A high-toughness transparent collagen hydrogel intraocular lens and a preparation method thereof

Abstract

The present application relates to a kind of high toughness transparent collagen hydrogel intraocular lens and its preparation method, comprising: dissolving type I collagen in glacial acetic acid solution containing glycerol, to obtain collagen precursor solution;Aldehyde group hyaluronic acid is added to collagen precursor solution and is homogenized, to obtain homogeneous mixture and adjust pH, then remove bubble to obtain molding liquid;Molding liquid is injected into intraocular lens mold, incubated in constant temperature incubator, to obtain collagen-hyaluronic acid original hydrogel;Then it is soaked in crosslinking soaking liquid and crosslinked, to obtain crosslinked hydrogel;Finally, it is soaked in PBS buffer solution and solvent is replaced, so that hydrogel reaches swelling equilibrium in physiological saline environment, to obtain high toughness transparent collagen hydrogel intraocular lens.The present application directly introduces polar molecule glycerol during the thermodynamic self-assembly process of collagen, so as to obtain high-transparency collagen hydrogel intraocular lens optical part.

Description

Technical Field

[0001] This invention belongs to the field of artificial lens technology, specifically relating to a high-toughness transparent collagen hydrogel artificial lens and its preparation method. Background Technology

[0002] Cataracts and severe refractive errors are among the leading causes of vision impairment and even blindness worldwide. Intraocular lens (IOL) implantation is currently the most effective treatment for restoring vision. In minimally invasive ophthalmic surgeries (such as phacoemulsification cataract surgery), a folded IOL is inserted into the intraocular capsular bag through a small corneal incision (typically 2.0–2.8 mm), allowing it to automatically unfold and restore its designed shape within the eye, thus replacing the diseased or cloudy natural lens. Therefore, the optical transmittance, biocompatibility, mechanical strength and flexibility (foldable insertion performance), and long-term stability of the IOL material within the intraocular environment are key factors determining surgical efficacy and the incidence of long-term complications.

[0003] Currently used intraocular lens (IOL) materials are mainly divided into rigid materials (such as polymethyl methacrylate (PMMA)) and soft hydrophobic / hydrophilic acrylate polymers. The foldable IOLs widely used clinically are mostly made of synthetic hydrophobic or hydrophilic acrylate materials. Their preparation process typically involves free radical polymerization of hydrophobic / hydrophilic monomers with crosslinking agents (such as divinylbenzene), followed by molding into a three-dimensional structure containing a central optic (approximately 0.5–1.2 mm thick) and lateral support haptics. Although synthetic acrylate materials have good folding properties and optical transparency, as heterogeneous synthetic polymers, they lack bioactivity after implantation, posing a long-term risk of inducing posterior capsule opacification (PCO), anterior capsule contraction, and chronic intraocular foreign body inflammation. In contrast, natural biomolecular materials possess inherent biocompatibility and cell affinity. Among them, collagen, as the main structural protein of the human natural lens and corneal stroma, exhibits excellent biocompatibility, low immunogenicity, and the ability to induce tissue repair, making it an ideal next-generation bio-based intraocular lens matrix material. For example, patent document CN117357703A discloses a collagen-based hydrogel for corneal damage repair. However, when directly applied or transferred to the field of intraocular lenses with complex three-dimensional geometry and high refractive accuracy requirements, the following serious technical defects and bottlenecks exist: (1) The inherent contradiction between optical transparency and mechanical strength: Unmodified natural collagen molecules are prone to self-assembly and aggregation during cross-linking or gelation, forming micron- or submicron-sized collagen fiber bundles, which produce severe sunlight scattering, causing the hydrogel to appear turbid or semi-transparent, which cannot meet the high transmittance requirements of ophthalmic optical devices. (2) Insufficient mechanical toughness and poor adaptability to minimally invasive implantation: The internal network of ordinary collagen hydrogel is relatively fragile and has a high water content, resulting in low tensile strength and elongation at break. During the injection and folding process through minimally invasive incisions such as 2.0-2.8 mm, the hydrogel is prone to local stress concentration at stress concentration points, leading to tearing, damage, or irreversible permanent deformation, which cannot meet the technical requirements of minimally invasive injection and implantation. (3) Poor intraocular stability: Pure natural collagen hydrogels are easily affected by the intraocular environment (such as enzymes and oxidative microenvironment in aqueous humor) and degrade, leading to structural instability or optical performance degradation. (4) The post-processing soaking method leads to uneven diffusion of polar molecules inside the three-dimensional thick structure (optical part), causing optical anisotropy and refractive error. Existing corneal hydrogel technology usually adopts the post-processing soaking process of "self-assembling to form a gel and then soaking in glycerol solution to depolymerize". This method is only suitable for two-dimensional films with a thickness of less than 0.2 mm. However, the central optical part of the intraocular lens has a significant three-dimensional thick structure. If the post-processing soaking method is used directly, the free diffusion of high-viscosity glycerol inside the thick gel is restricted, resulting in inconsistent depolymerization of collagen fibers in the surface and central regions of the gel. The surface depolymerization is thorough while the central depolymerization is insufficient, resulting in the generation of micro-density gradient and anisotropic stress concentration areas inside the optical part. When light passes through, birefringence and light scattering will occur. Moreover, the anisotropic swelling rate and refractive index distribution inside the hydrogel directly lead to distortion of the curvature of the lens surface, making it impossible to accurately predict and control the refractive power of the intraocular lens, and making it difficult to meet the ophthalmic optical-grade imaging quality requirements. (5) The single collagen network lacks a large strain molecular entanglement mechanism and cannot withstand the severe folding and high shear compression during minimally invasive injection, that is, the tear resistance and injection recovery are insufficient; In clinical minimally invasive surgery, the intraocular lens needs to undergo an extreme deformation process: the lens needs to be rolled and folded and forcibly squeezed into the narrow injector lumen with an inner diameter of only 2.0 to 2.8 mm. During the injection process, it is subjected to severe bending, compression and high shear stress. When undergoing large deformation folding, the local chemical cross-links are prone to irreversible breakage, especially at the junction of the optical part and the support loop (stress concentration area), where local micro-tears or breaks are extremely easy to occur; In addition, after the material is subjected to large strain compression, the plastic deformation ratio is high and the elastic recovery is slow. After the injection tube is removed, creases or optical micro-marks are easily left in the optical part, and it is impossible to achieve second-level non-destructive elastic recovery; (6) The overall flexural modulus of the material is low, lacking the biomechanical support and anti-capsule contraction ability required by the support haptics. After the intraocular lens is implanted in the eye, not only does the optical zone need to remain transparent, but the support haptics on both sides must resist the complex biomechanical environment inside the eye. However, the existing collagen hydrogel has a soft film shape, and its flexural modulus and compressive support are low, which makes it impossible for the support haptics to provide sufficient mechanical support to stably anchor the lens in the equator of the intraocular capsule. After cataract surgery, the capsule often undergoes natural organization and anterior capsule contraction. The lens support haptics with low modulus are very easy to bend, break or permanently tilt when compressed, which can lead to serious deviation or dislocation of the intraocular lens in the eye, resulting in severe postoperative astigmatism and refractive abnormalities.

[0004] Therefore, how to simultaneously and significantly improve the mechanical strength and tear resistance of collagen hydrogels while maintaining their high optical transparency and good biocompatibility, and endow them with long-term stability to achieve minimally invasive folding injection implantation, is a core technical challenge that urgently needs to be solved in the field of bio-based intraocular lenses. Summary of the Invention

[0005] Based on the aforementioned shortcomings and deficiencies in the prior art, one of the objectives of this invention is to at least solve one or more of the aforementioned problems in the prior art. In other words, one of the objectives of this invention is to provide a high-toughness transparent collagen hydrogel artificial lens and its preparation method that meet one or more of the aforementioned requirements.

[0006] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: A method for preparing a high-toughness transparent collagen hydrogel intraocular lens includes the following steps: (1) Type I collagen was dissolved in glacial acetic acid solution containing glycerol to obtain collagen precursor solution; (2) Add aldehyde-modified hyaluronic acid to collagen precursor solution for homogenization to obtain homogenized mixture and adjust pH to 7.2-7.4. Then remove air bubbles to obtain molding solution; (3) Inject the molding solution into the artificial lens mold and incubate it in a constant temperature incubator at 25-45℃ for 20-60 minutes to obtain collagen-hyaluronic acid original hydrogel; (4) The original collagen-hyaluronic acid hydrogel is immersed in a cross-linking solution to cross-link it, thereby obtaining a cross-linked hydrogel; wherein the cross-linking solution includes oxazolidine, glycerol and water; (5) The cross-linked hydrogel was immersed in PBS buffer for solvent replacement, so that the hydrogel reached swelling equilibrium in the physiological saline environment to obtain a high-toughness transparent collagen hydrogel artificial lens. Steps (1) and (2) are carried out at 0–4°C.

[0007] As a preferred embodiment, in step (1), the volume fraction of glycerol in the glacial acetic acid solution containing glycerol is 0.5-2%.

[0008] As a preferred embodiment, in step (1), the ratio of type I collagen to glacial acetic acid solution containing glycerol is (8-15) mg: 1 mL.

[0009] As a preferred embodiment, in step (1), the concentration of the glacial acetic acid solution is 0.5–2 M.

[0010] As a preferred embodiment, in step (2), the mass ratio of aldehyde-modified hyaluronic acid to type I collagen is 1:(2-10).

[0011] As a preferred embodiment, in step (2), homogenization is performed by stirring at a speed of 500-1000 rpm or by ultrasonic mixing for 10-20 min.

[0012] As a preferred embodiment, in step (2), the pH is adjusted by adding sodium hydroxide solution dropwise.

[0013] As a preferred embodiment, in step (2), air bubbles are removed by centrifugation at 10,000 to 20,000 rpm for 5 to 10 minutes.

[0014] The present invention also provides a high-toughness transparent collagen hydrogel intraocular lens prepared by the preparation method described in any of the preceding embodiments.

[0015] As a preferred option, the light transmittance of a high-toughness transparent collagen hydrogel intraocular lens is not less than 95%.

[0016] Compared with the prior art, the beneficial effects of this invention are: (1) This invention introduces polar glycerol directly during the thermodynamic self-assembly of collagen to achieve molecular-level uniform mixing of polar molecules and collagen molecules in the liquid-phase precursor stage, thereby in-situ regulating the depolymerization and nanoscale self-assembly of collagen fibers, completely eliminating the density gradient and stress concentration inside the thick gel, thus obtaining a collagen hydrogel artificial lens optical part with high light transmittance (>95%), isotropic properties and precise control of refractive power; (2) This invention introduces aldehyde-based hyaluronic acid HA-CHO into the system to construct a polymer entanglement network, and cooperates with oxazolidine to open the ring and undergo multifunctional chemical cross-linking to form a dual stress dissipation high toughness network of "physical entanglement-covalent cross-linking", thereby endowing the artificial lens with excellent tear resistance and large deformation elastic recovery, so as to achieve 180° folding, smooth passage through a 2.0-2.8mm micro-invasive injection lumen without micro-cracks, and rapid elastic recovery after exiting the tube; (3) This invention utilizes the rigid framework of aldehyde-modified hyaluronic acid polymer chains, multiple active amino sites, and the high-density cross-linking network of oxazolidine to synergistically enhance the flexural modulus and three-dimensional structural stability of the hydrogel, so that the support haptics of the artificial lens have sufficient biomechanical support force, which can effectively resist the natural organization and contraction pressure of the capsular bag after cataract surgery, prevent the lens from deviating or dislocating, and ensure its long-term centering and anatomical structural stability in the intraocular capsular bag. Attached Figure Description

[0017] Figure 1 This is a comparison chart of the transparency properties of the hydrogels Col-HA-CHO-OX and Col-HA-CHO in Example 1 of the present invention and the transparency properties of the thermally assembled collagen hydrogel in Comparative Example 1. Figure 2 This is a test diagram of the light transmittance of the hydrogel Col-HA-CHO-OX in Example 1 of the present invention; Figure 3 This is a diagram illustrating the rebound effect of the hydrogel Col-HA-CHO-OX from Embodiment 1 of the present invention; Figure 4 This is a curve showing the continuous stress relaxation behavior of the hydrogel Col-HA-CHO-OX under stepped strain in Embodiment 1 of the present invention. Figure 5 These are TEM images of collagen microfilaments generated by thermally induced self-assembly in Embodiment 1, Comparative Example 1, and Comparative Example 2 of the present invention; Figure 6 This is a test diagram of the light transmittance of the collagen hydrogel intraocular lens of Comparative Example 1 of this invention. Detailed Implementation

[0018] To more clearly illustrate the embodiments of the present invention, specific implementation methods will be described below with reference to the accompanying drawings. Obviously, the drawings described below are merely some embodiments of the present invention. For those skilled in the art, other drawings and other implementation methods can be obtained based on these drawings without any creative effort.

[0019] Example 1: The method for preparing the high-toughness transparent collagen hydrogel intraocular lens in this embodiment includes the following steps: (1) Synthesis of aldehyde-modified hyaluronic acid HA-CHO; 1.0 g of sodium hyaluronate (HA) with a molecular weight of 290 kDa (containing approximately 2.5 mmol of disaccharide repeating units) was dissolved in 100 mL of ultrapure water to prepare a 1 wt% homogeneous aqueous solution. The reaction flask was tightly wrapped with aluminum foil to protect it from light. 1 mL of 0.5 M sodium periodate (NaIO4) aqueous solution was added dropwise under rapid stirring. The reaction was carried out continuously at room temperature in the dark for 4 h. Sodium periodate was used to oxidize the ortho-hydroxyl group on D-glucuronic acid to a dialdehyde group through ring opening. After the reaction was completed, 0.5 mL of ethylene glycol was added, and the mixture was stirred in the dark for another 1 h to completely consume the residual NaIO4 and terminate the reaction. The reaction solution was then placed in a dialysis bag with a molecular weight cutoff of 3500 Da and purified by dialyzing with ultrapure water in the dark for 3 days to remove unreacted small molecules and byproducts. Finally, the purified product was pre-frozen and freeze-dried in a vacuum freeze dryer for 72 h to obtain a white, spongy aldehyde-modified hyaluronic acid (HA-CHO) solid. The solid was sealed and stored at -20 °C in the dark. (2) Preparation of highly transparent collagen-hyaluronic acid hydrogel Col-HA-CHO; Collagen acid dissolution and preparation of polar molecular precursor solution: Accurately weigh 10 mg of type I collagen (extracted from fetal bovine hide) and add it to 1 mL of 0.5 M glacial acetic acid aqueous solution containing 0.5% (v / v) glycerol. Stir continuously with magnetic force for 24 h under ice bath conditions at 4 °C to allow the collagen to fully swell and completely dissolve, and prepare a homogeneous collagen-glycerol acidic precursor solution without insoluble matter. Introduction and homogenization of polymer entanglement network components: Add a pre-prepared 2 mg / mL HA-CHO aqueous solution (or directly weigh 2 mg of HA-CHO solid) to the above collagen-glycerol acidic precursor solution at a mass ratio of 5:1 for type I collagen to aldehyde-modified hyaluronic acid HA-CHO. Stir at 1000 rpm for 10 min under 4°C ice bath and light-proof conditions to allow the aldehyde-modified hyaluronic acid polymer chains to fully diffuse and uniformly disperse between collagen monomer molecules, forming a homogeneous mixture with polymer entanglement potential. pH neutralization and physiological ionic environment construction: The entire process was carried out in an ice bath at 4°C (to prevent premature thermodynamic self-assembly of collagen). 5M sodium hydroxide solution was added dropwise to the homogenized mixture. The pH value of the mixture was monitored and precisely adjusted to the physiological neutral range, i.e., pH 7.2 to 7.4. The reaction solution was then centrifuged at 4°C and 10,000 rpm for 10 minutes to completely eliminate the tiny bubbles generated in the system during pH adjustment. Molding and in-situ nano-self-assembly: The neutral precursor mixture after degassing was rapidly injected into a pre-cleaned and sterilized polytetrafluoroethylene mold containing the optical part of an artificial lens and a support loop structure. The mold cover was then tightly closed to prevent moisture evaporation. The mold was then placed in a 37°C constant temperature incubator and incubated for 30 minutes. During this process, glycerol participated in in-situ regulation in the liquid phase, synergistically inhibiting excessive coarsening of collagen fibers with HA-CHO. This enabled collagen monomers to self-assemble in situ into a nanoscale microfilament network structure with a fiber diameter of less than 20 nm. At the same time, HA-CHO molecular chains interpenetrated in the collagen network to form physical entanglements, ultimately obtaining a collagen-hyaluronic acid original hydrogel Col-HA-CHO with a fixed shape, complete gelation, and extremely high optical transparency. (3) Preparation of strong and tough collagen-based intraocular lenses; Preparation of crosslinking soaking solution: Accurately measure ultrapure water and glycerol, mix them at a volume ratio of 1:1 to prepare a 50% (v / v) glycerol aqueous solution; add oxazolidine crosslinking agent to the above solution, stir magnetically until completely dissolved, and prepare a chemical crosslinking soaking solution with 2% (w / v) oxazolidine mass volume percentage and containing 50% (v / v) glycerol, for later use; Multiple covalent crosslinking and three-dimensional network curing: The demolded collagen-hyaluronic acid original hydrogel Col-HA-CHO was completely immersed in the above chemical crosslinking soaking solution and placed in a constant temperature shaking shaker at 37℃, and gently shaken at a low speed of 50 rpm for 30 min. During the soaking process, the active groups generated by the ring opening of oxazolidine undergo multifunctional covalent crosslinking with the free amino groups on the collagen chain and the functional groups on the aldehyde-modified hyaluronic acid HA-CHO. At the same time, the high concentration of glycerol maintains and consolidates the stable dispersion of collagen nanofibers, and constructs a dual stress dissipation three-dimensional tough network in the hydrogel, which combines the "collagen-HA-CHO" covalent network with polymer physical entanglement. Solvent replacement and equilibration washing: The cross-linked hydrogel was removed and washed three times with 0.01M PBS buffer (pH 7.4) to remove residual cross-linking agent on the surface. Then, the hydrogel was immersed in 0.01M PBS buffer for equilibration soaking for 48 hours (with the PBS washing solution changed three times during this period) to completely replace and wash away unreacted oxazolidine small molecules and excess glycerol, allowing the hydrogel to reach swelling equilibrium in physiological saline environment, and finally obtaining high toughness transparent collagen hydrogel artificial lens Col-HA-CHO-OX, which was sealed in sterile PBS buffer and stored at 4°C in the dark.

[0020] Example 2: The method for preparing the high-toughness transparent collagen hydrogel intraocular lens in this embodiment includes the following steps: (1) The synthesis of aldehyde-modified hyaluronic acid HA-CHO is the same as in Example 1, and will not be repeated here; (2) Preparation of highly transparent collagen-hyaluronic acid hydrogel Col-HA-CHO; Collagen acid dissolution and preparation of polar molecular precursor solution: Accurately weigh 8 mg of type I collagen (extracted from fetal bovine hide), add it to 1 mL of 1 M glacial acetic acid aqueous solution containing 2% (v / v) glycerol, and continuously stir magnetically for 12 h under 0℃ ice bath conditions to allow the collagen to fully swell and completely dissolve, thus obtaining a homogeneous collagen-glycerol acidic precursor solution without insoluble matter; Introduction and homogenization of polymer entanglement network components: Add a pre-prepared 4 mg / mL HA-CHO aqueous solution (or directly weigh 4 mg of HA-CHO solid) to the above collagen-glycerol acid precursor solution at a mass ratio of 2:1 for type I collagen to aldehyde-modified hyaluronic acid HA-CHO. Stir at 500 rpm for 20 min under 0°C ice bath and light-proof conditions to allow the aldehyde-modified hyaluronic acid polymer chains to fully diffuse and uniformly disperse between collagen monomer molecules, forming a homogeneous mixture with polymer entanglement potential. pH neutralization and physiological ionic environment construction: The entire process was carried out in an ice bath at 0°C (to prevent premature thermodynamic self-assembly of collagen). 5M sodium hydroxide solution was added dropwise to the homogenized mixture. The pH value of the mixture was monitored and precisely adjusted to the physiological neutral range, i.e., pH 7.2 to 7.4. The reaction solution was then centrifuged at 2°C and 20,000 rpm for 5 minutes to completely eliminate the tiny bubbles generated in the system during pH adjustment. Molding and in-situ nano-self-assembly: The neutral precursor mixture after degassing was rapidly injected into a pre-cleaned and sterilized polytetrafluoroethylene mold with an artificial lens optical part and a support loop curved surface structure. The mold cover was then tightly closed to prevent moisture evaporation. The mold was then placed in a 25°C constant temperature incubator and incubated for 60 minutes. During this process, glycerol participated in in-situ regulation in the liquid phase, synergistically inhibiting excessive coarsening of collagen fibers with HA-CHO. This enabled collagen monomers to self-assemble in situ into a nanoscale microfilament network structure with a fiber diameter of less than 20 nm. At the same time, HA-CHO molecular chains interpenetrated in the collagen network to form physical entanglements, ultimately obtaining a collagen-hyaluronic acid original hydrogel Col-HA-CHO with a fixed shape, complete gelation, and extremely high optical transparency. (3) The preparation of the tough collagen-based intraocular lens is the same as in Example 1, and will not be repeated here.

[0021] Example 3: The preparation method of the collagen hydrogel intraocular lens in this embodiment includes the following steps: (1) The synthesis of aldehyde-modified hyaluronic acid HA-CHO is the same as in Example 1, and will not be repeated here; (2) Preparation of highly transparent collagen-hyaluronic acid hydrogel Col-HA-CHO; Collagen acid dissolution and preparation of polar molecular precursor solution: Accurately weigh 15 mg of type I collagen (extracted from fetal bovine hide), add it to 1 mL of 2 M glacial acetic acid aqueous solution containing 1% (v / v) glycerol, and continuously stir magnetically for 18 h under ice bath conditions at 3℃ to allow the collagen to fully swell and completely dissolve, thus obtaining a homogeneous collagen-glycerol acidic precursor solution without insoluble matter; Introduction and homogenization of polymer entanglement network components: Add a pre-prepared 1.5 mg / mL HA-CHO aqueous solution (or directly weigh 1.5 mg HA-CHO solid) to the above collagen-glycerol acidic precursor solution at a mass ratio of 10:1 for type I collagen to aldehyde-modified hyaluronic acid HA-CHO. Stir at 800 rpm for 15 min under 3°C ice bath and light-proof conditions to allow the aldehyde-modified hyaluronic acid polymer chains to fully diffuse and uniformly disperse between collagen monomer molecules, forming a homogeneous mixture with polymer entanglement potential. pH neutralization and physiological ionic environment construction: The entire process was carried out in an ice bath at 3°C ​​(to prevent premature thermodynamic self-assembly of collagen). 5M sodium hydroxide solution was added dropwise to the homogenized mixture. The pH value of the mixture was monitored and precisely adjusted to the physiological neutral range, i.e., pH 7.2 to 7.4. The reaction solution was then centrifuged at 3°C ​​and 15,000 rpm for 8 minutes to completely eliminate the tiny bubbles generated in the system during pH adjustment. Molding and in-situ nano-self-assembly: The neutral precursor mixture after degassing was rapidly injected into a pre-cleaned and sterilized polytetrafluoroethylene mold with an artificial lens optical part and a support loop curved surface structure. The mold cover was then tightly closed to prevent moisture evaporation. The mold was then placed in a 45°C constant temperature incubator and incubated for 20 minutes. During this process, glycerol participated in in-situ regulation in the liquid phase, synergistically inhibiting excessive coarsening of collagen fibers with HA-CHO. This enabled collagen monomers to self-assemble in situ into a nanoscale microfilament network structure with a fiber diameter of less than 20 nm. At the same time, HA-CHO molecular chains interpenetrated in the collagen network to form physical entanglements, ultimately obtaining a collagen-hyaluronic acid original hydrogel Col-HA-CHO with a fixed shape, complete gelation, and extremely high optical transparency. (3) The preparation of the tough collagen-based intraocular lens is the same as in Example 1, and will not be repeated here.

[0022] Comparative Example 1: The preparation method of the collagen hydrogel intraocular lens in this comparative example differs from that in Example 1 in that: The glacial acetic acid aqueous solution in step (2) does not contain glycerol, and the remaining steps are the same as in Example 1.

[0023] Comparative Example 2: The preparation method of the collagen hydrogel intraocular lens in this comparative example differs from that in Example 1 in that: Replace glycerol with ethanol in step (2); The other steps are the same as in Example 1.

[0024] like Figure 1 As shown, the thermally assembled collagen hydrogel obtained in Comparative Example 1 (i.e., the hydrogel obtained before crosslinking soaking) is prone to disorder and excessive aggregation of collagen molecules during thermally induced self-assembly, which leads to severe light scattering, resulting in an overall turbid state and poor light transmittance of the gel, and the "ZJU" text mark at the bottom of the gel is relatively blurry. However, after introducing glycerol to synergistically regulate the self-assembly process of collagen fibers, glycerol effectively limits the excessive lateral aggregation of fibers, promoting the formation of a uniform nanoscale filament structure in the gel network. Therefore, the self-assembled hydrogel Col-HA-CHO exhibits excellent optical transparency, and the "ZJU" text mark at the bottom can be clearly seen through the gel. After further chemical crosslinking modification with oxazolidine OX, the gel Col-HA-CHO-OX still perfectly retains its high light transmittance characteristics, and the details of the flower pattern at the bottom are still clear and bright, indicating that crosslinking has not destroyed the uniformity of its microstructure. like Figure 2 As shown, the high-toughness transparent collagen hydrogel intraocular lens Col-HA-CHO-OX prepared in Example 1 maintains a transmittance T of over 95% in the ultraviolet-visible light band of 350-800nm. Its optical performance is comparable to the transmittance standard of clinical intraocular lenses (IOLs), and it has great potential as a high-quality ophthalmic optical biomaterial. As an ophthalmic implant material such as an intraocular lens, hydrogels, in addition to excellent optical transparency, must also possess outstanding mechanical toughness and superelasticity to meet the clinical operational needs of repeated folding and compression during minimally invasive surgeries (such as injection implantation through small incisions) and rapid recovery to their original shape after implantation. Figure 3 As shown, the collagen hydrogel intraocular lens Col-HA-CHO-OX of Example 1 exhibits extremely excellent flexibility and structural recovery. After undergoing multiple 180° drastic folding and high strain compression, it can quickly rebound to its initial shape without any cracks or brittle fractures. Further continuous stress relaxation cycle testing, such as Figure 4 As shown, the stress relaxation time of the collagen hydrogel intraocular lens Col-HA-CHO-OX in Example 1 remained highly consistent under different strain levels, demonstrating independence from strain levels. This not only confirms the uniform distribution of dynamic covalent bonds and physical entanglements within the cross-linked network, but also illustrates its excellent structural durability and mechanical stability in complex mechanical microenvironments, providing a solid mechanical guarantee for clinical compliance during minimally invasive implantation. like Figure 5 As shown, in Comparative Example 1, if glycerol is not added to the precursor solution for collagen thermal self-assembly, i.e., only thermal assembly occurs, collagen molecules will rapidly undergo disordered lateral hydrophobic aggregation under thermodynamic drive, forming relatively thick collagen fiber bundles of 50 nm with large pore size and uneven distribution. In contrast, Example 1 introduces glycerol in the liquid-phase precursor stage, utilizing the polyhydroxy structure of glycerol to form extensive and uniform hydrogen bonds with the side chains of collagen molecules, increasing the viscosity of the solvent phase and intermolecular damping. Subsequently, when thermally induced self-assembly is initiated at 37°C, glycerol in the liquid phase... The position restricts excessive lateral aggregation of collagen monomers, anchoring the collagen self-assembly process in a nanoscale microfilament network structure with a fiber diameter of 12.5 nm and uniform pore size. In contrast, in Comparative Example 2, if glycerol is replaced with ethanol, the self-assembly forms a coarser collagen fiber bundle of 46 nm, which is much larger than the fiber diameter in Example 1. According to Rayleigh scattering theory, the intensity of scattered light is proportional to the sixth power of the fiber diameter. The coarse fibers formed in the liquid phase of Comparative Example 1 without the addition of glycerol will produce severe light scattering of visible light in the 350–800 nm range, resulting in gel turbidity (e.g., ...). Figure 1 As shown), the light transmittance is less than 70%, such as Figure 6 As shown; however, in Example 1, the diameter of collagen microfilaments generated by thermally induced self-assembly is limited to the nanoscale (<20nm) by utilizing hydrogen bonding coordination between glycerol and collagen molecules in the liquid phase. This significant reduction in the size of the nanonetwork completely eliminates the light scattering phenomenon of collagen gel, thereby increasing the light transmittance of the three-dimensional thick lens to over 95%, eliminating the optical anisotropy inside the thick optical part, and endowing the material with high tear resistance and rapid shape memory recovery performance during the minimally invasive folding injection process.

[0025] Given that there are numerous embodiments of the present invention, and the raw materials and quantities involved can be selected within a limited range according to actual needs, and that the experimental data for each embodiment are extensive and numerous, it is not suitable to list and describe them one by one here. However, the content to be verified and the final conclusions obtained in each embodiment are similar. Therefore, the verification content of each embodiment will not be described one by one here.

[0026] The above description is merely a detailed explanation of preferred embodiments and principles of the present invention. For those skilled in the art, there may be changes in specific implementation methods based on the ideas provided by the present invention, and these changes should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a high-toughness transparent collagen hydrogel intraocular lens, characterized in that, Includes the following steps: (1) Type I collagen was dissolved in glacial acetic acid solution containing glycerol to obtain collagen precursor solution; (2) Add aldehyde-modified hyaluronic acid to collagen precursor solution for homogenization to obtain homogenized mixture and adjust pH to 7.2-7.

4. Then remove air bubbles to obtain molding solution; (3) Inject the molding solution into the artificial lens mold and place it in a constant temperature incubator at 25-45℃ for 20-60 minutes to obtain collagen-hyaluronic acid original hydrogel; (4) The original collagen-hyaluronic acid hydrogel is immersed in a cross-linking solution to cross-link it, thereby obtaining a cross-linked hydrogel; wherein the cross-linking solution includes oxazolidine, glycerol and water; (5) The cross-linked hydrogel was immersed in PBS buffer for solvent replacement to obtain a high-toughness transparent collagen hydrogel artificial lens; Steps (1) and (2) are carried out at 0–4°C.

2. The preparation method according to claim 1, characterized in that, In step (1), the volume fraction of glycerol in the glacial acetic acid solution containing glycerol is 0.5-2%.

3. The preparation method according to claim 2, characterized in that, In step (1), the ratio of type I collagen to glacial acetic acid solution containing glycerol is (8-15) mg: 1 mL.

4. The preparation method according to claim 2, characterized in that, In step (1), the concentration of the glacial acetic acid solution is 0.5–2 M.

5. The preparation method according to claim 1, characterized in that, In step (2), the mass ratio of aldehyde-modified hyaluronic acid to type I collagen is 1:(2-10).

6. The preparation method according to claim 1, characterized in that, In step (2), homogenization is performed by stirring at a speed of 500-1000 rpm or by ultrasonic mixing for 10-20 minutes.

7. The preparation method according to claim 1, characterized in that, In step (2), the pH is adjusted by adding sodium hydroxide solution dropwise.

8. The preparation method according to claim 1, characterized in that, In step (2), air bubbles are removed by centrifugation at 10,000 to 20,000 rpm for 5 to 10 minutes.

9. A high-toughness transparent collagen hydrogel intraocular lens prepared by the preparation method according to any one of claims 1-8.

10. The high-toughness transparent collagen hydrogel intraocular lens according to claim 9, characterized in that, Light transmittance is not less than 95%.

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