze-drying to obtain the hydrogel scleral plug.
4. The method according to claim 3, wherein the mixing temperature is 20-40 ℃ and the mixing time is 12-48 h.
5. The method according to claim 3, wherein the crosslinking reaction is carried out at a temperature of 20 to 40 ℃ for a time of 12 to 48 hours.
6. Use of a hydrogel scleral plug according to any one of claims 1-2 or a hydrogel scleral plug prepared by a method according to any one of claims 3-5 in a pharmaceutical carrier, an ocular wound plugging material or in the preparation of an ocular anti-infective drug.
7. The use of claim 6, wherein the ocular wound comprises a scleral wound or an ocular trauma wound following vitrectomy of the eye.
8. The use according to claim 6, wherein the infection comprises one or more of endophthalmitis, scleritis and conjunctivitis.
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