CN106632833B - A kind of Injectable temperature sensitive hydrogel artificial crystalline lens material and preparation method thereof with cellular membrane biomimetic - Google Patents

Abstract

The invention discloses an injectable temperature-sensitive hydrogel intraocular lens material with bionic cell membrane and a preparation method thereof, belonging to the field of biomedical materials. The material is formed by free-radical polymerization of polymerized monomers and initiators; the polymerized monomers are divided into three types: the first is N-isopropylacrylamide, vinylpyrrolidone or dimethylaminoethyl methacrylate Isotherm-sensitive functional monomer; the second is 2-phenoxyethyl methacrylate or 2-phenoxyethyl acrylate; the third is 2-methacryloyloxyethyl phosphorylcholine; The initiator is azobisisobutyronitrile. The material is temperature-sensitive, and has good water solubility and fluidity at low temperatures, which is convenient for injection operations; within the temperature range of the human body, the material gels and has good mechanical and optical properties; the intraocular lens has a cell membrane The characteristics of bionics and good biocompatibility can reduce the proliferation of human epithelial cells on the surface of the intraocular lens, and effectively reduce the surgical incision by means of injection.

Description

An injectable temperature-sensitive hydrogel intraocular lens material with cell membrane biomimesis and its preparation method

technical field

The invention belongs to the field of biomedical materials, in particular to a cell membrane bionic injectable temperature-sensitive hydrogel intraocular lens material and a preparation method thereof.

technical background

Cataract is a common middle-aged and elderly eye disease. It mainly manifests as opacity of the lens itself or the lens capsule. Clinically, surgery can only be used to restore vision to the patient, that is, cataract extraction and intraocular lens implantation. Intraocular lenses have been used clinically for decades and are mainly composed of polymers and cross-linking agents. By changing the chemical composition of the polymer, the refractive index, hardness and other properties of the intraocular lens can be changed. According to its hardness, it can be divided into hard intraocular lens and soft intraocular lens, and soft intraocular lens is also called foldable intraocular lens. The main material of rigid intraocular lens is polymethacrylate (PMMA). Although it has the characteristics of good optical performance, it is easy to cause corneal damage due to its high hardness, which has many limitations in surgery. Foldable intraocular lens is a product widely used clinically at present, and the materials of foldable intraocular lens mainly include silicone gel, hydrophilic acrylate and hydrophobic acrylate. The material has good flexibility, the surgical incision is small, and the postoperative reaction is light. However, because the folding intraocular lens is limited by materials and implantation methods, it is easy to cause glare problems and posterior cataracts.

Contents of the invention

The purpose of the present invention is to use an injectable temperature-sensitive hydrogel with cell membrane bionics as an artificial lens material, improve its biocompatibility, reduce complications after implantation and the proliferation of epithelial cells on the surface of the artificial lens. The hydrogel material provided by the present invention is different from other intraocular lens materials in that it has the characteristics of temperature sensitivity, and introduces a bionic 2-methacryloyloxyethylphosphorylcholine component with cell membrane into the material to improve the biocompatibility of the material. The cell membrane bionic feature of this component can effectively resist the adhesion and proliferation of proteins and intraocular epithelial cells on the surface and interior of the intraocular lens, and reduce inflammation and other complications after implantation of the intraocular lens.

The temperature-sensitive hydrogel has good fluidity at low temperature. When the temperature is adjusted to reach the set temperature, the material will gel, making it have good mechanical strength. Select a temperature-sensitive gel material whose transition temperature is the temperature of the human body, inject it into the eye at low temperature, and gel it at body temperature to obtain an intraocular lens material with good mechanical strength and optical properties. This implantation method can effectively fill the capsular bag of the entire lens, effectively reducing complications such as hindrance and glare.

The biocompatibility of intraocular lens directly affects the long-term visual function after operation. Most studies on the surface modification of intraocular lenses focus on inhibiting cell adhesion and reducing the interaction with surrounding tissues by constructing a biologically inert or low-adhesion surface, which is beneficial to inhibit inflammatory reactions. In order to construct a surface with low adhesion, improve the hydrophilicity of the surface of the material and reduce the non-specific protein adsorption on the surface, constructing a modified layer with the same charge as the protein can further increase the resistance to adsorption of the protein.

The present invention is realized through the following technical solutions:

A cell membrane biomimetic injectable temperature-sensitive hydrogel, which is polymerized from three monomers, the first monomer is a temperature-sensitive functional monomer; the second monomer is 2-phenoxyethylmethyl acrylate or 2-phenoxyethyl acrylate; the third monomer is 2-methacryloyloxyethyl phosphorylcholine.

As an option, in the above cell membrane biomimetic temperature-sensitive hydrogel, the temperature-sensitive functional monomer is N-isopropylacrylamide or vinylpyrrolidone or dimethylaminoethyl methacrylate.

As an alternative, in the above cell membrane biomimetic thermosensitive hydrogel, the amount of the first monomer accounts for 20% to 45% of the total mass of the polymerized monomers; the amount of the second monomer accounts for 20% to 45% of the total mass of the polymerized monomers; 20%~45% of the total mass of the polymerized monomers; the amount of the third monomer accounts for 10%~35% of the total mass of the polymerized monomers

As an alternative, in the above cell membrane biomimetic injectable temperature-sensitive hydrogel, the material is formed by free radical polymerization of polymerized monomers, temperature-sensitive functional monomers and initiators.

As an alternative, in the above cell membrane biomimetic injectable temperature-sensitive hydrogel, the initiator is azobisisobutyronitrile.

As an alternative, in the above cell membrane biomimetic injectable temperature-sensitive hydrogel, the amount of the initiator accounts for 0.1%-2% of the total mass of the polymer monomers.

As an option, the cell membrane bionic injectable temperature-sensitive hydrogel material has a refractive index greater than 1.5, a light transmittance of more than 90%, and a deformation recovery rate of more than 95%, which is suitable as an intraocular lens material.

The present invention also provides a preparation method of the injectable cell membrane biomimetic injectable temperature-sensitive hydrogel, which is characterized in that the three monomers and an initiator are subjected to free-radical polymerization.

As an alternative, in the above preparation method, the polymerized monomer and the initiator are mixed and then reacted at 50ºC~100ºC for 0.5~24 h under vacuum conditions, and the product is separated to remove unreacted small molecule monomers to obtain temperature-sensitive water gel.

As an alternative, in the above preparation method, the polymerized monomer, the temperature-sensitive functional monomer and the initiator are mixed according to a certain ratio under the protection of nitrogen; after mixing evenly, pour it into a glass mold, and then place it in a vacuum oven ; First react at 50 ºC~70 ºC for 0.5~24 h, then raise the temperature to 80~100 ºC and continue the reaction for 1~24 hours. After the reaction, the glass mold was placed in 40ºC deionized water for swelling balance, and the polymer material was released from the mold. During this period, unreacted small molecular monomers were removed by replacing the deionized water, and finally a sensitive polymer material was obtained.

In the present invention, the gel transition temperature of the material is adjusted by adjusting the ratio of the monomers to obtain a hydrogel with good mechanical properties and optical properties as the intraocular lens material; it has a refractive index greater than 1.5, and the light transmittance exceeds 90%. The recovery rate exceeds 95%, which is suitable as an intraocular lens material.

The present invention also provides an application of the above-mentioned cell membrane biomimetic temperature-sensitive hydrogel, which is characterized in that it is used in a temperature-sensitive intraocular lens capable of cell membrane biomimesis.

All features disclosed in this specification, or steps in all methods or processes disclosed, may be combined in any manner, except for mutually exclusive features and/or steps.

Beneficial effects of the present invention:

The injectable temperature-sensitive hydrogel used as the intraocular lens material of the present invention can effectively reduce the surgical incision through the injection implantation method and avoid the occurrence of postoperative complications; The material has a high degree of biocompatibility, which can effectively resist the adhesion and proliferation of proteins and intraocular epithelial cells on the surface and interior of the intraocular lens, and reduce the inflammatory response after implantation of the intraocular lens. At the same time, it can effectively avoid the glare problem caused by the microbubble phenomenon and the mirror effect of the hydrophobic intraocular lens implanted in the eye.

Detailed ways:

The above-mentioned content of the present invention will be further described in detail through the specific implementation of the examples below. It should be understood that the specific examples described here are only used to explain the present invention, not to limit the present invention. Any modification made without departing from the spirit and principles of the present invention, as well as equivalent replacements or improvements made according to ordinary technical knowledge and conventional means in the field shall be included in the protection scope of the present invention.

Part of the raw material structural formula used in the following examples is shown in the table below:

Example 1:

Selected monomers: the first monomer is N-isopropylacrylamide, the second monomer is 2-phenoxyethyl acrylate, and the third monomer is 2-methacryloyloxyethyl phosphoryl chol The base, the initiator is azobisisobutyronitrile. Among them, the content of N-isopropylacrylamide is 40%, 2-phenoxyethyl acrylate is 40%, 2-methacryloyloxyethyl phosphorylcholine is 19%, and azobisisobutyronitrile is 1%. . The polymerizable monomer and the initiator were mixed uniformly under the protection of nitrogen and injected into the glass mold, heated and polymerized in an oven at 60ºC for 18 hours, then the temperature was raised to 90ºC, and the reaction was continued for 6 hours. Put the glass mold in deionized water at 40 ºC for swelling balance, and the polymer material is demoulded. During this period, the unreacted small molecular monomers are removed by replacing the deionized water, and finally a temperature-sensitive polymer material that can be used as an intraocular lens material is obtained . The material has good water solubility below 12 ºC, has good fluidity, and can be injected; when the temperature is 37 ºC at body temperature, the aqueous solution of the polymer gels rapidly, and has good mechanical strength and optical properties; The gel material has a refractive index of 1.52, a gel time of 5 minutes at 37 ºC, an equilibrium water content of 15%, a light transmittance of more than 90%, and a deformation recovery rate of more than 95%.

HUVEC cell adhesion experiment: HUVEC cells were cultured at 37 ºC for 48 h and observed under a fluorescence microscope. The results are shown in Figure 1. Figure A shows the polymer material without phosphorylcholine, and it can be seen that a large number of cells adhere to the surface. Figure B shows the adhesion of cells on the surface of the material containing phosphorylcholine, indicating that the phosphorylcholine-modified material has a large Good anti-cell adhesion performance, this is because the phosphorylcholine zwitterion makes the surface of the material form a hydration layer, which effectively prevents cell adhesion. The material obtained in this example has excellent anti-cell adhesion properties.

Example 2:

Selected monomers: the first monomer is vinylpyrrolidone, the second monomer is 2-phenoxyethyl methacrylate, the third monomer is 2-methacryloyloxyethyl phosphorylcholine, The initiator is azobisisobutyronitrile. Among them, the content of vinylpyrrolidone is 40%, 2-phenoxyethyl methacrylate is 45%, 2-methacryloyloxyethyl phosphorylcholine is 14%, and azobisisobutyronitrile is 1%. The polymerizable monomer and initiator were mixed evenly under the protection of nitrogen and then injected into a glass mold, heated and polymerized in an oven at 70 ºC for 8 hours, and then the temperature was raised to 100 ºC to continue the reaction for 12 hours. The glass mold was placed in deionized water at 40 ºC for swelling balance, and the polymer was released from the mold. During this period, the unreacted small molecular monomers were removed by replacing the deionized water, and finally a temperature-sensitive polymer material that could be used as an intraocular lens material was obtained. The material has good water solubility below 15 ºC, has good fluidity, and can be injected; when the temperature is 37 ºC at body temperature, the aqueous solution of the polymer gels rapidly, has good mechanical strength and Optical properties: The material has a refractive index of 1.5, a gel time of 10 minutes at 37 ºC, an equilibrium water content of 12%, a light transmittance of more than 90%, and a deformation recovery rate of more than 95%.

HUVEC cell adhesion experiment: HUVEC cells were cultured at 37 ºC for 48 h and observed under a fluorescence microscope. The results are shown in Figure 2. Figure A shows the polymer material without phosphorylcholine, and it can be seen that a large number of cells adhere to the surface. Figure B shows the adhesion of cells on the surface of the phosphorylcholine-containing material, indicating that the phosphorylcholine-modified material has a large Good anti-cell adhesion performance, this is because the phosphorylcholine zwitterion makes the surface of the material form a hydration layer, which effectively prevents cell adhesion. The material obtained in this example has excellent anti-cell adhesion properties.

Example 3:

Selected monomers: the first monomer is dimethylaminoethyl methacrylate, the second monomer is 2-phenoxyethyl methacrylate, and the third monomer is 2-methacryloyloxyethyl Phosphorylcholine, the initiator is azobisisobutyronitrile. Among them, the content of dimethylaminoethyl methacrylate is 43%, 2-phenoxyethyl methacrylate is 42%, 2-methacryloyloxyethyl phosphorylcholine is 14%, azobisisobutyl Nitrile 1%. The polymerizable monomer and the initiator were mixed uniformly under the protection of nitrogen and injected into the glass mold, heated and polymerized in an oven at 60 ºC for 16 hours, and then the temperature was raised to 100 ºC to continue the reaction for 8 hours. The glass mold was placed in deionized water at 40 ºC for swelling balance, and the polymer was released from the mold. During this period, unreacted small molecular monomers were removed by replacing the deionized water, and finally a temperature-sensitive polymer material that could be used as an intraocular lens material was obtained. The material has good water solubility below 7 ºC, has good fluidity, and can be injected; when the temperature is 37 ºC at body temperature, the aqueous solution of the polymer gels rapidly, has good mechanical strength and Optical properties: The material has a refractive index of 1.54, a gel time of 7 minutes at 37 ºC, an equilibrium water content of 17%, a light transmittance of more than 90%, and a deformation recovery rate of more than 95%.

HUVEC cell adhesion experiment: HUVEC cells were cultured at 37 ºC for 48 h and observed under a fluorescence microscope. The results are shown in Figure 3. Figure A shows the polymer material without phosphorylcholine, and it can be seen that a large number of cells adhere to the surface. Figure B shows the adhesion of cells on the surface of the phosphorylcholine-containing material, indicating that the phosphorylcholine-modified material has a large Good anti-cell adhesion performance, this is because the phosphorylcholine zwitterion makes the surface of the material form a hydration layer, which effectively prevents cell adhesion. The material obtained in this example has excellent anti-cell adhesion properties.

The above is only a preferred embodiment of the present invention, and for the present invention, it is only illustrative and not restrictive; those of ordinary skill in the art understand that within the scope of the patent requirements of the present invention, they can Many changes, modifications, and even equivalent changes can be made, but all will fall within the protection scope of the present invention.

Claims (10)

1. a kind of cellular membrane biomimetic Injectable temperature sensitive hydrogel, which is characterized in that formed by three kinds of monomer polymerizations, wherein first Kind monomer is Thermo-sensitive functional monomer；Second of monomer is 2- phenoxyethyl methacrylate or 2- benzene oxygen ethylacrylic acid Ester；The third monomer is 2- methylacryoyloxyethyl Phosphorylcholine, and the hydrogel is the temperature that transition temperature is human body temperature Quick property gel rubber material has mobility under cryogenic, can be injected at low temperature intraocularly, realizes under body temperature solidifying Gelatinization.

2. cellular membrane biomimetic Injectable temperature sensitive hydrogel according to claim 1, which is characterized in that the Thermo-sensitive function Energy property monomer is n-isopropyl acrylamide or vinyl pyrrolidone or dimethylaminoethyl methacrylate.

3. cellular membrane biomimetic Injectable temperature sensitive hydrogel according to claim 1, which is characterized in that the first monomer Dosage accounts for the 20% ~ 45% of polymerized monomer gross mass；The dosage of second of monomer accounts for the 20% ~ 45% of polymerized monomer gross mass；Third The dosage of kind monomer accounts for the 10% ~ 35% of polymerized monomer gross mass.

4. cellular membrane biomimetic Injectable temperature sensitive hydrogel according to claim 1, which is characterized in that the material is by polymerizeing Monomer and initiator are formed by free radical polymerization.

5. cellular membrane biomimetic Injectable temperature sensitive hydrogel according to claim 4, which is characterized in that the initiator is Azodiisobutyronitrile.

6. cellular membrane biomimetic Injectable temperature sensitive hydrogel according to claim 4, which is characterized in that the initiator Dosage accounts for the 0.1% ~ 2% of polymer monomer gross mass.

7. a kind of preparation method of cellular membrane biomimetic temperature-sensitive hydrogel described in claim 1, which is characterized in that by three kinds of lists Body carries out free radical polymerization with initiator and forms.

8. preparation method according to claim 7, which is characterized in that in vacuum item after mixing polymerized monomer with initiator 50oC ~ 100oC reacts 0.5 ~ 24 h under part, and separation product removes unreacted small molecule monomer to get temperature-sensitive hydrogel is arrived.

9. preparation method according to claim 7, which is characterized in that polymerized monomer and initiator exist according to a certain percentage It is mixed under nitrogen protection；After mixing in implantation glass mold, it is subsequently placed in vacuum drying oven；First in 50 oC ~ 70 OC reacts 0.5 ~ 24 h, temperature is then risen into 80 ~ 100 oC, the reaction was continued 1 ~ 24 hour；After reaction, by glass molds Tool, which is placed in 40oC deionized water, carries out swelling equilibrium, polymer release, is during which removed by replacement deionized water unreacted Small molecule monomer finally obtains temperature sensing polymer material.

10. a kind of application of cellular membrane biomimetic Injectable temperature sensitive hydrogel described in claim 1, which is characterized in that by it For injectable cellular membrane biomimetic temperature-sensitive hydrogel intraocular lens.