A light-triggered intelligent drug delivery coating, an intraocular lens and a preparation method and application thereof

Abstract

The present application relates to a kind of light trigger intelligent drug delivery coating, intraocular lens and its preparation method and application, specifically, hollow mesoporous silica nanovescle / polydopamine composite coating structure.The nanovescle is used as nanowarehouse, and hydrophilic antibiotic moxifloxacin hydrochloride and hydrophobic anti-inflammatory drug dexamethasone and other drugs are jointly loaded;The polydopamine layer has strong adhesion and photo-thermal conversion capacity, can firmly adhere to matrix, and realize the accurate release of drug under the external near-infrared light irradiation.The present application realizes the active and synergistic prevention and control of postoperative complications on demand, can provide long-acting "standby" protection by single implantation, significantly improves the safety, efficiency and convenience of treatment, effectively reduces the risk of endophthalmitis and postoperative cataract.The present application overcomes the technical defects of low bioavailability, poor patient compliance, uncontrollable drug release, single function, coating easy to fall off and other technical defects in the prior art of preventing complications by relying on eye drops after cataract surgery.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials and ophthalmic implantation devices, specifically relating to a light-triggered intelligent drug delivery coating, an intraocular lens, its preparation method, and its application. Background Technology

[0002] Cataract surgery is one of the most commonly performed surgical procedures worldwide, and intraocular lens (IOL) implantation is a standard postoperative procedure. However, postoperative complications remain a major challenge affecting surgical outcomes and patient prognosis, with endophthalmitis caused by bacterial infection and posterior cataract (PCO) resulting from lens epithelial cell proliferation being the most serious.

[0003] Current clinical prevention strategies have significant technical shortcomings: passive postoperative medication relies on frequent instillation of antibiotics and steroid eye drops, a model with serious limitations. Patient compliance is poor; complex medication frequencies and multiple drug combinations easily lead to errors or treatment interruptions in elderly patients. Intraocular bioavailability is extremely low (<5%); eye drops are lost through the nasolacrimal duct, making it difficult to penetrate the cornea and reach the target site, failing to form effective drug concentrations on the IOL surface and within the capsular pocket. Pharmacokinetics are poor; pulsatile dosing causes drastic fluctuations in intraocular drug concentration, exhibiting a "peak-trough" phenomenon—peak values ​​may cause toxic reactions, while trough values ​​fail to effectively inhibit pathogens.

[0004] Existing drug-loaded IOL technology also has limitations: (1) Uncontrollable drug release: Most drug-loaded IOLs in the study use drug blending, surface immersion or simple coating technology, which rely on free diffusion of drugs and have a serious initial burst release effect—more than 70% of the drug is rapidly released within 24-48 hours after implantation, making it difficult to maintain therapeutic concentration during the critical postoperative risk period (several days to several weeks).

[0005] (2) Single function and lack of synergy: Most designs are only for a single complication (or antibacterial or anti-PCO), which cannot cope with the complex and potentially concurrent pathological environment after surgery, and lack intelligent systems that can release different drugs on demand.

[0006] (3) Challenges in coating stability and biocompatibility: The physical adsorption coating has weak adhesion to the hydrophobic acrylate IOL substrate and is prone to detachment due to friction during implantation. The long-term biocompatibility of nano-coating materials in the eye also presents significant challenges.

[0007] (4) Dilemma of biofilm therapy: Once bacteria form a biofilm on the surface of IOL, their antibiotic resistance can increase by up to a thousand times. Conventional continuous low-concentration drug release modes are difficult to penetrate the biofilm, ultimately leading to prevention and treatment failure.

[0008] There is an urgent need in this field for novel functionalized IOL technologies that can overcome the aforementioned deficiencies. An ideal solution should possess: ① extremely high drug loading and stability, eliminating initial burst release; ② on-demand intelligent release capability, initiating pulse therapy upon the appearance of signs of complications; ③ synergistic therapeutic function, simultaneously addressing infection and inflammation / proliferation; ④ excellent coating durability and biocompatibility. Summary of the Invention

[0009] The purpose of this invention is to overcome the shortcomings of the prior art and provide a light-triggered smart drug delivery coating, an artificial lens, its preparation method, and its application.

[0010] To achieve the above objectives, the present invention provides the following technical solution: In a first aspect, this application provides a light-triggered smart drug delivery coating for ophthalmic implants, comprising: Nanocarrier units loaded with at least two therapeutic agents, wherein the at least two therapeutic agents have different water solubility; A polydopamine-responsive layer covering the outside of the nanocarrier unit; The polydopamine responsive layer can absorb external near-infrared light and generate a thermal effect, thereby triggering the on-demand and synergistic release of different drugs from the nanocarrier unit.

[0011] Optionally, the nanocarrier unit is an inorganic hollow mesoporous nanomaterial; the inorganic hollow mesoporous nanomaterial is a hollow mesoporous silica nanovesicle.

[0012] Optionally, the at least two therapeutic agents include a hydrophilic antibiotic and a hydrophobic anti-inflammatory drug; The hydrophilic antibiotic is selected from fluoroquinolone antibiotics, and the hydrophobic anti-inflammatory drug is selected from glucocorticoids.

[0013] Optionally, the hydrophilic antibiotic is moxifloxacin hydrochloride, and the hydrophobic anti-inflammatory drug is dexamethasone or dexamethasone acetate.

[0014] Optionally, the coating is configured such that different drugs have differentiated release kinetic curves under a single near-infrared light triggering, in order to achieve time-sequential release.

[0015] Secondly, this application provides a smart artificial lens, wherein at least a portion of the surface of its optical part is provided with the aforementioned light-triggered smart drug delivery coating.

[0016] Thirdly, this application provides a method for preparing the above-mentioned intelligent artificial lens, comprising the following steps: Provide an artificial lens substrate and perform surface activation treatment; Provide nanocarriers loaded with therapeutic drugs; The surface-activated artificial lens substrate, the drug-loaded nanocarrier, and the dopamine monomer are placed together in an alkaline buffer solution for a one-step in-situ oxidative polymerization reaction, so that the polydopamine layer coats the nanocarrier and is simultaneously and firmly deposited on the surface of the substrate to form the coating.

[0017] Optionally, the surface activation treatment is: oxygen plasma treatment or ultraviolet ozone treatment; The alkaline buffer solution is a Tris-HCl buffer solution with a pH of 8.0-9.0; The one-step in-situ oxidative polymerization reaction was carried out at room temperature, in the dark, and with slow stirring for 4-24 hours.

[0018] Fourthly, this application provides the use of the above-described intelligent intraocular lens in the preparation of a medical device for the prevention or treatment of postoperative ophthalmic complications, including bacterial endophthalmitis and / or posterior cataract. The thermal effect generated by the near-infrared light triggering has a synergistic effect with the released antibacterial drugs in preventing and eliminating bacterial biofilms.

[0019] Fifthly, this application provides a method for preventing and controlling postoperative complications of the eye, including: implanting the aforementioned intelligent intraocular lens into the patient's eye; When drug administration is required, the intraocular lens is irradiated with near-infrared light with a wavelength of 780-1100 nm at a power density of 0.3-1.5 W / cm² to trigger drug release. Drug release kinetics can be regulated by controlling irradiation parameters.

[0020] Compared with existing technologies, the significant advantage of this invention lies in its construction of a three-in-one intelligent coating structure: a core-shell-trigger system. Using hollow mesoporous silica nanovesicles as the "core," its unique cavity-mesoporous structure enables the regional co-loading of hydrophilic antibiotics and hydrophobic anti-inflammatory drugs. Using polydopamine as the "shell," it acts as both a "molecular glue" firmly adhering to the surface of the artificial lens and a photothermal conversion agent functioning as a "smart switch." Finally, precise "triggering" is achieved through non-invasive near-infrared light. During illumination, a local thermal effect is generated, prompting a synergistic pulsed release of the drug. The release automatically slows down when illumination ceases, thus achieving on-demand, precise, and synergistic prevention and treatment of postoperative complications. A single implantation provides long-lasting "standby" protection, significantly improving treatment safety, efficiency, and convenience, and effectively reducing the risk of endophthalmitis and secondary cataracts. This technology overcomes the shortcomings of existing cataract surgery reliance on eye drops for complication prevention, such as low bioavailability, poor patient compliance, uncontrollable drug release, limited function, and easy coating detachment. Specifically: (1) A revolutionary on-demand drug delivery model: shifting from "continuous flooding" to "precision dripping", releasing drugs only when doctors determine that they are needed, greatly improving treatment efficiency and safety, and avoiding drug waste and potential toxicity.

[0021] (2) Excellent synergistic treatment advantages: Simultaneously address the dual threats of bacterial infection and inflammation / PCO, and achieve synergistic effects of two drugs with a single trigger, which is in line with the complex pathophysiological mechanism after surgery.

[0022] (3) Breakthrough coating stability: The strong adhesion properties of polydopamine ensure that the coating remains intact during implantation, avoiding the risk of detachment during folding injection.

[0023] (4) Long-lasting intelligent protection characteristics: The nano-warehouse structure ensures excellent initial drug loading and long-term storage stability, enabling the artificial lens to have "standby" prevention and control capabilities for several months after implantation.

[0024] (5) Outstanding clinical feasibility: Near-infrared light has both deep tissue penetration and safety, is easy to integrate with existing ophthalmic equipment (such as slit lamp), is easy to operate, and is conducive to clinical promotion. Attached Figure Description

[0025] Figure 1 This is a schematic diagram illustrating a light-triggered intelligent drug delivery coating, an intraocular lens, its preparation method, and its application according to the present invention. Detailed Implementation

[0026] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Furthermore, in this invention, an element referred to as fixed to or disposed on another element can be directly disposed on the other element, or there may be an intermediate element present. When an element is considered to be connected to another element, it can be directly connected to the other element, or there may be an intermediate element present simultaneously. The terms vertical, horizontal, left, right, and similar expressions used herein are for illustrative purposes only and do not represent the only possible embodiments.

[0028] The following examples are combined Figure 1This application provides a light-triggered smart drug delivery coating for ophthalmic implants, comprising: a nanocarrier unit loaded with at least two therapeutic drugs, wherein the at least two drugs have different water solubility; a polydopamine responsive layer covering the outside of the nanocarrier unit; wherein the polydopamine responsive layer is capable of absorbing external near-infrared light and generating a thermal effect, thereby triggering the on-demand and synergistic release of different drugs from the nanocarrier unit.

[0029] The nanocarrier unit is preferably mesoporous silica nanoparticles or polylactic-co-glycolic acid copolymer (PLGA) nanospheres, which have high specific surface area, ordered mesoporous structure, and good biocompatibility. It can load at least two drugs, such as the lipid-soluble anti-inflammatory drug dexamethasone and the water-soluble antibiotic levofloxacin, targeting common post-ophthalmic implantation inflammatory reactions and bacterial infections, respectively. The different water solubilities allow for spatial distribution differences in the drugs within the carrier: lipid-soluble drugs are mostly embedded in the mesopores inside the carrier, while water-soluble drugs are adsorbed onto the carrier surface. The polydopamine-responsive layer uniformly coats the outside of the nanocarrier unit through a self-polymerization reaction. Its rich catechol groups not only endow the coating with excellent bioadhesion, enhancing the adhesion between the coating and the ophthalmic implant surface, but also efficiently absorb 700-1100nm near-infrared light and convert it into heat energy, raising the local temperature to 40-45℃. This temperature range does not damage ocular tissue but can trigger drug release. When exposed to near-infrared light, the thermal effect of polydopamine initially causes the water-soluble drug on the surface of the nanocarrier to be rapidly released due to changes in the carrier's surface charge and disruption of the hydration layer, quickly reaching an effective therapeutic concentration to address acute infections. Subsequently, the sustained thermal effect gradually expands the mesopores within the carrier, weakening the hydrophobic interaction between the lipid-soluble drug and the carrier, promoting its slow and continuous release, and achieving long-term control of chronic inflammation. This design, based on differences in drug water solubility and thermal response mechanisms, can meet the treatment needs at different stages after ophthalmic surgery, such as the need for rapid infection control 1-3 days post-surgery and the need for sustained inflammation suppression 1-2 weeks post-surgery. It enables the on-demand release and synergistic effect of two drugs, significantly improving drug utilization efficiency and reducing the side effects of overdose of a single drug.

[0030] In one specific embodiment, the nanocarrier unit is an inorganic hollow mesoporous nanomaterial; the inorganic hollow mesoporous nanomaterial is a hollow mesoporous silica nanovesicle.

[0031] In one specific embodiment, the nanocarrier unit is an inorganic hollow mesoporous nanomaterial; the inorganic hollow mesoporous nanomaterial is a hollow mesoporous silica nanovesicle with a regular core-shell structure, the core being a hollow cavity (approximately 100-200 nm in diameter), and the shell being ordered mesoporous channels (pore size 2-5 nm). Its high specific surface area (800-1200 m² / g) and large pore volume (0.5-1.0 cm³ / g) enable efficient encapsulation of water-soluble drugs (such as levofloxacin) within the hollow cavity (loading capacity up to 20-30 wt%) and precise anchoring of lipid-soluble drugs (such as dexamethasone) within the mesoporous channels (loading capacity 15-25 wt%). The wall thickness of the mesoporous channels is 10-20 mm. The pore size (nm) can be controlled by adjusting the amount of hexadecyltrimethylammonium bromide (CTAB) template agent to match the diffusion kinetics of different drug molecules. In addition, the surface of the hollow mesoporous silica nanovesicles is rich in silanol groups, which can form hydrogen bond interactions with the catechol groups of the polydopamine responsive layer, further enhancing the binding stability of the coating and the nanocarrier and preventing premature drug leakage. At the same time, its good biocompatibility (cell survival rate >95%, no obvious inflammatory reaction after 1 month of implantation in rabbit eyes) ensures the safety of ophthalmic applications.

[0032] In one specific embodiment, the at least two therapeutic agents include a hydrophilic antibiotic and a hydrophobic anti-inflammatory drug; the hydrophilic antibiotic is selected from fluoroquinolone antibiotics, and the hydrophobic anti-inflammatory drug is selected from glucocorticoids.

[0033] In one specific embodiment, the at least two therapeutic agents include a hydrophilic antibiotic and a hydrophobic anti-inflammatory drug; the hydrophilic antibiotic is selected from fluoroquinolone antibiotics, preferably levofloxacin, moxifloxacin, or ciprofloxacin. These drugs have broad-spectrum antibacterial activity and strong inhibitory effects on pathogenic bacteria commonly found after ophthalmic surgery, such as Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa. They also have good water solubility and can fully fill the hollow mesoporous silica nanovesicles with a diameter of 100-200 nm, achieving a high loading of 20-30 wt% through the large pore volume of the cavity; the hydrophobic anti-inflammatory drug is selected from glucocorticoids, preferably dexamethasone, prednisolone, or fluorometholone. Its lipid-soluble molecular structure can form van der Waals forces and hydrophobic interactions with the inner wall of the mesoporous channels with a pore size of 2-5 nm, achieving a loading of 15-25 wt%. With precise anchoring at wt%, this type of drug can effectively inhibit complications such as anterior chamber inflammation and posterior synechia caused by foreign body reaction after intraocular lens implantation. It works synergistically with fluoroquinolone antibiotics to exert a dual therapeutic effect of anti-infection and anti-inflammation, covering the two key pathological processes of infection and inflammation commonly seen after ophthalmic surgery.

[0034] In one specific embodiment, the hydrophilic antibiotic is moxifloxacin hydrochloride, and the hydrophobic anti-inflammatory drug is dexamethasone or dexamethasone acetate.

[0035] Moxifloxacin hydrochloride, a representative drug of fluoroquinolone antibiotics, has excellent water solubility and can completely fill the hollow cavities of mesoporous silica nanovesicles with a diameter of 100-200 nm. Relying on the large pore volume of the cavity, it can achieve a high loading of 25-30 wt%, and has a strong inhibitory effect on pathogenic bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa, which are common in ophthalmic surgery. Dexamethasone or dexamethasone acetate is a commonly used variety of glucocorticoid. Its lipid-soluble molecular structure can form stable van der Waals forces and hydrophobic interactions with the inner wall of mesoporous channels with a pore size of 2-5 nm, achieving precise anchoring of 18-25 wt%. It can specifically inhibit complications such as anterior chamber inflammation and posterior synechiae caused by foreign body reaction after intraocular lens implantation. The two work synergistically to cover the broad-spectrum anti-infective needs with moxifloxacin hydrochloride and enhance the anti-inflammatory effect with dexamethasone / dexamethasone acetate, comprehensively covering the two key pathological processes of postoperative ophthalmic infection and inflammation, and significantly improving the therapeutic effectiveness of the light-triggered smart drug delivery coating.

[0036] In one specific embodiment, the coating is configured such that different drugs have differentiated release kinetic curves under a single near-infrared light triggering, thereby achieving time-sequential release.

[0037] Specifically, moxifloxacin hydrochloride, because it is filled in a hollow cavity with a diameter of 100-200 nm, has only weak electrostatic or hydrogen bond interactions with the cavity wall. Under the photothermal effect triggered by near-infrared light, the cavity structure expands slightly, and the drug can achieve a rapid burst release of 40%-50% within 30 minutes, quickly reaching an effective concentration to inhibit pathogenic bacteria such as Staphylococcus aureus and Staphylococcus epidermidis. On the other hand, dexamethasone / dexamethasone acetate is anchored in mesoporous channels with a pore size of 2-5 nm. Its lipid-soluble molecules have stronger van der Waals forces and hydrophobic interactions with the inner wall of the channels. After photo-triggered release, these interactions need to be gradually overcome, resulting in a slow and continuous release. The release rate reaches 60%-70% within 24 hours, and low-dose continuous release can be maintained for the following 72 hours. This "rapid-continuous" sequential release pattern precisely matches the pathological progression of ophthalmic surgery: rapid infection control in the early stage (0-24 hours), sustained inflammation suppression in the middle stage (24-72 hours), and prevention of chronic adhesions in the late stage (over 72 hours). The rapid release of moxifloxacin in the early stage quickly inhibits bacterial growth at the wound site, while the sustained release of dexamethasone in the middle stage effectively suppresses anterior chamber inflammation caused by foreign body reaction. The low-dose maintenance release in the late stage further reduces the risk of long-term complications such as posterior iris adhesions. Compared to systems that release two drugs simultaneously, this sequential release pattern increases the inhibition rate of postoperative infection by 25%-30% and the relief rate of anterior chamber inflammation by 18%-25%, further enhancing the anti-infective and anti-inflammatory therapeutic effects and significantly improving the clinical application value of the light-triggered intelligent drug delivery coating.

[0038] Secondly, this application provides a smart artificial lens, wherein at least a portion of the surface of its optical part is provided with the aforementioned light-triggered smart drug delivery coating.

[0039] This coating, once implanted with the intraocular lens (IOL), precisely triggers drug release via external light stimulation. Its rapid and continuous time-sequential release perfectly matches the dynamic pathological process of intraocular wound repair after cataract surgery. Early rapid release of moxifloxacin inhibits bacterial colonization of the surgical incision and anterior chamber; mid-term continuous release of dexamethasone alleviates inflammation of the lens capsule and iris; and late-stage low-dose maintenance release reduces the risk of long-term complications such as capsule opacification and posterior synechiae. Compared to traditional IOLs without this coating, the intelligent IOL significantly reduces the frequency of postoperative topical eye drops from 4-6 times daily to 1-2 times, improving patient adherence. Simultaneously, the targeted and time-sequential drug release further enhances the stability of the postoperative intraocular microenvironment, reducing the incidence of complications such as macular edema and capsular contraction, providing a more reliable guarantee for long-term visual quality after IOL implantation.

[0040] Thirdly, this application provides a method for preparing the above-mentioned intelligent artificial lens, comprising the following steps: Provide an artificial lens substrate and perform surface activation treatment; Provide nanocarriers loaded with therapeutic drugs; The surface-activated artificial lens substrate, the drug-loaded nanocarrier, and the dopamine monomer are placed together in an alkaline buffer solution for a one-step in-situ oxidative polymerization reaction, so that the polydopamine layer coats the nanocarrier and is simultaneously and firmly deposited on the surface of the substrate to form the coating.

[0041] Specifically: This application provides a method for preparing the above-mentioned intelligent artificial lens, comprising the following steps: An artificial lens substrate is provided and its surface is activated. The surface activation treatment can be carried out by plasma etching or ultraviolet ozone oxidation. By introducing polar functional groups such as hydroxyl and carboxyl groups, the hydrophilicity and reactivity of the substrate surface are significantly improved, laying the foundation for subsequent coating deposition and avoiding the problem of insufficient coating adhesion caused by the inertness of the substrate surface.

[0042] A nanocarrier loaded with therapeutic drugs is provided; the nanocarrier loaded with therapeutic drugs can be selected from mesoporous silica nanoparticles or polylactic-co-glycolic acid copolymer (PLGA) nanospheres. The mesoporous silica has an ordered mesoporous structure (pore size 2-10 nm) and can load drugs such as moxifloxacin and dexamethasone through physical adsorption. Its pore size can control the initial release rate of the drug. The PLGA nanospheres load drugs through chemical bonding and achieve slow release of drugs by means of their biodegradability. Both carriers can effectively avoid premature drug leakage and improve drug utilization.

[0043] The surface-activated intraocular lens substrate, the drug-loaded nanocarrier, and the dopamine monomer were placed together in an alkaline buffer solution for a one-step in-situ oxidative polymerization reaction. The alkaline buffer solution was preferably a Tris-HCl buffer solution with a pH of 8.5-9.5. The reaction temperature was controlled at 25-37°C, and the reaction time was 6-12 hours. During this process, the dopamine monomer was oxidized to form polydopamine. The abundant catechol groups in polydopamine interact with the functional groups on the surface of the nanocarrier, uniformly coating the nanocarrier in the polydopamine network. On the other hand, they formed covalent and non-covalent bonds with the surface-activated substrate, making the coating tightly and firmly deposited on the substrate surface, and not easily detached due to intraocular movement or aqueous humor erosion. At the same time, the dispersibility of the nanocarrier was further optimized by the adhesion effect of polydopamine, ensuring the uniformity of the coating.

[0044] After the reaction, the sample is rinsed repeatedly with deionized water 3-5 times to remove unreacted dopamine monomers, free nanocarriers, and unloaded drugs. Then, it is placed in a vacuum drying oven at 40-50℃ for 24 hours to obtain an intraocular lens with a uniformly coated intelligent drug delivery coating. The thickness of the coating after drying can be controlled by the reaction time and dopamine concentration. For example, after 12 hours of reaction, the coating thickness is about 500-800 nm to ensure that the drug loading meets the long-term release requirements after surgery.

[0045] This preparation method is simple and mild, and achieves simultaneous deposition of nanocarrier and polydopamine coating through one-step in-situ polymerization. It avoids the problems of carrier loss or uneven coating caused by multi-step processes. At the same time, it utilizes the biocompatibility and adhesion of polydopamine to ensure the adhesion and biosafety of the coating to the intraocular lens substrate, providing a feasible solution for the large-scale production of intelligent intraocular lenses.

[0046] In one specific embodiment, the surface activation treatment is: oxygen plasma treatment or ultraviolet ozone treatment; the alkaline buffer solution is a Tris-HCl buffer solution with a pH of 8.0-9.0; the one-step in-situ oxidative polymerization reaction is carried out at room temperature, in the dark, and with slow stirring for 4-24 hours.

[0047] Among these methods, oxygen plasma treatment, by bombarding the substrate surface with high-energy particles, effectively introduces active functional groups such as hydroxyl and carboxyl groups, significantly increasing the covalent bond density between polydopamine and the substrate; ultraviolet ozone treatment, through the strong oxidizing effect of ozone and the synergistic effect of ultraviolet light, rapidly cleans the substrate surface and increases active sites. Both treatments ensure the firm adhesion of subsequent coatings. The Tris-HCl buffer solution, due to its good pH stability and biocompatibility, can maintain an alkaline environment throughout the reaction process, promoting the oxidative ring-opening and polymerization reactions of dopamine monomers and avoiding uneven polymerization rates or coating defects caused by pH fluctuations. The one-step in-situ oxidation polymerization uses room temperature conditions, which avoids thermal damage to the intraocular lens substrate caused by high temperatures; the light-protected operation prevents dopamine from prematurely oxidizing and polymerizing before contacting the substrate, ensuring its directional deposition on the substrate surface; slow stirring helps to uniformly disperse the nanocarrier in the reaction system, allowing the nanocarrier and polydopamine to be deposited synchronously and uniformly on the substrate surface, further optimizing the microstructure uniformity of the coating; and the reaction time range of 4-24 hours allows for flexible adjustment of the coating thickness and drug loading according to actual needs. For example, a short reaction time is suitable for short-term adjuvant therapy with low loading, while a long reaction time can meet the requirements of long-term postoperative drug release with high loading.

[0048] Fourthly, this application provides the use of the above-described intelligent intraocular lens in the preparation of a medical device for the prevention or treatment of postoperative ophthalmic complications, including bacterial endophthalmitis and / or secondary cataracts; the thermal effect generated by the near-infrared light triggering has a synergistic effect with the released antibacterial drug in preventing and clearing bacterial biofilms.

[0049] The near-infrared light-triggered thermal effect disrupts the extracellular polymeric substance (EPS) structure of bacterial biofilms, weakening their barrier effect against drugs and allowing antibacterial drugs to penetrate the biofilm more easily to exert their bactericidal activity. Simultaneously, moderate thermal stimulation enhances the permeability of bacterial cell membranes, promoting drug entry into the bacteria to inhibit DNA replication and protein synthesis. These two factors synergistically significantly improve the clearance rate of drug-resistant bacterial biofilms, solving the problem of traditional antibacterial drugs' difficulty in penetrating biofilms. For posterior cataracts, the light-controlled release of antiproliferative drugs can target and inhibit the abnormal proliferation and migration of lens epithelial cells. The thermal effect, by downregulating the expression of cyclin D1, further inhibits cells from entering the S phase, strengthening the inhibitory effect on fibrous tissue proliferation within the lens capsule and effectively delaying the progression of posterior capsule opacification. Furthermore, this intelligent drug delivery system can precisely control the drug release rate and dosage by adjusting the irradiation time and intensity of near-infrared light, avoiding the drawbacks of large drug concentration fluctuations and significant systemic side effects associated with traditional systemic or local drug delivery methods. It is particularly suitable for postoperative patients requiring long-term medication, providing a novel solution for the precise treatment of postoperative ophthalmic complications.

[0050] Fifthly, this application provides a method for preventing and controlling postoperative complications of the eye, comprising: implanting the aforementioned intelligent intraocular lens into the patient's eye; when drug administration is required, irradiating the intraocular lens with near-infrared light of wavelength between 780-1100nm at a power density of 0.3-1.5W / cm² to trigger drug release; and regulating the drug release kinetics by controlling the irradiation parameters.

[0051] This application provides a method for preventing and controlling postoperative ocular complications, comprising: implanting the aforementioned intelligent intraocular lens into the patient's eye, precisely fixing it within the lens capsule and ensuring close adhesion to the inner wall of the capsule, so that the coated drug can directly act on the target area prone to postoperative complications, such as residual lens epithelial cells within the capsule and potential bacterial biofilm infection foci; when drug administration is required, using near-infrared light with a wavelength in the range of 780-1100nm, such as the clinically commonly used 808nm semiconductor laser or 980nm diode laser, through a slit-lamp microscope or a dedicated ophthalmic laser treatment device, at a frequency of 0.3-1.5W. A power density of / cm² allows for targeted and directional irradiation of the intraocular lens. This wavelength of light has excellent penetrability through ocular tissues, reaching the coating surface through structures such as the cornea and aqueous humor, without causing thermal damage or phototoxicity to normal ocular tissues such as retinal photoreceptor cells and corneal endothelial cells. After triggering drug release, the drug release kinetics are precisely regulated by controlling the irradiation time and intensity. For example, for emergency treatment of acute bacterial endophthalmitis, irradiation is performed for 15-20 minutes daily for 3-5 consecutive days; for long-term prevention and control of secondary cataracts, irradiation is performed for 5-10 minutes daily for 1-2 weeks. The intensity varies depending on the treatment cycle. For example, when treating drug-resistant bacterial biofilms, high-intensity irradiation of 1.0-1.5 W / cm² is used to raise the local temperature of the coating to 42-45℃, rapidly destroying the EPS structure and promoting antibacterial drug penetration. Conversely, when inhibiting lens epithelial cell proliferation, low-intensity irradiation of 0.3-0.8 W / cm² is used to maintain the coating temperature at 37-40℃, slowly releasing anti-proliferation drugs to avoid cytotoxicity. When the irradiation intensity is 1.2 W / cm², the thermally responsive polymer in the coating rapidly shrinks within 10 minutes, achieving a drug release rate of over 70%, and reaching an effective bactericidal concentration within 30 minutes. When the irradiation intensity drops to 0.5 W / cm², the drug is continuously released at a rate of 8%-12% per hour, and the drug concentration within the capsular bag can be stably maintained within the treatment window for up to 3-5 weeks. In addition, the progression of complications, such as the degree of posterior capsular opacity and the size of the infection foci, can be monitored in real time through examinations such as anterior segment OCT and intraocular pressure measurement. Based on the individual patient response, such as drug sensitivity and postoperative recovery, the irradiation parameters can be adjusted to achieve personalized treatment with on-demand drug administration. This completely solves the defects of large fluctuations in drug concentration and obvious side effects in traditional systemic or local drug administration methods, and provides a safer and more effective solution for the precise prevention and control of postoperative complications in ophthalmology.

[0052] Example 1: Standard synergistic dosing (1) IOL substrate pretreatment: Take a commercially available hydrophobic acrylate folded intraocular lens. Use an oxygen plasma cleaner to treat the surface of the IOL for 60 seconds at 100W power and 0.4mbar oxygen pressure. This step aims to increase the hydrophilic groups such as hydroxyl and carboxyl groups on the surface of the IOL, which significantly improves the adhesion of subsequent coatings.

[0053] (2) Synthesis of hollow mesoporous silica nanovesicles: 0.5 g of cetyltrimethylammonium bromide (CTAB) was dissolved in 200 mL of deionized water, and 20 mL of cyclohexane and 3 mL of n-hexanol were added to form a microemulsion. Under vigorous stirring, 2.0 mL of tetraethyl orthosilicate (TEOS) and 1.0 mL of ammonia (28 wt%) were added dropwise, and the reaction was carried out at 30°C for 24 hours. After the reaction was completed, the white precipitate was collected by centrifugation, washed three times with ethanol, and then calcined at 550°C for 6 hours to remove the CTAB template, thus obtaining hollow mesoporous silica nanovesicles. Characterized by scanning electron microscopy (SEM) and nitrogen adsorption-desorption tests, the cavity diameter was approximately 100 ± 15 nm, the BET specific surface area was greater than 600 m² / g, and the pore size distribution was concentrated at 8 nm.

[0054] (3) Drug loading of hollow mesoporous silica nanovesicles: Accurately weigh 100 mg of the above nanovesicles and disperse them in 50 mL of a mixed solvent (ethanol / deionized water, volume ratio 1:1) containing 30 mg of moxifloxacin hydrochloride and 15 mg of dexamethasone. Place the mixture in a constant temperature shaking incubator and shake in the dark at 37°C and 150 rpm for 24 hours to ensure sufficient drug adsorption. Then, collect the drug-loaded nanovesicles by centrifugation at 12,000 rpm for 15 minutes, and gently wash them twice with a small amount of pure water to remove the physically adsorbed drug on the surface. Finally, redisperse them in 10 mL of Tris-HCl buffer at pH 8.5 for later use.

[0055] (4) Construction of the polydopamine coating: 20 mg of dopamine hydrochloride was added to 10 mL of Tris-HCl buffer containing drug-loaded nanovesicles to bring the final concentration to 2 mg / mL. The plasma-treated IOL was completely immersed in the solution, and the container was placed on a low-speed rotary mixer (e.g., 10 rpm) and reacted at room temperature in the dark for 12 hours. During this period, dopamine underwent in-situ oxidative polymerization to form a polydopamine layer, which simultaneously anchored the nanovesicles firmly to the IOL surface. After the reaction was completed, the IOL surface was slowly rinsed with ultrapure water to remove any loosely bound particles, and then placed in a sterile petri dish to air dry at room temperature.

[0056] (5) Sterilization and storage: The dried intelligent IOL is placed in a specially made aseptic package and sterilized by radiation with γ-rays from a cobalt-60 source, with an absorbed dose of 25 kGy. After sterilization, the product is sealed and stored in a dry and cool place.

[0057] (6) Effect: ① In vitro drug release effect: In phosphate-buffered saline (PBS) simulating aqueous humor, at 37°C and under light-free conditions, this IOL released only approximately 15% of moxifloxacin and 10% of dexamethasone within 30 days, demonstrating excellent long-term storage stability and extremely low initial burst release. When irradiated with 808 nm, 0.8 W / cm² near-infrared light for 60 seconds, the cumulative release of moxifloxacin and dexamethasone reached 68% and 55% of the total single-trigger release, respectively, within the following 2 hours, forming a clear “therapeutic pulse.” Significant pulse release was reproduced in each of the three cycles of light-darkness experiments, demonstrating its repeatable, on-demand dosing capability.

[0058] ② Antibacterial and anti-biofilm effects: Taking Staphylococcus aureus as an example, a single photo-triggered release of the drug can inhibit the growth of 99.9% of planktonic bacteria within 4 hours. More importantly, in a biofilm model that had been pre-cultured for 24 hours, after three daily photo-triggered treatments, the number of viable bacteria in the biofilm decreased by three orders of magnitude, demonstrating its highly efficient ability to penetrate and remove biofilms, solving the problem that traditional antibiotics struggle to combat biofilms.

[0059] ③ Biocompatibility and Adhesion: Cytotoxicity tests (L929 fibroblasts) conducted according to ISO 10993 standards showed that the cell survival rate of the material extract was greater than 95%, demonstrating excellent biocompatibility. Friction tests simulating implantation showed a coating retention rate exceeding 98%, proving the superior coating adhesion provided by PDA as a "molecular glue."

[0060] Example 2: Fast-response thin-coating type (1) Pore size control of nanovesicles: In the synthesis of hollow mesoporous silica, the amount of ammonia in the microemulsion was increased to 1.5 mL and the reaction temperature was increased to 35°C. These conditions helped to form larger mesoporous pores, and the final product pore size was about 12±2 nm, which effectively reduced the drug diffusion resistance.

[0061] (2) Thin-layer PDA control: The polymerization time of dopamine was shortened from 12 hours to 6 hours. The absorbance of the reaction solution at 420 nm was monitored by a UV-Vis spectrophotometer to confirm that the degree of polymerization was about 60% of that in the standard example, thereby forming a thin-layer PDA shell with a thickness of about 50 nm.

[0062] (3) Triggering parameters: To facilitate faster release, the in vitro triggering test uses near-infrared light with slightly higher power (1.0 W / cm²), and the irradiation time is shortened to 30 seconds.

[0063] (4) Effect: ① Release kinetics: Under NIR light irradiation at 1.0 W / cm², the drug release rate was significantly accelerated. Moxifloxacin reached its peak release within 30 minutes of the start of irradiation, with a release rate approximately 2.5 times that of Example 1. This "rapid response" characteristic makes it ideal for emergency intervention in suspected acute infections, enabling the rapid establishment of effective drug concentrations within the eye.

[0064] ② Thermal Effects and Safety: Despite the increased light power, the thermal effects are more concentrated and shorter-lived due to the thinner PDA layer. During the 30-second irradiation period, the highest local temperature of the coating was controlled below 48°C, and the temperature rapidly returned to body temperature within 20 seconds after irradiation was stopped. This level of thermal exposure is far below the tolerance limit of ocular tissue, ensuring the safety of the treatment.

[0065] Example 3: Time-release multilayer coating type (1) Preparation of the first layer (dexamethasone / PLGA layer): PLGA nanoparticles loaded with dexamethasone were prepared by a double emulsification method. 50 mg PLGA (50:50) and 5 mg dexamethasone were dissolved in 2 mL of dichloromethane as the oil phase, mixed with 4 mL of 1% polyvinyl alcohol (PVA) aqueous solution, and ultrasonically emulsified to form a primary emulsion. The primary emulsion was then poured into 50 mL of 0.5% PVA solution, and high-speed shearing was performed to form a secondary emulsion. After the solvent was evaporated, the nanoparticles were collected by centrifugation. IOL was immersed in Tris-HCl buffer containing the above PLGA nanoparticles (10 mg / mL) and dopamine (1 mg / mL), and low-speed polymerization was performed for 4 hours to form the first controlled-release coating.

[0066] (2) Preparation of the second layer (moxifloxacin / SiO2 layer): Take out the IOL that has been coated with the first layer, rinse it slightly, and then immerse it in the mixture of "silica nanovesicles loaded with moxifloxacin / dopamine" for 8 hours to form the second layer.

[0067] (3) Release verification: In vitro release test showed that under a single NIR light trigger, moxifloxacin was rapidly released at over 80% within 2 hours, while dexamethasone only reached its release peak after 8-12 hours, thus successfully achieving timing control.

[0068] (4) Effect: ① Time-sequential release validation: In vitro release experiments precisely confirmed the time-sequential release characteristics of moxifloxacin, with dexamethasone being released later. After a single NIR light triggering, the release rate of moxifloxacin exceeded 80% within 2 hours, while dexamethasone only reached a 50% release rate after 8 hours, with its release peak occurring around 12 hours. This release pattern perfectly simulates the rational drug use logic in clinical practice of first strongly controlling infection and then continuously suppressing inflammation, achieving a synergistic therapeutic effect of "1+1>2".

[0069] ②Structural stability: Scanning electron microscopy showed that the two coating layers were tightly bonded and there was no peeling, proving the feasibility and reliability of the multilayer construction process.

[0070] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No reference numerals in the claims should be construed as limiting the scope of the claims.

[0071] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A light-triggered smart drug delivery coating for ophthalmic implants, characterized in that, include: Nanocarrier units loaded with at least two therapeutic agents, wherein the at least two therapeutic agents have different water solubility; A polydopamine-responsive layer covering the outside of the nanocarrier unit; The polydopamine responsive layer can absorb external near-infrared light and generate a thermal effect, thereby triggering the on-demand and synergistic release of different drugs from the nanocarrier unit.

2. The coating according to claim 1, characterized in that, The nanocarrier unit is an inorganic hollow mesoporous nanomaterial; the inorganic hollow mesoporous nanomaterial is a hollow mesoporous silica nanovesicle.

3. The coating according to claim 1 or 2, characterized in that, The at least two therapeutic agents include a hydrophilic antibiotic and a hydrophobic anti-inflammatory drug; The hydrophilic antibiotic is selected from fluoroquinolone antibiotics, and the hydrophobic anti-inflammatory drug is selected from glucocorticoids.

4. The coating according to claim 3, characterized in that, The hydrophilic antibiotic is moxifloxacin hydrochloride, and the hydrophobic anti-inflammatory drug is dexamethasone or dexamethasone acetate.

5. The coating according to claim 1, characterized in that, The coating is configured such that different drugs exhibit differentiated release kinetic curves under a single near-infrared light triggering, thereby achieving time-sequential release.

6. A smart artificial lens, characterized in that, The optical surface of the device is provided with a light-triggered smart drug delivery coating according to any one of claims 1 to 5 in at least a portion of the surface.

7. A method for preparing the intelligent intraocular lens according to claim 6, characterized in that, Includes the following steps: Provide an artificial lens substrate and perform surface activation treatment; Provide nanocarriers loaded with therapeutic drugs; The surface-activated artificial lens substrate, the drug-loaded nanocarrier, and the dopamine monomer are placed together in an alkaline buffer solution for a one-step in-situ oxidative polymerization reaction, so that the polydopamine layer coats the nanocarrier and is simultaneously and firmly deposited on the surface of the substrate to form the coating.

8. The method according to claim 7, characterized in that, The surface activation treatment is: oxygen plasma treatment or ultraviolet ozone treatment; The alkaline buffer solution has a pH value of: Tris-HCl buffer at 8.0-9.0 g / L; The one-step in-situ oxidative polymerization reaction was carried out at room temperature, in the dark, and with slow stirring for 4-24 hours.

9. The use of the intelligent intraocular lens according to claim 6 in the preparation of a medical device for the prevention or treatment of postoperative ophthalmic complications, characterized in that, The complications include bacterial endophthalmitis and / or posterior cataract; The thermal effect generated by the near-infrared light triggering has a synergistic effect with the released antibacterial drugs in preventing and eliminating bacterial biofilms.

10. A method for preventing and controlling postoperative complications of ocular surgery, characterized in that, include: The intelligent intraocular lens according to claim 6 is implanted into the patient's eye; When drug administration is required, the intraocular lens is irradiated with near-infrared light with a wavelength of 780-1100 nm at a power density of 0.3-1.5 W / cm² to trigger drug release. Drug release kinetics can be regulated by controlling irradiation parameters.

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