SYSTEM, METHOD AND MATERIAL COMPOSITION FOR USE IN CORRECTION OF EYE CONDITIONS
20210022922 ยท 2021-01-28
Assignee
Inventors
- Zeev Zalevsky (Rosh Haayin, IL)
- Jean Paul LELLOUCHE (Ashdod, IL)
- David SMADJA (Tel Aviv, IL)
- Yifat HAREL (Holon, IL)
- Rivka BEN ISHAY (Yakir, IL)
Cpc classification
B82Y5/00
PERFORMING OPERATIONS; TRANSPORTING
International classification
Abstract
A system, technique and material composition for use in correction of eye condition are disclosed. The system comprising a processing utility and an etching utility. The processing utility comprises: correction pattern module configured for providing a selected two-dimensional pattern in according with input data indicative of vision impermanent of a user, and for generating operational instructions for forming said selected two-dimensional pattern on the surface of the cornea by said etching utility. The etching utility is configured to etching the selected patter on surface of the cornea of a user. The material composition comprises aqueous solution comprising a plurality of nanoparticles, said nanoparticles comprising maghemite nanoparticles wrapped by biocompatible protein chains. The material composition may be used as eye drops thereby allowing the nanoparticles to occupy etched region on the cornea, thereby maintaining correction of eye condition
Claims
1-24. (canceled)
25. A material composition, comprising: an aqueous solution including a plurality of nanoparticles; wherein the plurality of nanoparticles includes maghemite nanoparticles wrapped by biocompatible protein chains.
26. The material composition of claim 25, wherein the biocompatible protein chains include human serum albumin proteins.
27. The material composition of claim 25 for use in correction of visual impediment.
28. The material composition of claim 25, configured for use as eye drops.
29. The material composition of claim 28, configured for use as eye drops after applying etching of selected patterns to a cornea of a user, the plurality of nanoparticles being dispersed within surface relief of the cornea to provide optical power addition to that of an eye of the user.
30. The material composition of claim 25, wherein the maghemite nanoparticles include ceric ammonium nitrate Fe.sub.2O.sub.3 nanoparticles.
31. The material composition of claim 25, wherein the maghemite nanoparticles wrapped by the biocompatible protein chains are further configured for carrying one or more selected drugs.
32. The material composition of claim 25, wherein the nanoparticles are configured to provide a location modification of a refractive index when applied as a selected patter on a user's cornea.
33. The material composition of claim 25, wherein the aqueous solution includes at least one of water, bacteriostatic water, sodium chloride solutions, glucose solutions, liquid surfactant, or pH-buffered solution.
34. A material composition for use in treatment of visual impediments, the material composition comprising: nanoparticles including maghemite-based particles within a protein shell.
35. The material composition of claim 34, wherein the nanoparticles are further configured as drug carrier and delivery.
36. A kit for use in correction of visual impediments, the kit comprising: a system for use in correction of eye condition, the system including a processing utility and an etching utility, the processing utility including: correction pattern module configured for providing a selected two-dimensional pattern in according with input data indicative of vision impermanent of a user, and for generating operational instructions for forming the selected two-dimensional pattern on the surface of the cornea by the etching utility; wherein the etching utility is configured to etching the selected two-dimensional pattern on surface of the cornea of a user; and eye drops including a material composition including an aqueous solution having a plurality of nanoparticles, the plurality of nanoparticles including maghemite nanoparticles wrapped by biocompatible protein chains.
37. The kit of claim 36, further comprising an instruction manual for operating the system for etching a selected pattern on the user's cornea and applying the eye drops into the eye.
38. The kit of claim 36 suitable for use at home or at a doctors' clinic.
39. The kit of claim 36, wherein the maghemite nanoparticles wrapped by the biocompatible protein chains are configured for increasing stability of an optical effect of the selected two-dimensional pattern, thereby enabling an optical correction effect lasting between a few days and a few months.
40. The kit of claim 36, configured for correction of at least one of myopia, hyperopia, presbyopia, or astigmatism.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0036] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:
[0037]
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[0039]
[0040]
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[0048]
DETAILED DESCRIPTION OF EMBODIMENTS
[0049] As indicated above, the present technique provides for correction of visual impediments such as myopia, hyperopia and presbyopia.
[0050] The processing utility 200 may generally include one or more processors and further include one or more hardware or software modules such as correction pattern module 210. The correction pattern module 210 is configured for receiving and processing input data indicative of required optical correction for a user's eye (each eye may require different optical correction) and for determining, or retrieving from a storage utility, a selected two-dimensional pattern suitable for the optical correction. The processing utility 200 is further configured for generating operational instructions for etching the selected pattern on cornea of the user to provide the selected optical correction.
[0051] The processing utility 200 transmits the generated instructions to the etching utility 300 for providing optical radiation and directing it for generating the selected pattern on cornea of a user's eye.
[0052] Generally, the etching utility 300 is configured to apply the selected patterns as incision onto the epithelial layers of the cornea. The etching may generally be provided using optical etching with selected wavelength ranges, ultra-sonic etching and/or mechanical incision of the cornea. For simplicity the etching utility is exemplified herein as optical etching utility 300 configured with laser light source, and a beam steering unit 320. The laser light source 310 is configured to provide optical radiation at wavelength and power suitable for etching within epithelial cell later and the steering unit 320 is configured for varying path of the output light beam to enable projection of the selected pattern on the user's cornea. Operation speed of the steering unit 320 and power of the light source unit 310 are selected to provide light etching of the cornea, typically, within superficial epithelial layers, e.g. at depth of single cell layer.
[0053] More specifically, the pattern is generally to be etched onto user's cornea with depth of no more than one cell layer, or up to a few micrometers, to avoid any damage to the user's eye and allow the cornea to heal and renew the etched cell layer. It should also be noted that the selected optical pattern is effectively stamped onto the superficial epithelial layers of the cornea.
[0054] As indicated above, the pattern is selected to provide additional optical power, or vary depth of focus of the user's eye. To provide lasting effect, the present technique utilizes appropriate eye drop solution, including selected nanoparticles having refractive index different than that of the cornea and/or tears around the eye. To this end, the eye drop formulation generally includes maghemite particles carried by albumin shell. More specifically, the albumin shell is typically in the meaning of protein folding around the maghemite particles. The nanoparticles may be based on Ceric Ammonium Nitrate (CAN) modified Maghemite (-Fe.sub.2O.sub.3) particles.
[0055] It should be noted that the particles of the eye solution are configured to provide optical effect of the inscribed pattern to be steady in time. More specifically, the nanoparticles generally enter the incision/etching region thus presenting tears from arriving to the location. This enables to maintain the optical effect and limits healing process of the epithelial layers to provide the optical effect to last from a few days to a few months. Generally, in regular conditions without the use of the nanoparticles' eye drops, the etching pattern may be healed within 1-2 days.
[0056] Generally, protein-based NPs, often used as drug carrier particles, may be of high interest for the eye drop solution, based on high stability during storage, and biocompatibility, e.g. being non-toxic and non-antigenic. Albumin proteins provide macromolecular carrier that has been shown to be biodegradable, non-immunogenic, non-toxic, and metabolized in vivo.
[0057] In some embodiments of the invention the nanoparticles may include Human Serum Albumin (HSA, 66.5 kDa). HAS may be preferred since it is the most abundant plasma protein (35-50 g/L human serum) and has an average half-life of 19 days, and is thus used in the following, however it should be noted that the nanoparticles of the present invention may typically be associated with any albumin type protein including various animal serum and/or synthetic albumin. Generally, albumin contains 35 cysteinyl residues forming one sulfhydryl group and 17 disulfide bridges. HSA is robust towards pH, it is stable in the pH range of 4-9. Further, HSA can be heated at 60 C. for up to 10 h.
[0058] The inventors of the present invention have identified a technique enabling to provide and characterize HSA-based nanoparticles (NPs) having robust and controllable particle size. The technique utilizes desolvation/cross-linking-type Divinyl Sulfone (DVS)-mediated nanofabrication method exemplified in
EXAMPLE 1
HSA Core Nanoparticles Fabrication
[0059] HSA Core Nanoparticles Fabrication HSA (50.0 mg) was dissolved in 1.0 mL of purified water (ddH.sub.2O). Ethanol was added during the desolvation process to get a total volume of 5.0 mL for a final HSA concentration of 10 mg/ml. 140.0 L of DVS (5% w/w in EtOH) was added to induce protein chain cross-linking The cross-linking process was performed by stirring the suspension for 1 hour at 55 C. followed by 20 minutes in an ultra-sonication bath. The resulting HSA nanoparticles were then purified by three cycles of differential centrifugation (at conditions of 13,500 rpm, 60 min, 4 C.) and were then re-dispersed to the original volume of ddH.sub.2O. Each redispersion step was performed in an ultra-sonication bath for 10-15 min. To enable long-term storage and to avoid agglomeration, the nanoparticles were stored in a refrigerator at 4 C.
EXAMPLE 2
CAN Maghemite Nanoparticle Preparation
[0060] The CAN Maghemite NP ((CeL.sub.n).sup.3/4+--Fe.sub.2O.sub.3) preparation was executed in a two-step procedure which included basic co-precipitation of two types of Fe.sup.2+/3+ salts. This procedure yielded magnetite (Fe.sub.3O.sub.4) NPs as the less oxidized starting NP material that was then oxidized by mono-electronic oxidant cerium ammonium nitrate (CAN) and surface modified by (CeL.sub.n).sup.3/4+ cation/complex NP surface doping, to obtain 6.612.04 nm-sized positively charged (+45.7 mY) CAN--Fe.sub.2O.sub.3 NPs.
EXAMPLE 3
Hybrid CAN Maghemite-Containing HSA Nanoparticles Preparation
[0061] To provide the desired nanoparticle structures, having suitable refractive index for affecting vision in accordance with selected pattern on the cornea, both of the nanoscale components of HSA and CAN--Fe.sub.2O.sub.3 NPs were assembled for CAN--Fe.sub.2O.sub.3 NPs to be entrapped into HSA nanocomposite particles during this same DVS-mediated NP fabrication/component cross-linking For this purpose, the hybrid CAN maghemite containing HSA nanoparticles were prepared by procedure identical to the one described above for HSA NPs. In brief, to HSA (50.0 mg in 1.0 mL of ddH.sub.2O), CAN--Fe.sub.2O.sub.3 NPs were added at weight ratio of 25:1, and incubated for 1 hour at room temperature followed by a desolvation and cross-linking process. The resulting composite nanoparticles were then purified by three cycles of differential centrifugation (13,500 rpm, 60 min, 4 C.), magnetically decanted (using a strong external magnet) and re-dispersed into the original volume of ddH.sub.2O. At each performed re-dispersion step, the reaction vessel was placed in a low power ultra-sonication bath for 15 min before processing. For a long-term storage and to avoid agglomeration, the nanoparticles were stored in a refrigerator (4 C.).
[0062] The resulting HSA core NPs were further characterized by various combined analytical, spectroscopic, and microscopic methods.
[0063]
[0064] Additional measurement of the nanoparticles has been performed for determining cross-linking of the HSA polymeric chains by the DVS reagent.
[0065] Additionally, X-ray photoelectron (XPS) spectroscopy was used to confirm the participation of this electrophilic DVS reagent during the HSA polymeric chain cross-linking
[0066] The main functional groups, generally including the primary amine (NH.sub.2) and the carboxylic groups (COOH), have been successfully quantified using a UV-sensitive Kaiser Test (1,3-diaminopropane use for EDC-activated COOH group amidation/derivatization). Both the obtained differential EDC and the non-EDC-based Kaiser results revealed that for 1.0 g of HSA NPs, there are 0.632 and 1.127 millimole of both the NH.sub.2 and the COOH groups, respectively. (These quantified surface functionalities enable the future uses of HSA NPs as a biocompatible biodegradable drug carrier, as it allows further binding of additional therapy and/or tumor and diseased cell targeting agents).
EXAMPLE 4
Hybrid HSA Entrapped-CAN-Maghemite NPs (CAN--Fe.SUB.2.O.SUB.3.) Nanocomposite Particles
[0067] Both nanoscale components HSA and positively charged CAN--Fe.sub.2O.sub.3 having size of 6.612.04 nm and electric potential of +45.7 mV) were assembled by entrapment of the CAN--Fe.sub.2O.sub.3 nanoparticles into the HSA NPs during the DVS-mediated NP fabrication step. For this purpose, hydrophilic water-compatible CAN--Fe.sub.2O.sub.3 NPs have been used. Hybrid HSA/CAN--Fe.sub.2O.sub.3 NPs were synthesized based upon the same DVS-mediated process as mentioned above. The weight ratio between both HSA and CAN--Fe.sub.2O.sub.3 NPs phases were has been found to be 25:1 for an optimal encapsulation of a maghemite composition into a HSA nano shell. Generally, the weight ratio may be in the range between 15:1 and 40:1.
[0068] Thus, the DLS hydrodynamic diameter, the size distribution, and the electric potential values of the corresponding composite particles, have been determined. A DLS hydrodynamic diameter of 130 nm was measured with a polydispersity index below 0.3. An electric potential analysis was also performed in order to check the colloidal stability of the resulting hybrid NPs (the entrapment method) towards an aggregation control, meaning that composite particles were always found to be negatively charged with an average electric potential value of 25 mV.
[0069] Reference is made to
[0070]
[0071] ICP-AES elemental analyses were also carried out in order to confirm iron encapsulation during the hybrid NP formation. ICP measurements demonstrated an entrapment efficiency of 95% of elemental iron into the HSA phase. Additional concentration measurements of both the hybrid NPs and the CAN-maghemite NPs revealed that the weight percentage of the CA-maghemite NPs phase is nearly 40% out of the total weight of corresponding hybrid NPs.
[0072] Accordingly, the present technique utilizes solution formulation including albumin shell CAN--Fe.sub.2O.sub.3 nanoparticles as eye drops enabling variation of refractive index at the selected etched patterns on the user cornea. The nanoparticles generally remain on the cornea for time period between a few days and a few months enabling correction of the user eye condition in accordance with optical operation of the selected pattern. The inventors have conducted tests on pig eyes validating optical effect of the etched pattern and selected nanoparticles for correction of optical vision impediment.
[0073] To this end, Refractive error of eight fresh pig eyes was measured with an automated refractometer before and after realization of a corneal superficial pattern and then after instillation of eye drops filled with the selected nanoparticles at a specific known concentration of between 0.1 mg/ml and 10 mg/ml. The nanoparticles' concentration used in this example was 1 mg/ml. In these tests, the pattern was applied to the cornea of the eye using a stamper, built by a 3-D printer with a calibrated optical pattern.
[0074] The stamper in this example is used to provide micro superficial erosion onto the cornea in order to let the nanoparticles penetrating the corneal epithelium, and thus enable desired optical power variation determined by the pattern. The pattern itself was selected to be a Fresnel plate zone diffractive pattern provide optical power of 2.5 diopters. Such additional optical power is generally suitable for vision assistance to user having Myopia. The optical power of the eye lenses was measured and recorded 5 times at each of the steps associated with the present technique. More specifically a baseline optical power was measured, optical power with patterned applied to the cornea, after application of the eye drop onto the eye at different time of immediately after drops instillation, 5 min, 10 min, 20 min and 30 min after instillation. The various measures were conducted to avoid bias due to large standard deviation.
[0075] Thus, after selection of the desired pattern in accordance with required. optical correction, the two-dimensional pattern was applied to the cornea. When the pattern is etched on the cornea, the eye was washed with eye drop solution including HAS Maghemite nanoparticles. The nanoparticles were identified within the eye using iron marking of a portion of the nanoparticles. This enables identifying the nanoparticles using electron microscope (e.g. SEM) analysis.
[0076] Reference is made to
[0077] Accordingly, as shown, the use of selected pattern applied/etched on the cornea with suitable eye drops providing refractive index variation for reasonably long period enable correction of various eye conditions that requires no additional elements and is generally noninvasive. Generally, the pattern may be diffractive (e.g. Fresnel zone plate/rings) or configured to introduce light interference enabling extension of depth of focus of the eye.
[0078] Typically, the eye drops and corresponding nanoparticles as described here may be suitable for use in various additional conditions. For example, the eye drops solution described herein may be used for treatment of Dry eye disease (DED) where the nanoparticles provide lubrication to the eye operating as synthetic tears. DED represents a heterogeneous group of conditions with tear film insufficiency and signs and/or symptoms of ocular surface irritation. These conditions may be associated with various factors, including for example Meibomian gland dysfunction (MGD).
[0079] The use of the nanoparticles containing eye drops as described herein may be used for creating biological bond with the molecules of lipid composing the lipid layers of a user's eye. This results in both, greater stability of the tear film as well as longer effect onto the corneal surface.
[0080] Further, is should also be noted that the above described nanoparticles, being in eye drop solution may be used as drug delivery carriers. Generally, the anatomical barriers and physiological clearance mechanisms on the ocular surface presents challenges for development of ocular drug delivery devices. More invasive methods, such as intravitreal injections, can improve the ocular bioavailability of therapeutic agents but often result in vision-threatening side effects.
[0081] The use of the selected nanoparticles described herein may enhance the ocular bioavailability of one or more suitable therapeutic agents (e.g. drugs, proteins, peptides for example). The above described nanoparticles may provide major potential advantages, including for example improving of the penetration/bioavailability/delivery of any bioactive agent in deeper tissue for curing more severe affection such as bacterial, fungal or parasitic infection. Additional major advantage is associated with improving the bioavailability, which may lead to a significant decrease of eye-drops instillations frequency in chronic diseases such as glaucoma or dry eye diseases, as well as a potential external controllable drug delivery by portable device.
[0082] Thus, the present invention provides eye drop material composition carrying maghemite based nanoparticles with albumin shell. The eye drop composition may be used in combination with suitable patterning applied to cornea of a user's eye for providing selected optical correction to various eye conditions.