Systems, methods, and material compositions for modifying ocular conditions

Abstract

This invention discloses a system, technology, and material composition for correcting eye condition. The system includes a processing device and an etching device. The processing device includes a pattern correction module configured to provide a selected two-dimensional pattern based on visually non-permanent input data instructing a user, and configured to generate operating instructions to form the selected two-dimensional pattern on the surface of the cornea via the etching device. The etching device is configured to etch the selected pattern onto the surface of a user's cornea. The material composition includes an aqueous solution containing a plurality of nanoparticles, the nanoparticles comprising magnetite nanoparticles encapsulated by biocompatible protein chains. The material composition can be used as eye drops, thereby allowing the nanoparticles to occupy the etched area on the cornea, thus maintaining the correction of eye condition.

Description

[0001] This application is a divisional application of application number CN 201980016190.7 (PCT application number PCT / IL2019 / 050219), filed on February 27, 2019, entitled "System, method and material composition for correcting eye condition". Technical Field

[0002] This invention belongs to the field of visual correction technology, and particularly relates to the correction of visual impairments such as myopia, hyperopia, presbyopia, astigmatism and other visual impairments. Background Technology

[0003] Various eye conditions are known to limit vision. These conditions can broadly include nearsightedness (myopia), farsightedness (hyperopia), and age-related eye conditions (typically associated with presbyopia). Various technologies are known to provide correction for such eye conditions, including eyeglasses, contact lenses, and intraocular lenses (IOLs). The lenses used have one or more selected optical powers and / or selected patterns designed to increase the depth of focus of the lens according to the user's eye condition. A common approach to overcoming various eye conditions, such as presbyopia symptoms, is based on advanced IOL technology, via accommodating IOLs, multifocal IOLs, or more recently, IOLs with extended depth of focus.

[0004] Optical power can generally be provided by manipulating the refraction of the light path. However, diffraction techniques used to manipulate the light path can also provide suitable optical power. Such techniques can include Fresnel zone plates, or rings, which provide light diffraction in a crystalline manner. Other optical manipulation techniques can utilize optical interference to extend the depth of focus.

[0005] For example, U.S. Patent No. 7,859,769 provides an imaging configuration and method for extending depth of focus. The imaging configuration includes an imaging lens having a specific effective aperture and an optical element connected to the imaging lens. The optical element is configured as a phase-affecting, non-diffractive optical element that defines a spatially low-frequency phase transition. The optical element and the imaging lens define a predetermined pattern formed by several spatially separated, substantially optically transparent features with different optical properties. The position of at least one phase transition region of the optical element in the plane of the imaging lens is determined by at least one scale of the effective aperture.

[0006] Protein-based drug delivery systems enable the encapsulation of selected drugs and the provision of stable, non-toxic, and typically non-antigenic carriers. Human serum albumin, a highly abundant plasma protein with a long half-life, has attracted attention as a drug carrier compound. Summary of the Invention

[0007] This invention provides a new technique for correcting eye conditions that cause visual difficulties in users. The technique involves applying a pattern to the user's cornea and introducing a selected material composition that provides a change in refractive index onto the applied pattern. The pattern is selected based on the user's eye condition. Generally, the selected material composition is in the form of an eye drop containing synthetic nanoparticles that provide localized modification of the cornea's refractive index through an enhanced optical pattern printed onto the surface epithelium of the cornea. This optical pattern provides temporary and targeted correction of refractive errors without modifying the corneal shape.

[0008] The selected material composition can generally be provided in the form of eye drops, which comprise magnetite nanoparticles typically carried by an albumin shell, such as human serum albumin (HAS). The material composition is selected to be a biocompatible, non-toxic material composition exhibiting high stability both on shelf and on the user's cornea. The magnetite-albumin nanoparticles are characterized by a high refractive index, which is designed to modify the refractive index and overall ocular refraction according to the selected pattern when the material is confined to the corneal epithelium by applying a pattern to it.

[0009] Furthermore, the present invention provides a system for correcting an eye condition associated with a visual state, such as myopia, hyperopia, or presbyopia. The system includes a processing device and an etching device configured to receive input data indicating the user's eye condition. The processing device is configured to respond to the input data and to determine a two-dimensional pattern for correcting visual impairment based on the input data. The processing device may typically include a pattern correction module configured to determine the drafting of the selected two-dimensional pattern based on the input data indicating a user's visual impairment. The processing device is further configured to generate a plurality of operational instructions to form the selected two-dimensional pattern by the etching device. The etching device typically includes at least one laser unit and a beam steering module. The etching device is configured to provide light energy and to etch the selected pattern onto the cornea of ​​the user's eye according to the plurality of operational instructions.

[0010] Therefore, according to a broad perspective, the present invention provides a system for correcting eye conditions, the system comprising: a processing device and an etching device; the processing device comprising:

[0011] A pattern correction module is configured to provide a selected two-dimensional pattern based on visually non-permanent input data instructing a user, and is configured to generate multiple operation instructions to form the selected two-dimensional pattern on the surface of the cornea by means of the etching device.

[0012] The etching apparatus is configured to etch the selected pattern onto the surface of a user's cornea.

[0013] According to some embodiments, the etching device is configured to transmit selected ultrasonic waves for etching the pattern onto the user's cornea.

[0014] According to other embodiments, the etching apparatus is configured to mechanically etch the cornea.

[0015] According to some other embodiments, the etching apparatus includes at least one laser unit and a beam steering module, and is configured to provide light energy for etching selected patterns on the cornea of ​​a user's eye according to multiple operating instructions.

[0016] The laser unit can be configured to provide etching at a depth reaching a single cell layer of the cornea.

[0017] According to some embodiments, the two-dimensional pattern includes a diffraction pattern. For example, the pattern may include a Fresnel ring pattern.

[0018] According to some embodiments, the two-dimensional pattern includes or phase-affected interferometry patterns. The pattern may, for example, include an extension of a depth-of-field pattern.

[0019] According to some embodiments, the selected pattern enables optical corrections between 0.1 and 0.3 diopters of optical power resolution. Generally, this allows corrections below 0.25 diopters, which is a typical limit for conventional optical corrections.

[0020] According to another broader aspect of the present invention, the present invention provides a material composition comprising a solution containing a plurality of nanoparticles, the nanoparticles comprising magnetite nanoparticles encapsulated by biocompatible protein chains.

[0021] According to some embodiments, the protein chain comprises human serum albumin.

[0022] The material composition can be configured for use in the correction of visual impairment. The material composition is preferably configured for use as an eye drop.

[0023] According to some embodiments, the material composition can be configured for use as an eye drop after etching a selected pattern onto a user's cornea, wherein the nanoparticles are dispersed in the surface undulations of the cornea to provide additional optical power to the user's eye.

[0024] According to some embodiments, the magnetohyperite nanoparticles comprise ammonium cerium nitrate Fe2O3 nanoparticles.

[0025] According to some embodiments, the magnetohyperite nanoparticles encapsulated by biocompatible protein chains are further configured to carry one or more selected drugs.

[0026] According to another broader aspect of the invention, the invention provides a material composition for use in the correction of visual impairment, the material composition comprising nanoparticles, the nanoparticles comprising magnetohyperite substrate particles in a protein shell. The nanoparticles can be further configured as drug carriers and delivery products.

[0027] The present invention further considers a macrostructure of magnetite, a formulation comprising said macrostructure, and a method for preparing said formulation.

[0028] The formulations provided according to the present invention may, for example, be ophthalmic formulations (for ocular use) in the form of eye drops, the ophthalmic formulation comprising a magnetite macrostructure, the macrostructure typically comprising a modified magnetite associated with a biocompatible macrocarrier, such as a peptide, a polysaccharide, or others. The modified magnetite comprises magnetite (iron oxide having repeating γ-Fe₂O₃ units) linked to cerium ammonium nitrate (CAN). The macrostructure is formed by encapsulating the modified magnetite nanoparticles within a matrix of the macrocarrier, thereby forming the macrostructure.

[0029] In some embodiments, the macrocarrier is a peptide. In some embodiments, the macrocarrier is albumin, such as human serum albumin (HAS).

[0030] The macrostructure can be provided as a rehydrated solid powder or as a liquid ophthalmic formulation for reading in an aqueous carrier. The aqueous carrier can be water, antibacterial water, sodium chloride solution, glucose solution, liquid surfactant, pH-buffered solution, or any of the following.

[0031] When the macrostructure is provided in an aqueous matrix, it can be processed to provide the rehydrated powder form. The powder form can be obtained by freeze-drying or spray-drying techniques.

[0032] A kit is also provided, optionally in the form of eye drops or a rehydrationable powder, said powder comprising a solid powder in a rehydratable form or an aqueous formulation, and instructions for use. When said kit contains said powder, it may also contain at least one aqueous carrier for rehydration of the macrostructure.

[0033] In another broader sense, the present invention provides a kit for correcting visual impairment, the kit comprising: the system as described above, and the eye drops comprising the material composition described above.

[0034] The kit may further include an instruction manual for operating the system to etch a selected pattern onto the user's cornea and administer the eye drops into the eye. Generally, the kit allows for optical corrections for users who cannot undergo LASIK surgery because the pattern etching on the cornea is shallow and can be performed on a thin cornea. Therefore, the kit is suitable for use at home or in a physician's outpatient clinic. Furthermore, the kit and technology also enable corrections for users who have undergone cataract surgery, allowing for additional corrections to be made on the intraocular lens already in use by the user.

[0035] According to some embodiments, the material composition comprises magnetite nanoparticles encapsulated by biocompatible protein chains, configured to increase the stability of the optical effect of the pattern, thereby enabling the optical correction effect to last from several days to several months.

[0036] According to some embodiments, the kit can be configured to correct any of myopia, hyperopia, presbyopia, and astigmatism. Attached Figure Description

[0037] To better understand the subject matter disclosed herein and to illustrate how it can be implemented in practice, several embodiments will be described herein by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0038] Figure 1 This is a schematic diagram of a system for correcting eye conditions according to some embodiments of the present invention;

[0039] Figure 2 Examples of Fresnel band patterns suitable for correcting eye condition by adding / subtracting optical power;

[0040] Figure 3 and Figure 4 Examples of ocular correction patterns associated with depth of focus extension of the eye lens;

[0041] Figure 5 An example of the desolvation process of albumin according to some embodiments of the present invention;

[0042] Figure 6A and 6B The dimensions and potential measurements of nanoparticles manufactured according to some embodiments of the present invention are shown.

[0043] Figures 7A to 7C Showing TEM and low-temperature TEM micrographs and size distribution bar charts of HAS core nanoparticles;

[0044] Figure 8A and 8B The FTIR spectra of HAS core nanoparticles carrying magnetite nanoparticles are shown according to some embodiments of the present invention. Figure 8A Show FTIR results and Figure 8B Focusing on the peak values ​​in the absorption spectrum of magnetohyperite carrying HSA nanoparticles;

[0045] Figure 9A and 9B Display of unprocessed HAS ( Figure 9A ) and the HAS nanoparticles described in this article ( Figure 9BThe X-ray photoelectron (XPS) spectrum of )

[0046] Figures 10A to 10D The morphology and size measurements of hybrid HSA / CAN-γ-Fe2O3 nanoparticles characterized using TEM, low-temperature TEM, and HR-SEM are shown.

[0047] Figures 11A to 11D Using HR-SEM images to display the measured values ​​of the quantity of selected elements ( Figure 11A ) and, according to some embodiments of the present invention, the carbon ( Figure 11B ),oxygen( Figure 11C ) and iron ( Figure 11D Linear scan analysis;

[0048] Figure 12 The reflection measurements obtained from the super-reflective iron particles embedded in the HAS nanoparticles are shown, displaying the nanoparticles in the etched area of ​​the cornea.

[0049] and

[0050] Figure 13A and 13B Measurements of changes in the optical power of a pig's eye, provided by applying a selected pattern to the eye and providing an eye drop solution according to some embodiments of the invention. Detailed Implementation

[0051] As noted above, this technology is designed to correct visual impairments such as myopia, hyperopia, and presbyopia. Figure 1 A schematic diagram of a system 100 for correcting eye conditions is shown. The system 100 includes a processing device 200 and an etching device 300. The system can generally be configured as a computer system and associated with the etching device 300 to provide output pattern writing. For this purpose, the system 100 may also include a storage device 400 and other storage devices not in use. Figure 1 The input / output devices and user interface that are specifically displayed in the text.

[0052] The processing device 200 may generally include one or more processors and further include one or more hardware or software modules, such as a correction pattern module 210. The correction pattern module 210 is configured to receive and process input data indicating the optical correction required for one of a user's eyes (each eye may require different optical corrections), and to determine, or retrieve from a storage device, a selected two-dimensional pattern suitable for the optical correction. The processing device 200 is further configured to generate multiple operating instructions for etching the selected pattern onto the user's cornea to provide the selected optical correction.

[0053] The processing device 200 transmits the generated instructions to the etching device 300, which provides optical radiation, and guides it to produce the selected pattern on the cornea of ​​a user's eye. Figure 2 , Figure 3 and Figure 4 Three possible patterns are illustrated schematically based on the user's eye condition. Figure 2 The Fresnel band pattern is shown, which includes multiple concentric rings of different widths; Figure 3 and Figure 4 Examples of patterns selected to extend the depth of focus, such as those suitable for correcting presbyopia, are shown. Generally, the optical characteristics of such patterns and the exact configuration of each pattern can be determined based on the selected eye correction, such as the required optical power or the desired increase in depth of focus.

[0054] Generally, the etching apparatus 300 is configured to apply the selected pattern as an incision to the epithelial layer of the cornea. The etching can generally be provided using optical etching, ultrasonic etching, and / or mechanical etching of the cornea with a selected wavelength range. For simplicity, the etching apparatus is illustrated herein as an optical etching apparatus 300, which is configured with a laser source and a beam steering unit 320. The laser source 310 is configured to provide optical radiation at a wavelength and energy suitable for etching in subsequent epithelial cells, and the steering unit 320 is configured to change the path of the output beam so that the selected pattern can be projected onto the user's cornea. The operating speed of the steering unit 320 and the energy of the light source unit 310 are selected to provide photolithography of the cornea, typically in the surface epithelial layer, for example, at a depth of a single cell layer.

[0055] More specifically, the pattern is generally etched onto the user's cornea at a depth of no more than one cell layer, or up to several micrometers, to avoid any damage to the user's eye and to allow the cornea to heal and renew the etched cell layer. It should also be noted that the selected optical pattern is effectively imprinted onto the surface epithelium of the cornea.

[0056] As indicated above, the pattern is selected to provide additional optical power or to alter the depth of focus of the user's eye. To provide a sustained effect, this technique employs a suitable eye drop solution comprising selected nanoparticles having a refractive index different from that of the cornea and / or the tears surrounding the eye. For this purpose, the eye drop formulation typically comprises magnetite particles carried by an albumin shell. More specifically, the albumin shell typically means a protein folded around the magnetite particles. The nanoparticles may be based on magnetite (γ-Fe₂O₃) particles modified with cerium ammonium nitrate (CAN).

[0057] It should be noted that the particle configuration of the ophthalmic solution is designed to provide stable optical effects of the etched pattern over time. More specifically, the nanoparticles generally penetrate the cut / etched area, thus allowing tears to reach that area. This allows the optical effects to be maintained and limits the healing process of the epithelial layer to provide the optical effects to last from several days to several months. Generally, under normal circumstances without the use of eye drops containing the nanoparticles, the etched pattern may heal within 1 to 2 days.

[0058] Generally, protein-based nanoparticles, often used as drug carrier particles, are of great interest for use in eye drop solutions due to their high stability during storage and biocompatibility, such as non-toxicity and non-antigenicity. Albumin proteins provide polymeric carriers that have been shown to be biodegradable, non-immunogenic, non-toxic, and metabolizable in vivo.

[0059] In some embodiments of the invention, the nanoparticles may comprise human serum albumin (HSA, 66.5 kDaltons). HAS is likely preferred because it is the most abundant plasma protein (35-50 g / L human plasma) and has an average half-life of 19 days, and is therefore used hereinafter. However, it should be noted that the nanoparticles of the invention can typically be associated with any albumin-type protein, including various animal plasma albumins and / or synthetic albumins. Generally, albumin contains 35 cysteine ​​residues forming a hydrogen sulfide group and 17 disulfide bonds. HSA is pH tolerant and is stable in a pH range of 4 to 9. Furthermore, HSA can be heated at 60°C for up to 10 hours.

[0060] The inventors of this invention have identified a technique that makes it possible to provide and characterize HSA-based nanoparticles (NPs) with robust and controllable particle sizes. This technique utilizes examples from... Figure 5The desolvation / crosslinking divinyl sulfone (DVS)-mediated nanofabrication method is described. During the desolvation process, coacervates are formed, followed by hardening / stabilization through crosslinking promoted by DVS. In this context, intra- or inter-chain folding of an HSA-based polymer chain can originate from a controlled bivalent covalent Michael reaction utilizing the strong electrophilic properties of the difunctional divinyl sulfone (DVS) reactant. Using DVS as a crosslinking agent in the preparation of such HSA nanoparticles provides the availability of various free functional groups on the surface of the nanoparticles, which can be used for further second-step functionalization. Furthermore, related hybrid organic / inorganic nanosystems composed of HSA nanoparticles encapsulating hydrophilic (NH4)2Ce(lV)(NO3)6 (cerium ammonium nitrate-CAN) modified γ-Fe2O3 nanoparticles (CAN-maghemite or CAN-γ-Fe2O3) nanoparticles have also been fabricated and characterized. Several suitable nanoparticles are manufactured and characterized as illustrated below, as nanoparticle variants / species and / or nanoparticles associated with intermediate preparation stages according to the present technology.

[0061] Example 1 - HSA Core Nanoparticle Manufacturing

[0062] HSA core nanoparticles were used to prepare HSA (50.0 mg), which was dissolved in 1.0 mL of purified water (ddH2O). To achieve a final HSA concentration of 10 mg / mL, ethanol was added during desolvation to obtain a total volume of 5.0 mL. 140.0 μL of DVS (5% by weight in EtOH) was added to induce protein chain crosslinking. This crosslinking process was performed by stirring the suspension at 55°C for 1 hour, followed by an ultra-sonication bath for 20 minutes. The resulting HSA nanoparticles were then purified by three cycles of differential centrifugation (13500 rpm, 60 minutes, 4°C) and then redispersed in the original volume of ddH2O. Each redispersion step was performed in an ultrasonic bath for 10 to 15 minutes. To enable long-term storage and prevent aggregation, the nanoparticles were stored in a refrigerator at 4°C.

[0063] Example 2 - Preparation of CAN Magnesite Nanoparticles

[0064] The CAN magnetohyperite nanoparticles (CeLn) 3 / 4+ The preparation of γ-Fe₂O₃ is performed in a two-step procedure, which includes two types of Fe.2+ / 3+ Alkaline co-precipitation of salts. This procedure yields magnetite (Fe3O4) nanoparticles, which, as a less oxidized starting material, are then oxidized with the single-electron oxidant cerium ammonium nitrate (CAN) and further oxidized with (CeL... n ) 3 / 4+ Surface modification by cation / composite nanoparticle doping was used to obtain positively charged (+45.7mY) CAN-γ-Fe2O3- nanoparticles with a size of 6.61±2.04 nm.

[0065] Example 3 - Preparation of hybrid CANHSA nanoparticles containing magnetite

[0066] To provide the desired nanoparticle structure with a suitable refractive index to influence vision according to a selected pattern on the cornea, a nanoscale composition of both HSA nanoparticles and CAN-γ-Fe2O3 nanoparticles was combined so that the CAN-γ-Fe2O3 nanoparticles were trapped within the HSA nanocomposite particles in the same DVS-mediated nanoparticle preparation / component crosslinking process. For this purpose, the hybrid CAN magnetohyrite containing HSA nanoparticles was prepared using the same procedure described above for the HSA nanoparticles. Briefly, CAN-γ-Fe2O3 nanoparticles were added to HSA (50.0 mg in 1.0 mL ddH2O) at a weight ratio of 25:1, followed by incubation at room temperature for 1 hour, and then a desolvation and crosslinking process. The resulting composite nanoparticles were then purified by three cycles of differential centrifugation (at 13,500 rpm, 60 minutes, and 4 degrees Celsius), magnetically decanted (using a strong external magnet), and redispersed in the original volume of ddH₂O. In each redispersion step, the reaction vessel was placed in a low-energy ultrasonic bath for 15 minutes prior to processing. For long-term storage and to avoid aggregation, the nanoparticles were stored in a refrigerator (4 degrees Celsius).

[0067] As a result, the HSA core nanoparticles were further characterized by various analytical, spectroscopic, and microscopic methods. Figure 6A and 6B Showing the size distribution of the nanoparticles ( Figure 6A ) and charge distribution (ζ potential, Figure 6B As a result, the fabricated HSA nanoparticles exhibit a nanoparticle hydrodynamic volume (OLS) of 149.56 ± 1.8 nm and a strong negative ζ (electric) potential of -35.4 ± 2.4 mV. Therefore, the nanoparticles exhibit low dispersion, associated with a polydispersity index (PDI) value of 0.17.

[0068] Figure 7A and7B TEM and cryo-TEM micrographs and size distribution histograms of HAS core nanoparticles are shown. These measurements show the formation of spherical and substantially homogeneous HAS core nanoparticles with an average size of 23.05 ± 5.3 nm.

[0069] Additional measurements of the nanoparticles were performed to determine the crosslinking of the HSA polymer chains caused by the DVS reactant. Figure 8A and 8B The FTIR spectral measurements demonstrate the structural differences between standard HAS G2 and HSA nanoparticles G1 with magnetohematite as described herein. Figure 8A The display is along 4050cm -1 and 550cm -1 The relative intensity of the spectra between them, Figure 8B Focus on Figure 8A The region marked by the rectangle is specifically shown as the peak value in the absorption spectrum G1. The structural differences between the particles, exemplified by the FTIR absorption peaks, are generally attributed to the presence of DVS in the core HSA nanoparticles. The spectral differences between the unprocessed HSA spectrum and the HSA nanoparticle spectrum can be... Figure 8B The middle is 800cm -1 Up to 1100cm -1 The peaks were easily observed within the specified range. The graph shows several peaks in the HSA nanoparticle spectrum G1 that were not present in the standard HSA FTiR spectrum G2. Located at 880 cm⁻¹ -1 The first peak corresponds to the stretching vibration of the CS bond. At 1047 cm⁻¹ -1 and 1083cm -1 The other two peaks can be attributed to the stretching vibrations of the sulfoxide group (RS=O).

[0070] In addition, X-ray photoelectron (XPS) spectroscopy was used to confirm the participation of this electrophilic DVS reactant in the crosslinking of the HSA polymer chain. Figure 9A and 9B The XPS spectrum of the unprocessed HAS is shown. Figure 9A ) and the XPS spectra of the HAS nanoparticles described in this paper ( Figure 9BXPS analysis of the HSA nanoparticles revealed that sulfur exists in two oxidation states: a first state corresponding to the RS species (BE binding energy = 164.0 eV) and a second state at a higher binding energy, typically 168.5 eV, corresponding to the SO2 sulfoxide group derived from the DVS sulfone group. This peak at 168.5 eV was not observed in the initial XPS analysis of the unprocessed HSA protein.

[0071] The main functional groups, generally including primary amine (NH2) and carboxyl (COOH) groups, have been successfully quantified using a UV-sensitive ninhydrin test (1,3-diaminopropane for amidation / derivation of COOH groups via EDC activation). The differentially derived EDC and non-EDC-based ninhydrin results both showed 0.632 mmol and 1.127 mmol of NH2 and COOH groups, respectively, for 1.0 g of HSA nanoparticles. (These quantified surface functional groups make HSA nanoparticles potentially usable as a biocompatible and biodegradable drug carrier in the future, as they allow for the further conjugation of additional therapeutic and / or drug agents targeting tumors and diseased cells.)

[0072] Example 4 - Hybrid HSA-trapped CAN-magnesite nanoparticles (CAN-γ-Fe2O3) nanocomposite particles

[0073] The nanoscale component HSA and the positively charged CAN-γ-Fe2O3 (both with dimensions of 6.61 ± 2.04 nm and a potential of +45.7 mV) were both assembled by trapping CAN-γ-Fe2O3 nanoparticles within HSA nanoparticles during the DVS-mediated nanoparticle fabrication step. For this purpose, hydrophilic, water-compatible CAN-γ-Fe2O3 nanoparticles were used. The hybrid HSA / CAN-γ-Fe2O3 nanoparticles were synthesized based on the same DVS-mediated process as described above. The weight ratio of the HSA and CAN-γ-Fe2O3 nanoparticles has been found to be 25:1 for optimal encapsulation of a magnetite component into an HSA nanoshell. Generally, this weight ratio can be in the range of 15:1 to 40:1.

[0074] Therefore, the DLS hydrodynamic diameter, size distribution, and potential value of the corresponding composite particles have been determined. A DLS hydrodynamic diameter of 130 nm was measured with a polydispersity index of less than 0.3. A potential analysis was also performed to examine the resulting hybrid nanoparticles (trapped) for polymer-controlled colloidal stability, meaning that the composite particles were always found to have an average potential value of -25 mV with a negative charge.

[0075] refer to Figures 10A to 10D , Figures 10A to 10D The morphological and size distribution measurements of the hybrid HSA / CAN-γ-Fe2O3 nanoparticles were characterized using TEM, low-temperature TEM, and HR-SEM. Figure 10A and 10B TEM and low-temperature TEM images of an HSA nanoparticle phase (slightly lower contrast gray area) containing trapped and highly contrasting CAN magnetohyrite nanoparticles are shown. The CAN magnetohyrite nanoparticles can be easily visualized and identified (dark spots) within the HSA phase. Thus, electron-dense metal nanoparticles are successfully incorporated into the surrounding HSA matrix, and the distribution of the CAN magnetohyrite nanoparticles between and within each particle is found to be quite homogeneous. This homogeneity may contribute to promoting the interaction between the positively charged CAN-γ-Fe₂O₃ nanoparticles and the negatively charged HSA phase. Nanoparticle crystallinity has been demonstrated as shown in... Figure 10D This was further confirmed by TEM / selected area electron diffraction (SAED). Furthermore, the nanoparticle size distribution was also observed through TEM. Figure 10C The measured value is 44.6 ± 4.18 nanometers, showing an average size.

[0076] Figures 11A to 11D Displaying HR-SEM images obtained in scanning transmission electron microscopy (STEM) mode. Figure 11A ) and carbon ( Figure 11B ),oxygen( Figure 11C ) and iron ( Figure 11DLinear scan analysis was performed. The energy lines used to analyze the elements were labeled L1 to L3 for carbon, oxygen, and iron, respectively. The graphs show that CA magnetite nanoparticles exist as completely encapsulated clusters within the HSA matrix, while the HSA phase appears as a surrounding cloud. The linear scan elemental analysis, based on energy-scattered X-ray spectroscopy (EDS), confirmed that the encapsulation of CAN-γ-Fe2O3 nanoparticles mainly occurs within the resulting HSA nanocomposite particles. Indeed, iron (top right), carbon (bottom left), and oxygen (bottom right) are present simultaneously. The peak value for iron is much thinner than the other peak values, thus demonstrating the encapsulation of CAN-γ-Fe2O3 nanoparticles within the HSA nanoparticles. Furthermore, Figure 12 The reflection of iron particles embedded in the HSA nanoparticles is shown. As illustrated, from the reflection of the iron particles, the HSA nanoparticles are positioned in the incision region of the cornea to enhance the etched pattern.

[0077] ICP-AES elemental analysis was also performed to confirm iron encapsulation during the formation of the hybrid nanoparticles. ICP measurements showed a 95% encapsulation efficiency of elemental iron into the HSA phase. Additional concentration measurements of both the hybrid nanoparticles and the CA-maghemite nanoparticles showed that the weight percentage of the CA-maghemite nanoparticle phase was approximately 40% of the total weight of the corresponding hybrid nanoparticles.

[0078] Therefore, this technology utilizes a solution formulation comprising albumin-shelled CAN-γ-Fe2O3 nanoparticles as eye drops, enabling a change in refractive index at the selected etched pattern on the user's cornea. The nanoparticles typically remain on the cornea for periods ranging from several days to several months, allowing the user's eye condition to be corrected according to the optical manipulation of the selected pattern. The inventors have performed tests on pig eyes to verify the optical effects of the etched pattern and the selected nanoparticles in correcting optical visual impairment.

[0079] For this purpose, the refractive error of eight fresh pig eyes was measured before and after the creation of a corneal surface pattern using an automated refractometer, followed by the instillation of eye drops. The eye drops were filled with selected nanoparticles at specific known concentrations between 0.1 mg / mL and 10 mg / mL. In this example, the concentration of the nanoparticles used was 1 mg / mL. In these tests, the pattern was applied to the cornea of ​​the eye using a mold constructed by a 3D printer, the mold having a calibrated optical pattern.

[0080] In this example, the molding is used to provide a superficial micro-erosion of the cornea, allowing the nanoparticles to penetrate the corneal epithelium and thus permitting a desired change in optical power determined by the pattern. The pattern itself is selected as a Fresnel strip diffraction pattern, providing an optical power of 2.5 diopters. Such additional optical power is generally suitable as a visual aid for users with myopia. The optical power of the lens is measured and recorded five times at each step associated with this technique. More specifically, a baseline optical power is measured, and the patterned optical power is applied to the cornea at different times after the eye drops are applied to the eye, immediately following the eye drops, and at 5, 10, 20, and 30 minutes after instillation. These different measurements are performed to avoid bias due to large standard deviations.

[0081] Therefore, after selecting the desired pattern according to the required optical corrections, the two-dimensional pattern is applied to the cornea. Once the pattern is etched onto the cornea, the eye is cleaned with an eye drop solution containing HAS magnetohematite nanoparticles. The nanoparticles are identified in the eye using an iron marker on a portion of the nanoparticles. This allows for analysis and identification of the nanoparticles using an electron microscope (e.g., SEM).

[0082] refer to Figure 13A and 13B , Figure 13A and 13B The results of optical power changes in pig eyes after correction using the techniques described above are shown. 13A shows the average measurement changes in four pig eyes after correction by adding 2.5 diopters of optical power suitable for myopia correction. Figure 13B The results show similar results when adding -2.5 diopters, which are generally suitable for correction of age-related eye conditions. Figure 13A and 13B Measurements of corneal central keratometry, indicating changes in the curvature of the central region of the cornea, are also presented. As shown, the applied pattern, combined with the nanoparticle eye drops, provided an average correction of -2.24 ± 0.07 diopters for myopia after 30 minutes and an average correction of 2.74 ± 0.2 diopters for presbyopia after 45 minutes. The corneal curvature measurements did not show a statistically significant change in the central corneal curvature.

[0083] Therefore, as illustrated, the selected pattern applied / etched onto the cornea, along with the use of appropriate eye drops, provides a change in refractive index over a reasonably long period, enabling various ocular conditions to be corrected non-invasively and without the need for additional components. Generally, the pattern may be diffractive (e.g., Fresnel strips / rings) or configured to introduce optical interference, allowing for an extension of the depth of focus in the eye.

[0084] Typically, the eye drops and corresponding nanoparticles described herein can be adapted for use in a variety of other conditions. For example, the eye drop solutions described herein can be used to treat dry eye syndrome (DED), while the nanoparticles act as a synthetic tear film, providing lubrication to the eye. DED represents a heterogeneous group of conditions with signs and / or symptoms of tear film insufficiency and ocular surface irritation. These conditions may be associated with a variety of factors, including, for example, meibomian gland dysfunction (MGD).

[0085] The use of eye drops containing nanoparticles, as described herein, can be used to create a biological connection with lipid molecules that make up the lipid layer of a user's eye. This results in both greater stability of the tear film and a longer-lasting effect on the corneal surface.

[0086] Furthermore, it should be noted that the nanoparticles described above can be used as drug delivery carriers in eye drop solutions. Generally, anatomical barriers and physiological clearance mechanisms on the ocular surface pose challenges to the development of ocular drug delivery devices. More invasive methods, such as intravitreal injections, can improve the ocular bioavailability of therapeutic agents, but often lead to vision-threatening side effects.

[0087] The use of the selected nanoparticles described herein can enhance the ocular bioavailability of one or more suitable therapeutic agents (e.g., drugs, proteins, peptides, for example). The nanoparticles described above can provide significant potential advantages, including, for example, improved penetration / bioavailability / delivery of any bioactive agent in deeper tissues to treat more serious infections such as bacterial, fungal, or parasitic infections. An additional significant advantage associated with improved bioavailability is that this improvement may lead to a significant reduction in the frequency of eye drop instillation in chronic diseases such as glaucoma or dry eye, and a potential for externally controlled drug delivery via portable devices.

[0088] Therefore, the present invention provides an eye drop material composition carrying magnetohyperite-based nanoparticles with an albumin shell. The eye drop composition can be used in combination with a suitable pattern applied to the cornea of ​​a user's eye. The suitable pattern is designed to provide selected optical corrections for various eye conditions.

Claims

1. A kit for correcting a user's visual impairment, characterized in that: The set includes: A patterning device, configured and controllably operable to create a selected pattern in the form of a surface undulation on the cornea of ​​a user, wherein the selected pattern is configured as a vision correction pattern capable of providing a targeted optical effect of refractive error correction without modifying the corneal shape, based on the user's visual impairment; and An eye drop comprising an aqueous solution containing a plurality of albumin protein-based nanoparticles configured such that when the nanoparticles are dispersed in several cut regions of the pattern, they stabilize the pattern and enhance the optical effect of the pattern, such that the optical effect can be sustained for months.

2. The set as described in claim 1, characterized in that: The albumin protein-based nanoparticles contain proteins based on human serum albumin.

3. The set as described in claim 1 or 2, characterized in that: The nanoparticles are selected to have a different refractive index than the user's cornea and / or the tears surrounding the eye.

4. The set as described in claim 1 or 2, characterized in that: The albumin protein-based nanoparticles comprise metal nanoparticles encapsulated by human serum albumin protein chains.

5. The set as described in claim 1 or 2, characterized in that: The albumin protein substrate nanoparticles contain metal particles carried by an albumin shell, such that the albumin protein folds around the metal particles.

6. The set as described in claim 1 or 2, characterized in that: The nanoparticles comprise cerium ammonium nitrate Fe2O3 nanoparticles.

7. The set as described in claim 1 or 2, characterized in that: The selected pattern configuration is a localized modification that causes a change in the refractive index of the user's cornea.

8. The set as described in claim 1 or 2, characterized in that: The drawing device has one of the following configurations: The patterning device is configured to transmit selected ultrasonic waves for etching the pattern onto the user's cornea; The patterning device is configured to mechanically etch the cornea; The patterning device includes at least one laser unit and a beam steering module, and is configured to provide light energy for creating the selected pattern.

9. The set as described in claim 8, characterized in that: The patterning device includes at least one laser unit and a beam steering module, the laser unit being configured to provide etching at a depth reaching a single cell layer of the cornea.

10. The set as described in claim 1 or 2, characterized in that: The pattern includes a diffraction pattern.

11. The set as described in claim 1 or 2, characterized in that: The pattern includes a Fresnel ring pattern.

12. The set as described in claim 1 or 2, characterized in that: The pattern has at least one of the following configurations: The pattern includes a phase-effect interferometry pattern; The pattern includes an extension of the depth pattern; The pattern enables optical correction down to 0.25 diopters, with optical power resolution between 0.1 and 0.3 diopters.

13. The set as described in claim 1 or 2, characterized in that: The nanoparticles are further configured to carry one or more selected drugs.

14. The set as described in claim 1 or 2, characterized in that: The aqueous solution is formed from at least one of the following groups: water, antibacterial water, sodium chloride solution, glucose solution, liquid surfactant, and pH buffered solution.

15. The set as described in claim 1 or 2, characterized in that: The kit is suitable for use at home or in the outpatient clinic of an eye care provider.

16. The set as described in claim 1 or 2, characterized in that: The selected pattern configuration is used to correct at least one of the following refractive errors: myopia, myopia control, hyperopia, presbyopia, and astigmatism.

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