CN114712332B - Modified water-based material and preparation method and application thereof - Google Patents
Modified water-based material and preparation method and application thereof Download PDFInfo
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- CN114712332B CN114712332B CN202210251271.9A CN202210251271A CN114712332B CN 114712332 B CN114712332 B CN 114712332B CN 202210251271 A CN202210251271 A CN 202210251271A CN 114712332 B CN114712332 B CN 114712332B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J5/00—Manufacture of articles or shaped materials containing macromolecular substances
- C08J5/18—Manufacture of films or sheets
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- G—PHYSICS
- G02—OPTICS
- G02B—OPTICAL ELEMENTS, SYSTEMS OR APPARATUS
- G02B1/00—Optical elements characterised by the material of which they are made; Optical coatings for optical elements
- G02B1/04—Optical elements characterised by the material of which they are made; Optical coatings for optical elements made of organic materials, e.g. plastics
- G02B1/041—Lenses
- G02B1/043—Contact lenses
-
- G—PHYSICS
- G02—OPTICS
- G02C—SPECTACLES; SUNGLASSES OR GOGGLES INSOFAR AS THEY HAVE THE SAME FEATURES AS SPECTACLES; CONTACT LENSES
- G02C7/00—Optical parts
- G02C7/02—Lenses; Lens systems ; Methods of designing lenses
- G02C7/04—Contact lenses for the eyes
- G02C7/049—Contact lenses having special fitting or structural features achieved by special materials or material structures
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2389/00—Characterised by the use of proteins; Derivatives thereof
Abstract
The invention relates to a modified water-based material, a preparation method and application thereof, wherein the protein film is adhered to the surface of the water-based material, and the protein film is a film formed by inducing protein by a modifier. The protein nano film for modifying hydrogel/biological tissue not only has good stability, biocompatibility and excellent optical transparency, but also can encapsulate functional molecules, keep the activity and realize controllable release, the protein film for encapsulating the functional molecules can be used for modifying common commercial contact lenses, the prepared therapeutic contact lenses can be applied to the field of ophthalmology, and the preparation process is simple and efficient, the cost is low, and the application prospect is good.
Description
Technical Field
The invention relates to the field of materials, in particular to an application of a protein nano film on the surface modification of a water-based material, a modified water-based material, a preparation method of the modified water-based material, a composition of the modified water-based material and a modified contact lens.
Background
Immediate adhesion can be achieved after the coating is in contact with the surface of the dry material by inter-molecular forces such as hydrogen bonding, electrostatic interactions and van der Waals interactions. However, this immediate modification is difficult to achieve on wet surfaces such as hydrogels because the water separates the molecules of the coating from the hydrogel surface, making it impossible to form the necessary interactions between the coating and the hydrogel for permanent adhesion. Although it is currently possible to modify the surface of hydrogels by limiting the graft polymerization reaction to occur only at the surface of the hydrogel, this approach is complex to react, difficult to control coating thickness, poor biocompatibility, and requires active sites on the hydrogel surface (e.g., surfaces covered with amine groups). Thus, developing a method for modifying the surface of hydrogels that is fast-reacting, biocompatible, simple-procedure, versatile and gentle while maintaining the overall properties of the hydrogels remains a key need and a central challenge in this field.
The surface modification of the hydrogel can widen the applicability of the hydrogel and enrich the performance of the hydrogel, so that the hydrogel has wide application in the aspects of contact lenses, soft electrons, drug delivery and the like. Contact lenses, which are currently used primarily for vision correction and cosmetic purposes, are probably the most common application of hydrogels in our society. More and more research has shown that contact lenses are a unique platform for wearable electronics or ophthalmic drug delivery systems because they are in constant contact with our tears. Compared with eye drops, the contact lens serving as an ophthalmic drug delivery system (therapeutic contact lens) has longer residual time and more controllable release before cornea, thereby improving the bioavailability of the drug, reducing the possibility of ocular surface irritation and systemic side effects, and being more convenient and effective in treatment. Although there are some methods of preparing therapeutic contact lenses, such as simply immersing the contact lens in a drug solution, embedding drug-loaded colloidal nanoparticles in the contact lens, or molecular imprinting, these methods have limitations such as long drug loading time, low drug loading, rapid drug release, and most importantly, the mechanical properties of the contact lens, which are important parameters in the practical use of the contact lens, may be altered. There is therefore a need to develop a therapeutic contact lens that is simple to operate, meets the therapeutic requirements and does not affect the actual use.
Disclosure of Invention
Object of the Invention
The invention aims to provide a modified hydrogel/biological tissue, a protein nano-film, a preparation method of the protein nano-film, a method for modifying the hydrogel/biological tissue and application of the modified hydrogel/biological tissue in contact lenses.
The invention adopts the modifier to induce the protein to self-assemble on the gas-liquid interface to form the protein film, and the surface of the protein nano film exposed on the air can realize stable adhesion and modification of the surface of the protein nano film at the moment of contacting the hydrogel/biological tissue.
Solution scheme
In order to achieve the above purpose, the present invention provides the following technical solutions:
in a first aspect, the invention provides an application of a protein nano film on surface modification of an aqueous material, wherein the protein film is adhered to the surface of the aqueous material, and the protein film is a film formed by inducing protein by a modifier.
Further, the aqueous material is in contact adhesion with a protein film formed on the gas-liquid interface.
Further, the raw materials of the protein film comprise: 2-20 mg/mL protein aqueous solution and 15-100 mmol/L modifier aqueous solution; optionally, the raw materials of the protein film comprise: 5-15 mg/mL protein aqueous solution and 40-100 mmol/L modifier aqueous solution; optionally, the raw materials of the protein film comprise: 7-15 mg/mL protein aqueous solution and 40-60 mmol/L modifier aqueous solution; optionally, the pH value of the modifier is 5-12.
Further, the protein film is a protein nano film formed by self-assembling a protein aqueous solution and a modifier aqueous solution on a gas-liquid interface; alternatively, the volume ratio of the aqueous protein solution to the aqueous modifier solution is 1:1.
In a second aspect, the present invention provides a method of modifying an aqueous material comprising: mixing and culturing the protein aqueous solution and the aqueous solution of the modifier, and assembling at a gas-liquid interface to form a protein film; contacting and adhering an aqueous material with the surface of the protein film to obtain a modified aqueous material adhered with the protein film; optionally, the modified aqueous material is a hydrogel or biological tissue.
Further, the protein nano film is formed by mixing and culturing 2-20 mg/mL protein aqueous solution and 15-100 mmol/L modifier aqueous solution and assembling at a gas-liquid interface; optionally, the concentration of the aqueous protein solution is 2-15 mg/mL, optionally 5-15 mg/mL, optionally 7-10 mg/mL, optionally 7mg/mL; optionally, the modifier is present in a concentration of 40 to 100mmol/L, optionally 40 to 60mmol/L, optionally 50mmol/L.
Further alternatively, the pH of the modifier is 5 to 12.
Further alternatively, the volume ratio of the aqueous protein solution to the aqueous modifier solution is 1:1.
Further alternatively, the incubation time is 1 to 12 hours, alternatively 1 to 3 hours, alternatively 2 hours.
In a third aspect, a modified aqueous material is provided, wherein a protein film is adhered to the surface of the aqueous material.
Further, the protein film is a nano film formed by assembling a protein aqueous solution and an aqueous solution of a modifier at a gas-liquid interface after mixing and culturing.
Alternatively, the modified hydrogel/biological tissue is made using the method of the second aspect.
In a fourth aspect, a contact lens is provided, including a contact lens body and a protein film adhered to the contact lens body, wherein the protein film is a nano film formed by assembling at a gas-liquid interface after mixed cultivation of a protein aqueous solution and an aqueous solution of a modifier; optionally, the protein nano film is internally coated with slow-release functional molecules.
Further, the protein nano film is formed by mixing and culturing 2-20 mg/mL protein aqueous solution and 15-100 mmol/L modifier aqueous solution and assembling at a gas-liquid interface; optionally, the concentration of the aqueous protein solution is 2-15 mg/mL, optionally 5-15 mg/mL, optionally 7-10 mg/mL, optionally 7mg/mL; optionally, the modifier is present in a concentration of 40 to 100mmol/L, optionally 40 to 60mmol/L, optionally 50mmol/L.
Further alternatively, the pH of the modifier is 5 to 12.
Further alternatively, the volume ratio of the aqueous protein solution to the aqueous modifier solution is 1:1.
Further alternatively, the incubation time is 1 to 12 hours, alternatively 1 to 3 hours, alternatively 2 hours.
In a fifth aspect, there is provided a composition for modifying an aqueous material comprising an aqueous protein solution of 2 to 20mg/mL and an aqueous modifier solution of 15 to 100 mmol/L; optionally, the modified aqueous material is a hydrogel or biological tissue.
Further, the method comprises 2-15 mg/mL protein aqueous solution and 40-100 mmol/L modifier aqueous solution; optionally comprising 5-15 mg/mL aqueous protein solution and 40-100 mmol/L aqueous modifier solution; optionally comprising 7-15 mg/mL aqueous protein solution and 40-60 mmol/L aqueous modifier solution; optionally comprising 7-10 mg/mL aqueous protein solution and 40-60 mmol/L aqueous modifier solution; optionally comprising 7mg/mL aqueous protein solution and 50mmol/L aqueous modifier solution.
Further, the equilibrium state of the hydrogel is a water-absorbing saturated state, so that the protein film is effectively adhered.
The raw materials in the above examples may be as follows:
further, the protein nano-film is coated with functional molecules, optionally, the functional molecules comprise drugs, dye molecules, fluorescent molecules and nano-particles, and optionally, the drugs comprise antibiotics and/or hyaluronic acid.
Further, the modifier is a strong oxidant or a strong reducing agent; the strong reducing agent is any one or more of dithiothreitol, beta-mercaptoethanol, tri (2-carboxyethyl) phosphine hydrochloride, cysteine, reducing glutathione, dimercaptosuccinic acid and sodium sulfite, and the strong oxidizing agent is any one or more of trivalent cobalt salt, chlorate, potassium permanganate, persulfate, potassium dichromate, concentrated sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid, perchloric acid, ozone, hydrogen peroxide, fluorine gas, chlorine gas, sodium bismuthate, periodic acid, sodium ferrate, lead dioxide, guanidine hydrochloride, urea, trifluoroethanol, hexafluoroisopropanol and trifluoroacetic acid; optionally one or more of tri (2-carboxyethyl) phosphine hydrochloride, cysteine and glutathione;
further, the method comprises the steps of, the protein is human lactoferrin, lysozyme, bovine serum albumin, insulin, alpha-lactalbumin, human serum albumin, fibrinogen, beta-amyloid protein, abeta peptide, prion protein, alpha-synuclein, cystatin C, huntingtin, immunoglobulin light chain, whey albumin, beta-lactoglobulin, ribonuclease A, cytochrome C, alpha-amylase horseradish peroxidase, pepsin, myoglobin, collagen, keratin, soy protein, lactoferrin, hemoglobin, DNA polymerase, casein, trypsin, chymotrypsin, thyroglobulin, transferrin, fibrinogen, goat serum, fetal calf serum, mouse serum, immunoglobulins, milk proteins, ovalbumin, concanavalin, fish skin collagen any one or more of superoxide dismutase, pancreatic lipase, laccase, histone, collagenase, cellulase, glutelin, mucin, transglutaminase, beta-galactosidase or PEGylated film-forming proteins including PEGylated human lactoferrin, PEGylated lysozyme, PEGylated bovine serum albumin, PEGylated insulin, PEGylated alpha-lactalbumin, PEGylated human serum albumin, PEGylated fibrinogen, PEGylated beta-amyloid, PEGylated A beta peptide, PEGylated prion, PEGylated alpha-synuclein, PEGylated cystatin C, PEGylated huntingtin, PEGylated immunoglobulin light chain, PEGylated whey albumin, PEGylated beta-lactoglobulin, PEGylated ribonuclease A, PEGylated cytochrome C, PEGylated alpha-amylase, PEGylated horseradish peroxidase, PEGylated pepsin, PEGylated myoglobin, PEGylated collagen, PEGylated keratin, PEGylated soybean protein, PEGylated lactoferrin, PEGylated hemoglobin, PEGylated DNA polymerase, PEGylated casein, PEGylated trypsin, PEGylated chymotrypsin, PEGylated thyroglobulin, PEGylated transferrin, PEGylated fibrinogen, PEGylated goat serum, PEGylated fetal calf serum, PEGylated mouse serum, PEGylated immunoglobulin, PEGylated milk protein, PEGylated ovalbumin, PEGylated canavanin, PEGylated fishskin collagen, PEGylated superoxide dismutase, PEGylated pancreatic lipase, PEGylated laccase, PEGylated histone, PEGylated collagenase, PEGylated cellulase, PEGylated gluten, PEGylated transglutaminase, PEGylated beta-galactosidase; optionally one or more of human lactoferrin, bovine serum albumin and lysozyme.
Further, a cross-linking agent (which can be added when needed) is also added in the formation of the protein nano film, and optionally, the concentration of the cross-linking agent is 0.01-0.5wt%; optionally, the cross-linking agent is any one or more of glutaraldehyde, genipin, glutamine transaminase and carbodiimide.
Further, the aqueous material is a hydrogel or biological tissue.
Further, the biological tissue is any one of skin, liver, muscle, stomach and intestine; optionally, the biological tissue is in an equilibrium state.
Further, the hydrogel is formed by any one or more of small molecules, natural polymers (including polysaccharides, polypeptides and nucleic acids) and synthetic polymers (including polyethers, polyacrylic acid and derivatives thereof and polyesters); optionally, the small molecule comprises one or any several of fluorenyl dipeptide, octapeptide and oligopeptide derivatives; optionally, the polysaccharide comprises one or more of starch, cellulose, alginic acid, hyaluronic acid, chitosan, k2 type carrageenan, locust bean gum, gelatin and agarose, the polypeptide is one or more of collagen, fibrin, poly-L-lysine and poly-L-glutamic acid, and the polyether comprises one or more of polypropylene oxide, polyethylene glycol and polyethylene oxide; the polyacrylic acid and the derivatives thereof comprise one or more of polyacrylamide, polyisopropyl acrylamide, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone and polyvinyl alcohol; the polyester comprises one or more of polyhydroxyethyl methacrylate, polypropylene fumarate, polycaprolactone and polydimethylaminoethyl methacrylate; optionally, the hydrogel is in an equilibrium state (i.e., saturated with water); optionally, the hydrogel is a contact lens.
Further, the water in the hydrogel can be replaced by an organic solvent, and optionally, the organic solvent comprises benzene, carbon tetrachloride, 1-methylene dichloride, 1, 2-methylene dichloride, chloroform, 2-methoxyethanol, 1, 2-trichloroethylene, 1, 2-dimethoxyethane, tetrahydronaphthalene, 2-ethoxyethanol, sulfolane, pyrimidine, formamide, N-hexane, chlorobenzene, dioxane, acetonitrile, vinyl ethylene glycol and N, N-dimethylamide, toluene, methanol, cyclohexane, N-methylpyrrolidone, pentane, formic acid, acetic acid, diethyl ether, acetone, anisole, 1-propanol, 2-propanol, 1-butanol, 2-butanol, amyl alcohol, butyl acetate, tributylmethyl ethyl ether, isopropyl acetate, methyl ethyl ketone, dimethyl sulfoxide, isopropyl benzene, ethyl acetate, ethyl formate, isobutyl acetate, methyl acetate, 3-methyl-1-butanol, methyl isobutyl ketone, 2-methyl-1-propanol, propyl acetate, 1-diethoxypropane, 1-dimethoxymethane, 2-dimethoxypropane, isooctane, isopropyl ether, methyl isopropyl ketone, methyl tetrahydrofuran, petroleum ether, trichloroacetic acid, trifluoroacetic acid.
Advantageous effects
The protein film obtained by preparing protein nano film protein and carrying out phase transition by the modifier can realize stable adhesion and modification on the surface of hydrogel/biological tissue within 2 seconds. The protein nano film for modifying hydrogel/biological tissue not only has good stability, biocompatibility and excellent optical transparency, but also can encapsulate functional molecules, keep the activity and realize controllable release, the protein film for encapsulating the functional molecules can be used for modifying common commercial contact lenses, the prepared therapeutic contact lenses can be applied to the field of ophthalmology, and the preparation process is simple and efficient, the cost is low, and the application prospect is good.
Drawings
One or more embodiments are illustrated by way of example and not limitation in the figures of the accompanying drawings. The word "exemplary" is used herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
FIG. 1 is a graph showing the visible light transmittance of the protein nanofilm of example 1 of the present invention;
FIG. 2 is a schematic diagram of the process of modifying hydrogel with protein nanofilm according to the present invention;
FIG. 3 is a photograph of a protein nanofilm modified agarose gel after Congo red staining according to example 2 of the present invention;
FIG. 4 is a photograph showing the protein nanomembrane modified hydrogel of example 3 of the present invention before and after being subjected to various severe conditions;
FIG. 5 is a graph showing the adhesion strength between a protein film and a hydrogel measured by a surface tensiometer according to example 4 of the present invention;
FIG. 6 is a typical peel curve of the surface tensiometer test of example 4 of the present invention;
FIG. 7 is a photograph of the stable adhesion in a contact lens care solution after modification of a contact lens with a protein film of example 13 of the present invention;
FIG. 8 shows that the protein nanofilm of example 14 of the present invention can be used as a drug loading platform to encapsulate drugs of different qualities of cyclosporin A.
FIG. 9 is a graph showing the drug release profile of therapeutic contact lenses made after the modified contact lenses have been coated with cyclosporin A as a drug loading platform with the protein nanofilm of example 15 of the present invention;
FIG. 10 is a cellular biocompatibility characterization of the therapeutic contact lens of example 16 of the present invention;
FIG. 11 is a graph of sodium corneal fluorescein staining following therapeutic contact lens intervention in dry eye mice in accordance with example 17 of the present invention.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. 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. Throughout the specification and claims, unless explicitly stated otherwise, the term "comprise" or variations thereof such as "comprises" or "comprising", etc. will be understood to include the stated element or component without excluding other elements or components.
In addition, numerous specific details are set forth in the following description in order to provide a better illustration of the invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In some embodiments, materials, elements, methods, means, etc. well known to those skilled in the art are not described in detail in order to highlight the gist of the present invention.
The present invention will be described in detail below.
Reagents used in the examples of the present invention, such as human lactoferrin, tris (2-carboxyethyl) phosphine, etc., are commercially available products.
Example 1
0.1433g of tris (2-carboxyethyl) phosphine are added to 10mL of ultrapure water and the pH is adjusted to 7.0 with NaOH; adding 70mg of human lactoferrin into 10mL of ultrapure water to prepare 7mg/mL of aqueous solution of human lactoferrin;
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution (shown in figure 1), and then the surface of the protein nano film is contacted with agarose gel after water saturation to complete adhesion (shown in figure 2).
Example 2
Because the protein nanofilm is optically clear, to make the process of nanofilm modification of the hydrogel more intuitive, the self-floating protein nanofilm was transferred to a 0.1wt% congo red aqueous solution, stained for 3 minutes at room temperature, and then transferred to ultrapure water to flush the flooding. Then transferred to ultrapure water and modified with agarose gel (as shown in fig. 3).
Example 3
Nanofilm and nanofilm-modified hydrogels were subjected to various extreme conditions to test their stability. As shown in fig. 4, the nanomembrane-modified hydrogel (a) in example 1 was immersed in the organic solvents ethanol, n-hexane, diethyl ether, chloroform and (B) polar acid or polar alkali solution (ph=1 or ph=12) for 12 hours, respectively, (C) was sonicated in ultra-pure water at 40KHz for 30 minutes and (D) was sonicated in 0.5wt% polyoxyethylene ether aqueous solution at 40KHz for 30 minutes, and the nanomembrane remained stably adhered to the hydrogel.
Example 4
Peel strength test was characterized using a DCAT 21 instrument, with the balance automatically zeroed at the beginning of the test, balance applied to the biocoated copper plate (area 0.25cm 2 ) Force on the upper surface. The protein nanofilm modified hydrogel/tissue is then driven up by a micro motor to contact the copper plate. Once the copper plate contacts the nano-film coated hydrogel/tissue, the motor is moved up a further 2 mm at a speed of 0.2 mm/s to achieve sufficient interaction between the bio-gel and the nano-film modified hydrogel/tissue; the motor is then set to move down at the same speed, thereby separating the protein nanofilm and the hydrogel/tissue (as shown in fig. 5). At the critical point of complete separation, the peak indicates the adhesion between the protein nanofilm and the hydrogel/tissue. Typical peel curves were recorded throughout the near contact separation process and the protein nanofilm modified agarose gel of example 1 was tested, as shown in fig. 6, to demonstrate that the peel force between the protein nanofilm and the agarose gel can reach 0.588N, indicating good adhesion between the protein nanofilm and the hydrogel/tissue.
Example 5
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution, and then polyacrylamide hydrogel is used for approaching and contacting the surface of the protein nano film to complete adhesion.
Example 6
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution, and then the surface of the protein nano film is approached by using polyacrylic acid hydrogel to complete adhesion.
Example 7
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution, and then polyvinyl alcohol hydrogel is used for approaching and contacting the surface of the protein nano film to complete adhesion.
Example 8
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution, and then polyethylene glycol hydrogel is used for approaching and contacting the surface of the protein nano film to complete adhesion.
Example 9
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution, and then the surface of the protein nano film is approached and contacted by using the poly (hydroxyethyl methacrylate) hydrogel to complete adhesion.
Example 10
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution, and then DNA hydrogel is used for approaching and contacting the surface of the protein nano film to complete adhesion.
Example 11
200 mu L of 50mmol/L aqueous solution of tri (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of BSA are uniformly mixed, then the mixture is dripped on a 18 mm-18 mm glass sheet, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution self-floats on the aqueous solution, and then agarose gel is used for approaching and contacting the surface of the protein nano film to complete adhesion.
Example 12
200 mu L of 50mmol/L aqueous solution of tri (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of BSA are uniformly mixed, then the mixture is dripped on a 18 mm-18 mm glass sheet, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution self-floats on the aqueous solution, and then agarose glycerol gel is used for approaching and contacting the surface of the protein nano film to complete adhesion.
Example 13
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 7mg/mL aqueous solution of human lactoferrin are uniformly mixed and then are dripped on 18 mm-18 mm glass sheets, after standing for 2 hours at room temperature, a transparent protein film formed on the surface of the mixed solution floats on the aqueous solution, and then a commercial contact lens (for example, a Haichang EASY DAY parabolic contact lens) is used for approaching and contacting the surface of the protein nano film to complete adhesion. The human lactoferrin nanofilm modified contact lens was immersed in 10ml of commercial care solution and the solution was changed once a day. After one year (12 months), the protein nanofilm remained stably adhered to the contact lens (as shown in fig. 7).
Example 14
0.1433g of tris (2-carboxyethyl) phosphine are added to 10mL of ultrapure water and the pH is adjusted to 7.0 with NaOH; adding 70mg of human lactoferrin into 10mL of ultrapure water to prepare 7mg/mL of aqueous solution of human lactoferrin; 90mg of hyaluronic acid was added to 10mL of ultrapure water to prepare an aqueous solution of 9mg/mL of hyaluronic acid; 30mg of cyclosporin A was added to 4mL of a 50% aqueous ethanol solution to prepare a 7.5mg/mL cyclosporin A solution. Among them, sodium hyaluronate is a natural humectant and can be antibacterial and adhesive, and cyclosporin a is a drug for treating dry eye.
After mixing 150. Mu.L of 7mg/mL aqueous solution of human lactoferrin, 150. Mu.L of 9mg/mL aqueous solution of hyaluronic acid and 150. Mu.L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine uniformly, dropping the mixture onto a glass sheet of 18mm x 18mm, standing the mixture at room temperature for 12 hours, and forming a protein film coated with hyaluronic acid on the surface of the mixture.
The method comprises the steps of uniformly mixing 150 mu L of 7mg/mL of aqueous solution of human lactoferrin, 150 mu L of 9mg/mL of aqueous solution of hyaluronic acid, 150 mu L of 50mmol/L of aqueous solution of tris (2-carboxyethyl) phosphine and 10/20/30/40/50/60 mu L of 7.5mg/mL of solution of cyclosporin A, then dripping the mixture on a 18mm glass sheet, standing for 12 hours at room temperature, and forming protein films (shown in figure 8) for encapsulating the hyaluronic acid and the cyclosporin A with different qualities on the surface of the mixture, wherein the results show that the protein films can well encapsulate functional molecules, namely the cyclosporin A, and the defects of poor stability and low utilization rate of free drugs can be overcome, the drug loss after encapsulation can be slowly released (shown in figure 9), and the problem that a large dose of drug eye drops is required in the prior art (because the eye drops are subjected to blink, tear flushing and the like and multiple large dose of drug administration is required, and a certain side effect is caused) is solved.
Example 15
A contact lens modified with the protein nanofilm of example 14 was immersed in 5ml of freshly prepared simulated tear fluid (STF, ingredients: naCl 0.67g, naHCO) 3 0.20g、CaCl 2 ·2H 2 O0.008 g and 100mL of ultrapure water), and shaking at a speed of 100rpm at 37℃to conduct a drug release experiment. STF contained 0.5wt% of polyoxyethylene ether (POE) to achieve the drug run-out condition. During the release experiments, 2ml of the released solution was continuously aspirated over a predetermined time interval, and then 2ml of fresh STF containing 0.5wt% poe was added to the release sample. Cyclosporin a content was determined by uv method (as shown in figure 9).
Example 16
The surfaces of the cell climbing sheets were modified as in FIG. 2 using the nano-films of example 1 and example 14, and were divided into human lactoferrin film, human lactoferrin film-coated hyaluronic acid and 21. Mu.g of cyclosporin A, human lactoferrin film-coated hyaluronic acid and 22. Mu.g of cyclosporin A, human lactoferrin film-coated hyaluronic acid and cyclosporin 25. Mu. g A, human lactoferrin film-coated hyaluronic acid and 34. Mu.g of cyclosporin A and human lactoferrin film-coated hyaluronic acid and 49. Mu.g of cyclosporin A, respectively, according to the composition and the drug loading amount of the nano-films. In cytotoxicity experiments, in order to detect cytotoxicity of the human lactoferrin membrane, the hyaluronic acid entrapped by the human lactoferrin membrane and the cyclosporin of different masses, respectively, the human lactoferrin membrane/hyaluronic acid and the five nano-film modified cell climbing slices with different drug loading amounts were incubated with the human corneal epithelial cells for 2, 4, 7 and 10 hours respectively, and then CCK-8 detection reagent was added to continue the co-incubation for 2-4 hours. The OD of each group at 450nm was then measured with a microplate reader and the cell activity was calculated to show that the activity of human keratocytes was 90% after incubation of all groups of samples with human keratocytes (see FIG. 10). Therefore, the protein nano film after the medicine is entrapped has negligible toxicity to mammalian cells and has good safety in ocular surface application.
Example 17
The modified tear test strip was used to measure the tear level after intervention in dry eye SD rats. First, reforming a tear test strip: the sodium fluorescein ophthalmic tear test strip (Tianjin JingMing New Technological Development co., ltd) was cut along the midline and split into two strips of width 2-3 mm. The anterior segment was then folded over along the sodium fluorescein indicator tape, placed about 1/3 of the way outside the lower eyelid of the SD rat, and removed after 20 seconds, and the distance (mm) traveled by the sodium fluorescein was recorded. Each eye was measured 3 times. The eye surface tear content of the rat in the dry eye model is extremely low, and as treatment progresses, the contact lens coated with the hyaluronic acid protein film modification, the contact lens coated with the hyaluronic acid and cyclosporin A protein film modification and the commercial products are obtainedThe tear content of the eye drop intervention treatment group gradually increases, and the difference of the eye drop intervention treatment group and the control group has statistical significance. Among them, the rats of the contact lens group coated with hyaluronic acid and cyclosporin A protein film modified had the best recovery of tear content after 5 days of intervention, even higher than the commercial +.>Tear content 7 days after eye drop group intervention. As shown in fig. 11.
The inventors of the present invention found that the formation of the protein film and the achievement of adhesion to the hydrogel were conditioned, for example, in the following comparative examples
Comparative example 1
200 mu L of 0.5mmol/L of aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 0.05mg/mL of aqueous solution of human lactoferrin are uniformly mixed, then the mixture is dripped on a glass sheet with the thickness of 18mm and 18mm, and after standing for 12 hours at room temperature, a transparent protein film is not formed on the surface of the mixed solution.
Comparative example 2
200 mu L of 0.25mmol/L of aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 0.1mg/mL of aqueous solution of human lactoferrin are uniformly mixed, then the mixture is dripped on a glass sheet with the thickness of 18mm and 18mm, and after standing for 12 hours at room temperature, a transparent protein film is not formed on the surface of the mixed solution.
Comparative example 3
200 mu L of 50mmol/L aqueous solution of tris (2-carboxyethyl) phosphine and 200 mu L of 2mg/mL aqueous solution of lysozyme are uniformly mixed and then are dripped on a 18 mm-18 mm glass sheet, and after standing for 2 hours at room temperature, a transparent protein film is formed on the surface of the mixed solution, but the protein film has poor mechanical properties and is fragile, and the hydrogel surface cannot be modified by the method shown in figure 2. The protein film has certain conditions and requirements for the surface modification of the hydrogel. The inventors have also found that transferring the formed lysozyme film to a glutaraldehyde solution having a concentration of 0.01wt% for 3 minutes improves the mechanical properties of the protein film, after which the hydrogel surface can be modified as shown in FIG. 2.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (66)
1. The application of the protein nano film on the surface modification of the water-based material is characterized in that the protein nano film is adhered on the surface of the water-based material, and the protein nano film is a film formed by inducing protein by a modifier;
the aqueous material is hydrogel;
the aqueous material contacts and adheres to the upper surface of the protein nano film formed on the gas-liquid interface;
the protein nano film is formed by self-assembling a protein aqueous solution and a modifier aqueous solution on a gas-liquid interface;
the protein nano film comprises the following raw materials: 7-15 mg/mL protein aqueous solution and 40-60 mmol/L modifier aqueous solution;
The modifier is a strong reducing agent, and the strong reducing agent is any one or more of tri (2-carboxyethyl) phosphine hydrochloride, cysteine and reducing glutathione;
the protein is any one or more of human lactoferrin, lysozyme, bovine serum albumin, insulin, alpha-lactalbumin and human serum albumin.
2. The use according to claim 1, wherein the protein is any one or more of pegylated human lactoferrin, pegylated lysozyme, pegylated bovine serum albumin, pegylated insulin, pegylated alpha-lactalbumin, and pegylated human serum albumin.
3. The use according to claim 1, wherein the hydrogel is formed by any one or more of small molecules, natural polymers and synthetic polymers.
4. The use according to claim 3, wherein,
the small molecule comprises one or any of fluorenyl dipeptide and octapeptide;
the natural polymer comprises one or more of polysaccharides, polypeptides and nucleic acids; the polypeptide is one or more of collagen, fibrin, poly-L-lysine and poly-L-glutamic acid;
The synthetic polymer comprises one or more of polyether, polyacrylic and polyester.
5. The use according to claim 4, wherein the polysaccharides comprise one or more of starch, cellulose, alginic acid, hyaluronic acid, chitosan, type k2 carrageenan, locust bean gum and agarose;
the polyacrylic acid comprises one or more of polyacrylamide, polyisopropyl acrylamide, polyacrylic acid and polymethacrylic acid;
the polyether comprises one or more of polypropylene oxide, polyethylene glycol and polyethylene oxide;
the synthesized polymer comprises one or more of polyvinylpyrrolidone and polyvinyl alcohol;
the polyester comprises one or more of polyhydroxyethyl methacrylate, polypropylene fumarate, polycaprolactone and polydimethylaminoethyl methacrylate.
6. The use according to claim 1, wherein the hydrogel is in an equilibrium state.
7. The use according to claim 1, wherein the hydrogel is a contact lens.
8. The use according to claim 1, wherein the protein nanofilm has functional molecules entrapped therein.
9. The use of claim 8, wherein the functional molecule comprises a drug.
10. Use according to claim 9, wherein the medicament comprises antibiotics and/or hyaluronic acid.
11. The use of claim 8, wherein the functional molecule comprises a dye molecule.
12. The use of claim 8, wherein the functional molecule comprises a fluorescent molecule.
13. The use of claim 8, wherein the functional molecule comprises a nanoparticle.
14. The use according to claim 1, wherein the raw materials of the protein nanofilm comprise: 7-10 mg/mL protein aqueous solution and 40-60 mmol/L modifier aqueous solution.
15. The use according to claim 1, wherein the pH of the modifier is between 5 and 12.
16. The use according to claim 1, wherein the volume ratio of aqueous protein solution to aqueous modifier solution is 1:1.
17. The use according to any one of claims 1 to 16, wherein the protein nanofilm further comprises a cross-linking agent.
18. The use according to claim 17, wherein the concentration of the cross-linking agent is 0.01-0.5 wt%.
19. The use according to claim 17, wherein the cross-linking agent is any one or more of glutaraldehyde, genipin, glutamine transaminase, and carbodiimide.
20. A method of modifying an aqueous material, comprising: after the aqueous solution of protein and the aqueous solution of modifier are mixed and cultivated, assembling at the gas-liquid interface to form the protein nano film; contacting and adhering an aqueous material with the upper surface of the protein nano film to obtain a modified aqueous material adhered with the protein nano film; the modified aqueous material is hydrogel;
the protein nano film is formed by mixing and culturing 7-15 mg/mL protein aqueous solution and 40-60 mmol/L modifier aqueous solution and then assembling at a gas-liquid interface;
the modifier is a strong reducing agent, and the strong reducing agent is any one or more of tri (2-carboxyethyl) phosphine hydrochloride, cysteine and reducing glutathione;
the protein is one or more of human lactoferrin, lysozyme, bovine serum albumin, insulin, alpha-lactalbumin and human serum albumin.
21. The method of claim 20, wherein the protein is one or more of pegylated human lactoferrin, pegylated lysozyme, pegylated bovine serum albumin, pegylated insulin, pegylated alpha-lactalbumin, and pegylated human serum albumin.
22. The method of claim 20, wherein the aqueous protein solution has a concentration of 7 to 10mg/mL in the formation of the protein nanofilm.
23. The method of claim 20, wherein the aqueous protein solution concentration in the protein nanofilm formation is 7mg/mL.
24. The method of claim 20, wherein the concentration of modifier in the protein nanofilm formation is 50mmol/L.
25. The method of claim 20, wherein the pH of the modifier is between 5 and 12 during the formation of the protein nanofilm.
26. The method of claim 20, wherein in the protein nanofilm formation, the volume ratio of the aqueous protein solution to the aqueous modifier solution is 1:1.
27. The method of claim 20, wherein the incubation time is 1-12 hours in the formation of the protein nanofilm.
28. The method of claim 20, wherein the incubation time is 1-3 hours in the formation of the protein nanofilm.
29. The method of claim 20, wherein the incubation time in the protein nanofilm formation is 2 hours.
30. The method of claim 20, wherein the hydrogel is formed from any one or more of small molecules, natural polymers and synthetic polymers;
the small molecule comprises one or any of fluorenyl dipeptide and octapeptide;
the natural polymer comprises one or more of polysaccharides, polypeptides and nucleic acids; the polysaccharide comprises one or more of starch, cellulose, alginic acid, hyaluronic acid, chitosan, k2 carrageenan, locust bean gum and agarose; the polypeptide is one or more of collagen, fibrin, poly-L-lysine and poly-L-glutamic acid;
the synthetic polymer comprises one or more of polyether, polyacrylic acid and polyester; the polyether comprises one or more of polypropylene oxide, polyethylene glycol and polyethylene oxide; the polyacrylic acid comprises one or more of polyacrylamide, polyisopropyl acrylamide, polyacrylic acid and polymethacrylic acid; the polyester comprises one or more of polyhydroxyethyl methacrylate, polypropylene fumarate, polycaprolactone and polydimethylaminoethyl methacrylate; alternatively, the synthetic polymer may comprise one or more of polyvinylpyrrolidone and polyvinyl alcohol.
31. The method of any one of claims 20 to 30, wherein a cross-linking agent is also added to the protein nanofilm formation.
32. The method of claim 31, wherein the cross-linking agent concentration is 0.01-0.5 wt%.
33. The method of claim 31, wherein the cross-linking agent is any one or more of glutaraldehyde, genipin, glutamine transaminase, and carbodiimide.
34. The method of any one of claims 20 to 30, wherein the protein nanofilm has functional molecules entrapped therein.
35. The method of claim 34, wherein the functional molecule comprises a drug.
36. The method of claim 34, wherein the drug comprises an antibiotic and/or hyaluronic acid.
37. The method of claim 34, wherein the functional molecule comprises a dye molecule.
38. The method of claim 34, wherein the functional molecule comprises a fluorescent molecule.
39. The method of claim 34, wherein the functional molecule comprises a nanoparticle.
40. A modified aqueous material is characterized in that a protein nano film is adhered on the surface of the aqueous material;
The modified aqueous material is hydrogel;
the modified hydrogel is prepared by the method of any one of claims 20 to 39.
41. The contact lens is characterized by comprising a contact lens body and a protein nano film adhered to the contact lens body, wherein the protein nano film is formed by assembling a protein aqueous solution and an aqueous solution of a modifier at a gas-liquid interface after mixing and culturing; the protein nano film is internally coated with slow-release functional molecules;
the protein nano film is formed by mixing and culturing 7-15 mg/mL protein aqueous solution and 40-60 mmol/L modifier aqueous solution and then assembling at a gas-liquid interface;
the contact lens is contacted and adhered with the upper surface of the protein nano film formed by assembling the gas-liquid interface;
the modifier is a strong reducing agent; the strong reducing agent is any one or more of tri (2-carboxyethyl) phosphine hydrochloride, cysteine and reducing glutathione;
the protein is one or more of human lactoferrin, lysozyme, bovine serum albumin, insulin, alpha-lactalbumin and human serum albumin.
42. The contact lens of claim 41, wherein the protein is one or more of PEGylated human lactoferrin, PEGylated lysozyme, PEGylated bovine serum albumin, PEGylated insulin, PEGylated alpha-lactalbumin, PEGylated human serum albumin.
43. The contact lens of claim 41, wherein the aqueous protein solution is used in the formation of the protein nanofilm at a concentration of 7 to 10mg/mL.
44. The contact lens of claim 41, wherein the aqueous protein solution is used in the formation of the protein nanofilm at a concentration of 7mg/mL.
45. The contact lens of claim 41, wherein the concentration of modifier in the protein nanofilm formation is 50mmol/L.
46. The contact lens of claim 41 wherein the pH of the modifying agent is from 5 to 12.
47. The contact lens of claim 41 wherein the volume ratio of aqueous protein solution to aqueous modifier solution is 1:1.
48. The contact lens of claim 41, wherein the aqueous protein solution and the modifying agent are incubated for 1-12 hours.
49. The contact lens of claim 41, wherein the aqueous protein solution and the modifying agent are incubated for 1-3 hours.
50. The contact lens of claim 41 wherein the aqueous protein solution is incubated with the modifying agent for a period of 2 hours.
51. The contact lens of any one of claims 41 to 50, wherein the protein nanofilm forming solution further comprises 5-15 mg/mL of an aqueous solution of hyaluronic acid and/or 2-15 mg/mL of a drug solution.
52. The contact lens of claim 41, wherein the concentration of the aqueous solution of hyaluronic acid in the protein nanofilm forming solution is 7-11 mg/mL.
53. The contact lens of claim 41, wherein the concentration of the aqueous solution of hyaluronic acid in the protein nanofilm forming solution is 9-11 mg/mL.
54. The contact lens of claim 51, wherein the concentration of the aqueous solution of hyaluronic acid in the protein nanofilm forming solution is 9 mg/mL.
55. The contact lens of claim 51, wherein the concentration of the drug in the protein nanofilm forming solution is 5-10 mg/mL.
56. The contact lens of claim 55, wherein the concentration of the drug in the protein nanofilm forming solution is 7.5 mg/mL.
57. The contact lens of claim 51 wherein the drug is an antibiotic.
58. The contact lens of claim 51 wherein the drug is cyclosporin a.
59. The contact lens of claim 41, wherein the modifier is any one or more of tris (2-carboxyethyl) phosphine hydrochloride, cysteine, and glutathione.
60. The contact lens of claim 59, wherein the protein is any one or more of human lactoferrin, bovine serum albumin, lysozyme.
61. The contact lens of claim 41, wherein a cross-linking agent is further added to the protein nanofilm formation.
62. The contact lens of claim 61, wherein the concentration of crosslinking agent is 0.01-0.5 wt%.
63. The contact lens of claim 62, wherein the cross-linking agent is any one or more of glutaraldehyde, genipin, glutamine transaminase, and carbodiimide.
64. The contact lens of claim 41 wherein the functional molecule further comprises a dye molecule.
65. The contact lens of claim 41 wherein the functional molecule further comprises a fluorescent molecule.
66. The contact lens of claim 41 wherein the functional molecule further comprises a nanoparticle.
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